This week, please join author Gregory Wyant and Associate Editor Gabriele Schiattarella as they discuss the article "Induction of DEPP1 by HIF Mediates Multiple Hallmarks of Ischemic Cardiomyopathy."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240830.316198

This week, please join author Gary Owens and Associate Editor Iris Jaffe as they discuss the article "A Novel Mouse Model of Myocardial Infarction, Plaque Rupture, and Stroke Shows Improved Survival With Myeloperoxidase Inhibition."

For the episode transcript, visit: 

https://www.ahajournals.org/do/10.1161/podcast.20240825.966308

This week, please join Social Media Editors Shirin Doroudgar and Susmita Sahoo as they speak with the 2024 Loscalzo Award recipient, Mark C. Blaser, regarding his article "Multiomics of Tissue Extracellular Vesicles Identifies Unique Modulators of Atherosclerosis and Calcific Aortic Valve Stenosis." The Loscalzo Award recognizes the best Basic/Translational article published in Circulation in the preceding 12 months.

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240621.715149

This week, please join authors Jonas Oldgren and Signild Åsberg as they discuss the article "Early Versus Delayed Non–Vitamin K Antagonist Oral Anticoagulant Therapy After Acute Ischemic Stroke in Atrial Fibrillation (TIMING): A Registry-Based Randomized Controlled Noninferiority Study."

Dr. Carolyn Lam:

Welcome to Circulation on The Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Today's featured paper is a very important discussion, and in fact, the first study to compare early versus delayed NOACs after acute ischemic stroke in patients with atrial fibrillation. The timing study. You're not going to want to miss this, but you're going to have to wait for it, because we're going to discuss all the papers in today's issue. Can I start, Greg? Because I want to start, or is it too early to start with a Greg quiz? With the quiz question being, what is cell-free DNA?

Dr. Greg Hundley:

Oh, thank you Dr. Lam. I really appreciate your wonderment into the world of preclinical science. So something maybe short DNA fragments, but I'm not sure.

Dr. Carolyn Lam:

Aw, you're absolutely right. It's circulating DNA fragments predominantly from mononuclear zones that represent cell injury and/or turnover. So what we know is elevated total cell-free DNA concentration has been associated with worse prognosis in a variety of conditions such as sepsis, trauma, malignancy. In addition, and this may be where a lot of us have heard of cell-free DNA, it's become clinically relevant as a noninvasive marker of solid organ transplant rejection as well as a tool for genotyping and surveillance in oncology.

However, in today's paper, given the parallels in the pathogenesis of pulmonary artery hypertension, two of the diseases I've talked about before that are characterized by increased cell proliferation and turnover, like the cancers and inflammatory mediated tissue injury. Now this particular study sought to determine if plasma cell-free DNA concentrations were elevated in pulmonary artery hypertension, and if those levels would correlate with disease severity or predict outcomes.

Dr. Greg Hundley:

Oh wow, Carolyn, this sounds really informative. So what did they find?

Dr. Carolyn Lam:

Well, this study from corresponding authors, Dr. Solomon from NIH Clinical Center and Dr. Agbor-Enoh from NHLBI in Bethesda and their team found that circulating cell-free DNA is elevated in patients with pulmonary arterial hypertension compared to healthy controls. In two independent PAH patient cohorts, cell-free DNA concentrations increased with severity of disease and predicted transplant free survival in the larger of the two cohorts.

Interestingly, methylation patterns revealed increased cell-free DNA originating from biologically plausible sites including erythrocyte progenator and myeloid lineage inflammatory cells, vascular endothelium, and cardiac myocytes. So the implications are that in pulmonary arterial hypertension, cell-free DNA concentrations could serve as a non-invasive biomarker of underlying disease activity, may add prognostic value to currently use risk scores, and may provide a unique noninvasive window into its pathogenesis.

Dr. Greg Hundley:

Wow, Carolyn. So another interesting technique and pathophysiologic study highlighting the utility of circulating cell-free DNA. Wow. Well, Carolyn, how about I start in with my first study and it comes to us from the world of clinical science and refers to the paradise MI echocardiographic substudy. So Carolyn, the prospective RNE versus ACE inhibitor trial to determine superiority in reducing heart failure events after myocardial infarction.

So the Paradise MI echo study tested the effect of Sacubitril/Valsartan compared to Ramipril on LV function and adverse remodeling following high risk acute myocardial infarction. So this substudy included 544 Paradise MI participants that underwent echocardiography at randomization, and then again later at eight months. Patients were randomized within a half to seven days of their presentation with their index, myocardial infarction, to receive a target dose of Sacubitril/Valsartan of 200 milligrams or Ramipril five milligrams twice daily.

Dr. Carolyn Lam:

All right. So the Paradise MI echo substudy, what did they find?

Dr. Greg Hundley:

Right Carolyn, so treatment with Sacubitril/Valsartan compared to Ramipril following acute myocardial infarction did not result in changes in left ventricular ejection fraction or left atrial volume at eight months. Patients randomized to Sacubitril/Valsartan had less LV enlargement and greater improvement in filling pressure, and thus there are new insights here in that treatment with Sacubitril/Valsartan compared to Ramipril early following acute myocardial infarction may beneficially impact LV size and diastolic properties possibly due to reductions in LV filling pressure.

Dr. Carolyn Lam:

Oh, very nice, Greg. Thank you. Another clinical study here, and this time a paper aimed to evaluate the influence of sex on the effects of empagliflozin in patients with HFpEF enrolled in the Emperor Preserved trial.

Dr. Greg Hundley:

Ah, Carolyn, two of your favorite things, sex differences and SGLT2 inhibitors. So Carolyn, remind us, what did Emperor Preserved show us?

Dr. Carolyn Lam:

Ah, so Emperor Preserved studied the sodium glucose cotransporter 2 or SGLT2 inhibitor empagliflozin in patients with HFpEF, which is an ejection fraction above 40%, and showed a significant reduction in the risk of cardiovascular death or heart failure hospitalization. In the current paper, corresponding author Dr. Javed Butler from University of Mississippi Medical Center and colleagues found that empagliflozin reduced the risk of the primary outcome of cardiovascular death or hospitalization for heart failure to a similar degree in both women and men with HFpEF irrespective of baseline left ventricular ejection fraction.

Empagliflozin produced comparable benefits for the pre-specified secondary outcomes of total heart failure hospitalizations, cardiovascular death, and all-cause mortality, as well as physiologic measures and health status. The pattern of the effects of empagliflozin and HFpEF in both sexes in EMPEROR- Preserved stands in contrast to the influence of sex on the response to neprilysin inhibition. So very interesting paper. I encourage everyone to pick it up, of course, because it's two of my favorite topics.

Dr. Greg Hundley:

Very nice, Carolyn. Well, my next paper comes to us from the world of pre-clinical science, and it's from Dr. Chunyu Zeng from Diping Hospital, the third military medical university. Carolyn, adverse environmental exposure during the prenatal period can lead to diseases in offspring, including hypertension. Now whether or not the hypertensive phenotype can be trans-generationally transmitted is really not new.

Dr. Carolyn Lam:

Wow, that's interesting. So what did this paper find?

Dr. Greg Hundley:

Carolyn, this was really interesting. So these authors in a rat model, they found that prenatal lipopolysaccharide exposure can impair the ability to excrete a salt load and induce hypertension from the first to the third generations, with the fourth and fifth generations inducing salt-sensitive hypertension. And Carolyn, really interestingly, and based on these findings, they treated lipopolysaccharide exposed pregnant rats with the reactive oxygen species scavenger temple, which successfully prevented hypertension in the first-generation offspring and the transgenerational inheritance of hypertension.

So Carolyn, these findings show that adverse prenatal exposure induces transgenerational hypertension through an epigenetic regulated mechanism. And these findings identify potentially preventive and therapeutic strategies for this form of generationally transmitted hypertension. Really interesting.

Dr. Carolyn Lam:

Wow, that sounds wild. Very, very interesting. Well, let's go through the other things that are in today's issue. There's a research letter by Dr. Moayedi on anteroposterior pacer pad position is more likely to capture than anterolateral for transcutaneous cardiac pacing.

Dr. Greg Hundley:

Great, Carolyn. And I've got a research letter from Professor Porrello entitled, “Defining the Fetal Gene Program at Single Cell Resolution in Pediatric Dilated Cardiomyopathy.” And then lastly, there's an ECG Challenge from Dr. Chen entitled, “A Shark Thin Electric Cardiogram in the Intensive Care Unit.” Well Carolyn, how about we get onto that featured discussion and learn more about non-vitamin K antagonists after acute ischemic stroke?

Dr. Carolyn Lam:

Yep. In patients with EF, here we go.

Today's feature discussion is all about atrial fibrillation, how it's a risk factor for stroke, but also about how we've never known really how soon after an acute stroke can we start oral anticoagulation to prevent recurrent strokes? Today we're going to talk about the timing study. It's the first randomized controlled study to evaluate the efficacy and safety of initiation of treatment with NOACs within 10 days of acute ischemic stroke in patients with atrial fibrillation.

Wow. What an exciting study, and also how exciting that we have two co-first authors. We have Dr. Jonas Oldgren and Dr. Signild Åsberg from Uppsala University in Sweden, and this represents a partnership between neurology and cardiology. I mean really unique in many aspects as well as the way this study was performed, which is truly, truly a feat in itself. May I ask you both please to tell me the story of how this study came to be in the first place?

Dr. Signild Åsberg:

Well, we like to mention the late Professor Gesteruen student who actually was the first to bring this question to the table. Together we talked with the cardiology department and Jonas Oldgren to see if we can collaborate to solve this important question for us that works with stroke patient, because it's on a weekly or even a daily basis, troublesome question.

Dr. Jonas Oldgren:

My background is as a cardiologist and professor of coagulation research. I've been very interested in anticoagulants, antithrombotic treatments, and had the pleasure and privilege to be part of the development of the novel oral anticoagulants. And in all those pivotal trials, we excluded patients with a recent stroke at least seven days from the stroke, sometimes even 30 days from the acute stroke we excluded them from the studies.

So when we found the exciting results with at least as good efficacy as warfarin and at least as good safety as warfarin and the tremendous reduction in intracerebral or intracranial bleeds, that was a finding which was not evaluated in acute stroke patients with atrial fibrillation. And when Signild approached me with this idea, I said, "Well this is absolutely a very important question and why hasn't it been resolved earlier?"

And the problem is, of course, that these are patients who are in a sensible setting earlier after the acute ischemic stroke, and when are we able to safely start an effective treatment?

Dr. Carolyn Lam:

Oh, I couldn't agree more with you about how important that is. I mean, when we have an acute stroke patient, we just don't know whether we should start the NOAC early or delay it and we definitely need that evidence gap filled. But I'm also so intrigued with the way you did it with the Swedish Stroke Register. I mean, what a powerful way to look at important questions like this. Could you tell us a bit more about the method used?

Dr. Jonas Oldgren:

Yeah, so in cardiology we started rather early by using our national health registries for doing randomized controlled trials. We did a lot of observational studies in our registries, both in stroke and in cardiovascular medicine, otherwise in every other area of medicine. But in the end we realized that we could at best be hypothesis generating, but we still needed to add randomized controlled studies to have the last piece of the puzzle to provide good evidence.

And then we ran a lot of studies in cardiologists, especially in myocardial infarction patients, by just adding to simplify, by adding a randomization module, and then follow the patients in the registries because we know that we have high quality data in the registry. For instance, in the stroke registry. So we anyway collect every important data on each and every patient in the register. So by adding a randomization module, we can facilitate the conduct of a clinical study.

Dr. Carolyn Lam:

Wow. The way you say it, you make it sound so simple, but I can tell you what you have there in Sweden is like the envy of the whole world, and everybody's thinking about how to do a registry based trial like that. So maybe after you tell us the results, you could also share a little bit of how difficult and challenging it can be as well. But would either of you like to share the results?

Dr. Signild Åsberg:

Well, the major result from our trial is that initiating NOAC within four days is non-inferior to starting in a delayed phase of up to 10 days. So that's our key finding. But equally important is that we didn't have any patients explaining as symptomatic and terrible hemorrhage, and that is extremely good news for us who worked with these patients.

Dr. Carolyn Lam:

That is such an important message. The early initiation was non-inferior. Could you expand on non-inferior in terms of what primary outcome?

Dr. Jonas Oldgren:

Yeah, so the primary outcome was really a clinically important outcome we think, both from the cardiac perspective but also from stroke specialists. So we had a combination composite of symptomatic intracerebral hemorrhages, ischemic strokes and death. And this is what matters to patients and to doctors. We would like to avoid strokes, and it doesn't matter if it's an ischemic stroke or if it's a hemorrhagic stroke. We would like to avoid them. And of course we would not like to have an increased mortality as well.

So it's a relevant endpoint. And when we designed the study, the main drug used was warfarin, and there we knew that there was a lot of hemorrhagic transformations and a lot of intracerebral hemorrhages. So we designed the trial to look at these three endpoints to prevent ischemic strokes, but to avoid hemorrhagic strokes. And that is why we choose to have a non-inferiority design, because we also have the advantage of starting early if we can make the decision to start with the stroke specialists sometimes in collaboration with the cardiologist, and then we can have the patient step down unit earlier if the treatment is already started.

So that was the choice of a non-inferiority design. We of course also tested for superiority, but unfortunately we didn't meet that superiority testing endpoint. But as Signal mentioned, I think thrilling results is to have no symptomatic intracerebral hemorrhage in any of the groups. That really speaks in favor of the safety of this drug or these drugs that we used, but also the concept to start early. We can also note that we had some ... I mean there were numerically lower rates of both ischemic strokes and deaths in the early group, albeit not meeting the significance for superiority, but it's important. And as we see also the events tend to occur very early. So we really gain with treating our patients earlier with this intervention.

Dr. Carolyn Lam:

Oh indeed. And to all the listeners, do pick up the paper because if you look at the Kaplan-Meier curves, they're really impressive, exactly like you said, numerical differences, although the trial did demonstrate non-inferiority and could not demonstrate the superiority. But have a look at those figures. And if I could just clarify the comparator arm, notice that we've been saying NOACs, not a particular NOACs. So could you expand on that a bit?

Dr. Signild Åsberg:

We used all the four NOACs that we have in Sweden, so that was to the physician's discretion to choose between them. So that was not a part of the randomization. So we only randomized the timing to the early phase or the delayed phase.

Dr. Carolyn Lam:

I love that. And then if you could please educate the cardiologist in me, please. There are symptomatic intracerebral hemorrhages, and then there are all kinds of little things that you can pick up if you image the brain and hemorrhagic transformation and microbleeds and all these things. So I think one of the things here was their systematic imaging and does it matter? Could you teach us a little bit more about these different types of bleeds?

Dr. Signild Åsberg:

We did not have a systematic imaging, but in Sweden that is performed mostly by CT on admission. So that was for all patients. And then on events, the imaging was performed and reported through the registry. And yes, there were hemorrhagic transformation actually in three patients, two in the early phase, and one in the delayed phase, but only one before day 10. So all blood that was seen on imaging was reported, but we used symptomatic criteria from the stroke severity scale.

Dr. Carolyn Lam:

Thank you. That's a good clarification. And then the study aimed for a larger number, and here perhaps if either of you could tell us the story, the struggles, and how you ended up with these beautiful results.

Dr. Signild Åsberg:

Yeah, struggle is the word. It was troublesome and we had long talks. So why was this happening? Why didn't science recruit more? But I think one issue might have been that NOACs had been on the market for a while once we started, and even the stroke physicians were getting used to it and had trouble not to start. Before the timing study started, we did a observational pre-timing study just to see how we were doing in Sweden at this stage. Because we didn't really know that.

We know that a lot of patients were discharged with oral anticoagulation, but we didn't really know when they started. And so by that study we could see that in median time to initiation was five days, already before the timing study. So one thought was that this was for some physicians then had to delay their start. They were getting used to start early. So that could have been one explanation.

Dr. Jonas Oldgren:

And of course there has been a lot of observational studies looking at the safety of NOACs or other oral anticoagulants in the early setting after acute ischemic stroke in patients with atrial fibrillation. And of course with the evidence from such studies, albeit observational doctors felt perhaps more confident starting very early despite the lack of evidence from randomized control trials.

So we had the opportunity to follow those patients as well in the stroke registry. Every patient with an acute stroke in Sweden attending a stroke unit is registered. So we have in the supplement of the paper in circulation, we have observational data from the centers participating in stroke, but patients not randomized in the timing study. And we also have observational data from all stroke centers in Sweden. So we can see that many start very earlier with NOACs based on observational data, based on experiences.

And perhaps we're more and more reluctant to randomize the patient in the study because as Signal says, that means there is a 50% chance of delayed treatment by randomization. And when we started this study, there were no evidence from randomized controlled trials within the first 14 days. But while running the study for a couple of years, you start to believe that there seemed to be safety because no one saw any symptomatic intracerebral hemorrhage. And we discussed that, of course, at investigative meetings that this seemed to be a very good treatment, which is bad for running a clinical study, but it's of course good for the patients.

Dr. Carolyn Lam:

Interesting. So echo points kind of may have shifted a little bit even during the course of the trial. So just thank you so much all the more. Thank you for seeing this to completion in the sense of a beautiful manuscript with very meaningful results. If I could ask you both to each summarize just very quickly what the take home message is for clinical practice from neurologist's point of view and cardiologist's point of view?

Dr. Signild Åsberg:

Yeah, what I would say, it seems both safe and reasonable to initiate NOAC earlier after an acute ischemic stroke. So I think that's the key take home message that really to consider the acute secondary prevention.

Dr. Jonas Oldgren:

I may bring that from another perspective. I think when there's lack of data in collaboration, we can do a lot. So in this case, we had a great collaboration in the student committee, cardiologist and stroke specialists collaborating to run such a study. And we are extremely grateful for all the sites and all the investigators at the sites participating in the study. And then of course grateful to circulation for publishing it because we are very proud of this study.

Dr. Carolyn Lam:

And we are proud to be publishing this. So ladies and gentlemen, you heard it right here in Circulation On The Run. Remember this is about early versus delayed initiation of NOACs in patients after an acute stroke who also have atrial fibrillation. And this is a very, very, I think, important study that fills an important evidence gap. We're so grateful to both of you for being here to discuss it, and to the audience for listening today. You've been listening to Circulation On The Run. And don't forget to tune in again next week.

Dr. Greg Hundley:

This program is Copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit AHAjournals.org.

This week, please join authors Hanna-Kaisa Nordenswan and Jukka Lehtonen, as well as Associate Editor Mark Link as they discuss the article "Incidence of Sudden Cardiac Death and Life-Threatening Arrhythmias in Clinically Manifest Cardiac Sarcoidosis With and Without Current Indications for an Implantable Cardioverter Defibrillator."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

And I'm Dr. Peder Myhre, Social Media Editor in Circulation from Akershus University Hospital, and University of Oslo, Norway.

Dr. Carolyn Lam:

Oh, I am so excited about our feature paper today. It is about a condition that may not be as commonly encountered, but this paper can change clinical practice. It's about cardiac sarcoidosis and the indications for an ICD. Listen up. Very important stuff and discussion coming right up. But first, let's grab coffees and discuss the other papers in today's issues. Shall we?

Dr. Greg Hundley:

Right. So Carolyn, Peder, how about I go first? And so, both of you... we start with a really interesting, very practical study. It's somewhat unclear whether replacing an oral glucose tolerance test with just a hemoglobin A1C measurement for diagnosing diabetes is justified. And so these authors led by Adam Tabák, from University College of London in the United Kingdom, aimed to assess proportion of oral glucose tolerance tests, diagnosed diabetes cases that can be confirmed with hemoglobin A1C measures. And to examine whether individuals with oral glucose tolerance test diagnoses, but non-diagnostic hemoglobin and A1C are at higher risk of macro and microvascular disease. So the study included 5,773 men and women from the population based Whitehall II prospective of cohort study in the United Kingdom.

New oral glucose tolerance tests, diabetes cases diagnosed in clinical examinations between the years of 2002 and 2004. And again, in 2007 and 2009 were assessed for hemoglobin A1C confirmation of a value greater than 6.5% in these. And then again, so in those years, and then again, in subsequent clinical examinations in the periods of 2012 to 2013 and 2015 to 2016, now all participants were followed for major cardiovascular events via linkage to electronic health records until the year of 2017. And for incident chronic kidney disease by an estimated glomerular filtration blade of less than 60 mLs per minute per meter squared, until the last clinical examination.

Dr. Peder Myhre:

Thank you, Greg. That is such an important study with direct clinical implications. And I'm so curious to know what did they find?

Dr. Greg Hundley:

Right, Peder. Right, Carolyn. Carolyn's in the background, it's like a mind meld with Peder. She's going to keep pounding me with these same questions. Okay. So in this population based cohort study, with five yearly repeated oral glucose tolerance tests and hemoglobin A1C measurements, only 59.3% of the oral glucose tolerance tests diagnosed diabetes cases were confirmed by hemoglobin A1C at the same or a subsequent examination during 4.1 years of follow up. Incident oral glucose tolerance test diagnosed diabetes cases with hemoglobin A1C confirmation, and preexisting diabetes cases had similarly increased risks of cardiovascular disease and chronic kidney disease. While notably unconfirmed oral glucose tolerance test cases had a similar risk as the diabetes free population.

Dr. Peder Myhre:

Wow. That is really remarkable, Greg. Thank you for that summary. But can you please just give us, from this complicated paper, can you just give us some take-home points for the listeners.

Dr. Greg Hundley:

Right, Peder. So first, in this study, people with oral glucose tolerance tests diagnosed diabetes without diagnostic hemoglobin A1C have a risk of cardiovascular disease and chronic kidney disease, similar to the diabetes free population. And therefore, replacement of oral glucose tolerance tests with hemoglobin A1C based diagnoses appears justified. Second, there seems to be no need to consider oral glucose tolerance testing when hemoglobin A1C and fasting glucose levels are apparently inconclusive. Fasting glucose tests are needed only in exceptional circumstances where hemoglobin A1C results are felt to be unreliable. And then, finally, these findings lend confidence to widespread use of hemoglobin A1C for diagnosing diabetes in the vast majority of clinical settings.

Dr. Peder Myhre:

Wow. Greg, thank you so much. This was so helpful. Well, I'm going to move on to the second original research article. And that is from the DAPA-HF trial, that I know Carolyn has been quizzing you throughout the years about. So I'm not going to quiz you, but I'm just going to ask you. Did you know that SGLT-2 inhibitors increase hematocrit and that it has been identified as one of the key mediators of the clinical benefits on this class of drugs.

Dr. Greg Hundley:

So Peder, they're really interesting. And the second week of this you're popping out with these quizzes. I didn't do this to Carolyn. It was like a couple months. So anyway, but-

Dr. Carolyn Lam:

Way to go, Peder. Way to go.

Dr. Greg Hundley:

Yeah. Well, the good news is, I can just say yes. I did know that.

Dr. Peder Myhre:

That's nice. And in this paper, we're going to learn even more. Because the authors are taking this further by looking into the iron metabolism and assessing iron deficiency in the DAPA-HF trial. So just to remind you, although, you are familiar with it at this point, Greg, and of course, Carolyn, the DAPA-HF trial was large RCT testing efficacy and safety of the SGLT-2 inhibitor compared to placebo in patients with heart failure and a reduced ejection fraction. And in this post talk analysis, the authors examine the prevalence and consequences of iron deficiency and the effect of dapagliflozin on markers of iron metabolism. They also analyze the effect dapagliflozin on outcomes according to iron status at baseline.

Dr. Greg Hundley:

Oh, wow, Peder. So what did they find?

Dr. Peder Myhre:

So in total, 44% of patients in DAPA-HF were defined as iron deficient. And that was defined as having less than 100 nanogram per milliliter of ferritin or a key set of less than 20% and a ferritin level between 100 and 299 nanogram per milliliter. So the rate of the primary outcome was higher in patients with iron deficiency compared to those without. That was 16 versus 10 per 100% years. And the effect of dapagliflozin on the primary outcome was consistent in iron deficient compared to iron replace patients with a fever interaction of 4.59.

And similar findings were observed for cardiovascular death, heart failure hospitalizations and all-cause mortality. And finally, and very importantly, ferritin, T cell, and hepcidin were reduced with dapagliflozin versus placebo. So the authors conclude that iron deficiency was common in DAPA-HF. And associated with worse outcomes. Dapagliflozin, appeared to increase iron utilization, but improved outcomes, irrespective of iron status at baseline.

Dr. Greg Hundley:

Very nice, Peder. Wow. Just another important piece of information that we're learning about SGLT-2 inhibition. Well, Peder, my next paper comes from the world of preclinical science and it's from a group of authors led by Dr. Osamu Takeuchi from Kyoto University. Primary pulmonary arterial hypertension, Peder, is often characterized by obliterative pulmonary vascular remodeling, resulting in right heart failure. And although, the pathogenesis of pulmonary arterial hypertension is not fully understood. Inflammatory responses and cytokines have been shown to be associated with pulmonary arterial hypertension, particularly with connective tissue disease. So in this sense, Regnase-1 and RNAs, which regulates mRNAs in coding genes related to immune reactions was investigated in relationship to the pathogenesis of pulmonary hypertension.

Dr. Peder Myhre:

Wow, Greg. Pulmonary arterial, a hypertension and mRNA degradation of IL-6. So what did they find, Greg?

Dr. Greg Hundley:

Right, Peder. So these investigators examined the expression levels of Z3H12A in coding Regnase-1, in peripheral blood mononuclear cells from pulmonary hypertension patients classified under various types of pulmonary hypertension, searching for an association between the ZC3H12A expression and the clinical features associated with pulmonary hypertension. They then generated mice lacking Regnase-1 and myeloid cells, including alveolar macrophages and examined right ventricular systolic pressures, and histologic changes in the lung.

They found that Regnase-1 maintains lung innate immune homeostasis via the control of IL-6 and PDGF in alveolar macrophages, thereby, suppressing the development of pulmonary arterial hypertension in mice. And furthermore, the decreased expression of Regnase-1 in various types of pulmonary hypertension implied its involvement in pulmonary hypertension pathogenesis. And then, therefore, may serve as a disease biomarker as well as a therapeutic target for pulmonary hypertension. Very, very interesting work from the world of preclinical science. So how about we jump and see what else is in the mail bag?

Dr. Peder Myhre:

So we have From the Literature by Dr. Tracy Hampton, and this time we get three summaries from preclinical science papers published on their journals. First, there is a summary of a paper suggesting that circadian and pluripotency networks control longevity related genes, and that was published in cell metabolism. There is also a summary from a paper on the varied responses to a high fat diet using mouse models published in high science. And finally, there is a summary related to Brugada syndrome and how gene therapy is a potential future therapy. And that was published in scientific translational medicine. So Greg, what did you have in the mail bag?

Dr. Greg Hundley:

Sure. Well, Peder, I've got a research letter from Professor Fang entitled “Mitochondrial Stress Induces HRIEIF2A Pathway that's Protective for Cardiomyopathy.”

Dr. Peder Myhre:

And finally, we have clinical implications of basic research from Dr. Garry and colleagues entitled “Cardiac Xenotransplantation, the Clinical Impact of Science and Discovery.” So let's move on the future discussion, Carolyn.

Dr. Carolyn Lam:

Absolutely. Thank you for excellent summary, Greg and Peder. Now, let's go the feature discussion on cardiac sarcoidosis.

Dr. Greg Hundley:

You bet.

Dr. Carolyn Lam:

Wow. Today's feature discussion is on a rare, but very important topic. And it's that of cardiac sarcoidosis. And you have to listen up because today's paper could actually change practice. So I'm very pleased and grateful to have the authors of this paper. The corresponding author, Dr. Hanna-Kaisa Nordenswan and coauthor, Dr. Jukka Lehtonen both from Helsinki University Hospital. As well as our associate editor, Dr. Mark Link, from UT Southwestern to discuss this very important paper. Hannah-Kaisa if you don't mind, could you start by just telling us about your paper and what you found?

Dr. Hanna-Kaisa Nordenswan:

Thank you so much for inviting us to the podcast. So cardiac sarcoidosis predisposes to sudden cardiac death. But how well the current guidelines for implantable cardioverter-defibrillators in CS issued by the Heart Rhythm Society in 2014 and the American College of Cardiology, American Heart Association and Heart Rhythm Society, consortium guidelines from 2017, discriminate high from low risk of sudden cardiac death is unknown. And this is what we wanted to examine. So our study is a nationwide study, including 398 patients with cardiac sarcoidosis. All patients had clinical cardiac manifestations and a histological diagnosis of sarcoidosis.

The histological diagnosis was myocardial in nearly one half of the population. So patients with and without class 1 to 2A indications for an implantable cardioverting-defibrillator at presentation were identified from this population. The occurrence of fatal or aborted sudden cardiac death and sustained ventricular tachycardias in follow-up were recorded. We also noted ICD indications emerging first on, follow up.

Dr. Carolyn Lam:

Great. What did you find?

Dr. Hanna-Kaisa Nordenswan:

So, first of all, we found that by the current ICD guidelines, 85 to 100% of our patients had at least one strong to modest class 1 to 2a indication for an early ICD implementation. And we also found a 10%, five-year cumulative incidence of sudden cardiac death in our population of cardiac sarcoidosis patients. Further, we found that patients without an early indication for an ICD by the Heart Rhythm Society guidelines had nearly 5% cumulative risk of sudden cardiac death at five years. These patients further had a 53% cumulative risk of either developing an indication or suffering from a life-threatening ventricular arrhythmia at five years follow up. Finally, we also found that a diagnosis of cardiac sarcoidosis based on myocardial histology, IE definite CS. So definite cardiac sarcoidosis predicted twice higher combined five-year risk of sudden cardiac death and life-threatening ventricular arrhythmia than diagnosis based on extra cardiac histology, IE probable cardiac sarcoidosis.

Dr. Carolyn Lam:

Wow. Thank you so much, Hannah-Kaisa and congratulations on such impactful findings. 398 patients and if I read correctly, a cohort spanning 30 years. Jukka, could you tell us a little bit more on how these patients were identified? And I think this is important too, because it speaks to the generalizability of your findings.

Dr. Jukka Lehtonen:

Exactly. Yeah. So we have a very proactive approach to cardiac sarcoidosis. So basically, if I give you an example, so we screen all patients less than 60 years of age with MRI. And if the MRI shows that there's any signs of myocardial damage, we do endomyocardial biopsy. And then, if we do biopsy, once take 10 samples from the right ventricular septum. If that comes out negative, as it very often comes, then we do a PET study. And if there's an extra cardiac signal, then we do biopsy that side. So usually, it's lymph nodes very often. And that gives us a probable cardiac sarcoidosis.

So probable cardiac sarcoidosis is the terminology that's used in Heart Rhythm Society, 2014 guidelines. It has the same prognosis, basically, the definite cardiac sarcoidosis that's based on endomyocardial biopsy. So if the PET shows no signal outside the heart, we usually repeat the biopsy either right or left side, depending where there's most signal. And we can do that up to three times. So we have a very proactive approach. And that explains why we have so many patients.

So because you may end up taking 30 biopsy samples and you have one sample that's positive. So that explains why 5.3 million people can have such a huge number of sarcoid patients. We don't think that we are special. We just think that we are very active in biopsy area. And I know that this is something that differs in different places, and the different centers in the US have very different policies, and in Europe as well. So why I think this explains why we have such a large population and why they're all biopsy verified cases.

Dr. Carolyn Lam:

Thank you so much, Mark. I know that as editors we spotted immediately what a precious, valuable cohort in data we were looking at. Could you frame that for us? Take us behind the scenes a little bit on what you thought when this paper first crossed your desk.

Dr. Mark Link:

Yeah. This was a paper that caught our interest right away for a number of reasons. One, is the large number of sarcoid patients, nearly 400, that's one of the largest series that's ever been published. And two, is the systematic way in which sarcoid was approached. And what we found fascinating is that once you had a diagnosis of cardiac sarcoid, be it either probable or actual, there was a high risk of having ventricular arrhythmias. And this is something that in the guidelines, it's not so clear, because it's clear if the EF's less than 35%, you should get an ICD. But if your EF's greater than 35% by current guidelines, that's not a class 1 indication. So we thought this paper had the possibility to move guidelines and that perhaps we should think about an ICD and any patient that has diagnosis of cardiac sarcoid.

Dr. Carolyn Lam:

Wow. That's a brave postulation though. Exactly, as I said at the beginning, I think it may be practice changing. What do you think about that? Jukka and Hannah?

Dr. Jukka Lehtonen:

I think that's exactly what we have noticed that we have, most of the cardiac sarcoid patients are less than 50 years of age. So I think, the average age is 49 or something. And they're mostly females, so 70% are females. So it's pretty unique cardiac disease, that's more common in females than in males. And I think this population is benefiting tremendously from the ICD therapy, so that's something that we can see. It's not based on randomized data, it's follow up data, but these patients have lots of ICD events, events treated by an ICD. So we think that this is a major problem. Our previous papers have shown that the mortality in sarcoidosis is 90% is ventricle arrhythmia. So this conclusion fits with that previous findings as well.

Dr. Carolyn Lam:

Wow. Hannah has this impacted your personal clinical practice? I mean, do you now therefore think any patient, especially, if they've got confirmed cardiac sarcoidosis biopsy proven. Are you going to just, no matter what, regardless, anything else be more likely to put an ICD?

Dr. Hanna-Kaisa Nordenswan:

Yeah. Based on this study, we think that all cardiac sarcoidosis patients presenting with clinical cardiac manifestations and with histologically proven cardiac sarcoidosis should be considered for an ICD implantation. But with patients, with having non-definite cardiac sarcoidosis and without class 1 to 2A indications for an ICD in these patients, probably, the pros and cons of an ICD should be carefully discussed. Well, if an ICD is not implanted, at least repeated risk appraisal is needed regularly during follow up.

Dr. Carolyn Lam:

That's great comments. Mark, what do you think is going to be needed as future steps to get it to change practice? Or do you think this is it? Because, I mean, this is... the issue is, it's not easy to say let's just do a trial in cardiac sarcoidosis, right? Where are we going to find those patients and so on. What do you think, Mark?

Dr. Mark Link:

Yeah. That's a very good question. Because this isn't randomized trial data, and the strength of evidence is best with randomized trial data. And will we get a randomized trial in sarcoid? I doubt it. I really doubt it. So we're going to be left with registry data. And so where I would see this going is other registries coming out, showing their data. I think we do need confirmatory data from another large registry or two, and that's going to change practice, but are we there yet? I don't know. I don't know. Based on the lack of randomized trial data.

Dr. Carolyn Lam:

Thanks. If I could then for the last questions, if I could give it to the authors, what are your plans for next steps, if any. Maybe, Jukka, do you want to start first?

Dr. Jukka Lehtonen:

Well, I think cardiac sarcoidosis has lots of open questions. It has only open questions. I think the direction we are going is to go to the drug trial. So whether treatment of the inflammation by different agents would provide benefit in terms of arrhythmias and heart failure. So there's an idea that take patients with, for example, that's something that we haven't finalized yet, but take patients with normal ejection fraction, randomized them to cortisone and no cortisone and see how they do. Because we don't really know whether even corticosteroids actually make a huge difference.

I think we have more than 200 cardiac sarcoid patients under follow up in our hospital. And I can see that there are patients that have very good prognosis and no events whatsoever over many years or even decade. And then we have other patients that have lots of events, arrhythmias and develop heart failure. So I think we need trials that help us to distinguish those patients and also trials that help us select right medications for each group.

Dr. Carolyn Lam:

Thank you, Hannah?

Dr. Hanna-Kaisa Nordenswan:

Based on this particular study, we think that also the next study should preferably be a larger multicenter study that would focus on the prognostic factors in cardiac sarcoidosis. Perhaps, a risk score could be developed by using more detailed information of the presenting manifestations and ventricular function and imaging findings, cardiac magnetic resonance and positron emission tomography.

Dr. Mark Link:

Yeah. And we at the editorial staff thought this was important enough paper to have an editorial, to comment on its usefulness and way forward in dealing with cardiac sarcoid patients. And this editorial is written by Rick Patton and will accompany the printed issue.

Dr. Carolyn Lam:

Thanks. And so, you heard it, everyone pick up that editorial, pick up that paper. This is an important topic, and so grateful that it was published with us. Thank you once again to the authors. Thank you once again, Mark, for managing this paper. So lovely. And thank you, audience for joining us today from Greg and I, you've been listening to Circulation on the Run. Don't forget to tune in again next week.

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Jonathan Sterne and Associate Editor Shinya Goto as they discuss the article "Association of COVID-19 With Major Arterial and Venous Thrombotic Diseases: A Population-Wide Cohort Study of 48 Million Adults in England and Wales."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Oh, Greg, we've got a special treat for everyone today. We have a third co-host and he is none other than Peder Myhre from Norway! Really adding to the diversity of our podcast: me from Asia, you from the US, and Peder from Europe. Welcome, Peder.

Dr. Peder Myhre:

Thank you so much, Carolyn. It's truly an honor to be here and I'm looking forward to being part of this podcast today.

Dr. Carolyn Lam:

Awesome. Well, here we go. Looks like we have a feature paper, Greg?

Dr. Greg Hundley:

Absolutely, Carolyn. Peder, welcome. So, listeners, our feature today will involve COVID-19 and its association with arterial and venous thrombotic diseases. But before we get to that, we're going to all grab a cup of coffee from all over the world and get into some of the other articles in the issue. Peder, Carolyn, how about I go first?

My first study involves a prospective cohort of 94,000 individuals from the UK Biobank, who had device-measured physical activity from 2013 to 2015 and were free from myocardial infarction and heart failure. Now, Peder and Carolyn, the study was performed because although objectively measured physical activity has been found associated with acute cardiovascular outcomes, it has not been found associated with heart failure and, of course, a syndrome that's been expanding worldwide. As such this study led by Carlos Celis-Morales from the University of Glasgow aimed to investigate the dose response relationship between device-measured physical activity and heart failure by intensity of the physical activity. Now physical activity was measured with a wrist-worn accelerometer and time spent on light, moderate, and vigorous intensity physical activity was extracted. Incidental heart failure was ascertained from linked hospital and death records.

Dr. Peder Myhre:

Wow, Greg. That sounds amazing. Tell us, what did they find?

Dr. Greg Hundley:

You bet, Peder! These investigators found that, compared with participants who undertook no moderate to vigorous intensity physical activity, those who performed 150 to 300 minutes per week of moderate intensity physical activity or 75 to 150 minutes per week of vigorous intensity physical activity were at lower risk of heart failure. Now, interestingly, the association between vigorous intensity physical activity and heart failure was a reverse J-shaped curve with a potentially lower risk reduction above 150 minutes per week.

And so, the take-home message for this first paper is that device-measured physical activity, especially moderate intensity physical activity, was associated with a lower risk of heart failure. Probably current vigorous intensity physical activity recommendations should be encouraged, but not necessarily increased. In contrast, increasing moderate intensity physical activity may be beneficial, even among those meeting current recommendations.

Dr. Peder Myhre:

Wow, Greg. That was a great summary. And the second original research article today is about high density lipoproteins. As you know, raising HDL cholesterol levels to prevent cardiovascular disease remains a hot topic. HDL plays a key role in reverse cholesterol transport and may be cardioprotective and reduce infarct size in the setting of myocardial injury. Lecithin cholesterol acyl transferase, LCAT, is the rate limiting enzyme in the reverse cholesterol transport and a recombinant human LCAT called MEDI6012 has previously been shown to increase HDL cholesterol. So in this study from the corresponding author, Marc Bonaca from University of Colorado School of Medicine, the investigators in the real team is 63B multicenter placebo control trial investigated whether randomized patients to, MEDI6012 or placebo would reduce the infarct size as measured by cardiac MRI, 10 to 12 weeks after the STEMI.

Dr. Greg Hundley:

Very interesting, Peder. So, MRI assessments of LV mass after PCI. So, what did they find?

Dr. Peder Myhre:

So, Greg, the authors successfully enrolled 593 patients with a median age of 62 years and 78% males. And the median time from symptom onset to randomization was 146 minutes and only 13 minutes from hospitalization to randomization. And the index MI was anterior in 70% and 65% had TIMI Flow grade 0-1. And then to the main results at 12 weeks, the infarct size did not defer between the treatment group. So that was a 9.7% infarct size for MEDI6012 versus 10.5% for placebo with a P value of 0.79. And there was also no difference in noncalcified black volume. So the authors conclude that enhanced reverse cholesterol transport with recombinant human LCAT did not reduce infarct size or late regression of noncalcified coronary REPL at 12 weeks. Okay, Greg. So tell me about the 3rd paper you have today?

Dr. Greg Hundley:

Peder, what a great description on that previous paper, beautiful job there. So Peder, this next article pertains to cardio toxicity related to the administration of anthracycline-based chemotherapy. And an example would be Doxorubicin. And this occurs in patients often with certain types of cancer. As you know, Doxorubicin is still utilized for the treatment of leukemia, lymphoma, soft tissue sarcoma and in the setting of adjuvant breast cancer treatment. And so to this end, the authors, led by Lorrie Kirshenbaum from St. Boniface Hospital abstract research, wanted to assess cytokine mediated inflammation in myocellular injury, as a result of some of the inflammation that's induced by the administration of Doxorubicin. So as a little bit of background, cytokines, such as TNF alpha, have been implicated in cardiac dysfunction and toxicity associated with Doxorubicin. Now, while TNF alpha can elicit different cellular responses, including survival or death, the mechanisms underlying these divergent outcomes in the heart really somewhat remain cryptic.

The E3 ubiquitin ligase, TRAF2, provides a critical signaling platform for K63 length poly ubiquitin nation of rip K1, crucial for NF-kB activation by TNF alpha and survival. Whether alterations in TNF alpha, TRAF2, NF-kB activation signaling underlie the cardiotoxic effects of Doxorubicin, remains poorly understood. So herein, these authors investigated TRAF2 signaling in the pathogenesis of Doxorubicin cardio toxicity.

Dr. Peder Myhre:

Oh wow, Greg. So we're talking mitochondrial dysfunction in Doxorubicin cardiomyopathy. So please tell me, what did they find and what were the clinical implications?

Dr. Greg Hundley:

Very nice. Peder, you remind me of Carolyn, asking me the clinical implications. Okay, so first, in mouse models and in vitro measures in rats, mouse and human pluripotent stem cell derived cardiomyocytes, these investigators monitored TNF alpha levels, LDH, cardiac ultra structure and function, mitochondrial biogenics, as you just suggested, and cardiac cell viability. They found that a novel signaling axis exists that functionally connects the cardiotoxic effects of Doxorubicin to proteasomal degradation of TRAF2. Disruption of the critical TRAF2 survival pathway by Doxorubicin, sensitizes cardiomyocytes to TNF alpha and BNIP3 mediated necrotic cell death. Perhaps, interventions that stabilize TRAF2, so here's the clinical implication, may prove beneficial in mitigating the cardiotoxic effects in cancer patients undergoing anthracycline-based chemotherapy.

Dr. Carolyn Lam:

So Greg, he may sound like me, but this is me going what an amazing summary and especially in something that is your specialty cardio-oncology, that's amazing. Thank you. Peder, I assume you've got one more paper?

Dr. Peder Myhre:

So Greg, now I'm going to sound like you and say that we are going to stay within the world of preclinical science. So genome-wide association studies have identified many genetic loci that are robustly associated with coronary artery disease. However, the underlying biological mechanisms are still unknown for most of these loci, hindering the progress to medical translation. And there is evidence to suggest that the genetic influence of coronary artery disease sociability may partly act through vascular smooth muscle cells. So corresponding author, Shu Ye from University of Leicester, performed genotyping, RNA sequencing and cell behavior assays on the large bank of vascular smooth muscle cells with an N of almost 1500. And through these extensive analysis, they saw to identify genes whose expression was influenced by coronary artery disease associated variants.

Dr. Greg Hundley:

Very nice, Peder. So, more about cardiac gene expression. So, what did they find?

Dr. Peder Myhre:

Approximately 60% of the known coronary artery disease associated variants show statistically significant effects in vascular smooth muscle cells and the study identified 84 candidate causal genes whose expression quantitative trait, loci signals in vascular smooth muscle cells, significantly co-localized with reported coronary artery disease association signals, of which 38 of them are potentially druggable, so, that was the clinical implications. The authors conclude that a large percentage of coronary artery disease loci can modulate genes, gene expression in vascular smooth muscle cells and influence these cell behavior. Several candidate causal genes identified are likely to be druggable and thus represent potential therapeutic targets. And Greg, accompanying this paper is a beautiful editorial by doctors O'Donnell and Bradner entitled "Bridging the Gap to Translating Genome-Wide Discoveries into Therapies to Prevent and Treat Atherosclerotic Cardiovascular Disease."

Dr. Greg Hundley:

Very nicely done Peder, very nicely done. Well, as usual, we have some other items, we call it in the mail bag because we receive these wonderful research letters and also research correspondence. So I'll go first. First, Dr. Al-Khatib has a research letter entitled, "Duration of Anticoagulation Interruption before Invasive Procedures and Outcomes in Patients with Atrial Fibrillation Insights from the Aristotle Trial." And also there's a nice ECG analysis by Dr. Tsai entitled, "A Peculiar Wide-Complex Tachycardia During Flecainide Treatment."

Dr. Peder Myhre:

Nice, Greg, and there's also an exchange on letters to the editors and the response from Professors Zhao and Ding, and again, a response from Professor Zhang regarding the prior letter by Jin et al. pertaining to the previously published article "Micro RNA, 210 Controls, Mitochondrial Metabolism and Protects Heart Function in Myocardial Infarction."

Dr. Greg Hundley:

Beautifully done, Peder. Oh, wow. Welcome to this team. We're so excited to have you. And now Carolyn, I think we're going to jump over to that feature discussion and learn a little bit more about COVID-19 and arterial and venous thrombotic disease.

Dr. Carolyn Lam:

You bet! Let's go, Greg and Peder.

Now we all know that infection with COVID 19 induces a pro-thrombotic state, but the long term effects of COVID-19 on the incidence of vascular disease, both arterial and venous, remain unclear. That is until today's feature paper. We're so grateful to have corresponding author Dr. Jonathan Stern, from the University of Bristol, as well as our associate editor, Dr. Shinya Goto from Tokai University School of Medicine to join us and discuss this very important paper today. Jonathan, could you start us off on telling us why it's so important to look at this? Haven't we always known that infections, COVID or not, are associated with pro-thrombotic state? So what's so different about what you did and what you found this time?

Dr. Jonathan Stern:

So, yes, I think we already knew that serious infections, in particular infections leading to hospitalization, can result in thrombotic events, either arterial or venous. And it was also clear from January, February, March 2020, that COVID led to very serious infection and therefore was likely to lead to vascular events. The questions that we set out to address, beyond simply establishing that COVID does indeed do this, was to quantify by how much COVID multiplies the rate at which these thrombotic events occurred, to do that separately for different events, such as myocardial infarction, stroke, venous thromboembolism, pulmonary embolism. And then to importantly, because we analyzed a very large dataset, which we might want to talk about, to try to separate out the amount by which the rating events was multiplied over time and in important subgroups, for example, in hospital people who were hospitalized for their COVID, compared with people who weren't hospitalized for their COVID, by age and sex, and by other demographic characteristics.

Dr. Carolyn Lam:

I love that, you see, that really set out the novel information this added with, may I add, very important clinical implications, which we'll get to them. You've already teed me up to talk about this 48 million adults that you managed to look at. Oh my goodness! Tell us, how in the world did you do that?

Dr. Jonathan Stern:

Well, I think the first thing to say is that it's my absolute privilege to talk about this paper on behalf of a really incredible team that put the work together. And a lot of that work, or that work started with really unlocking the power of NHS data because of the COVID pandemic. So in the UK, we have a national health service, free at the point of delivery to everybody. The NHS assembled electronic health records, and there's been a long and proud history of research based on electronic health records in the UK. But for the first time, because of the pandemic, a combined data resource for the whole of England, so that's a population of about 58 million people, was established and that linked primary care data - data from family doctors, data on secondary care hospital admissions, data on COVID testing and subsequently, although it's not the subject of this paper, data on vaccination.

So those data were all linked and put into one place within what's called a trusted research environment with very strict controls on what can be output from the environment in order to protect patient privacy. And that was really done during 2020. And then the analyses for this paper took place during 2021, and it was an enormous amount of work by a large and absolutely fantastic team of people across multiple UK universities and national health service institutions.

Dr. Carolyn Lam:

Wow. Bravo! We talk about big data, we talk about using it. I trained in the NHS system. Who knew that this could come out to reveal such important results? So thank you for that as a background, but now, tell us what you found please?

Dr. Jonathan Stern:

So we found that rates of these conditions, they were primarily acute lymph infarction and ischemic stroke, which we grouped together with other conditions as arterial thrombotic events, and then deep vein thrombosis and pulmonary embolism, which we grouped together with other conditions as venous events. And we found that rates were substantially multiplied immediately after a diagnosis of COVID by up to 748 times, that the amount by which rates were multiplied diminished with time since COVID, but importantly that even six months to a year after that first diagnosis of COVID, rates of venous events were still about double in people who'd had COVID, compared to people who had COVID. And we found, it seemed quite clear that the persistence of the elevated risk was longer for venous events than for arterial events.

Dr. Carolyn Lam:

Just really fascinating results and Shinya, could I ask, what are your thoughts on this? And as you were managing this paper, the implications?

Dr. Shinya Goto:

First of all, thank you very much, Jonathan, for choosing saturation for your great paper. I'm handling quite a lot of papers, but your paper was very attractive. As Carolyn mentioned, it's huge data! 48 million, it's surprising, and also you also pick up booster rate of arterial embolism event for years, and you have also shown adjusted rate is initially increased quite a lot and then decreased gradually. And even after two months, three months still, there is a persisted higher risk. And as you mentioned, for the venous thrombo embolism, it's persisted for more than year to year. It's surprising. COVID-19's a different disease. Perhaps COVID-19 infection cuts to the vascular endarterial cell, perhaps, your research raised a lot of research questions, like endarterial damage induced by COVID-19 in the past 6 months; I would say more than half a year to one year. So that mechanistical insight is very important. And you raise a lot of any clinical questions.

Dr. Jonathan Stern:

Well, thank you very much for your kind words and you are right, I think we are left with questions about maybe in three areas. Firstly, for how long is there an elevation in risk? I should probably say, for those who haven't read the paper, that these results relate to events that occurred in England and Wales during 2020. And so that is in an era before vaccination and when we were dealing with the original variant, and to some extent, the alpha variant. So we are still waiting to see what the implications were over longer periods, and we will be doing that, we will be extending follow up. In fact, we are at the moment extending those results. I think, secondly, we are left with questions about the mechanisms, which you articulated, and thirdly, there's the question about, well, what are the implications for clinical management of patients with COVID-19? And in particular, for patients who've had severe COVID-19, for example, severe enough to be hospitalized for it?

Dr. Shinya Goto:

Yeah, you have also showed a very important point that even known hospitalization for COVID-19, the risk of thrombosis becomes high. So it's very surprising. And even non-hospitalized patients have a higher risk of thrombosis. That is probably the huge difference between other virus infections and COVID-19.

Dr. Jonathan Stern:

Yes. The good news, if you weren't hospitalized for your COVID, is that the elevation in risk declines more rapidly for people with less severe COVID who weren't hospitalized than for people with more severe COVID who were hospitalized. But nonetheless, as you say, particularly in the first week, two weeks, three weeks after COVID, there is a clear elevation in the risk of both arterial and venous events, even if you were not hospitalized for your COVID. We should probably also bear in mind that these results for 2020, when there were severe constraints for some of the time on health service resources. So you probably had to be pretty sick to get hospitalized at that time.

Dr. Carolyn Lam:

That was a very important caveat that you just highlighted. So thank you for contextualizing those findings for us, Jonathan, but then I kind of wish all podcast guests were like you, and you already asked a question, I was going to ask you. Which is, okay, so what's the clinical implication? Should we all be taking some low dose NOAC or aspirin? Whether you're hospitalized or not? Or if you were in 2020? Because, jokes aside, I know that you found some very important risk factors? Or these events which had clinical implications? Could you expand on it?

Dr. Jonathan Stern:

So maybe I'd start by saying that we didn't find that these patterns varied dramatically either by sex or by age. And in fact, when we were planning the analyses, I was convinced that we would see dramatic differences in these hazard ratios by age. And, broadly speaking, the facts on a multiplicative scale, the amount by which your rate is multiplied, looked similar across age groups and by sex. On the other hand, we did see the amount by rates of arterial and venous events were multiplied, appeared greater in people of Asian ethnicity or Black ethnicity than in people of White ethnicity. A counterintuitive finding was that the amount by which your rate was multiplied is lower, if you've had a prior event than if you hadn't. Those are the sorts of extents to which we can say something about how your own characteristics predict the consequences once you've had COVID.

In terms of management, obviously the pandemic has been tumultuous for medicine and for medical research and things have moved on greatly since the pre-vaccination era, 2020 and early 2021, to which these analyses relate. So the first thing to say is, don't get hospitalized with COVID, and the best way to not be hospitalized with COVID, is to be fully vaccinated for COVID. And that's a message that I think the whole of the medical profession has communicated loudly and clearly for a long time now.

So the second thing is, well, okay, what about if, nonetheless, you got COVID, particularly severe COVID, and we discussed this in the team extensively, and I particularly want to mention the senior clinical author, Dr. Will Whiteley from the University of Edinburgh in this regard, and I think the main message here is that risk factor management, cardiovascular risk factor management is always important, but it's probably particularly important in people who've had severe COVID to review risk factor management and make sure that existing guidelines in terms of cholesterol lowering, blood pressure lowering and so on, are being adhered to. We don't... So the most important thing is adherence to existing cardiovascular risk management guidelines. I think we don't have evidence that specific additional interventions are indicated in people who've had COVID, and COVID now in the era of Omicron and widespread vaccination is not the same as COVID during 2020.

Dr. Shinya Goto:

Jonathan, you have raised a very important issue. I strongly recommend all audiences to read this paper. We have to know persistent or higher risk of myocardial infarction, ischemic stroke, may be controlled more regularly controlled. Don't fear the COVID-19 infection to visiting the healthcare professional. In my country, some of the population stopped coming to the healthcare professional because they fear so much about infection from the hospital or clinic. But it's very important to keep that regular control like static and blood pressure control. Maybe we don't have that data about aspiring or not, but strong message your paper gave is that risk factor control after COVID-19 is very important.

Dr. Jonathan Stern:

I completely agree.

Dr. Carolyn Lam:

And I would add to that, remember the days when people were stopping their ACE inhibitors and so on for those fear? So what a great message and thank you for giving us a little bit of a peek into the future of what you're planning next with more follow up, in a population that is vaccinated from a different strain perhaps. And I think this still encourages hopefully more trials and research into this whole area of how we should be managing these patients. Well, thank you so much both of you for discussing this very, very current relevant, important paper. Thank you for publishing it in circulation with us. And to the audience, thank you for joining us today. From Greg and I, you've been listening to Circulation on the Run, and don't forget to tune in again next week.

Speaker 6:

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join authors Svati Shah and Senthil Selvaraj as well as Guest Editor and Editorialist Manuel Mayr as they discuss the article "Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction: DEFINE-HF" and the editorial "SGLT2 Inhibitors in Heart Failure: Targeted Metabolomics and Energetic Metabolism."

Dr. Carolyn Lam:

Welcome to Circulation On Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health Richmond, Virginia.

Dr. Carolyn Lam:

In today's feature paper, we will be talking about the metabolomic profiling of the effects of dapagliflozin in heart failure, and this is from the DEFINE-HF trial. It's just such a cool paper with a lot of insights you have to hear from the authors. But, before we get there, let's talk about some of the other papers in today's issue. Shall we, Greg?

Dr. Greg Hundley:

You bet, Carolyn. Well, how about if I go first?

Dr. Carolyn Lam:

Please.

Dr. Greg Hundley:

Thank you, Carolyn. My first paper comes to us from Professor Paulus Kirchhof from the Universitäres Herzzentrum in Hamburg. Carolyn, in the randomized EAST-AFNET 4 study, so the early treatment of atrial fibrillation for stroke prevention, these trial investigators demonstrated that systematic initiation of early rhythm control reduced adverse cardiovascular outcomes in patients with recently diagnosed atrial fibrillation and stroke risk factors. However, the effectiveness and safety of early rhythm control in patients with multiple cardiovascular comorbidities is not known. Carolyn, in this study, it was a prespecified sub-analysis of the EAST-AFNET 4 trial and it compared the effectiveness and safety of early rhythm control with usual care stratified into patients with high CHA2DS2-VASc scores of greater than or equal to 4.

Dr. Carolyn Lam:

Nice. Okay. Important question, what did they find?

Dr. Greg Hundley:

Right, Carolyn. Quite a bit of data in this study, so let's walk through it carefully. First, in regards to the study population, the EAST-AFNET 4 randomized 1093 patients with CHA2DS2-VASc scores of greater than or equal to 4, these were predominantly women, 61% female, and then also 1,696 patients with CHA2DS2-VASc of less than four, and these were predominantly men, so only 37% women.

Now let's get to the date. Early rhythm control reduced the composite primary efficacy outcome of cardiovascular death, stroke, or hospitalization for worsening heart failure or for acute coronary syndrome in patients with high CHA2DS2-VASc scores of greater than 4, but not in patients with CHA2DS2-VASc scores of less than 4. Second, now Carolyn, the primary safety outcome, so death, stroke, or serious adverse events of rhythm control therapy, was not different between study groups in patients with high CHA2DS2-VASc scores of greater than 4, but occurred more often in patients with low CHA2DS2-VASc scores randomized to early rhythm control. Now Carolyn, life threatening events or death were not different between the groups. When female sex was ignored for the creation of high and lower groups, the interaction P was not significant for the primary efficacy outcome, but remained significant for the primary safety outcome.

Dr. Carolyn Lam:

Oh, you are right. A lot of interesting data here. What's a take home message?

Dr. Greg Hundley:

Right, Carolyn. So the take home message is the following. Patients with recently diagnosed atrial fibrillation and multiple cardiovascular comorbidities should be considered to have priority access to early rhythm control to reduce cardiovascular outcomes, and a specific trial of early rhythm control in these patients is really needed as a next step.

Dr. Carolyn Lam:

Oh, thank you, Greg. The next paper focuses on arrhythmogenic right ventricular cardiomyopathy, which we know is characterized by a high propensity to life threatening arrhythmias and progressive loss of heart muscle. More than 40% of reported genetic variants linked to arrhythmogenic right ventricular cardiomyopathy, or ARVC, reside in a gene called plakophilin-2, or PKP2. In today's paper, Dr. Delmar and Lundby from NYU Grossman School of Medicine and University of Copenhagen, respectively, and their colleagues, described a comprehensive characterization of the ARVC molecular landscape using a multidisciplinary approach including human samples from ARVC patients with PKP2 mutations and left ventricular ejection fraction above 45%, as well as PKP2-deficient murine and human induced pluripotent stem cell-derived cardiomyocytes. They studied all of these with comprehensive proteomics and functional analysis.

Dr. Greg Hundley:

Wow, Carolyn, another great study in circulation combining both preclinical murine models as well as data from human subjects. So, what did they find?

Dr. Carolyn Lam:

Precisely, Greg. Here's what they found. Loss of nuclear envelope integrity and subsequent DNA damage is a key substrate in the molecular pathology of AR VC. The authors further showed transcriptional down regulation of proteins of the electron transcript chain as an early event in the molecular pathophysiology of the disease prior to an ejection fraction falling below 45%. This associates with increased oxidant production, with the clinical message being, therefore, that the authors propose therapies that limit oxidant formation may be a possible intervention to restrict DNA damage in ARVC.

Dr. Greg Hundley:

Very nice, Carolyn. Okay, our next paper comes from Dr. Donald Lloyd-Jones from Northwestern University, the Feinberg School of Medicine. Carolyn, you can tell the change in inflection of my voice because it's time for another Carolyn's quiz. Carolyn, open-ended question. Can you remind us of life's essential eight?

Dr. Carolyn Lam:

Oh boy, Greg. It's like asking me to name the dwarfs. I know I'm going to forget one, but here you go. Diet, exercise, cholesterol, weight, smoking, sugar must be there, diabetes, blood pressure. You see, I got seven. What's the eighth?

Dr. Greg Hundley:

Yeah. Remember seven dwarfs, Sleepy.

Dr. Carolyn Lam:

Sleep.

Dr. Greg Hundley:

Very good. Great job, Carolyn.

Dr. Carolyn Lam:

Thank you.

Dr. Greg Hundley:

Recently, the American Heart Association recently published an updated algorithm for quantifying cardiovascular health, the Life's Essential 8 score. In this study, the investigative team quantified US levels of cardiovascular health using the new score. They included non-pregnant, non-institutionalized individuals aged 2 through 79 years who were free of cardiovascular disease from the National Health and Nutrition Examination Surveys that were conducted between 2013 and 2018.

Now, for all participants, they calculated the overall cardiovascular health score, and it ranged from 0, which is really low, to 100, which is the highest, as well as the score for each component. And Carolyn, yes, you are very close. Remember the eight? Diet, physical activity, nicotine exposure, sleep duration, body mass index, blood lipids, blood glucose, and blood pressure, and they used published American Heart Association definitions of these. The cardiovascular health scores were assessed across strata of age, sex, race, ethnicity, family income, and depression.

Dr. Carolyn Lam:

Okay, Greg. What did they find?

Dr. Greg Hundley:

Right, Carolyn. There were 23,400 plus participants, representing 201,728,000 adults and 74 million children. The overall mean cardiovascular health score was 64.7 among adults using all eight metrics, and it was 65.5 for the three metrics available of diet, physical activity, and BMI among the children and adolescents that were aged 2 through 19 years.

Now, for the adults there were significant differences in mean cardiovascular health scores by sex, age, and racial ethnic group. Mean scores were lowest for diet, physical activity, and the BMI metrics. There were large differences in mean scores across demographic groups for diet, nicotine exposure, blood glucose, and blood pressure. In children, diet scores were low, 40.6, and were progressively lower in higher age groups. Large differences were also noted in mean physical activity and BMI by sociodemographic group.

Carolyn, this study basically identifies wide ranges of scores across multiple domains of the essential eight, and thus, this new Life's Essential 8 score helps identify large group and individual differences in cardiovascular health. Additionally, overall, cardiovascular health in the US population remains well below optimal levels, and there are both broad and targeted opportunities to monitor, preserve, and improve cardiovascular health across the life course in both individuals, as well as the population at large.

Dr. Carolyn Lam:

Wow. Thanks, Greg. Truly really interesting. Everyone's going to have to pick up that paper and all the other papers in this issue, because there's also an In Depth paper by Dr. Whelton on “Harmonization of the ACC/AHA and ESC/ESH Blood Pressure Hypertension Guidelines, Comparisons, Reflections, and Recommendations. There's a Research Letter by Dr. Munshi on the accurate classification of cardiomyopathy etiology by chromatin accessibility.

Dr. Greg Hundley:

Carolyn, I have got to report an exchange of letters from Professor Sun and Weng regarding the article, “Legumain Is an Endogenous Modulator of Integrin αvβ3 Triggering Vascular Degeneration, Dissection, and Rupture.” And then Carolyn, lastly, there's a Perspective piece from Professor Vidal-Petiot entitled, “Thresholds for Hypertension Definition, Treatment Initiation, and Treatment Targets: Recent Guidelines at a Glance.” Well, Carolyn, how about we get on to that feature discussion?

Dr. Carolyn Lam:

Yes, let's go Greg.

Wow, we have a star stud cast for today's feature discussion, and on a star studied topic, if I may. It's on the SGLT2 inhibitors, this time in the DEFINE-HF study and really going into the mechanism of action of SGLT2 inhibitors. Now, that's one question I personally get all the time. How do these things work? Today's paper brings us one step closer, for sure, in the understanding. I'm so grateful to have the first author, Dr. Senthil Selvaraj from University of Pennsylvania, as well as the corresponding author of the paper, Dr. Svati Shah, associate editor, as well as the corresponding author from Duke Molecular Physiology Institute. We also have Dr. Manuel Mayr who was both the guest editor and editorialist for this paper, and Dr. Mayr is from Kings College London, British Heart Foundation Center. Welcome, everyone. Senthil, get us started here. The DEFINE-HF study, just a quick summary, what that was about and then what you did, what you found.

Dr. Senthil Selvaraj:

Absolutely. Good morning, everyone, or maybe good evening for your time, Carolyn, but we were very excited about this study and the ability to do targeted metabolomic profiling in DEFINE. This audience is well familiar with the fact that SGLT2 inhibitors are foundational therapy in heart failure reduced ejection fraction, and the interesting thing is, despite a lot of literature, we still don't know why. Whether it relates to change in inflammation or endothelial function, but given the mechanism of action, metabolism is sort of at its core. So in this study we sought to identify metabolic pathways that were associated with dapagliflozin treatment using this targeted metabolomics platform in which we assayed 63 metabolites, acylcarnitine, which are markers of fatty acid oxidation, several amino acids, and ketone-related metabolites.

To do this, we studied 234 participants from DEFINE, which is a 12-week placebo-controlled trial of dapagliflozin in this population, and we perform principal components analysis for dimensionality reduction techniques. In this study, briefly we found that, first, our principal components analysis yielded 13 different factors that accounted for the substantial proportion in the variation of the data, and that two in particular, ketone-related metabolites and short acylcarnitines in factor 6, as well as medium-chain acylcarnitines in factor 7 were differentially associated with dapagliflozin treatment. Specifically, there were increases in several ketone-related metabolites and short acylcarnitines, as well as several medium-chain acylcarnitines, really speaking to, potentially, changes in fatty acid as well as ketone biology with dapagliflozin treatment.

The second aim of our study was to look at changes in metabolites and changes in endpoint studying DEFINE, which included NT-proBNP as well as KCCQ scores. We found that dicarboxylate long-chain acylcarnitines and aromatic amino acids really related to worsening heart failure endpoints there. So, a lot to impact, a lot that we found, and appreciative about the opportunity.

Dr. Carolyn Lam:

Oh, wow. Thank you so much for that amazing summary. Svati, I've heard you speak so many times on metabolomics on our calls, but this is really so important. First, I think the question is, congratulations for thinking ahead of time to collect the samples and to do all of this. Congratulations on that. Could I ask if you went in with any specific hypothesis or were you surprised by these findings, Svati?

Dr. Svati Shah:

Yeah, Carolyn, thank you so much. It was such a pleasure to work with Senthil on this and I really want to highlight what an incredible early career investigator he is. He's really going to set the metabolism world on fire. I also wanted to say thank you to the PI of the clinical trial, the parent clinical trial DEFINE-HF Mikhail Kosiborod, who did the really hard work of collecting the samples along with the clinical trial itself.

To me, what's really cool is to be able to take a clinical trial like this with really important clinical outcomes well adjudicated and to be able to dig into the mechanism at a metabolic level of what might be going on with SGLT2 inhibitors. Going into this, Carolyn, we suspected that ketone-related biology was at play. There have been studies in other populations, non-HFrEF populations, that have shown that SGLT2 inhibitors have what appears to be beneficial impacts on ketone biology and induced ketosis. So, going into this, we suspected that this ketone pathway was going to come up. I think what's exciting is, not only did we find that the ketone pathway was differential modified by dapagliflozin, but that it wasn't at the level of severe ketosis that we would be concerned about. And then secondly, we found pathways of fatty acid oxidation. Some related to the effects of the medication and some related to changes in functional outcome. So it really enhanced beyond what we already knew about ketone biology, expanded our understanding of potential mechanisms of SGLT2 inhibitors, and expanded this into the HFrEF space, Carolyn.

Dr. Carolyn Lam:

Oh, that's so nice. I'm bursting with questions, but I really, really have to ask Dr. Manuel Mayr, first, could you put these findings into context for us and tell us what they mean clinically?

Dr. Manuel Mayr:

Yeah, Carolyn. First of all, I want to join you in congratulating the authors to this important study. As Svati mentioned, previous studies have reported effects of SGLT2 inhibitors on ketone bodies, but the present study really adds to the literature because it uses the state of the art metabolomic techniques. It uses a technique called mass spectrometry, but they also have a rating of, I think, in total, 63 metabolites in over 200 patients. Mass spectrometry is becoming increasingly important for cardiovascular precision medicine because we can use it in clinical trials to provide an unbiased assessment of metabolites and proteins. So it's a very versatile technology. I think this study really adds to the rapidly growing literature that SGLT2 inhibition is a principle of unloading the failing heart from metabolic stress.

Dr. Carolyn Lam:

Wow, I really like that and your editorial is just beautiful. I love that you say, "After the serendipitous findings of improved heart failure outcomes with SGLT2 inhibitors, mechanisms were postulated, but studies, such as the one we're discussing, are needed to really uncover what's the real thing." Now, I know this may sound really oversimplified and so on, but I'd really love for Senthil or Svati to just bear with me as I ask, what are you going to say to people who go, "Okay, then we should just be downing ketones," Or, "We should be Working on the fatty acid parts of it," Or taking conclusions like that. What would you say to something like that?

Dr. Senthil Selvaraj:

I'm happy to go first. It's a really wonderful question and I do think that this study raises the question of whether we should be exogenously increasing ketone levels to provide some sort of benefit. I would say the jury's still out there. I think it's a hot topic right now. But there are also differences between how we raise key tone levels, whether you do that endogenously in the body, or whether you give something like a ketone supplement, so exogenous ketone supplementation. And I think that there are completely different physiologies there. So more to come. I think there are a lot of studies in this space.

The ketogenic diet is something that I'm often asked as well, whether that might provide benefit to heart failure. There are a lot of ways that I can, but one thing that we need to be mindful of is the fact that it will reduce glycogen stores as well, which may impact exercise capacity. So, we need more data. I would say the other thing that we found in our studies, while they were increased in ketone levels and markers of fatty acid oxidation with dapagliflozin treatment, we aren't necessarily sure that those mediate the benefits of SGLT2 inhibitors. DEFINE has important clinically relevant endpoints, but it is not an event-based trial. And so we don't know and we can't link the changes in metabolites with changes in outcomes quite yet.

Dr. Svati Shah:

Carolyn, just to add to the wonderful response that Senthil just gave, I think we do have to be careful. We don't know whether these are direct effects of SGLT2 inhibitors or whether these are related to the caloric loss that we know happens with these medications. I think it's important to point out that we're looking in the blood, we don't actually know what's happening at the tissue level, so we do have to be a little bit careful. We have made inferences that this is reporting on substrate fuel selection in the heart, but we also suspect that skeletal muscle and other organs are heavily involved in some of the pathways we're seeing. So I just wanted to make those important caveat to the epidemiologic work that we do.

Dr. Carolyn Lam:

And those are so important, so thank you Senthil and Svati. Manuel, I'd love to invite your thoughts because you did sort of point out some of these points in your editorial. Could you maybe discuss a bit of those and raise any questions, perhaps?

Dr. Manuel Mayr:

Yes. I think Svati and Senthil have nicely mentioned already that these measurements are performed in plasma. So the changes in plasma could be due to, for example, increased production in the liver due to decreased consumption in other tissues. So I guess the next step would be, and I would be really interested on what the authors want to pursue, is to provide direct evidence for the energetic hypothesis, that really the heart is consuming these keto bodies and what type of measurements could be performed to provide direct evidence in humans for these metabolic hypothesis.

Dr. Senthil Selvaraj:

That's a really great question, Manuel. There was a really nice study that was published about a year or two ago in Science in which the authors did coronary sinus sampling. So really to get arterial venous gradients, measure substances in the arterial system as well as the coronary sinus venous system and get extraction. I think that that study would be very interesting to understand. You take patients on SGLT2 inhibitors, those who are not, and to understand what is the heart chewing on. Obviously more invasive than some other approaches, but other studies that I think would be really interesting in those space would be flux studies and stable isotope studies. Again, as Svati really nicely mentioned, these are systemic physiology snapshots whenever we do less localized techniques like that, but they're still very important because heart failure is a systemic process.

Dr. Carolyn Lam:

Anything to add, Svati?

Dr. Svati Shah:

No, I think you said it beautifully. I'll just say on the sort of epidemiologic side, to be able to link this to harder outcomes, DEFINE-HF wasn't really designed to be able to do that. So as we expand our understanding of SGLT2 inhibitors, understand different populations, and to link these pathways to more objective outcomes, I think, will be really useful, also.

Dr. Carolyn Lam:

Indeed. Manual, in your editorial, you actually discuss some of your own work, which may be the ones that Senthil is actually talking about. What is your view?

Dr. Manuel Mayr:

Well, I think I'm very excited that beyond fatty acid metabolism and glucose metabolism, ketones have extracted increasing attention. Ketone body metabolism, I think, has long been underappreciated. We still need to understand to what extent it really acts as a fuel and that it can help to overcome the energy deficit that creates heart failure. I think, as mentioned by Svati and Senthil, we need more studies in this area, and of course other trials are ongoing where they're going to measure, for example, the phosphocreatine to ATP ratio by using phosphor-NMR spectroscopy. So we get direct evidence whether there really is an energetic improvement upon SGLT2 inhibition. I think this will be studies to look forward to and to add to the growing literature that metabolism is important as a therapeutic target for heart failure.

Dr. Carolyn Lam:

Oh, such exciting times. You mentioned the EMPA-VISION trial in your editorial. I think I'm trying to tell everybody, you have to pick up the paper and the editorial. You're going to learn so much. This is so cool. Thank you so, so much all of you for being on this podcast, for sharing your thoughts. I'm sure everyone has learned a lot and enjoyed it just as I have. On behalf of Greg and I, thank you for being here, thank you for joining us today, and don't forget to tune in again next week. Thank you.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Keith Channon as he discusses the article "Risk of Myocarditis After Sequential Doses of COVID-19 Vaccine and SARS-CoV-2 Infection by Age and Sex."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke-National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Oh, Greg, today's feature paper, something that's really been discussed a lot in the press and in lay public as well, the risk of myocarditis following sequential doses of the COVID-19 vaccine and SARS-CoV-2 infection by age and sex. Everyone's going to want to tune into that one. But before we get there, shall we go through some of the key papers in today's issue?

Dr. Greg Hundley:

You bet, Carolyn. How about if I go first?

Dr. Carolyn Lam:

Please.

Dr. Greg Hundley:

So Carolyn, this first manuscript involves the world of machine learning and ECG interpretation. And as you know, novel targeted treatments increase the need for prompt hypertrophic cardiomyopathy detection; however, it's low prevalence, 0.5%, and resemblance to common diseases really present challenges. So Carolyn, these authors, led by Dr. Rahul Deo from Brigham and Women's Hospital, sought to develop machine learning models to detect hypertrophic cardiomyopathy and differentiate it from other cardiac conditions using EKGs and echocardiograms with a robust generalizability across multiple cohorts.

So Carolyn, what did they do? They used single-institution hypertrophic cardiomyopathy EKG models that were then trained and validated on data from three academic medical centers in the United States and Japan using a federated learning approach, which enables training on distributed data without data sharing. Models were validated on held out test sets for each institution and from a fourth academic medical center and were further evaluated for discrimination of hypertrophic cardiomyopathy from aortic stenosis, long-standing hypertension, and cardiac amyloidosis. And then finally, automated detection was compared to manual interpretation by three cardiologists on a data set with a realistic hypertrophic cardiomyopathy prevalence.

Dr. Carolyn Lam:

Wow, incredible. So what were the results?

Dr. Greg Hundley:

Right, Carolyn. So the authors identified 74,476 EKGs for 56,129 patients and 8,392 echocardiograms for 6,825 patients across the four academic medical centers. Now, while ECG models trained on data from each institution displayed excellent discrimination of hypertrophic cardiomyopathy on internal test data, the generalizability was limited, most notably for a model trained in Japan and then subsequently tested in the United States. Now, however, when trained in a federated manner, discrimination of hypertrophic cardiomyopathy was excellent across all institutions, including for phenotypic subgroups. The models further discriminated hypertrophic cardiomyopathy from hypertension, aortic stenosis, and cardiac amyloid. Analysis of ECG and echocardiography paired data from 11,823 patients from an external institution indicated a higher sensitivity of automated HCM detection at a given positive predictive value compared with cardiologists.

So Carolyn, in conclusion, federated learning improved the generalizability of models that use EKGs and echocardiograms to detect and differentiate hypertrophic cardiomyopathy from other causes of left ventricular hypertrophy compared to training within a single institution. It will be really interesting to see the future applicability of these methods.

Dr. Carolyn Lam:

Oh, I'm such a fan of this work. Awesome. Thank you, Greg. My paper, it's a preclinical paper that uncovers a novel mechanism through which GATA4 mutations can lead to heart disease.

Dr. Greg Hundley:

All right, Carolyn, no quiz this time, I'm just coming right out. I'm reversing the question on the teacher. Tell me, what is GATA4?

Dr. Carolyn Lam:

I'm glad you asked, Greg. GATA4 is a zinc finger-containing DNA binding transcription factor essential for normal cardiac development and homeostasis in mice and humans, and mutations in this gene have been reported in human heart defects. Now, in today's paper, authors led by Dr. Srivastava from Gladstone Institutes in San Francisco, California, showed that GATA4 regulated cell-type-specific splicing through direct interaction with RNA and the spliceosome in human-induced pluripotent stem cell-derived cardiac progenitors.

An unbiased search for GATA4 interacting proteins in these human iPS cells revealed interaction with many members of the spliceosome complex. GATA4 also bound to pre-messenger RNAs in a sequence-specific manner that resulted in generation of alternatively spliced isoforms in human iPS cells. Many of these GATA4-dependent isoforms had distinct functional properties illustrating the importance of the splicing regulation to cardiac function.

Dr. Greg Hundley:

Wow, Carolyn, another really interesting study from the world of preclinical science. So what's the take home message here?

Dr. Carolyn Lam:

So these results essentially uncover a previously unrecognized function for GATA4 in regulating alternative splicing through direct RNA interaction. Several genes that have splicing regulated by GATA4 have functional consequences and many are associated with dilated cardiomyopathy, thus suggesting a novel role for GATA4 in achieving the necessary cardiac proteome in normal and stress-responsive conditions.

Dr. Greg Hundley:

Very nice, Carolyn, wow. Well, my next paper comes to us from back in the world of clinical science and it's from Professor Bertrand Cariou from L'institut du Thorax in Inserm UMR1087. So Carolyn, only a few genes causally related to plasma LDL-C levels have been identified so far, and only one, ANGPTL3, has been causally related to combined hypocholesterolemia. In this study, the authors aim to elucidate the genetic origin of an unexplained combined hypocholesterolemia inherited in four generations of a French family and used next generation sequencing and identified a novel dominant rare variant in the LIPC gene encoding for hepatic lipase, which co-segregates with the phenotype. They characterize the impact of this LIPC-E97G variant on circulating lipid and lipoprotein levels in family members using nuclear magnetic resonance based lipoprotein profiling and lipids.

Dr. Carolyn Lam:

Wow, what an interesting approach to study patients and families with hypocholesterolemia for once instead of hyper. Interesting. So what did they find?

Dr. Greg Hundley:

Right, Carolyn. So the investigative team found that this unique LIPC-E97G variant specifically increases the phospholipase activity of hepatic lipase without affecting triglyceride lipase activity. And second, the hypocholesterolemic phenotype related to LIPC-E97G variant is due to an increased clearance of cholesterol within triglyceride-rich lipoprotein remnants predominantly by extrahepatic tissues.

Dr. Carolyn Lam:

Wow, so what are the implications?

Dr. Greg Hundley:

Right, Carolyn. So the novel gain of function variant in LIPC potentially represents the second cause of familial combined hypocholesterolemia after loss of function variants in ANGPTL3. And second, this study highlights an unexpected and critical role of the phospholipase activity of hepatic lipase encoded by LIPC in LDL-C metabolism and identifies it as a potential novel drug target. And then finally, Carolyn, additional data, I think, are warranted to clarify the impact of LIPC-E97G-related combined hypocholesterolemia on atherosclerosis and atherosclerotic cardiovascular disease due to the occurrence of documented coronary stenosis and evolutive carotid atherosclerosis in index cases.

Dr. Carolyn Lam:

Oh, very, very interesting. Thanks, Greg. Well, let's wrap up with the discussion of what else is in today's issue. There's an In Depth paper by Dr. Hadley on protecting cardiovascular health from wildfire smoke. There's also a Research Letter by Dr. Mevorach on myocarditis after BNT162b2 COVID-19 third booster vaccine in Israel.

Dr. Greg Hundley:

Right, Carolyn. And then I've got an exchange of letters from Professors Condello and Doenst regarding the article Cytokine Hemoadsorption During Cardiac Surgery Versus Standard Surgical Care for Infective Endocarditis from the REMOVE study: Results From a Multicenter Randomized Controlled Trial. Well, how about we get on to that feature discussion and learn a little bit more about COVID-19 vaccine and SARS-CoV-2 infection.

Dr. Carolyn Lam:

Let's go, Greg, thanks.

Dr. Greg Hundley:

Listeners, welcome to this September 6th feature discussion. And with us today, very interesting topic pertaining to vaccination for SARS-CoV-2 virus prevention. And we have with us Dr. Keith Channon from Oxford, England, to discuss this very interesting paper.

Well, Keith, welcome. I wanted to start by asking you, can you describe for us a little the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address?

Dr. Keith Channon:

Thanks, Greg, for the opportunity to join you in this interesting conversation today. A group of cardiologists in the UK based at the University of Oxford, and principally at the University of Edinburgh, have been interested in the question as to whether COVID infection and/or COVID vaccination might lead to a higher incidence of myocarditis. And this is a topic that has been the subject of previous publications in the field.

And the provocation for us undertaking this study is that those previous studies have tended to be relatively small, and they've also not been able to necessarily test the details, time association, between myocarditis occurring in relation to sequential doses of vaccination. And that's important because, of course, we're now all receiving sequential doses of booster vaccines, and also those vaccines are often delivered, different vaccine types to different people in different countries. So we wanted to test whether there does appear to be a significant association between the occurrence of myocarditis and both COVID infection and the sequential different COVID vaccinations.

Dr. Greg Hundley:

Very nice. So Keith, can you describe for us, what study population did you enroll for this initiative? And then also, what was your study design?

Dr. Keith Channon:

Thank you. So, one of the really exciting things about this type of study and probably what makes it unique is that in countries with healthcare system, like that in the UK, which is the National Health Service, and universities, such as the University of Oxford and the University of Edinburgh, where there are very strong academic links between researchers and the National Health Service, we've been able to leverage an enormous data set, which is almost 43 million people in the UK who underwent vaccination against COVID-19. And rather than having to follow up 43 million people as part of a research study, we were able to take advantage of National Health Service centralized coded hospital records, number one. Number two, we took advantage of the UK's national database on COVID vaccination. And number three, we were able to look at hospital outcomes and also COVID testing.

So we were able to put together those three data sets for us to understand who developed COVID infection, who received COVID vaccination, and if so, which vaccine and when, and who then was admitted to hospital with a coded diagnosis of myocarditis. And in 43 million people, even though myocarditis is a very uncommon outcome, there were sufficient cases in that very large population to draw statistically meaningful conclusions.

I think that the UK is probably one of the few countries where this type of research can be done. And academic organizations, like our universities, the National Health Service, and also cardiovascular research funders, such as the British Heart Foundation, have put in a lot of resource and effort into giving us those capabilities to answer questions like this, and it's turned out to be a very powerful capability.

Dr. Greg Hundley:

Very nice. And so Keith, can you describe for us your study results?

Dr. Keith Channon:

So the study looked at a large 43 million people approximately over a period of time during the early to mid-phase of the COVID pandemic and looked at the likelihood that people would be diagnosed with myocarditis following either vaccination or COVID test positive. And we compared that likelihood with the likelihood of myocarditis occurring outside of those periods; because, of course, myocarditis occurs reasonably commonly in the general population. So this is another powerful aspect of the study design. It has a curated approach to look at the incidence of myocarditis in the 28 days after either vaccination or COVID infection, and it corrects, or it controls for that relative to the incidence of myocarditis outside of those sampling periods.

And what we found simply is that there is indeed, as previous studies have shown, a small but significant association between receiving a COVID-19 vaccine and being diagnosed with myocarditis in the following 28 days. However, in the population as a whole, the risk of myocarditis after vaccination is substantially lower than the risk of developing myocarditis after COVID infection, and I think that's an important finding. When we looked at subgroups, which is interesting, we found that the highest risk of developing myocarditis was in men less than age 40, so younger men, and that was one finding. And also, there did seem to be some differences in the risk of myocarditis occurring after different sequential vaccine doses.

Dr. Greg Hundley:

Keith, just a quick clarification point, what vaccines did you examine?

Dr. Keith Channon:

So in the UK, the three vaccines that have been largely used of the AstraZeneca Oxford viral vaccine, ChAdOx1, which was of course introduced very early in the UK, along with the Pfizer mRNA vaccine, and then laterally, Moderna vaccine, which of course in the UK was brought in rather later. And I think that's interesting because, as we can go on and discuss, there do appear to be some possible differences between those vaccines in terms of the likelihood of being diagnosed with myocarditis afterwards. But of course, even our experiment in 43 million people is not a perfect design because it's an observational study, and the periods in the pandemic when people were receiving principally the first two vaccines, which were by far the most numerous, was a different period in the natural history of the pandemic than when we started administering Moderna.

So it is important to recognize that it was not a prospectively controlled randomized trial of different vaccines; it was an observational study of pretty much a whole country and how it responded to the implementation of those different vaccines, which were all given to different people at different times of the pandemic. And of course, different times of the pandemic means that many different people will have already had a COVID infection and then gone on to have a booster or third vaccination. So, if you like, the immunological landscape in which these different vaccines were given in this very large population will have been different.

Dr. Greg Hundley:

Right. So I understand there are differences in timing, great point, but did you see any differences in the occurrence of myocarditis relative to either of the mRNA vaccines versus the adenovirus vaccine?

Dr. Keith Channon:

Yeah, we did. What we found is that, interestingly, there did appear to be a higher likelihood of being diagnosed with myocarditis in the 28 days after the mRNA-1273 vaccine, Moderna vaccine, and that was particularly, as I've already said, in men younger than the age of 40 years. I should say again, of course, that vaccine was given to the smallest number of people in the UK and it also tended to be rolled out later, so it was the second or third dose of the vaccine where that signal was most seen. But again, the second and third dose was by definition typically the booster vaccine later on in the pandemic. But that's what we found.

We did find these interesting differences. The incidence of myocarditis was increased after all of the vaccine doses compared with the period when people had not received a vaccine, but this was a very modest increase for most of the vaccines; but for the mRNA vaccines, particularly Moderna, it seemed to be more strikingly increased in the 28 days after the second or third dose of the vaccine. So I guess the message from that result is that there do seem to be these intriguing differences, both in the response to different COVID vaccines, either viral or mRNA or indeed even different types of mRNA vaccine, and possibly after the different dose of vaccines. In other words, after second or third sequential doses.

Dr. Greg Hundley:

And Keith, you mentioned a few minutes ago that you also had an opportunity to examine situations where maybe a patient had a vaccine and then subsequently contracted COVID, or vice versa, maybe they had had COVID and then later on had a vaccine, did you find any differences in the incidence of myocarditis in those situations as opposed to, perhaps, patients that really never had a documented episode of a COVID infection and then always had received the two vaccines and the booster dose?

Dr. Keith Channon:

Yeah, that's a harder question and is less powerfully addressed by our study, even though we were able to temporally control for that. Previous COVID infection did not preclude the risk of myocarditis after subsequent vaccine doses, but it wasn't a big enough signal to be able to give much detail over the relative risk between... Because if you think of the permutations of COVID infection plus or minus three vaccines, there's a lot of different sequential steps there, but having had COVID first doesn't prevent this small but significant signal; having a vaccine before you then get COVID infection does reduce your risk of myocarditis along with pretty much all other COVID complications.

So I think that's a really important public health message here and indeed the overarching finding of our study, which you could argue is the least exciting one but perhaps the most important, which is that you have a higher likelihood of suffering with myocarditis after COVID infection compared with after a COVID vaccination. And if you have COVID vaccination, in general, your risk of myocarditis is lower, obviously your risk of COVID infection is lower, and your risk of getting myocarditis after that COVID infection, should you still get one is also lower. So I think these are very intriguing, interesting findings that might make us think about mechanism and vaccine policy, but ultimately there are very strong endorsement of getting vaccinated to prevent the consequences of COVID-19.

Dr. Greg Hundley:

Excellent point. And then, Keith, just quickly, next study that maybe your group is considering in this space with this large database?

Dr. Keith Channon:

Yes. Well, I think there are two aspects to the study. Our group, which, as I've said, focuses mainly on large epidemiological data sets, having established this infrastructure in the UK led by universities like Oxford and Edinburgh and funded by the British Heart Foundation and others, means that we now have this infrastructure. So the surveillance and the data collection and the analysis is ongoing and we'll be able to add more cases and more power and more data, and there will be other studies that we can look at.

Second, I think there are some really quite interesting mechanistic studies that could be done based on these provocative findings to try to understand which different types of vaccines and, indeed, the immune responses which those vaccines generate. How are they linked to myocarditis and, indeed, to other cardiac and even other organ complications from COVID-19? And there are ongoing studies in the UK and elsewhere in the world that are very much focused on looking at the organ-specific consequences of COVID infection in patients who've been vaccinated or not. For example, using detailed cardiac MRI to look at the heart and look for subclinical myocarditis and to correlate any evidence of subclinical myocarditis with the immune signature, both the antibody and the cellular immune response, in the blood from those patients.

So I think what we're going to see here are enormous epidemiological studies with n=43 million, and we're also going to see more mechanistic experimental medicine immunology studies to try and tease out mechanism, and I think to understand two things. One is how to protect ourselves best against COVID-19, and what are the best vaccines and how best to use them. And second, if we can learn something about the mechanisms of myocarditis along the way, that's a really useful bonus that's come out of this pandemic.

Dr. Greg Hundley:

Very nice. Well, listeners, we want to thank Dr. Keith Channon for bringing us this very interesting article from Great Britain highlighting that, overall, the risk of myocarditis is greater following SARS-CoV-2 infection as opposed to a COVID-19 vaccination, and even really remains modest following sequential doses, including the booster dose of some of the mRNA vaccines.

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is a copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit AHAjournals.org.

This week, please join author Rod Stables and Associate Editor Nick Mills as they discuss the article "Routine Pressure Wire Assessment Versus Conventional Angiography in the Management of Patients With Coronary Artery Disease: The RIPCORD 2 Trial."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass through the journal and its editors. We're your co-hosts! I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Well, Carolyn, this week's feature... Very interesting. There is a lot of information about using fractional flow reserve during contrast coronary angiography. But how does that compare to just reviewing the angiograms when managing patients with coronary artery disease?

Well, we are going to hear some results from the RIPCORD 2 trial, and they may surprise you a little bit. But, before we get to that interesting feature discussion with authors and editors, how about we grab a cup of coffee and dive into some of the other articles in the issue?

Dr. Carolyn Lam:

Yeah, let's do that, Greg. Do you have a paper to share first?

Dr. Greg Hundley:

Oh, thanks Carolyn. Sure.

So Carolyn, as we know, Apolipoprotein B or apoB, provides an integrated measure of atherogenic risk. But whether apoB levels and apoB lowering hold incremental predictive information on residual risk after acute coronary syndromes, beyond that provided by low density, lipoprotein cholesterol, or LDLC, that's uncertain. So Carolyn this study emanates from the Odyssey Outcomes trial, which compared the Proprotein Convertase Subtilisin/Kexin Type 9 inhibitor, Evolocumab with placebo in 18,924 patients with recent ACS and elevated atherogenic lipoproteins despite optimized statin therapy. Now the primary outcome was major adverse cardiovascular events. So MACE was coronary heart disease, death, nonfatal myocardial infarction, fatal non-fatal ischemic stroke, and hospitalization for unstable angina. And associations between baseline ApoB or ApoB at four months and MACE were assessed in adjusted Cox proportional hazards and propensity score matched models over median of 2.8 years.

Dr. Carolyn Lam:

Oh, right. So what were the results, Greg?

Dr. Greg Hundley:

Right, Carolyn so impatience with recent ACS and elevated atherogenic lipoproteins, MACE increased across baseline ApoB strata, and now evolocumab reduced MACE across all strata of baseline ApoB, with larger absolute reductions in patients with higher baseline levels. Lower achieved ApoB was associated with lower risk of MACE, even after accounting for achieved LDLC or Non-HDLC indicating that ApoB provides incremental information. And therefore, Carolyn, if it is modified achievement of an ApoB level less than or equal to 35 milligrams per deciliter may reduce lipoprotein attributable residual risk after ACS. Isn't that interesting?

Dr. Carolyn Lam:

Yes. Very nice, Greg. Thank you. This next paper is a pre-specified analysis of the EMPEROR-Preserved trial, looking at patients with and without diabetes.

Dr. Greg Hundley:

So remind us, Carolyn, what was the EMPEROR-Preserved trial and what did it show?

Dr. Carolyn Lam:

Well, in EMPEROR-Preserved Empagliflozin, the SGLT2 inhibitor reduced risk of the composite of cardiovascular death or heart failure hospitalization, as well as first and recurrent heart failure hospitalizations and slowed renal function decline in patients with heart failure and an ejection fraction greater than 40%. So the current paper sought to determine if effects were consistent in patients with, and without diabetes, of the almost 6,000 patients enrolled, 49% had diabetes. The risk of adverse outcomes, first of all, was higher in patients with diabetes. Now the treatment effect of Empagliflozin was however, similar in that Empagliflozin reduced the rate of the primary outcome and total heart failure hospitalization, irrespective of diabetes status. The effect of Empagliflozen falls into attenuate GFR decline, however, was also present in patients with, and without diabetes, although more pronounced in patients with diabetes. Now across all these three endpoints, the effect of Empagliflozen did not differ in patients with prediabetes or normal glycemia. And importantly, there was no increased risk of hypoglycemic events in either subgroup compared with placebo. So a very nice paper there. And that was from Dr. Gerasimos Filippatos from Athens University Hospital Attikon and colleagues.

Dr. Greg Hundley:

Wow, Carolyn, just really interesting information coming out of the world of SGLT2 innovation. Well, Carolyn, my next paper comes to us from the world of preclinical science and it's from Dr. Kunhua Song from the University of Colorado Anschutz Medical campus. So Carolyn, abnormalities of calcium homeostasis are closely associated with cardiac arrhythmias and heart failure and conditions that cause death of millions of people every year. Now, Carolyn Triadin physically interacts with the Ryanodine receptor 2 and plays an important role in releasing calcium from the sarcoplasmic reticulum to increase the free intracellular calcium concentration in cardiomyocytes.

Now alternative splicing of a single Triadin gene produces multiple Triadin isoforms, the predominant cardiac Triadin isoform mouse Mt1 or human Trisk 32 is encoded by Triadin exons from one to eight. In humans, mutations in the Triadin gene that lead to a reduction in Trisk 32 levels in the heart cause cardiac dysfunction, cardiac arrhythmias and sudden death. Decreased levels of Trisk 32, in the heart, are also common in patients with heart failure. However, mechanisms that regulate alternative splicing of the Triadin gene to maintain levels of cardiac Triadin protein in the heart, remains somewhat elusive.

Dr. Carolyn Lam:

Wow. I am always learning from these cool papers. Thanks Greg. So what were the results?

Dr. Greg Hundley:

So Carolyn, the investigators found several things. First, the cardio MyoSite specific long non-encoding RNA or link RNA Triadin AS is essential for maintenance of cardiac function, exercise capacity and normal lifespan and Triadin AS knockout mice were found predisposed to cardiac arrhythmias in response to catecholamine challenge. And finally Carolyn, Triadin AS controls, levels, of cardiac Triadin isoforms, by regulating the splicing of the Triadin gene.

Dr. Carolyn Lam:

Oh, wow. All right. So could you bring it home for us, Greg? What are the clinical take home messages?

Dr. Greg Hundley:

Right, Carolyn. So cardiac explants from human heart failure patients as well as patients with cardiac arrhythmias, demonstrate reduced expression of Triadin AS and Triadin. And then next the mechanism of the Triadin AS and Triandin AS mediated alternative splicing of the Triadin gene to specifically control levels of cardiac isoforms of Triadin in the heart, provides a potential strategy for the treatment of cardiac arrhythmias and heart failure.

Dr. Carolyn Lam:

Wow. Thank you, Greg. Well, let's talk about what else is in today's issue. There's a Research Letter by Dr. Agarwal on Chlorthalidone for resistant hypertension and advanced chronic kidney disease.

Dr. Greg Hundley:

And Carolyn, I've got a perspective piece by Professor Cowie pertaining to atrial fibrillation entitled, “I'm Sorry, Mrs. Jones, but We Cannot Make You Feel Better Today.” Well, Carolyn, how about we get onto that feature discussion and review the utility of fractional flow reserve measurements, in patients undergoing contrast coronary angiography.

Dr. Carolyn Lam:

Great, let's go.

Dr. Greg Hundley:

Welcome listeners to this August 30th feature discussion. And we have with us this afternoon, Dr. Rod Staples from Liverpool and our own associate editor, Dr. Nick Mills from Edinburgh, Scotland. And gentlemen, welcome, Rod we'll start with you. Can you describe for us the background information that went into the preparation of your study and what was the hypothesis that you wanted to address?

Dr. Rod Staples:

Okay, well thanks very much for hosting today. I'm very grateful to be working circulation on this. I'm working with my co-lead investigator Professor Nick Harrison from Southampton, who's been doing an enormous amount of work on coronary physiology. He actually did the original RIPCORD study, what I suppose we'd now call RIPCORD 1, but it was called RIPCORD in the early days, an observational study that showed that systematic use of fractional flow reserve at the time of diagnostic angiography. Assessing the functional significance measured in each of the major coronary vessels, appeared in an observational study to have a dramatic effect on the subsequent management plans allocated to patients. And we decided to test this in a prospective randomized trial.

Dr. Greg Hundley:

Very nice. And so the exact hypothesis that you were going to test was what?

Dr. Rod Staples:

At the time of coronary angiography, a strategy of systematic measurement of fractional flow reserve in each and every coronary vessel, large enough to be considered for revascularization, would improve outcomes compared to a strategy based on angiographic assessments alone.

Dr. Greg Hundley:

Very nice. And so you mentioned a randomized trial. Can you describe further your study design and then which study population did you include?

Dr. Rod Staples:

Well, this is a classic multicenter randomized trial performed in the UK. We actually recruited in 17 different UK centers. We asked them to assess patients who were scheduled for invasive, currently angiography for participation against some very minimal inclusion and exclusion criteria, trying to keep the trial generalizable with good external validity. I think one important point to note is that we did allow the inclusion of both patients being assessed with elective angiography for stable symptoms, but in the end half of the population were recruited in the context of a stabilized acute coronary syndrome, a Non-ST-elevation event a day or so down the line.

Dr. Greg Hundley:

And just a quick breakdown, how many men, how many women?

Dr. Rod Staples:

Well, it's in that respect, the population is very, very typical for this type of cardiovascular trial. A 70, 30 split an age in the midsixties, a diabetic population in the high teens. So a very typical population we've seen in all this kind of trial environment.

Dr. Greg Hundley:

Very nice. And so about 1100 patients. And then what were your study results?

Dr. Rod Staples:

Well, I think there was a very good adherence to the study protocol, very, very few crossovers. And also we were pleased to see that our investigators stayed true to the protocol in that the median number of epicardial vessels assessed by FFR in that randomized arm was four. So there was a good assessment by FFR. The trial was interesting in another respect, in that we assessed an economic outcome based on all NHS hospital costs over the following year and a patient reported outcome based on quality of life using the WHOQOL, and interestingly we found no significant differences either in total subsequent hospital costs from randomization for a year, or indeed in patient reported quality of life by WHOQOL or Angina symptoms by the Canadian Cardiovascular Society classification.

Dr. Greg Hundley:

Very nice. And then, what about clinical events? Did you examine those as well?

Dr. Rod Staples:

We did. And again, just a little caveat here, the trial is again interesting in that, what is often in the UK these days called a lean efficient methodology. Whereby, rather than individually contacting individual trial participants or scouring medical records, we interrogated the central national NHS digital repository of all hospital admissions. And we examined electronically a download of every hospitalization event for every patient using algorithms based on diagnostic and procedural codes to define events. And again, we found a very credible representative rate exactly at incidents and events we would've predicted, but again, no difference between the randomized groups.

Dr. Greg Hundley:

Very nice, well listeners, now we're going to turn to our own Associate Editor, Dr. Nick Mills. And Nick, again, you see many papers come across your desk. What attracted you to this particular manuscript? And it's very interesting study results.

Dr. Nick Mills:

Thanks, Greg. Firstly, it addresses an important clinical question. Going beyond that, what appealed to me was it was investigator initiated. It was managed by independent trials unit. It recruited a target, it reported the registered outcomes and it was thoughtfully interpreted. And the fact that it didn't prove the hypothesis was irrelevant because it addresses a really important clinical question. And I think it requires some context, and that is that from the previous randomized trials The FAME series, we have been chastised as interventional cardiologists for not using FFR for relatively low use of FFR clinical practice. It's always around one in 20 patients in most series, given the evidence that FFR guided intervention improves outcomes. But actually what FFR is good at is discouraging you from stenting patients with stable Coronary Disease.

And so, I think a pragmatic trial that addresses that, the fundamental question, should we be doing more FFR more broadly in both acute and stable disease to guide revascularization with a definitive message that we shouldn't, it doesn't improve quality of life. It doesn't alter costs. Clinical outcomes are similar, but there are more complications associated with routine pressure wire use, gives us a very clear steer for the future. So this is a really important trial addressing a fairly fundamental clinical question.

Dr. Greg Hundley:

Very interesting. Well, Rod, we're going to turn back to you with Nick's comments and how we're really seeing an evolution in thought processes regarding both diagnostic angiography, and then also the use of functional testing. What do you see is the next study, really in this sphere of research that would be performed?

Dr. Rod Staples:

Well, I agree with Nick in a way that this raises important philosophical points about the use of intelligence, selective employment of tests or interventions, and that perhaps we need to reflect this in the way we conduct our future studies. I think we're all aware that fractional flow reserve and other measures of functional significance are tremendously valuable in certain clinical settings. And that value's been proven in randomized trials, but in PRECORD 2, for example, if a patient randomized to angiography only was an acute coronary syndrome patient, who had inverted their T waves in their anterior leads, had an associated troponin rise, an echocardiogram had shown some Hypokinesia in the anterior territory. Then I think the potential value of PCI in the LAD does not necessarily require FFR confirmation, and hence that patient will have an equivalent outcome in the angiography group. Similarly, high quality pre-angiography preparation in the elective population with functional testing, stress testing, other forms of imaging mean that we can reserve the use of invasive fractional flow reserve, tight indices to more selective use.

Dr. Greg Hundley:

And Nick, turning to you, what do you think is the next research study that could be informative in this space?

Dr. Nick Mills:

I think our whole philosophy by how to manage stable coronary disease is changing. In part because of some other landmark trials that the Ischemia trial and some of the key secondary analyses of the Ischemia trial that tells the Pathoma burden, low attenuation plaque, other aspects of chronic disease are vitally important in predicting major events in the future. And that leaves us with the role for FFR or CT FFR, primarily to manage symptoms. And I think we're getting increasingly good evaluating patients before they get to the Cathflow, optimizing their medical treatment. And so for me, the trial that we really need to help us, is a CT FFR trial to understand the role of Ischemia testing plus anatomical testing and how they dovetail in guiding treatment decisions before they get to the cath lab. I think we need to move this before the lab, always going to be a role for intelligent FFR testing in selected patients once we get to it. But I think that the question probably needs to be addressed before they get to the cath lab.

Dr. Greg Hundley:

Very nice. Well listeners, we want to thank, Dr. Rod Staples from Liverpool and Dr. Nick Mills from Edinburgh, Scotland for bringing us this very interesting study, highlighting that a strategy of systematic FFR assessment, when compared to angiography alone, did not result in a significant reduction in cost or improvement in quality of life.

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week On the Run.

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Kory Lavine and Associate Editor Thomas Eschenhagen as they discuss the article "Donor Macrophages Modulate Rejection After Heart Transplantation."

Dr. Carolyn Lam:            

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:          

I'm Dr. Greg Hundley, associate editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Well, Carolyn, this week's feature, we are going to the world of preclinical science and we are going to learn about a very important new finding pertaining to heart transplant rejection, and macrophages may modulate this, but before we get to that feature, how about we grab a cup of coffee and go through some of the other articles in the issue?

Dr. Carolyn Lam:            

I got mine. Would you like to go first, Greg?

Dr. Greg Hundley:          

You bet, Carolyn. Well, my first study comes to us from Dr. Michael Pencino from Duke University. Carolyn, this study was performed to understand the predictive utility of a previously derived polygenic risk score for long-term risk of coronary heart disease and its additive value beyond traditional risk factors and how that might be able to inform prevention strategies. To accomplish this, data from adults aged 20 to 59 free of cardiovascular health disease from the Framingham Offspring Study and the Atherosclerosis Risk in Communities, or ARIC Study, were analyzed. Now, since the polygenic risk score was derived from people of predominantly European ancestry, individuals who self-reported white race were those that were included.

Dr. Carolyn Lam:            

Oh, interesting, so what did they find, Greg?

Dr. Greg Hundley:          

Right, Carolyn. Somewhat surprisingly, they found that, among 9,757 participants, both the traditional risk factor score and the polygenic risk score where significantly associated with incident cardiovascular heart disease in young, early midlife, and late midlife. Now, the delta C index, when the polygenic risk score was added to the traditional risk factor, score was 0.03, 0.02, and 0.002 in the young, the early midlife, and the late-midlife participants, respectively.

Carolyn, despite a statistically significant association between the polygenic risk score and the 30-year risk of cardiovascular heart disease, the C index improved only marginally with the addition of the polygenic risk score to the traditional risk factor model among young adults and did not improve among midlife adults and, thus, Carolyn, the polygenic risk score, an immutable factor, has limited clinical utility for long-term cardiovascular heart disease prediction when added to a traditional risk factor model.

Dr. Carolyn Lam:            

I really like that, Greg, because I think it also tells us that the traditional risk factors, which we can do something about, are still very important. Isn't that great? Well, the next paper is about POTS. Remember what that is? Should I give you a quiz? All right. It's okay. POTS, or Postural Orthostatic Tachycardia Syndrome, is a disorder of orthostatic intolerance that primarily affects females of childbearing age. While the underlying pathophysiology of POTS is not fully understood, it has been suggested that autoimmunity may play a role. Now, the aim of this study was to compare concentrations of autoantibodies to cardiovascular G protein-coupled receptors between 116 POTS patients and 81 healthy controls, and they were from Calgary, Canada, and Malmo, Sweden.

Dr. Greg Hundley:          

Carolyn, really interesting, so what did they find here?

Dr. Carolyn Lam:            

The investigators, led by Dr. Raj from University of Calgary in Canada, found that commercially available autoantibody concentrations to G protein-coupled receptors were not increased or altered in POTS patients relative to healthy controls as assessed using ELISA. Now, while this study suggests that these G protein-coupled receptor autoantibody concentrations alone cannot explain the pathophysiology of POTS, autoantibody activity and signals not picked up by ELISA should still be explored as these results may provide more insights into the pathophysiology of POTS.

Dr. Greg Hundley:          

Very nice, Carolyn. Well, my next study comes to us from the world of pulmonary arterial hypertension. Carolyn, clinical worsening is commonly used as an endpoint in pulmonary arterial hypertension trials. These authors, led by Dr. Steeve Provencher from the Institut Universitaire de Cardiologie Pneumologie de Quebec, aimed to assess the trial-level surrogacy of clinical worsening for mortality in pulmonary artery hypertension trials and whether the various clinical worsening components were similar in terms of frequency of occurrence, treatment-related relative risk reduction and importance to patients.

Dr. Carolyn Lam:            

Okay, so what did they find?

Dr. Greg Hundley:          

Right, Carolyn, so they searched MEDLINE, Embase and the Cochrane Library for trials evaluating the effects of pulmonary arterial hypertension on clinical worsening and, among 35 independent cohorts, so 9,450 patients, the effects of pulmonary arterial hypertension-specific therapies on clinical worsening modestly correlated with mortality. Additionally, study-level clinical worsening was not found to be a surrogate for mortality in pulmonary arterial-hypertension trials. Moreover, components of clinical worsening largely vary in frequency, response to therapy and importance to patients and, thus, are not necessarily interchangeable.

Dr. Carolyn Lam:            

Thank you, Greg. Can I tell you about some other papers in today's issue? There's a Research Letter from Dr. Cosentino on cardiorenal outcomes with ertugliflozin by baseline metformin use, and this is a post hoc analysis of the VERTIS CV trial.

Dr. Greg Hundley:          

Oh, very good, Carolyn. Well, I've got an exchange of letters from Professors Boriani and Steinberg regarding the article “Driving Restrictions and Early Arrhythmias in Patients Receiving a Secondary Prevention Implantable Cardioverter-Defibrillator, the DREAM-ICD-II Study.” There's also an ECG Challenge from Professor Gao entitled “Syncope in a 3-Year-Old Child During the Perioperative Period. What is the diagnosis? What Signs Point Toward Impending Life-threatening Event?”

Then, finally, there's a nice, On My Mind piece from Professor Greenland entitled “Insurance Payers Should Cover Selective Coronary Artery Calcium Testing in Intermediate Risk Primary Prevention Patients.” Well, Carolyn, how about we get on to that feature discussion and dive into the world of rejection after heart transplantation?

Dr. Carolyn Lam:            

Yay. Here we go.

Dr. Greg Hundley:          

Welcome, listeners, to this feature discussion on August 23rd. We have a very interesting article today to discuss with our author and associate editor pertaining to preclinical science and cardiac transplant rejection. Our author today is Dr. Kory Lavine from Washington University in St. Louis and our associate editor today is Dr. Thomas Eschenhagen from Hamburg, Germany. Welcome gentlemen.

Kory, we'll start with you. Can you describe for us some of the background information pertaining to the construct of your study and what was the hypothesis that you wanted to address?

Dr. Kory Lavine:              

Well, thank you for having me. Our study focused on heart transplant rejection, which remains a major clinical challenge that limits both the survival of heart transplant recipients as well as availability of donor hearts. Current clinical practice really focuses on suppressing the immune system in a global way, and that is somewhat effective, but carries important risks that include infection and life-threatening malignancies.

Many studies have appropriately focused on immune cells that infiltrate the transplanted heart that come from the recipient to search for new ways to suppress the immune system safely. What we've understood and learned over the past several years is that the donor heart has its own immune system and its own immune cells, and the majority of those immune cells that come with the donor heart are macrophages that can be broadly divided into two distinct lineages with different functions, tissue-resident macrophages, which lack the cell surface receptors CCR2, and monocyte-derived macrophages with expressed cell surface receptors CCR2. We tested the hypothesis in this study that these macrophages that come with the donor heart remain active for a period of time after transplantation and play important roles in either suppressing or accelerating heart transplant rejection.

Dr. Greg Hundley:          

What was the hypothesis that you wanted to address with your study?

Dr. Kory Lavine:              

Yeah, so our prior work and others' work within this field had suggested that tissue-resident macrophages, CCR2-negative macrophages, are inflammatory, and CCR2-positive macrophages have the opposite functions being inflammatory and play roles in potentiating and initiating inflammation in the heart. In this study, we hypothesized that CCR2-negative macrophages would protect from rejection, while CCR2-positive macrophages may promote heart transplant rejection and could serve as a new therapeutic target to prevent rejection in transplant recipients.

Dr. Greg Hundley:          

Excellent. Kory, can you describe for us the study design that you used to test your hypothesis?

Dr. Kory Lavine:              

Yeah. The study design and approach we used involved a mouse model of heart transplantation where we transplant a donor heart into a recipient mouse that's fully mismatched at all the MHC loci, and this serves as a nice model for both cellular and antibody-mediated rejection. To facilitate tracking these donor macrophages, we used various genetic lineage tracing systems and, to study their phenotypes, we used single-cell RNA sequencing and, to understand their function, we used mouse models that allow us to specifically deplete each of the donor macrophage populations as well as genetic models to manipulate their activation and signaling.

Dr. Greg Hundley:          

The outcome measures were going to be what?

Dr. Kory Lavine:              

Yeah. The outcome measures for transplant rejection in this mouse model are allograph survival, so the survival of the transplanted heart. We're able to directly look at how much rejection is present by histopathology, and then we're able to observe various mechanistic features using detailed phenotyping such as single-cell RNA sequencing and T-cell activation assays.

Dr. Greg Hundley:          

Very nice, Kory. Well, all, our listeners, we're very excited to hear what were your study results?

Dr. Kory Lavine:              

We learned that donor macrophages are dynamic and they survive for a period of time after transplantation or eventually lost due to transplant rejection. When we phenotyped the macrophages that came from the donor heart, we learned that they remained transcriptionally distinct from immune cells that enter the heart that were derived from the recipients, and they had important and distinct functions. If we depleted the tissue-resident macrophages that were CCR2-negative, we observed reduced allograph survival and increased rejection. If we depleted CCR2-positive macrophages that came from the donor heart, we observed improved allograph survival and reduced rejection.

Mechanistically, we learned that CCR2-positive macrophages are activated through a MyD88-dependent pathway and, if we inhibited MyD88 cytokines which controls the expression of pro-inflammatory cytokines and chemokines, we could prolong the survival of the donor heart for a very significant period of time, reduce rejection and prevent the development of T-cells that would attack the donor heart. From a mechanistic aspect, what we uncovered is that this signaling pathway in CCR2-positive macrophages regulated the recruitment of an activation of antigen-presenting cells which played important roles in generating T-cells that would target the transplanted heart.

Dr. Greg Hundley:          

It sounds like a really informative and leap forward in the whole sphere of transplant rejection. Well, listeners, now we're going to turn to our associate editor, Dr. Thomas Eschenhagen.

Thomas, you have many papers come across your desk. What attracted you to this particular paper and then, secondly, how do you put the results of this study really in the context of other research examining heart transplant rejection?

Dr. Thomas Eschenhagen:          

Yeah, thanks for having me. I mean, first, we got attracted by this paper because it's somewhat an out-of-the-box approach. It's not the standard approach to improve the systemic immunosuppression as many studies did and with actually a lot of success over the last 30 years, survivor got much better. There had been a lot of progress in the field of transplantation medicine as we all know, but as Kory said already, we still have 30% rejection, and these immunosuppressions come at a price. Having this study which turns around somehow the argumentation and looks at the donor organ was something which really attracted us. It uses advanced methods and it applies somewhat in a practical way a concept which emerged over the last, I don't know, maybe decade this concept that macrophages are really very different kind of cells. They're all called macrophages, but they're quite different and even maybe in certain respects having opposing effect.

I think many people know about this M1/M2 concept. It's CCR2 receptor positive and negative. It's criticized by some people, but here we see that it really seems to be really important and, of course, then the third argument why we really like the story is that it has a specific, clear translation impact. I mean, looking at the heart, the donor heart, and potentially even treating the donor heart before transplanting it is something which comes immediately out of the story, and that's something which we found super attractive.

Dr. Greg Hundley:          

Really interesting, so really understanding the mechanism and focusing on donor hearts. Well, listeners, let's circle back with Kory.

Kory, given that, what do you think is the next study that really needs to be performed in this sphere of research?

Dr. Kory Lavine:              

I think Thomas said it exactly as we're thinking about it, so the next area that we're really excited to attack and we're hopeful that the field will focus on is ways to build methods and technologies to treat the donor heart between the time of procurement and the time of transplant, when it's being transported and potentially even being perfused for a period of time. We're really interested in finding approaches to identify small molecules and other potential biologic therapies that could be used to prevent the activation of donor CCR2-positive macrophages.

It's a really attractive approach because treating the donor heart ex vivo decreases the risk of adversely affecting other organs that may be transplanted if you're treating the donor, for instance, and it may decrease the risk of immunosuppression and infection by not having to treat the recipient and we're catching the heart in this window where the risks are much lower.

The other area that we're really excited to focus on is trying to identify the exact mediators that are generated from donor CCR2-positive macrophages that mediate the recruitment and activation of antigen-presenting cells because that would represent another potential therapeutic target.

Dr. Greg Hundley:          

Very nice. Thomas, what are your thoughts about what might be the next study to be performed really in this sphere of research?

Dr. Thomas Eschenhagen:

It's obviously something rather a question to Kory than to me, but I agree to what he said. I think it is pretty obvious what are the next steps mechanistically on the one hand, but practically on the other hand. I mean, at this point, we are at the mouse level, so the question is to which extent can this concept be translated into larger animals and then finally in humans? I was wondering, given these newer methods to keep donor hearts alive for long, extended periods, I was wondering which extent you are already collaborating with the respective groups who develop this approach because that obviously would increase the window of opportunity here for drugs. I think it's really an exciting and pretty visible next steps which we see here, and I can just hope that you're going this path and that it will be successful.

Dr. Greg Hundley:          

Kory, any thoughts on those collaborations that Thomas just spoke of?

Dr. Kory Lavine:              

We're definitely establishing collaborations to focus on ex vivo profusion of donor hearts because that's, as Thomas mentioned, is a perfect window to manipulate the immune populations that are within the donor heart. Those studies have to be team science, they have to be collaborative and they have to have a focus on large animals and then moving into clinic. We're definitely forming those collaborations and excited to work as a group.

Dr. Greg Hundley:          

Very nice. Well, listeners, what an exciting paper to discuss here as part of this feature discussion from the world of preclinical science. We want to thank Dr. Kory Lavine from Washington University in St. Louis, Missouri, and also our own associate editor, Dr. Thomas Eschenhagen from Hamburg Germany, for really bringing us this research study highlighting that distinct populations of donor and recipient macrophages coexist within the transplanted heart, and donor CCR2-positive macrophages are key mediators of allograph rejection and deletion of MyD88 signaling in donor macrophages is sufficient to suppress rejection and extend allograph survival.

Well, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week on the run.

Dr. Greg Hundley:          

This program is copyright of the American Heart association, 2022. The opinions expressed by the speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Philipp Lurz and Editorialist Daniel Burkhoff as they discuss the article "Characteristics of Heart Failure With Preserved Ejection Fraction Across the Range of Left Ventricular Ejection Fraction" and the editorial "HF?EF: The Mysterious Relationship Between Heart Failure and Ejection Fraction Continues."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-host. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

I just cannot wait to tell you about today's feature discussion, Greg. It's about heart failure with preserved ejection fraction and characteristics in the range of that ejection fraction that's above 50%. So, okay. I know, I know. It's like, "Oh my gosh. Wow. How much are we going to be talking about this ejection fraction thing?" But I'm telling you, everybody has to listen to this. It's really a big stride forward in our understanding of these patients with heart failure and a higher ejection fraction. Plus it includes one of my mentors from Mayo Clinic days, and I just can't wait for everyone to hear this. But before we go there, we've got really, really cool original papers in today's issue too. Would you like to start first?

Dr. Greg Hundley:

You bet Carolyn, and I can't wait for that feature discussion, especially this is a real area of your expertise. So listeners, hold on for that feature discussion. Well, my first paper, Carolyn, really pertains to physical activity. And Carolyn, the study is led by Dr. Don Hoon Lee from the Harvard T.H. Chan School of Public Health. And it evaluated a total of 116,000 adults from two large prospective US cohorts, the Nurse's Health Study and the Health Professional's Follow up Study that took place from 1988 to 2018. And they were examining self-reported leisure time physical activity and assessed the association between long term leisure time physical activity intensity and all cause and cause specific mortality.

Dr. Greg Hundley:

Now Carolyn, two types of physical activity were assessed. First, moderate physical activity and we're going to abbreviate that as MPA and that was 150 to 300 minutes per week, which is really recommended. Or second, vigorous physical activity for which it's really recommended that one performs 75 to 150 minutes per week. Now, Carolyn, as you know, some individuals accomplish both of these in their routine, some neither, some one or the other. And so it really remains unclear whether higher levels of long term vigorous or moderate are independently or perhaps jointly associated with lower mortality.

Dr. Carolyn Lam:

Oh, that's so interesting, Greg. Quick, quick, quick, tell us the results.

Dr. Greg Hundley:

Right Carolyn. So the nearly maximum association with lower mortality overall was achieved by performing approximately 150 to 300 minutes per week of long term leisure time vigorous physical activity or 300 to 600 minutes per week of long term leisure time moderate physical activity or an equivalent combination of both, so mixing those minutes. Also Carolyn, very interestingly, higher levels, suppose you go beyond those limits of either long term leisure time vigorous physical activity of more than 300 minutes per week or moderate physical activity of more than 600 minutes per week did not show clearly further lower all cause cardiovascular disease or non-cardiovascular disease mortality and nor did they show harm. So if you went above those thresholds, you really didn't experience greater harm.

Dr. Carolyn Lam:

Thanks, Greg. You know I'm going to be trying to apply that. That's so cool. All right. Well the next paper refers to the Cabana Trial, which I'll remind you is a trial in which catheter ablation did not significantly reduce the primary endpoint of death, disabling stroke, serious bleeding or cardiac arrest compared to drug therapy by intention to treat, but did improve quality of life and freedom from atrial fibrillation recurrence. In Cabana, the heart failure subgroup, ablation appeared to improve both survival and quality of life. The current paper led by Dr. Mark and colleagues from Duke Clinical Research Institute looked at the cost effectiveness of this ablation versus angio-rhythmic drug therapy in atrial fibrillation and which was a pre-specified Cabana secondary endpoint.

Dr. Greg Hundley:

Ah, Carolyn. So what did they find?

Dr. Carolyn Lam:

Well in this trial based economic evaluation, catheter ablation was estimated to cost $57,893 per QALY or Quality Adjusted Life Year gained compared to drug therapy in the overall cohort. And this was primarily driven by improvement in quality of life. It also cost $54,135 per QALY gained in the heart failure subgroup, driven by both gains in quality of life and survival. In summary, catheter ablation of atrial fibrillation was found to be economically attractive compared to drug therapy in the Cabana trial overall at present benchmarks of healthcare value in the US and based on projected incremental qualities, but not live years alone.

Dr. Greg Hundley:

Very nice Carolyn. Well, my next paper comes to us from the world of Preclinical Science and it's corresponding author is Dr. Swapnil Sonkusare from University of Virginia School of Medicine. So Carolyn, calcium signals in smooth muscle cells contribute to vascular resistance and control blood pressure. Now increased vascular resistance in hypertension has been attributed to impaired smooth muscle cell calcium signaling mechanisms. And in this regard, transient receptor potential vanilloid four or TRPV4 smooth muscle cell ion channels are crucial calcium entry pathways for smooth muscle cells. However, their role in blood pressure regulation has not been identified.

Dr. Carolyn Lam:

Wow. TRPV4 smooth muscle cells. Cool Greg. So what did they find?

Dr. Greg Hundley:

Right, Carolyn. So these authors provide the first evidence that TRPV4 smooth muscle cell channel activity elevates resting blood pressure in normal mice. A1AR stimulation activated TRPV4 smooth muscle cell channels through protein kinase calcium signaling, which contributed significantly to vasoconstriction and blood pressure elevation.

Dr. Greg Hundley:

Surprisingly, intraluminal pressure induced TRPV4 smooth muscle cell channel activity, opposed vasoconstriction through activation of calcium sensitive potassium channels indicating functionally opposite pools of TRPV4 smooth muscle cell channels. And so Carolyn, this team identified novel smooth muscle cell calcium signaling nano domains that regulate blood pressure and demonstrate impairment in hypertension.

Dr. Carolyn Lam:

Oh wow, Greg. Thank you so much for that. Well, let's cover the other articles in today's issue. There's a primer by Dr. Jaffe on High Sensitivity Cardiac Troponin and the 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR guidelines for the evaluation and diagnosis of acute chest pain. There's also Research [Letter] in there by Dr. Fordyce on the eligibility for non-invasive testing based on the 2021 American Heart Association and ACC guideline for the evaluation and diagnosis of chest pain, implications from the Promise trial.

Dr. Greg Hundley:

Great Carolyn. Well, I've also got an exchange of letters to the editor from Professors Benali and Professor Della Bella regarding a previously published article, “Does Timing of Ventricular Tachycardia Ablation Affect Prognosis in Patients with an Implantable Cardioverter Defibrillator, Results from the Multicenter Randomized Partita Trial.” And also there's a very nice Perspective piece from Dr. Udelson entitled “Glucose Insulin Potassium Therapy for Acute Myocardial Infarction, 50 years on and Time for a Relook.” Well, Carolyn, I can't wait to hear more of the discourse between you, the authors and editors on heart failure and preserved ejection fraction.

Dr. Carolyn Lam:

Yay. Here we go. I'm so excited about today's feature discussion. It's on my favorite topic, heart failure with preserved ejection fraction. Although thanks to one of the authors, Dr. Daniel Burkhoff of the editorial that accompanies it, I don't even know how to pronounce, it's Heart Failure question mark Ejection Fraction. I love it. How would you pronounce that?

Dr. Daniel Burkhoff:

Yeah, no, we debated how to pronounce it. HFQRef…a question mark?

Dr. Carolyn Lam:

HFQRef. Oh my goodness. What are we going to come up with next?

Dr. Daniel Burkhoff:

And we actually thought the editors would have a problem with that. Whenever we put something cute in the title, we always get knocked down. So we haven't yet got knocked down, so we'll see.

Dr. Carolyn Lam:

No, I'm not knocking you down.

Dr. Daniel Burkhoff:

But it just really emphasizes that we're in a very confusing time now as it comes to heart failure and ejection fraction, that we have to move on beyond ejection fraction. And although we have these strict buckets and upper and lower limits for each range, that maybe this is in a little bit of a way, doing us a disservice and doing the patients at disservice in terms of treatment.

Dr. Carolyn Lam:

That's really great. And everybody that was Dr. Daniel Burkhoff from the Cardiovascular Research Foundation in New York. He's the editorialist of today's feature paper. And I'm so excited that we have the corresponding author of today's feature paper as well, Dr. Philipp Lurz from Heart Center Leipzig in Germany. So first, I mean, or second, heartfelt congratulations on this beautiful paper, Philipp. If you could start with telling us all about what you did and what you looked at and what made Dr. Daniel Burkhoff call it now, Heart Failure, QREF?

Dr. Philipp Lurz:

Yeah. So thank you so much, first of all, obviously for having me for the kind introduction and your kind words about our work. The whole thing started with the observation that in recent drug trials, the response in HFpEF patients to drugs which were before proven to be quite successful in HFrEF actually showed a quite heterogeneous response in HFpEF patients. And that there were some patterns according to the range of ejection fractions. So it seemed that those HFpEF patients with the lower ejection fractions, they respond a little bit better to HFrEF medication than those with a higher ejection fraction.

Dr. Philipp Lurz:

And HFpEF studies, they included patients within and ejection fraction or 40 and above who normally would probably would consider HFpEF to start with 50 and above. But even in those truly HFpEF patients, so from 50 and anything above to 70, there was a suggestion that there might be differences. 50 to 60 might be something else and then 60 and above. And this is where we started to look into our cohort and to group them according to ejection fraction and see whether we can see some important and clinically meaningful differences in morphology, obviously in function, but then even also in terms of our biopsy results.

Dr. Philipp Lurz:

And that also implies that we did quite a deep phenotyping of our patients. So we use imaging, echo obviously. We use magnetic resonance imaging. We were able to acquire in a larger percentage of that cohort, by the way, it was 56 patients in total, we were able to get some left ventricular biopsies. And most importantly, when it comes to the functional properties of the left ventricle, we also acquired pressure volume loops. And that has the great advantage that we obviously we can look at low dependent parameters, but more important, also low independent in disease of both systolic and diastolic function. And that's pretty much what we did.

Dr. Carolyn Lam:

Oh my goodness. I mean, as an editor at Circulation, can I just first tell you that's what really, really stood out? It's the comprehensive, careful, in-depth characterization. It may be 56 patients, but MRI, echo, biopsies, exercise, PV loops. I mean, it was a lot, a lot that you did. Could you boil it down to what you found and maybe just to first clarify to the audience, how did you bend the ejection fraction? And then what you found?

Dr. Philipp Lurz:

We divided the cohort in two groups. One with an ejection fraction 50 to 60, and the other groups higher than 60% left ventricular ejection fraction. We ended up in lower group, 21 patients, in the higher group with 35 patients. And they were quite different. They had distinct features in terms of morphology, means that the lower injection fraction group, they had larger ventricles. That's probably what you would expect when you group them according to eject fractions. So not that surprising.

Dr. Philipp Lurz:

And at that point, and they had the same stroke volume. The low ejection fraction group, you could say that they had a certain degree of eccentric modeling, whereas those were the high ejection fraction group, that concentric modeling. When we then looked at the biopsies, the group with the low ejection fraction group, so 50 to 60, they had higher percentage of myocardial fibrosis at 15%.

Dr. Philipp Lurz:

And then on left ventricular biopsy, we saw that patients with a high ejection fraction group, they had less myocardial fibrosis, so more fibrosis in those with the lower ejection fraction group. And this is really interesting because when we then look at the real size of the pressure volume loop analysis, despite the fact that the high ejection fraction group had less fibrosis, they had the most stiff ventricles on pressure volume loop analysis. So that's already a very important point because it illustrates once again that we should not mistake fibrosis with stiffness, and also not the other way around. There are other parameters which can cause stiffness such as cellular stiffness, and it's not just the extracellular matrix.

Dr. Philipp Lurz:

So that's an important point. Those patients with high ejection fraction, they had the most stiff ventricles. They had the most relevant limitations in left ventricular filling, so the most marked diastolic dysfunction. We also looked at systolic parameters and there we found that they had a very high contractility. So this is the end systolic pressure volume relationship or also called elastics and that's a marker for contractility. So these ventricles with high ejection fraction, they can contract very well. They have high contractivity. But this is also a marker of systolic stiffness. So they stiff, both in terms of diastolic properties, but also systolic properties. And there, their most important limitation is the limitation in filling.

Dr. Philipp Lurz:

The other group, injection fraction 50 to 60, they do have some stiffness. Obviously we are talking about HFpEF. This is a disease of a diastolic dysfunction. So they have increased stiffness, but to a lesser extent. They can feel a little bit better, but what we see there is a reduction in contractility, so systolic properties. So you could argue that in some extent, that group 50 to 60, they behave a little bit more like HFrEF. Whereas those with high ejection fraction, they're completely different. Very stiff, both doing diastolically and sistolly.

Dr. Carolyn Lam:

Thank you so much. Now I really have to get the gurus insight into this. And of course by guru, I mean, Dr. Daniel Burkhoff. First, I'm going to take this opportunity to share a little private personal story that it's very hard for me to call Dr. Burkhoff, "Dan", although if you will allow me it's because I was a fellow when I first met Dr. Burkhoff. And one of my first papers was actually communicating with Dr. Burkhoff trying to draw these PV loops based on the noninvasive measurements that I was obtaining at the Mayo Clinic in the Olmsted County Cohort. And so this is just really making me smile. So Dan, if I may, what do you make of all this? And if you could give us what you think may be the clinical take home message.

Dr. Daniel Burkhoff:

Thank you so much, Carolyn. And also again, Philipp, congratulations on really a really important paper. I think as Carolyn was saying, one of the many things that impressed me was the multifaceted aspects of the thorough evaluation using multi modality characterization, which is in my mind, unprecedented, especially for this particular group of patients. And you summarized the main results very well. But to me, the thing that really struck me and that we really tried to emphasize in our editorial was the differential response to exercise, to hand grip exercise in this point.

Dr. Daniel Burkhoff:

As you already said, and I don't think this could be understated, that in the lower range, the 50 to 60, these patients were able to fill, the ventricle was able to fill more, the end diastolic pressure still went up significantly into an abnormal range, which is of course is one of the requirements for the diagnosis of HFpEF. But those patients, the end diastolic volume was able to increase and that helped them to increase their cardiac output.

Dr. Daniel Burkhoff:

In the higher EF group, the greater than 60, the end diastolic pressure went up, but the volume did not increase. So the end diastolic pressure volume relationship became higher elevated. And this of course, was reminiscent of what was identified in the early nineties by Dalane Kitzman. And really, he didn't make this distinction between the lower half and the higher half. And we had also in a paper that we did with David K and others, seen a similar finding a couple years ago. And I think this is really, to me, was the along with the apparently disparate findings on myocardial biopsies with fibrosis going the wrong way, if you will, as you already commented on. So this is at least for the higher EF group, is identifying what I would refer to as really true diastolic dysfunction.

Dr. Daniel Burkhoff:

That means that the patients can't fill, there really is some problem why the EDP can go up, but the volume does not increase. And this is obviously for future research, we have to understand what is the difference between these two groups. There are several speculations about why it might. For example, one thing that has been proposed in the literature is the pericardial restraints. If the heart is constrained in a tight pericardium, the volume is recruited from the venous system, which is another what I think is a very important part of this HFpEF phenotype, but the heart is already constrained. That would elevate both the CVP and the wedge pressure without concomitant increases in RV or LV volumes, and therefore limit the ability to increase the cardiac output.

Dr. Daniel Burkhoff:

Another alternative is delayed relaxation. That means a true abnormality of active relaxation. The tau if you will, but I believe in your study, if I remember correctly, the tau was not that abnormal and did not really change very much in either group. So it was harder to really pin it on an abnormality of active relaxation. So that was one really, I think, really important finding.

Dr. Daniel Burkhoff:

The second is now in the group 50 to 60 where they could fill, one of the limitations of the study that you pointed out was that there's no control group. So why this population, this HFpEF population, the EDP increased, but the EDV the end diastolic volume also increased, so what's different between those patients and normals? That we don't really have an answer for yet. So that would be one thing is to compliment these findings with results in a true control group that does not have HFpEF.

Dr. Daniel Burkhoff:

So we still have this mystery of why does EDP go up in this group? My perspective is not an abnormality of diastolly. It's not a diastolic dysfunction, even though it's a HFpEF. I've been trying to promote this idea for more than 20 years, that all HFpEF is not an abnormality of diastolic ventricular properties. There may be extra cardiac factors even beyond the pericardium in this group. So I think these results are just further telling us how complicated and individualized our approach to the pathophysiology of these patients should be.

Dr. Daniel Burkhoff:

And also just one final comment, making a strict cutoff at 60% or 57% as we saw from Valsartan Cuba trial, Valsartan study, is clearly also not going to do us justice. Let's say that we're dealing with anyway, patients with two different pathophysiologies. There's going to be a distribution of these different mechanisms and there's going to be an overlap of these distributions. So we need to start thinking about how we individualize and characterize the pathophysiology in individual patients. So maybe patients with EF of 55, certain patients with EF 55 will not respond to Sacubitril- Valsartan and maybe some patients with an EF of 62 will. So we need to go more deep into the clinical characterization.

Dr. Daniel Burkhoff:

And methods that you use in particular, the pressure volume loop, seem to separate, very nicely, these two different, at least two different subtypes. So I think it's very exciting, and I think people should really take notice of what you found and build on this as a foundation and understand that we need to go deeper on the clinical side to phenotype these patients.

Dr. Carolyn Lam:

Philip, what are your thoughts?

Dr. Philipp Lurz:

No, I think that the concept about stress and unstressed volume is extremely important and fascinating, but that's where it gets really complex because you could make the conclusion from our results that especially the high ejection fraction group, they are have a very high preload sensibility, which means that when we reduce pre-load too much in them, they drop the stroke volume very suddenly. So that's probably also the clinical question for the future. There are many patients, HFpEF patients in whom we should reduce stress volume and they can benefit from that.

Dr. Philipp Lurz:

But I also believe that there is a cord of patients, and those are probably more those with high ejection fraction. They actually, they could experience some harm if you reduce preload too much because of the severe filling restrictions, because of the inability to increase end diastolic volumes, especially as an adaptation to exercise. And I think if we find out ways to differentiate who will benefit from preload reduction and from decongestion and who actually might experience even harm from these interventions, then we are certainly one step further.

Dr. Carolyn Lam:

If I may, I just, I could go on forever, but I know that there's going to be this question that the audience is immediately thinking. Here we are going into the weeds, hemodynamics, we all love it. In fact, I think we're all kind of a little bit geeky about it, but then you've got, Emperor preserved, the Deliver Trial sort of being positive in heart failure with ejection fraction above 40. So, do we really need to understand the different hemodynamic? What do you think is happening that this sort of blanket benefit can occur?

Dr. Philipp Lurz:

I don't think that everyone will benefit. And I think that a better understanding of the underlying pathophysiology will help to even increase the rate of responders and dissect of those who will not respond or we need a different therapy. Obviously here we group patients according to ejection fraction. We just discussed that this is a very rough way to characterize patients. So the next step certainly would be to understand or to see distinct patterns in left ventricular functional behavior irrespective of ejection fraction. Because you might can skip ejection fraction at one day, but the conclusion is not, at least not in my opinion, that all heart failure is the same.

Dr. Carolyn Lam:

Nice. And Dan, what do you think?

Dr. Daniel Burkhoff:

Well, I think with STLT2 inhibitors, first of all, we're looking forward to actually seeing the results from Deliver what the details of it in terms of mortality versus hospitalizations and quality of life. But with regard to HSGL2 inhibitors, I don't think we know the mechanism. I mean, I've read about six papers that definitively talk about different mechanisms of action. I think we don't know. And even despite, let's say positive studies, there's still a significant residual risk that these patients have. So these are not the end of the story by any means. I think this is the beginning of the story and there's still going to be a lot to learn.

Dr. Daniel Burkhoff:

I think with SGLT2 inhibitors, I think it's difficult to identify who is or how do you define a responder on an individual patient basis? When we look at groups and you look at mortality and hospitalizations, yes, you can identify them. But that group does not overlap exactly with those who have an improvement in quality of life. So I think that we're just at the beginning,

Dr. Daniel Burkhoff:

I do think that a deeper phenotyping is going to be the way to go ultimately and I think we're going to need more therapies. Thanks again, Carolyn for inviting me to do the editorial and to participate in this. And I would really be remiss if I did not mention the extraordinary contributions for Mickey Brener and also Barry Borlaug who were equal contributors to this editorial and the evaluation of this paper. So I'm really indebted to both of them for this interpretations. And thank you again, Philipp, for just a wonderful paper.

Dr. Carolyn Lam:

Couldn't have said it better and I just want to thank you once again for providing that deeper phenotyping for opening the door. Many of us said it again and again, this is the beginning and we need more studies, frankly, in yours. I mean, I think Dr. Burkhoff wants you to send normal, healthy people for MRI biopsies, exercise, echo. I'm kidding, on PV loops, but it's true. We need that data. We need the same and the HFrEF and really just to understand the whole thing. I'm so excited about what this paper opens up.

Dr. Carolyn Lam:

I am thrilled to see your editorial, Dan. I'm sure it's going to be well received. Everyone who's listening to this, Pick up the paper, pick up the editorial. Thank you so much for joining us today. You've been listening to Circulation on the Run and from Greg and I, don't forget to tune in again next week,

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit hajournals.org.

This week, please join authors John McMurray and David Cherney, editorialist Kausik Umanath, as well as Associate Editors Ian Neeland and Brendan Everett as they discuss the original research articles "Initial Decline (Dip) in Estimated Glomerular Filtration Rate After Initiation of Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction: Insights from DAPA-HF" and "Renal and Vascular Effects of Combined SGLT2 and Angiotensin-Converting Enzyme Inhibition" and editorial ""Dip" in eGFR: Stay the Course With SGLT-2 Inhibition."

Dr. Carolyn Lam:

Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Centre and Duke National University of Singapore.

Dr. Greg Hundley:

I'm Dr. Greg Hundley, Associate Editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, it's the season of double features. Except this time, we're having a forum discussion of two related articles and an editorial that discusses both. What is it on? SGLT2 inhibitors. In the first paper, an analysis from the DAPA-HF trial, looking specifically at that initial dip in GFR that follows initiation of dapagliflozin in patients with HFrEF. Then we will discuss further, in a mechanistic way, the renal and vascular effects of combining SGLT2 inhibition on top of ACE inhibition. Lots and lots of good learning and insights, but let's go on first to the other papers in today's issue. Shall we?

Dr. Greg Hundley:

You bet, Carolyn, and I'm going to grab a cup of coffee. Carolyn, in this issue, wow, so many exciting original articles. In fact, there are two more articles that were going to pair together, both clinical and pertaining to TAVR procedures. In the first one, it was a group of authors led by Dr. Duk-Woo Park from the Asan Medical Center at the University of Ulsan College of Medicine. They conducted a multicenter, open-label randomized trial comparing edoxaban with dual antiplatelet therapy or DAPT, aspirin plus clopidogrel, in patients who had undergone successful TAVR and did not have an indication for anticoagulation. Now in this study, Carolyn, the primary endpoint was an incidence of leaflet thrombosis on four-dimensional computed tomography, CT, performed at six months after the TAVR procedure. Key secondary endpoints were the number and volume of new cerebral lesions on brain magnetic resonance imaging or MRI and the serial changes of neurological and neurocognitive function between six months and that time immediately post the TAVR procedure.

Dr. Carolyn Lam:

Oh, interesting. What did they find?

Dr. Greg Hundley:

Right, Carolyn. In patients without an indication for long-term anticoagulation after successful TAVR, the incidence of leaflet thrombosis was numerically lower with edoxaban than with dual antiplatelet therapy, but this was not statistically significant. The effect on new cerebral thromboembolism and neurological or neurocognitive function were also not different between the two groups. Now because the study was underpowered, the results should be considered really as hypothesis generating, but do highlight the need for further research.

Dr. Greg Hundley:

Carolyn, there's a second paper pertaining to transcatheter aortic valve prosthesis. It's led by a group directed by Dr. Paul Sorajja from the Minneapolis Heart Institute Foundation and Abbott Northwestern Hospital. Carolyn, these authors prospectively examined 565 patients with cardiac CT screening for HALT, or what we would define as hypoattenuating leaflet thickening, at 30 days following balloon-expandable and self-expanding TAVR. Now, deformation of the TAVR prosthesis, asymmetric prosthesis leaflet expansion, prosthesis sinus volumes, and commissural alignment were analyzed on the post-procedural CT. For descriptive purposes, an index of prosthesis deformation was calculated, with values greater than 1 representing relative midsegment underexpansion. A time-to-event model was also performed to evaluate the association of HALT with the clinical outcomes.

Dr. Carolyn Lam:

Oh, interesting. What did they find?

Dr. Greg Hundley:

Right, Carolyn. Nonuniform expansion of TAVR prosthesis resulting in frame deformation, asymmetric leaflet, and smaller neosinus volume was related to the occurrence of HALT in patients who underwent TAVR. What's the take home here, Carolyn? These data may have implications for both prosthesis valve design and deployment techniques to improve clinical outcomes in these patients. Now, Carolyn, both of these articles are accompanied by an editorial from Dr. Raj Makkar from the Smidt Heart Institute at Cedars-Sinai's Medical Center. It's a very lovely piece entitled Missing Pieces of the TAVR Subclinical Leaflet Thrombosis Puzzle.

Well, how about we check what else is in this issue? My goodness, this was a packed issue. First, Carolyn, there are three letters to the editor from Professors Ennezat, Dweck, and then a response from Dr. Banovic pertaining to a follow-up from a previously published study, the AVATAR study, in evaluating valve replacement in asymptomatic aortic stenosis. There's also a Perspective piece from Dr. Wells entitled “Treatment of Chronic Hypertension in Pregnancy: Is It Time For A Change?” There's a Global Rounds piece from Professor Berwanger entitled “Cardiovascular Care in Brazil: Current Status, Challenges, and Opportunities.” Then there's also a Research Letter from Professor Eikelboom entitled “Rivaroxaban 2.5 mg Twice Daily Plus Aspirin Reduces Venous Thromboembolism in Patients With Chronic Atherosclerosis.”

Dr. Carolyn Lam:

There's another Research letter by Dr. Borlaug on longitudinal evolution of cardiac dysfunction in heart failure with normal natriuretic peptide levels. There's also a beautiful Cardiology News piece by Bridget Kuehn on the post-COVID return to play guidelines and how they're evolving. Well, that was a great summary of today's issue. Let's hop on to our feature forum. Shall we?

Dr. Greg Hundley:

You bet, Carolyn. Can't wait.

Dr. Carolyn Lam:

Today's feature discussion is actually a forum because we have two feature papers in today's issue. They all surround the cardiorenal interaction, should I say, of the SGLT2 inhibitors. For the first paper, discussing that initial decline or that dip in the GFR following initiation of dapagliflozin would be Dr. John McMurray, who's the corresponding author of this paper from DAPA-HF. Dr. John McMurray's from the University of Glasgow. Now next, we have also the corresponding author of another paper, really going into the mechanistic insights of the renal and vascular effects of combined SGLT2 and ACE inhibition. Dr. David Cherney is from Toronto General Hospital, University of Toronto.

Dr. Carolyn Lam:

We have the editorial list of these two wonderful papers, Dr. Kausik Umanath from Henry Ford Health in Michigan. Finally, our beloved associate editors, Dr. Ian Neeland from Case Western Reserve and Dr. Brendan Everett from Brigham and Women's Hospital, Harvard Medical School. Thank you, gentlemen. Now with all of that, what an exciting forum we have in front of us. Could I start by asking, of course, the respective authors to talk a little bit about your papers? I think a good place to start would be with Dr. McMurray. John, please.

Dr. John McMurray:

Thanks, Carolyn. I think our paper had three key messages. The early dip in eGFR that we saw was, on average, very small in patients with heart failure, about 3 mLs/min or about 5%. Very few patients had a large reduction in the eGFR. It was around 3%. Dapagliflozin-treated patients had a 30% or greater decline compared to about 1% of placebo patients. Finally, very few of those patients had a decline in the eGFR below a critical threshold, which for cardiologists might be around 20 mLs/min. We saw that in only five patients; that's 0.2% of the dapagliflozin-treated patients. Second message was that that early decline partially reverses. The nadir in our study was about 14 days. But by 60 days, on average, eGFR had increased again. Hold your nerve if you see an early decline in eGFR.

Dr. John McMurray:

Maybe the most important message was that that decline in the eGFR is not associated with worse cardiovascular or renal outcomes. In fact, if anything, the opposite. If you look at the patients in the dapagliflozin group with a 10% or greater decline in eGFR, then compare it to patients who didn't have that decline, these individuals were about 27% less likely to experience the primary composite outcome of worsening heart failure and cardiovascular death. If you look at the placebo group, we saw exactly the opposite. Amongst those who had a greater than 10% decline in eGFR compared to those who didn't, those people with the early decline in eGFR were 45% more likely to experience the primary composite endpoint. The same is true for other cardiovascular outcomes for worsening kidney function. In the dapagliflozin group, decline in eGFR was not associated with more adverse events, not associated with more treatment discontinuation. That small decline in the eGFR is not a bad prognostic sign. If anything, it might be the opposite.

Dr. Carolyn Lam:

Thank you so much. That was really clear. David, are you going to tell us why this decline occurs?

Dr. David Cherney:

Yeah. Perhaps the paper that we published gives some insights into the mechanisms that are responsible for some of those changes in GFR that are thought to be acute hemodynamic effects. In the between trial, which is the trial that we published examining the effect of ACE inhibition followed by SGLT2 inhibition in patients with type 1 diabetes, we also saw that there was an expected effect of adding SGLT2 inhibition on top of an ACE inhibitor in people with uncomplicated type 1 diabetes. This acute dip in GFR was seen in this cohort of patients. We included only 30 patients in this small mechanistic study. At the same time, along with that dip in GFR, we also saw an increase in measures of proximal natriuresis. That proximal sodium loss is linked with changes in sodium handling in the kidney, which then causes changes in both probably afferent and efferent tone, which causes this dip in GFR primarily through natriuresis in this phenomenon called tubuloglomerular feedback. That was one major observation that gives insight into what we see in larger trials around the dip in GFR.

Dr. David Cherney:

In our mechanistic study, we also saw an additive effect on blood pressure. Blood pressure went down further with the addition of empagliflozin on top of an ACE inhibitor. In terms of the mechanisms that are responsible for the reduction in blood pressure, natriuresis certainly may be in part responsible, but we also saw a novel observation whereby there was a reduction in peripheral vascular resistance using noninvasive measures. There are likely several mechanisms that are responsible for the reduction in blood pressure. Then finally, we also saw reductions in markers of oxidative stress, which may also account for some of the effects that we see in blood pressure, as well as potentially some of the anti-inflammatory and anti-fibrotic effects that we see at least in experimental models that may have some clinical translatability to humans as well around the clinical benefits. I think the blood pressure, the renal hemodynamic effects, and some of the neurohormonal mechanisms are the major observations that we saw that may in part explain some of the really nice changes that were seen in Dr. McMurray's study.

Dr. Carolyn Lam:

Right. Thanks, David. But these were patients with type 1 diabetes and no heart failure. John, do you have any reflections or questions about how that may apply? By the way, what a beautiful study. Thank you, David.

Dr. David Cherney:

Pleasure. Thank you.

Dr. John McMurray:

Yes, David. I really enjoyed your study. In fact, I think, Carolyn, it does shed some insights perhaps to what's going on. As David pointed out, the reduction in peripheral arterial resistance, reduction in blood pressure, that may play some role in that early dip in eGFR as well as autoregulation in the kidney. Then the other interesting thing is that the distal nephron seems to adapt to that effect in the proximal tubule. Again, that may account for some of that recovery in eGFR, that reversal in the early dip that I spoke about, and which I think is very clinically important because, of course, physicians should make sure that they recheck eGFR if they see that early dip. Because they may find that few weeks later that that dip is much smaller and of much less concern.

Dr. Carolyn Lam:

Thank you, John. In fact, you're saying, stay the course, right-

Dr. John McMurray:

I have.

Dr. Carolyn Lam:

... with the SGLT2 inhibitors. I'm actually stealing the words of the title of the editorial, a beautiful editorial by Kausik. I love that. Stay the course. Kausik, please, could you frame both papers and then with an important clinical take home message for our audience?

Dr. Kausik Umanath:

Sure. I think the analysis by John and his group was really relevant with the large sample size. What's impressive? Similar to a lot of these other SGLT2 studies that have come out, both in heart failure and in kidney disease progression and so on, it's remarkable how the other analysis, like the analysis of EMPA-REG and CREDENCE and so on, of similar dips. All show more or less the same magnitude, the same relative proportions of this GFR trajectory. I think the mechanistic study only highlights that though it's working with a slightly different population of type 1 patients and much earlier in their course in terms of where their GFRs are.

Dr. Kausik Umanath:

The other piece is that ultimately we need to understand this dip and know to monitor for it and so on. But I think the general clinician should really understand that a dip of greater than 10% really occurs in less than half the population that takes these agents. That dip, if it occurs, certainly doesn't do any harm. That said, if they see a bigger dip in the 30% range, monitor more closely and consider making sure that there aren't any other renal issues out there for that patient because they are a much smaller proportion of patients in these large trials that generate that level of dip. They should be monitored.

Dr. Kausik Umanath:

The other thought that we had, and thinking through this in a practical sense, is because you expect this dip, many of our cardiologists or even the nephrologists when we titrate these drugs, they're on a suite of other drugs. It's probably best to not adjust their Lasix or their loop diuretic, or their RAAS inhibitor at the same time as you're adjusting the SGLT2 inhibitor or starting it because then you may just introduce more noise into the GFR changes that you see over the next several weeks. It may be a sequential piece or at least holding those other agents constant while this gets titrated and introduced is a prudent course of action, so you don't misattribute changes.

Dr. Carolyn Lam:

Thanks so much. What clinically relevant points. In fact, that point about the diuretic especially applies in our heart failure world. You see the dip. Well, first, make sure the patient's not overdiuresed. Remember, there's more that the patient's taking. Thank you. That was a really great point. Brendan and Ian, I have to get you guys to share your views and questions right now. But before that, can I take a pause with you and just say, aren't you just so proud to be AEs of Circulation when we see papers like these and we just realize how incredible the data are and the clinical implications are? I just really had to say that. All right. But with that, please, what are your thoughts, Brendan?

Dr. Brendan Everett:

Yeah, sure. Thank you, Carolyn. Hats off to all three of our authors today for doing some amazing science. Thank you for sending it to Circulation. I think, in particular, I handled David's paper. I'm not a nephrologist and I'm probably the furthest thing from a nephrologist. Had to do my best to try and understand these concepts that I'm not sure I ever even was exposed to in medical school many years ago. I think it shows the breadth of the interest in our readership. The fact that these changes in eGFR have become a primary focus for our cardiovascular patients and that the clinical implications are really important. I guess my question, David, is... In your paper, you talked a little bit about this hypothesis of hyperfiltration and the role that hyperfiltration plays in setting patients with diabetes up for kidney disease. Is that playing a role in John's observation or not? Again, as a non-nephrologist, I have trouble connecting the dots in terms of that hypothesis and John's observation of the clinical benefit for patients that have a reduction in eGFR as opposed to no change.

Dr. David Cherney:

Yeah. It's a great question. It's very difficult to know with certainty in a human cohort because we can't measure the critical parameter, which is intraglomerular pressure, which we think these changes in GFR are a surrogate for. But if we go along with that train of thought, along reductions in glomerular hypertension, it very much makes sense that the patients who dip are those who have the... They're taking their medication, number one. Number two, they respond physiologically in the way that you expect them to, which is that their GFR dips at least transiently and then goes back up again through some of the compensatory mechanisms that John mentioned earlier. As was mentioned not only in this paper, but also in previous analyses from CREDENCE and previous analyses from VERTIS CV and others have shown that indeed that dip in GFR is linked with longer term renal benefits, at least. That is reflected in a reduction in the loss of kidney function over time.

Dr. David Cherney:

The patients who are on an SGLT2 inhibitor and those who dip by around 10% or less, those patients tend to do the best over time in terms of preserving GFR, not losing kidney function compared to patients who are on an SGLT2 inhibitor but do not dip, or those patients who actually have an increase in GFR. That is consistent with this idea that there may be a reduction in glomerular pressure, which is protective over the long term. That ties back into your question around hyperfiltration that this may indeed be due to a reduction in glomerular pressure, which is linked with risk over the long term.

Dr. Carolyn Lam:

Ian?

Dr. Ian Neeland:

I wanted to echo Brendan's comments about the excellent science. When I read these papers, it really speaks to the existential struggle that cardiologists have between kidney function and these medications that we know have cardiovascular benefits. How do we manage that practically? It's so clinically relevant, both the observation that John's paper made about the dip in the DAPA-HF trial as well as, David, your mechanistic insights.

Dr. Ian Neeland:

I wanted to ask John potentially about the most fascinating aspect to me of this paper was that patients with a dip of 10% or more actually ended up doing better in terms of cardiovascular outcomes, specifically hospital heart failure and hospitalizations than people on placebo with a greater than 10% dip. It speaks to the fact that... Is the physiology going on here different between those individuals whose GFR went down on placebo versus those who are on SGLT2 inhibitors? All the mechanistic insight that David's paper had in terms of blood pressure and intraglomerular pressure, how does that feedback and speak to why heart failure is strongly linked to this mechanism? We see this not just with SGLT2 inhibitors, but there are other medications now coming out showing that there's a relationship between this dip in GFR and heart failure. Can you speak to why this heart failure-kidney connection is so important and becoming greater and greater in terms of our understanding?

Dr. John McMurray:

Well, thank you for asking me the hardest question and one that I truly don't think I have a good answer to. I think it's obvious to all of us that the kidney is central in heart failure and perhaps cardiologists have neglected that fact, focusing more on the other organ. But by definition, almost the fluid retention that characterizes heart failure in terms of signs, and probably is the primary cause of symptoms, that clearly is a renally-mediated phenomenon. The kidney must be central to all of this. I think David right. I think the decline in eGFR that you see with this drug is simply a marker that the drug is having its physiological effect or effects. Whatever those are, they're beneficial. Clearly, patients who have an eGFR decline on placebo are different and they reflect, again, the patients that we see all the time. As our patients with heart failure deteriorate, one of the things that we commonly see, in fact becomes one of the biggest problems that we have to deal with, is that their kidney function declines. As their symptoms get worse, as their cardiac function gets worse, their kidney function also declines.

Dr. John McMurray:

I think you're seeing two contrasting effects here. One is the background change in eGFR, which is the placebo patients, and we've always known that that's a bad thing. Then we're seeing that early within 14 days marker of the pharmacological or physiological action of the drug. I hope you don't ask me how SGLT2 inhibitors work in heart failure. That's the other most difficult question I can think of, but I think this is just a marker of the fact that they are working.

Dr. David Cherney:

Yeah. Just to add to that briefly, there is this difficulty in sorting out the mechanisms that are relevant around the acute effects in the kidney that the dip in GFR reflects natriuresis that could keep patients out of heart failure; that the reduction in glomerular pressure reduces albuminuria. Albuminuria reduction is linked with kidney protection. It's linked with heart failure and ASCVD protection. Then there's also this concept of if you dip and then you stay stable afterwards, your GFR stays stable afterwards, those patients with stable kidney function that's not declining, the dippers in other words, those patients are probably able to maintain salt and water homeostasis better than someone who's declining more rapidly. All these things probably tie together in order to reflect, of course, there's a renal protective effect, but that some of those mechanisms may also tie into the heart failure mechanisms that John was mentioning.

Dr. John McMurray:

But, David, it's hard to imagine if we don't protect the kidney, we won't protect patients with heart failure given how fundamental, as I said, the kidney is, and how fundamentally important worsening kidney function is. Not only because it is a marker of things going badly, but also because it often results in discontinuation or reduction in dose of other life-saving treatments. To Kausik's point, it was very important about the risk of changing background life-saving disease modifying therapy. Actually, we didn't see that in DAPA-HF, which was very intriguing. There was no reduction in use of renin-angiotensin system blockers or mineralocorticoid receptor antagonists.

Dr. Carolyn Lam:

Thank you so much, gentlemen. Unfortunately, we are running out of time, but I would really like to ask one last question to the guests, if possible. Where do you think the field is heading? What next? What's the next most important thing we need to know? David, do you want to start? Then John, then Kausik.

Dr. David Cherney:

I think one of the aspects that we need to know in the future is where else can we extend these therapies into novel indications and extend the boundaries of where we currently work with these therapies. People with type 1 diabetes, for example, with either heart failure or with significant kidney disease, patients with kidney transplantation, is there a renal or cardiovascular protective effect? Then another high risk cohorts who have not been included in trials, those on immunosuppressants, for example, who were excluded from the trials. I think those are some of the areas that we need to extend into now that we understand how these therapies work in even very sick patients and that we also know that they likely have at least some benefit through suppressing inflammation, and possibly reducing infectious risks. That would provide a rationale for extending into some of these new areas. I think that's certainly, hopefully on the horizon for us.

Dr. Carolyn Lam:

John?

Dr. John McMurray:

Carolyn, obviously I think looking at post myocardial infarction population, that's an obvious place to go. There are a couple of trials there. I suppose the trial that I would love to see, and which I think would address the core question that we've been discussing today, which is: Is this all about the effect in the kidney and how important is the diuretic and natriuretic action of these drugs in heart failure? I think the key study that would address this would be doing a study in patients on dialysis. Because in those patients we could, I think, separate the issue of natriuresis, diuresis, and maybe even the dip in EGR that we've been talking about. If these drugs prove to be effective in end-stage kidney disease, patients on dialysis, that would be really fascinating.

Dr. Carolyn Lam:

Kausik?

Dr. Kausik Umanath:

That is a very interesting point. I don't know that we know necessarily outcomes, but I think from working with the DAPA-CKD, we do have a little bit of the safety data because we did continue it. I was the US MLI for that study and we did continue the SGLT2 passed into renal failure. There is a little bit of safety data there. But I don't think once you've declared an outcome, you're not collecting outcomes data after that point. That's a very interesting area to look into.

Dr. Kausik Umanath:

I also think the other place where this field's heading is trying to better tier and layer the multitude of agents. I think we've been waiting for about 20 to 30 years, at least in the kidney field, for something new to affect the progression of kidney disease after the ACE/ARB trials and so on. This one we've got SGLT2 inhibitors. We've got the new MRA, finerenone, and so on, which also have very beneficial cardiovascular effects. The question becomes: How do we layer these therapies? Which sequence to go in? Some of the others that are in pipeline as well that are out there that have very beneficial cardiovascular effects that may indeed also help kidney function and diabetes control, which do you go with first and so on?

Dr. Carolyn Lam:

Wow! Thank you so much. We really could go on forever on this topic, but it has been tremendous. Thank you once again. On behalf of Brendan, Ian, Greg, thank you so much for joining us today in the audience. You've been listening to Circulation On the Run. Don't forget to tune in again next week.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join authors Paul Ridker and Eric Van Belle, editorialist Robert Harrington, and Guest Editor Allan Jaffe as they discuss the original research articles "Effects of Randomized Treatment With Icosapent Ethyl and a Mineral Oil Comparator on Interleukin-1β, Interleukin-6, C-Reactive Protein, Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine, Lipoprotein(a), and Lipoprotein Associated Phospholipase A2: A REDUCE-IT Biomarker Substudy" and “Cerebral Microbleeds During Transcatheter Aortic Valve Replacement: A Prospective Magnetic Resonance Imaging Cohort” and the editorial "Trials and Tribulations of Randomized Clinical Trials."

Dr. Carolyn Lam:            

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University of Singapore.

Dr. Greg Hundley:          

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:            

It's double feature time Greg. We've got two totally unique and interesting papers that we'll be discussing. The first, a biomarker substudy from the REDUCE-IT trial, that is looking at the effects of randomized treatment with icosapent ethyl, versus a mineral oil comparator, on inflammatory biomarkers. Now, don't use roll your eyes at me, because I'm telling you, this has results that you may not expect, and very, very important clinical implications, and implications for clinical trials.

The second paper, very much up your alley, Greg, is a prospective MRI study of cerebral microbleeds during TAVR. But okay, enough now to whet your appetite, let's now just first grab coffees, and discuss the other papers and the issue, shall we?

Dr. Greg Hundley:          

You bet, Carolyn. And how about if I go first?

Dr. Carolyn Lam:            

Please.

Dr. Greg Hundley:          

So, Carolyn, my first paper comes from a group of investigators led by Dr. Araz Rawshani from the Institute of Medicine, and it included 715,143 patients with diabetes, registered in the Swedish National Diabetes Register, and compared them with over two million match controls, randomly selected from the general population, to determine the role of diabetes in the development of valvular heart disease, and particularly, the relation with risk factor control.

Dr. Carolyn Lam:            

Huh? Interesting, diabetes and valve disease. All right. What did they find, Greg?

Dr. Greg Hundley:          

Right, Carolyn. So they found, that individuals with type one and two diabetes, have greater risk for stenotic lesions. Whereas, risk for valvular regurgitation was lower in type two diabetes. Patients with well controlled cardiovascular risk factors, continued to display higher risk for valvular stenosis, without a clear stepwise decrease in risk between various degrees of risk factor control. So Carolyn, diabetes and a link with valvular heart disease.

Dr. Carolyn Lam:            

Wow. Really interesting, Greg. Thanks. Well, the next paper is a preclinical study with really interesting clinical implications. Now, we know the human heart has limited capacity to regenerate new cardiomyocytes, and that this capacity declines with age.

Now, because loss of cardiomyocytes may contribute to heart failure, it is important to explore how stimulating endogenous cardiac regeneration, to favorably shift the balance between loss of cardiomyocytes and birth of new cardiomyocytes, occurs in the aged heart.

Now, these authors, Doctors Rosenzweig, from Massachusetts General Hospital, and Dr. Lee from Harvard University and colleagues, previously showed that cardiomyogenesis can be activated by, guess what? Exercise in the young adult mouse heart. However, whether exercise also induces cardiomyogenesis in aged hearts, however, is not yet known. So in today's paper, the authors aim to investigate the effect of exercise on generation of new cardiomyocytes in the aged heart. And here, we're talking about 20 month old mice, who were subjected to an eight week voluntary running protocol, and age matched sedentary animals who served as controls.

Dr. Greg Hundley:          

Wow, Carolyn. Really interesting evaluation of exercise on cardiomyogenesis. So what did they find?

Dr. Carolyn Lam:            

Endogenous cardiomyogenesis can be stimulated by exercise in aged hearts. Comparative global transcriptional analysis further revealed, that exercise and age specific changes occurred in gene programs. The regulator of calcineurin RCAN1.4 was specifically found to be induced with exercise in aged hearts, and was accompanied by reduced calcineurin activity. So what's a take-home message? Exercise induced cardiomyogenesis may counter the increased cardiomyocyte loss and reduced cardio myogenic capacity in elderly patients.

Dr. Greg Hundley:          

Great, Carolyn. Well from the mail bag, there's an exchange of letters to the editor from Professor Zhou and Veith regarding a prior letter to the editor from Professor Jin and associates, pertaining to the previously published article “SPARC, A Novel Regulator of Vascular Cell Function in Pulmonary Hypertension.” And also, there's a Perspective piece, from Professor Mentz entitled, “Catastrophic Disruptions in Clinical Trials.”

Dr. Carolyn Lam:            

There's also a Research Letter by Dr. Kumar on [entitled] “von Willebrand Factor Is Produced Exclusively by Endothelium, Not Neointima, in Occlusive Vascular Lesions in Both Pulmonary Hypertension and Atherosclerosis.” There's also this beautiful tour of Cardiology News from the literature, from Tracy Hampton, which ranges from a study linking COVID-19 to higher long term cardiovascular risks, which was published in Nature Med, to uncovering alternative metabolic pathways involving cell fate transitions, published in Nature, to designing an autonomous biohybrid fish, from human stem cell derived cardiac muscle cells, that was published in Science. Wow. Isn't that amazing, Greg? Well, let's get on now though, to our two feature papers. Shall we?

Dr. Greg Hundley:          

You bet.

Welcome listeners, to these two feature discussions on this particular day. And our first feature today, we have with us Dr. Paul Ridker, from Brigham and Women's Hospital in Boston, Massachusetts. Dr. Bob Harrington, from Stanford University in California. And also, Dr. Allan Jaffe, from Rochester, Minnesota. Welcome to you all.

And Paul, we're going to start for you. Can you describe for us, the background information that really went into the construct of your study, and what was the hypothesis that you wanted to address?

Dr. Paul Ridker:

Sure, Greg. So first of all, my thanks to the AHA and the Circulation for publishing this paper, we always want to support the AHA, and we're delighted to be here today for these podcasts.

The field of omega-3 fatty acids has been a complicated one for a long time. Epidemiology suggested that, fish consumption would lower cardiovascular risk, and there was a number of trials done. And my friend and colleague here at the Brigham, Deepak Bhatt, was the lead of a very big trial, called REDUCE-IT. Some 8,000 plus patients who received EPA alone, and they got a terrific result. A 25% reduction in their primary endpoint. And this was a New England Journal paper, back in 2019 or so. But another friend of mine, Steve Nicholls, ran another large trial of a combination of eicosapentaenoic acid, or EPA, plus docosahexaenoic acid that's DHA called STRENGTH. And that one showed, really, no benefit. And so, there's been some controversy out there.

In any event, when Deepak and his colleagues published their original paper, they said it's interesting, because they got this big risk reduction, but it wasn't apparently due to the triglyceride lowering of the drug. And so, my interest, as many people know, has largely been in inflammation biology. And so we said, well maybe we should just do a test. Well, we said, we'll measure a number of biomarkers that we know were associated with atherosclerosis, some inflammatory, some with coagulation. And so, that was the core hypothesis, was simply to look at some other markers, and see what we might learn. And sometimes, you learn things that you didn't expect. And I think, that goes to the heart of what complicated clinical trials are all about. And I'd also say perhaps, what the roles of surrogate endpoints are, as compared to hard clinical endpoints, and things that make this whole field kind of interesting.

Dr. Greg Hundley:          

Right. Very nice, Paul. So you mentioned REDUCE-IT, so describe a little bit more for your study. What was the study population, and what was your study design?

Dr. Paul Ridker:

We were fortunate enough to work with REDUCE-IT investigators, to use their biobank. They had put together, again, it's 8,000 plus patients. I think, it was two thirds secondary prevention, one third primary prevention. And when they received the combination of EPA and DHA, as I said earlier, they had about a 25% reduction in the risk of their primary endpoint, which was cardiovascular death, nonfatal AMI, nonfatal stroke, coronary revascularization, and the like.

What we did is, we basically said, "Okay, since the mechanism was uncertain, why don't we go ahead and measure a series of biomarkers?" Things that a lot of us are interested in, homocysteine, LPLa, oxidized LDL, my own interest in inflammation. We measured, IL-1β, we measured, IL-6, we measured CRP. We measured another molecule, Lp-PLA2, that people have been interested in.

And the hypothesis, of course, was to see what the drug did, as compared to the comparator did. And the findings were interesting to us, in that, to simplify them, the actual icosapent ethyl arm didn't do much to most of those biomarkers, very little change. But the mineral oil comparator arm had some small to modest effects on all those biomarkers, all of which went up again. Now, some of these effects are pretty small, two to 3% for things homocystine, LPLa. Others were moderate, 10 to 20% increases in oxidized LDL, Lp-PLA2. And the inflammatory markers went up about 25%, sometimes, even a little more. So it's complicated.

It's important to point out, that these changes on an absolute scale are relatively small. On a percent scale, they're different. The REDUCE-IT investigators themselves, to their credit, had earlier published that, they saw some increase in LDL cholesterol as well, about 10, 11% in those who had received the mineral oil comparator. So it's not exactly what we thought we were going to find, I guess, is the simplest way to express it.

Dr. Greg Hundley:          

Very nice. And so, describe for us just a little bit more, any differences in men and women, and what about age? Or for example, premenopausal, postmenopausal women.

Dr. Paul Ridker:

No, the effects were quite consistent across all various subgroups. It's a very large study. There were, again, 8,000 patients, lots of blood samples been drawn. And I should again, commend the REDUCE-IT investigators, for allowing us to do this work with them. And again, as I point out, sometimes you find things out that weren't what you expected. And the hard part, I was glad this got tossed over with Dr. Harrington, is sort to figure out well, what's it really mean? Because again, as a clinical trial list, I will say, my instincts are to trust the primary endpoint of the trial. That's what they did. They're going to go out and lower heart attacks and strokes. And then, here we are a couple years later, trying to figure out what the mechanism might be, and just came across some puzzling results.

Dr. Greg Hundley:          

Very nice. Well, next listeners, we're going to turn to the editor that actually processed this manuscript, Dr. Allan Jaffe. Allan, what drew you to this particular article?

Dr. Allan Jaffe:  

Well, I was asked to be a guest editor this week, by the Journal, because of some conflicts that were intrinsic to the editorial board. And since I have an interest in biomarkers, and had for a long time, it made perfect sense for me to become involved. I was particularly interested in this particular area, because I was aware that there were these two trials that had found different endpoints, and that there were some controversy as to what the mechanisms might be by which these effects could occur. And so I was pleased to get involved. And I think it's a compliment to the REDUCE-IT investigators, and to Dr. Ridker, that they were willing to put the data out there so that everybody could see it. And we could then begin to look.

So it was of interest to me. I thought it was important to the field, to get really good reviewers who would be, make sure that the data that would eventually be published was clear, so that readers would understand it. And so that, at the end, we'd be able to at least, come to some conclusions that we could end up having an expert in clinical trials. And I thought about Bob Harrington, right from the beginning, might be able to comment on.

Dr. Greg Hundley:          

Very nice. Well, Bob he's setting you up here nicely, both Paul and Allan, to really help us put these results in perspective with other studies that have been performed in this space. What are your thoughts?

Dr. Robert Harrington:  

So first off, Greg, thanks for having me. And Allan, thanks for inviting me to review and comment on the paper. As both Allan and Paul have indicated, that I've spent the last 30 plus years doing clinical trials of all sizes. Very small, where we try to understand mechanisms, and very large, where what we're trying to understand is clinical outcomes. And I've been intrigued in this field, because of the inconsistency of the data across the field. Where in some trials, Paul had indicated this STRENGTH, there seemed to be no effect of omega-3 fatty acids, and in REDUCE-IT, there was quite a pronounced effect of the test agent. And so, when one sees discordance in a field, one tries to understand, well, why might that be? And so in the editorial, I took the position that, well, what are we trying to do in clinical trials?

And in outcomes trials, we're trying to figure out what matters to patients. Do they live longer? Do they feel better? Do they avoid bad stuff happening to them? Like having to undergo revascularization procedure. So you're trying to do things that are really clinically meaningful, but that doesn't say that you're also not trying to understand mechanism. And as Allan said, there have been some questions raised. And so, trying to understand mechanism in the edit in trials can be quite useful, not just to understand that trial results, but to really form hypothesis for a field going forward. And so, I took the approach of, we learn things from different trials, and sometimes we learn things in the same trial. Meaning that, there's mechanistic work embedded in the large trial. One of the most famous examples of this, in the GUSTO trial 30 years ago, we learned through the mechanistic substudy, that it was rapid reprofusion TIMI-3 establishment of TIMI-3 flow, that really explained the difference between TPA and streptokinase. So I was very intrigued by how we might use these data to explore the results.

And I find the findings fascinating, as Paul said. It is complicated, but it raises a really fundamental issue in clinical trials. There's an assumption in a placebo control trial, that because randomization is allowing you to balance everything, except for the randomized treatment groups, and therefore, that comparison has causal information in it. There's an underlying assumption that's really important. And that is, that the placebo is inert. That it has no biological effect of its own. Well, that assumption was violated here. The placebo is not inert in this clinical trial.

Now, the investigators, I think to their credit, have said, "Well, this is small, probably doesn't matter." And that might be right, but it also may be wrong. And you can't just say, well, it doesn't matter, these are small effects. As Paul said, some of the effects are small, some are medium, some are large. So what explains it? And I made a point in the editorial, you could model all of this. If you get 5% of this, and 10% of this, and 20% of this, you could make some assumptions and say, well, the magnitude of the benefit was so great that it couldn't have been overcome by this. But that's just modeling, and there's uncertainty. So for me, as a trialist, and somebody who really believes in using evidence to guide practice and to guide public policy, I think there's uncertainty here.

It's likely that the treatment effect is not as large as was observed, but how large is it? And how large is important? And how large might we want to consider to put into our practice guidelines? I think all of those open questions, particularly in a field where there is inconsistency across trials, in terms of the observation of the outcome. So my conclusion is, we need more work. We need another trial, if we really want to understand this. And we need to use an inert placebo, to really understand what the contribution was. I'd like nothing better to see that it didn't matter. But I can't say that it doesn't matter because I don't know.

Dr. Greg Hundley:          

Well, listeners, boy, we've got kind of some interest here in that an unexpected result. So Paul, it's nice doing an interview like this listeners, because each speaker sets up the next one. Paul, Bob is saying, well, what should we do next to clarify the results here? So maybe we'll go through each of you, and start with Paul. Just describe for us, what do you think is the next study that we need to perform?

Dr. Paul Ridker:

Well, Greg, it's a really interesting issue. We saw it, as authors, to write as neutral a paper as we could possibly write, and sort of do our academic job and say, here are the data. And I think we did it that way because, we don't really know what the interpretation should be. On the one hand, you have a very big beneficial result, which is great for patients. And there's a prior clinical trial called JELIS, which was open label, the same drug, and also got a large benefit. And we were trying to figure out mechanism. That being said, as Bob pointed out, I think what we stumbled into is some level of uncertainty. And the question is, how uncertain would it be, and does it matter in the big picture?

Allan was interesting, because the Journal asked us to use the word comparator, rather than placebo. Now this was designed as a placebo controlled trial, but our paper uses the word comparator, because of the possibility, that as Bob Harrington points out, it may not be totally inert. So the writing of this was quite carefully done. I think, at the end of the day, my REDUCE-IT colleagues, who I have great respect for, and really worked terribly hard to do the main trial, understandably feel, that the trial would've showed, and I have a lot of sympathy for that, because it's the hard endpoints we should go with.

On the other hand, I have sympathy with the idea that it never hurts to have more data. And if there could be a way to have a second trial, and I might change the population a little bit, maybe I'd do it in true primary prevention. This was one third primary prevention. My colleague, Joanne Manson had done her, she had a trial where they showed some potential benefit in the black populations. Maybe you might over sample some minority groups. But just the pragmatic issues here, make it tough to have a second trial. And so, uncertainty is just part of what we, as physicians, have to learn to live with.

Dr. Greg Hundley:          

Allan, turning to you. What do you think is a next study to perform in this space?

Dr. Allan Jaffe:  

Well, I think what Paul has said is correct. That it would be very hard to generate enthusiasm funding for a large trial. But it might not be nearly as difficult to begin to explore the effects of the mineral oil comparator, versus the active agent, versus perhaps, another potential placebo, and see over time what happens in primary prevention patients, as a way of beginning to put some context around what these results might mean. So for example, it could turn out that, the active agent actually kept the values from rising as they normally would've, and mineral oil had no effect at all. Alternatively, mineral oil may well have been a negative. It had a negative effect. And I think, those are the sorts of questions that could be explored reasonably in the short term, without doing another multimillion dollar randomized trial.

Dr. Greg Hundley:          

And Bob, your thoughts.

Dr. Robert Harrington:  

Well, and I mentioned this in the editorial, Greg. I didn't make my recommendation lightly. I know that these trials are expensive. I know these trials take a great deal of time, a great deal of energy. And I know that the REDUCE-IT investigators worked enormously hard over the years to get this done. So I don't say tritely, "Oh, just do another trial."

But if you think about the magnitude of the public health issue here, there are millions of people to who this kind of therapy might apply globally. And so, shouldn't we be more certain than less certain, if we want to include it, for example, in ACC/AHA guidelines? I would say, the answer to that is yes. And so, I think of it as, okay, let's make some assumptions. Let's assume, that the effect that was observed in JELIS and REDUCE-IT, is the true effect. That's ground truth.

Well, there are different study designs one might think about, from an analytic perspective, using Bayesian statistics, as opposed to frequency statistics. One might think about an intense interim analysis plan, to understand where the data are going, and be able to pull in the prior data for evaluation. I would advise getting a smart group of people together, who spend their lives thinking about trials in the atherosclerotic space, and the REDUCE-IT team is pretty darn good, and say, "How could we do this efficiently?"

I do think, there's enough uncertainty that it would be ethical, from an equipoise perspective, to include high risk patients in a second evaluation, because we do have uncertainty. And if we really want to nail this down, I think we could look at high risk patients with hypertriglyceridemia, and try to use some interesting design issues, and some interesting analytical issues, to try to reduce the sample size, lot of attention in interim analyses, to try to answer the question. I'd like, as I said, nothing better to say, "Oh look, REDUCE-IT was the truth." This next trial is consistent. That'd be, to me, a terrific outcome of this.

On the other hand, if you said to me, "Well, the effect's not 25%, it's more in the 15% range." Well, maybe then we think about how we apply it to our patients a little differently, maybe a little more cautiously. So I don't make the recommendation lightly, as I said, but I do think that there are some conversations that could be had, being respectful of the effort and the expense that goes into these kind of things. To try to answer the question efficiently.

Dr. Greg Hundley:          

Very nice. Well listeners, we want thank Dr. Paul Ridker, from Brigham and Women's Hospital, Dr. Bob Harrington from Stanford University, Dr. Allan Jaffe, from the Mayo Clinic, for bringing us the results of a substudy of the REDUCE-IT trial, that assessed a variety of serum biomarkers, pertaining to systemic inflammation, and highlighting uncertainty around the mechanism regarding the efficacy of icosapent ethyl, that's been used previously for primary or secondary prevention of cardiovascular events.

And next listeners, we are going to move to our second feature discussion and review some data pertaining to microbleeds in the central nervous system, during and after TAVR procedures.

Welcome listeners, to our second feature discussion on this August 2nd. And we are going to explore some of the world of TAVR and its potential complications. And we have with us today, Dr. Eric Van Belle, from Lille, France. And also, Dr. Manos Brilakis, from Minneapolis, Minnesota. Welcome gentlemen.

And Eric, we'll start with you. Can you describe for us a little, the background information that you use to assemble and construct your study, and describe, or list for us, the hypothesis that you wanted to address?

Dr. Eric Van Belle:          

Yes. Thanks a lot for the question. So we knew for many years, that some of the complication of the TAVR procedure relate to the brain. And it has been described by many others, that there were some complication in the brain of patient undergoing TAVR. And there was no previous investigation on potential bleeding or microbleeding in this population.

And on the other side, there are previous publication on, of course, initially chronic microbleeding, in patient with some of, let's say, disease in the brain, but also, a possibility of acute microbleeding. And especially, in some interesting population relating to the TAVR feed, that is patient with valve disease, patient with endocarditis, or patient with assist device.

In this population, microbleedings, acute microbleeding, have been described. And what is interesting, if you look at all these populations, these are population in which the Von Willebrand factor has been impacted and modified, and could be one of the reason of the microbleeding. And one of the similar feature of the patient with aortic stenosis that undergo TAVI, or TAVR, that are patient with indeed also, this kind of Von Willebrand disease.

So if we put everything together that is previously, we only looked at antibody complication in those population, and that Von Willebrand disease, which is present in patient with aortic valve stenosis, could promote a bleeding, in particular, bleeding in the brain. We decided to look at the potential appearance of microbleeding, in patient undergoing TAVR procedure.

Dr. Greg Hundley:          

Very nice. And Eric, can you describe for us, your study design, and who was your study population?

Dr. Eric Van Belle:          

Yes. So basically, the study population is a basic population of patient undergoing TAVI. Just to make sure that one of the difficulty of this study, was to conduct and perform an MRI, a brain MRI, before the procedure, and as short as possible after the procedure, within three days, which is logistically challenging. And also, to make sure that we keep most of the population to undergo the MRI, we had to exclude patient with a high risk of pacemaker, or patient with pacemaker that could not undergo the MRI. But basically, without this, it's just a regular population.

And if we indeed, compare to some of the previous work I was mentioning, about describing the acute MRI, it was important for us to make sure, or to be as sure as we could get, that indeed, this microbleeding, if we observe them, could be related to the procedure. And it means that, the MRI, after the procedure, should be done as short as possible. And also, that an MRI, a baseline MRI, should be performed. Because we know, that in this population, you could have some microbleedings also observed before starting the procedure.

Dr. Greg Hundley:          

So a cohort study design where MRIs are performed before, and then very soon after, TAVR procedures. So Eric, what did you find?

Dr. Eric Van Belle:          

So what we observed, the first thing that we confirmed was indeed, that in this population of that age, that is patient around 80 years old, when we do the baseline MRI, you find in about one out of four patients already, some microbleedings. And this was expected, and it is very similar to what is expected in this kind of population.

But what was indeed more striking, that when we repeated the MRI after three days, we observed another 23% of patient with a new microbleedings that were observed. This is indeed the most important observation. What was also important that, the patient with microbleedings, and the location of the microbleedings, were not related to the cerebellum brain, because indeed we could observe some cerebellum arise in this population, as it is expected. And there was no relation between the two. So it's also, an important observation, suggesting that this microbleeding are not hemorrhagic transformation of cerebellum brain, for instance. And we also observed that, the risk of microbleeding, or the chance to observe the microbleeding, was increased when the procedure was longer. And also, when the total duration of anticoagulation was longer, we also observed that, when the procedure was, when we used protamine at the end of the procedure, the risk of microbleeding was less. And also, importantly, the status of the Von Willebrand factor, and indeed, an alteration of the multimer of Von Willebrand factor, was also associated with the risk of microbleeding in this population.

Dr. Greg Hundley:          

Very nice. So in this cohort of 84 individuals, average age around 80, undergoing TAVR procedure, and about 50/50 men and women, you had several factors. Prior history of bleeding, amount of heparin, absence of protamine, all indicating a higher risk of these microbleeds. So very practical information. Well, Manos, you have many papers come across your desk. What attracted you to this particular paper? And then secondly, how do we put these results really, in the context of maybe other complications that can occur during or after TAVR procedures?

Dr. Emmanouil Brilakis:

Yes, thanks so much, Greg. And also, congratulations Eric, for a wonderful paper, and thanks for sending it to circulation.

I think, with increasing the number of targets, as you know, TAVR now is becoming the dominant mode for treating severe aortic stenosis. Safety is of paramount importance. And even though there's been a lot of progress, we still have issues with the safety of the procedure. So understanding how can make it safer is very important. And I think, what was unique in this paper, again, congratulations for creating this study, is that it opens a new frontier. We worry about stroke. We're all very worried about the stroke, and having the patient have a permanent neurologic damage during the procedure. But there may be more to it than the classic embolic stroke. And I think, this study opens actually, a new frontier with the micro cerebral bleeds.

Now we don't completely understand, despite the study, we don't understand the functional significance from this. And I think, that's one of the areas that will need further research. But I think, trying to understand what causes them, and preventing those microbleeds, would have a very important role in the future, for making TAVR even safer than it is.

Dr. Greg Hundley:          

Very nice. Well, Manos, you really lead us into the kind of the next question. So Eric, what do you see as the next study to be performed in this sphere of research?

Dr. Eric Van Belle:          

Again, to me, and to follow with the comment of Manos, we need to include, I would say, to solve two questions. We have to solve the question of, what could really impact these microbleedings. And what would be the impact of this microbleeding on the long term outcome of this patient? So it's means that we have to set, as part of the studies that we will design, potentially studies on aortic immolation. Or let's say for instance, we could investigate the role of protamine. It has been suggested that protamine could be something interesting, so it could be tested as part of a randomized study. But this means that, as part of such randomized study on the use of protamine, for instance, you would include a last cohort of patients with MRI after the procedure. And also, a long term follow of the neurological complication, which indeed, is the missing part of our current study. We would need to have a much larger cohort of patients, to be able to reconnect the neurological outcome to the MRI outcome, and also to include this.

So let's say, for me, one of the studies we would be interested to perform, is to conduct a study on the use of protamine, which is very simple, randomized, yes or no, and includes brain MRI in this population, as a systematic investigation, which is difficult to conduct. You have to know that it's difficult to do, but it will be very important. And then, to look at the long term neurological outcome.

Dr. Greg Hundley:          

And I see, Eric, you mentioned the long term, because really in the short term, so within six months, you really didn't see any changes in neurological functional outcome or quality of life. So Manos, just coming back to you. What do you see is the next study that should be performed in this space?

Dr. Emmanouil Brilakis:

Yeah, I agree actually, with Eric. The next step is, this was an 80 patient study. Right? It's a very small preliminary data, all that opens a new system for evaluation, we're still a very small number of patients. So having a larger number of patients, I think for me, the key thing is to understand the connection. Does this actually cause neurologic symptoms? What does it mean having a microbleed? I think right now, we're still confused on the study. There was not really much impact on the neurologic status of the patient.

So for me, the number one thing is, to understand how it impacts the patient's quality of life, the neurologic status. Perhaps more sensitive studies, neurocognitive studies, to understand exactly how it impacts. And then after doing that, I agree with Eric, if this is a bad, something really bad, then we can find different ways to prevent them from happening. Protamine is one of them during the procedure time, and not be a very feasible one. Or it could be interesting to see if different valves, for example, have different propensity for causing those microbleeds.

Dr. Greg Hundley:

Very nice. Well listeners, we want to thank Dr. Eric Van Belle, from Lille, France, and also, our own associate editor, Dr. Manos Brilakis, from Minneapolis, Minnesota for bringing this very important study, highlighting that one out of four patients undergoing TAVR has cerebral microbleeds before the procedure. And then, after the procedure, one in four patients develop new cerebral microbleeds. And then, procedural and antithrombotic management, and persistence of acquired Von Willebrand factor defects, were associated with the occurrence of these new cerebral microbleeds.

Well, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week On the Run.

Dr. Greg Hundley:          

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors, or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Laura Galian-Gay and Associate Editor Joshua Beckman as they discuss the article "Atorvastatin Effect on Aortic Dilatation and Valvular Calcification Progression in Bicuspid Aortic Valve (BICATOR): A Randomized Clinical Trial."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240614.566029

This week, please join authors Mikhail Kosiborod and Christian Schulze and Editorialist Stefan Anker as they discuss the original articles "Effects of Empagliflozin on Symptoms, Physical Limitations and Quality of Life in Patients Hospitalized for Acute Heart Failure: Results From the EMPULSE Trial" and "Effects of Early Empagliflozin Initiation on Diuresis and Kidney Function in Patients With Acute Decompensated Heart Failure (EMPAG-HF)" and the editorial "SGLT2 Inhibitors: From Antihyperglycemic Agents to All-Around Heart Failure Therapy."

Dr. Carolyn Lam:            

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:          

And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:            

I'm so excited about the feature discussion this week. It is a paired feature along with their editorial and it's all focused on SGLT2 inhibitors. The first, results from the EMPULSE trial, Effects of Empagliflozin on Symptoms, Physical Limitations and Quality of Life in Patients Hospitalized for Acute Heart Failure; and the second, the EMPAG-heart failure trial, The Effects of Early Empagliflozin Initiation on Diuresis and Kidney Function in Patients with Acute Heart Failure. Incredibly important topics, incredibly important discussion. Wait up for it. We're just going to tell you a little bit more about two other original papers in today's issue, and I'm going to go first, Greg. Is that okay?

Dr. Greg Hundley:          

You bet.

Dr. Carolyn Lam:            

Now, really interesting topic here. We have strong evidence supporting the effective blood pressure and cardiovascular disease risk lowering properties of healthy diet such as the DASH diet, Mediterranean diet, and so on and so on. But what about the diet consumed by a fifth of the entire world's population? The Chinese cuisine. Interestingly, today's paper addresses just that. This is from authors, Dr. Wu, from Peking University Clinical Research Institute and colleagues who performed a multicenter patient and outcome assessor blind randomized feeding trial among 265 participants with baseline systolic blood pressure of 130 to 159 in four major Chinese cuisines.

And these are the Shandong, Huaiyang, Cantonese, and Szechuan cuisines, and here's how they did it. After a seven day run in period on a control diet matching the usual local diets, participants were randomized to continue with the control diet or the cuisine based Chinese heart healthy diet for another 28 days. The primary outcome was systolic blood pressure. The study developed the first heart healthy Chinese diet that fits Chinese food culture and emphasizes its palatability by involving master shifts in developing the recipes.

Dr. Greg Hundley:          

Oh wow. Carolyn, this is really interesting, especially one fifth of the world's population in studying a heart healthy diet. So did it work? I can't wait to hear the results.

Dr. Carolyn Lam:            

Well, the change in systolic and diastolic blood pressure from baseline to the end of the study in the control group was five millimeters mercury and 2.8 millimeters mercury reduction, respectively. The net difference of change between the two groups in systolic and diastolic blood pressure were a reduction of 10 and almost four millimeters mercury, respectively. The effect size did not differ among cuisines, and so in summary, with a patient and assessor blind randomized feeding trial, this study really demonstrated that the blood pressure lowering effect of the Chinese heart health diet could indeed be substantial, and importantly, be compatible with medications while palatable and affordable in Chinese adults with high blood pressure, and so these results support the idea that food is medicine and will give many patients with high blood pressure the confidence to adopt heart healthy diets in their lifestyle treatment.

Dr. Greg Hundley:          

Wow, Carolyn, that is really an interesting article. So many of these articles today could all be features in and of themselves. That was just outstanding. Well, my next paper comes to us from the world of preclinical science, and it's from Dr. Sean Wu from Stanford University School of Medicine. So Carolyn, immune checkpoint inhibitors are monoclonal antibodies that are used to activate the immune system against tumor cells. Now, despite their therapeutic benefits, immune checkpoint inhibitors have the potential to cause immune mediated adverse events such as myocarditis, a rare but serious side effect with up to 50% mortality in affected patients. Now histologically, patients with immune checkpoint inhibitor of myocarditis have lymphocytic infiltrates in the heart implicating T-cell mediated mechanisms. However, the precise pathologic immune subsets and molecular changes in immune checkpoint inhibitor myocarditis are unknown.

Dr. Carolyn Lam:            

Wow. So insights into the etiology of these immune checkpoint associated myocarditis cases must be very important. So what did they find?

Dr. Greg Hundley:          

Right, Carolyn? So clonal cytotoxic, TEMRA CD8+ cells were found to be significantly increased in the blood of patients with immune checkpoint inhibitor myocarditis corresponding with an analogous increase in effector cytotoxic CD8+ cells in the blood and hearts of PD-1 deficient mice with myocarditis. These expanded effector CD8+ cells had unique transcriptional changes, including upregulation of the chemokines CCL5, CCL4, and CCL4L2, and they may serve as attractive diagnostic therapeutic targets for reducing life threatening cardiac immune related adverse events in immune checkpoint inhibitor treated cancer patients, and Carolyn, just like so many of our articles, there's a very nice accompanying editorial by Professor Gianluigi Condorelli that also offers an update on current research pertaining to non-systemic steroid therapy to treat immune mediated myocarditis. Well, Carolyn, how about we jump to some of the other articles in the issue?

Dr. Carolyn Lam:            

Oh, you bet, Greg. There's an exchange of letters between Drs. Madias and Knops regarding the article “Efficacy and Safety of Appropriate Shocks and Antitachycardia Pacing in Transvenous and Subcutaneous Implantable Defibrillators: The Analysis of All Appropriate Therapy in the PRAETORIAN Trial.”

Dr. Greg Hundley:          

And also in the mail bag, Professor Mark has a Research Letter entitled “Effect of Empagliflozin on Kidney Biochemical and Imaging Outcomes in Patients with Type 2 Diabetes, or Prediabetes, and Heart Failure with Reduced Ejection Fraction, The SUGAR-DM-HF Study,” and our own Tracy Hampton has several synopses from articles published elsewhere in our piece on cardiovascular news. Well, how about we get onto that feature forum discussion, two papers, two editorialists. I can't wait.

Dr. Carolyn Lam:            

Me too. Let's go, Greg.

Dr. Greg Hundley:          

Welcome, listeners to this July 26th feature forum discussion. So remember, listeners, for forum discussions, we have several manuscripts that focus on a singular topic and we bring together the authors, our associate editors, and also an editorialist, and today, I want to introduce, we have with us Dr. Mikhail Kosiborod from Mid America Heart Institute in Kansas City, Missouri, Dr. Christian Shults from University Hospital Jena in Germany, Stefan Anker from Charité in Berlin, Germany, and our Associate Editors, Brendan Everett from Brigham and Women's Hospital in Boston, Massachusetts, and Justin Grodin from University of Texas Southwestern Medical Center in Dallas, Texas. Welcome, gentleman, and we'll start with you, Mikhail. Could you describe for us the background information that went into the preparation of your study and what was the hypothesis that you wanted to address?

Dr. Mikhail Kosiborod:  

Well, thanks very much, Greg. The background for the study, which was the secondary analysis of the EMPULSE trial was patients that are hospitalized with acute decompensated heart failure represent a very high risk group. We know that they have high risk of death and hospitalizations, and we also know that they have very poor health status that's very high burden of symptoms, physical limitations, and poor quality of life, and so addressing those treatment goals, trying to reduce the risk of clinical events like death and hospitalizations and improve the symptoms and physical limitations in this patient population are very important treatment goals.

Now we previously demonstrated in the main results of the EMPULSE trials that using empagliflozin initiating empagliflozin SGLT2 inhibitor in this patient population as compared with placebo provided a significant total clinical benefit, which was a composite of total death, repeat hospitalizations for heart failure, or a change in a Kansas City cardiomyopathy questionnaire, which is a kind of a gold standard measure of patient's health status. What we tried to do in a much more granular fashion in this study is to understand the effects of empagliflozin as compared with placebo on this very important outcome, the Kansas City cardiomyopathy questionnaire, and we actually evaluate all of the key domains and composite symptoms, physical limitations, as well as quality of life.

Dr. Greg Hundley:          

Very nice, and Mikhail, can you describe for us what study population specifically, and then what was your study design?

Dr. Mikhail Kosiborod:  

Well, this was a population of patients that were hospitalized with heart failure and that EMPULSE was unique in its design because first of all, previous SGLT2 inhibitor trials mostly focused on patients with chronic heart failures that were in an outpatient setting, including prior trials of empagliflozin, and EMPULSE really focused on acutely hospitalized patient population, but it included patients regardless of ejection fraction. So as they were hospitalized with decompensated heart failure and reduced or preserved ejection fraction. They were enrolled regardless of if they had type 2 diabetes, they were enrolled essentially, regardless of kidney function, only patients with EGFR of less than 20 were excluded, and also importantly, was this study and a unique feature of the study in particular was that we enrolled patients whether they had acute de novo heart failure.

That means that was a new diagnosis of heart failure that was bad enough for them to be hospitalized or worsening chronic heart failure requiring hospitalization. So it was really an all-comer trial for patients acutely hospitalized for heart failure. So we had just over 500 patients and they were randomized in the hospital. After a brief period of stabilization, we use empagliflozin, 10 milligrams daily or placebo and treated for 90 days, and the primary outcome at 90 days was a total clinical benefit that I described that was a composite, hierarchical composite of total death hospitalizations, repeat hospitalizations for heart failure and changing KCCQ. In this study, again, we focused predominantly on KCCQ, trying to understand the effects on health status, again, symptoms, physical limitations, and quality of life.

Dr. Greg Hundley:          

Excellent. And Mikhail, what were your study results?

Dr. Mikhail Kosiborod:  

Well, what we observed, a couple of things. One is we first examined the effects of empagliflozin on the primary endpoint across the range of KCCQ and baseline, and what we found was that regardless of the degree of symptomatic impairment and baseline, empagliflozin was consistent in providing them total clinical benefits that I described previously, and then kind of shifting to what I think is the most interesting findings, the effects of empagliflozin versus placebo on KCCQ, what we found was that as you would imagine in this population of patients that were acutely hospitalized with heart failures, that had very poor health status, very low KCCQ at baseline, and within the first 90 days, which was observation period, both groups of patients had substantial improvements in KCCQs. As one would expect after acutely decompensated episode of heart failure and treatment in a hospital, everyone got better.

But patients treated with empagliflozin had significantly greater improvement in KCCQs than those that were treated with placebo, and that was first of all, a very substantial difference between the two groups. It was more than five points in favor of empagliflozin already at 15 days and was highly statistically significant, and it was maintained throughout the 90 day treatment period. So the fact that we saw both a clinical meaningful and statistically significant improvement in just 15 days, I think is a very important clinical message, and then finally, I guess what I will mention is these benefits of empagliflozin while main outcome we looked at was KCCQ total symptoms, we're focusing on the symptoms, but it was consistent when we looked at physical limitations as well as quality of life. So really, all key domains of KCCQ were impacted in a similar way.

Dr. Greg Hundley:          

Very nice. So in acute heart failure, marked symptomatic improvement after the administration of the SGLT2 inhibitor empagliflozin at 10 milligrams per day. Well, now listeners, we're going to turn to our associate editor, Dr. Brendan Everett, and Brendan, again, you have many papers come across your desk. What attracted you to this particular manuscript?

Dr. Brendan Everett:     

Well, thanks, Greg, and I think this manuscript caught my eye because of the importance of the clinical question, and Mikhail outlined why I think that was really relevant. So we understand that this class of medications or SGLT2 inhibitors have important effects on outcomes like re-hospitalization in patients with heart failure, and what was particularly striking about this paper is that it took patients rather than those with chronic heart failure, but as Mikhail mentioned, enrolled a patient population that was actually in the hospital, and I think this was an important frontier for this particular question about when to start the SGLT2 inhibitor and what kind of benefits there might be. Furthermore, I think the fact that they did not select the population based on ejection fraction was particularly striking, and of course, I think is remarkable, but now old news, they did not select on the presence or absence of diabetes as well.

And so those three components really attracted me to the paper. I also think the outcome is one that really is valuable and worth exploring, and specifically, I'm talking about how patients feel on the medication after a hospitalization for heart failure. Appropriately, we focused on re-hospitalization for heart failure and cardiovascular death in prior trials in this space, and I think we need to embellish those findings or further deepen those findings with a perspective on how patients actually feel when they get the medication, and of course, it goes without saying that what's particularly important here also is that it was a randomized placebo controlled trial, and so the results have some element of internal validity that I think is really important. So those were the things, Greg, that really attracted my attention as I read the paper for the first time.

Dr. Greg Hundley:          

Thank you so much, Brendan. Well, listeners, we've got a second paper today and we're next going to hear from Dr. Christian Shults, and he also is focusing on really another aspect of the administration of empagliflozin in patients with acute heart failure and that pertains to the renal function of the patients. So Christian, could you describe for us the background pertaining to your study and what was the hypothesis that you were intending to address?

Dr. Christian Schulze:    

Thanks, Greg. Well, it's great to introduce all study here in this running. So our study impacted those in acute decompensated heart failure. The impact HF trial was a study based on the hypothesis that we wanted to test, whether empagliflozin has effects in acute decompensated heart failure, and we focused on the patient population that was not addressed in EMPULSE, patients that came to the ER and needed to be treated right away, and we wanted to know and this was our main hypothesis, but are the diuretic and [inaudible 00:17:11] effects of the SGLT2 inhibitor on this case, empagliflozin, actually had an impact on diuretic regimens and kidney functions since this is one of the main end points that limits treatment, and also is one of the outcomes of patients with acute decompensated heart failure in the hospital.

Dr. Greg Hundley:          

Very nice. And so Christian, what study design did you implement and who was included in your study population?

Dr. Christian Schulze:    

So we also used the randomized two arm study design. We included patients with acute decompensated heart failure independent of left ventricular ejection fraction. Patients needed to have an NT-proBNP of more than 500. The average NT-proBNP in fact was 4,300 in our entire patient population, and we included patients within 12 hours of presentation. So many of these patients have been recruited in the ER, they presented two hour cardiology heart failure service, and then were immediately randomized to the trial in the two arms, and we tested not 10 milligrams of empagliflozin. We actually tested 25 milligrams of empagliflozin based on in-house data that 25 milligrams potentially had a stronger diuretic effect compared to 10 milligrams.

Dr. Greg Hundley:          

And what did you find?

Dr. Christian Schulze:    

So we followed patients for five days. It was a relatively short period of time. It was designed to address the in-house phase of patients with acute decompensated heart failure. The mean duration of stay was 6.3 days in the hospital so this was exactly the time that we wanted to test. We had a 30 day endpoint for safety issues, and what we could see is that patients on 25 milligrams on empagliflozin on top of standard diuretic regimens and medical care had 25% higher diuretic outputs compared to patients in the placebo group. We also found no differences in markers of renal injury dysfunction, and could in fact confirm that after 30 days, patients in the empagliflozin group had a better EGFR compared to patients in the placebo group. On top, we saw a more rapid decrease in body weight and also a more profound decrease in NT-proBNT values.

Dr. Greg Hundley:          

And Christian, just for our listeners to put a little bit of this in perspective, what was the range of serum creatinine for the patients that were enrolled in your study?

Dr. Christian Schulze:    

So the main EGFR in the entire population was around 60 and the creatinine values were around 107 on average in the entire cohort. So this is a very typical population. We had around 30% of the population with de Novo heart failure, around 20 to 30% of the population was pre-treated for preexisting heart failure. So very typical population of patients with heart failure presenting to the emergency room.

Dr. Greg Hundley:          

And did you have any kind of lower level EGFR cutoff, I mean, for enrollment into this study?

Dr. Christian Schulze:    

So when we designed the trial, we actually still had the sub classification of diabetes or impaired glucose or homeostasis as an inclusion criteria. We dropped it before we started the trial because the data came out that this is actually, in fact, not a critical issue for patients with heart failure. So diabetes was not a subgroup in our trial and the lower limit of EGFR was actually a thoroughly defined protocol.

Dr. Greg Hundley:          

Very nice. Well, listeners, now we're going to turn to our second associate editor, Dr. Justin Grodin from University of Texas Southwestern Medical Center in Dallas, Texas, and Justin, similar to Brendan, and you see many papers come across your desk and so what attracted you to this particular paper by Christian and his colleagues?

Dr. Justin Grodin:           

Well, Greg, I think first and foremost, and I think very similar to Brendan, but I think what's always striking is if I may just take a step back, decompensated heart failure in the United States is the number one cause for hospitalization among Medicare beneficiaries. So I think really, the brunt and really the truly public health message of the disease is very important in the applicability, and even though that decompensated heart failures is one of the most common things that we ever encounter when we practice, internists, cardiologists, et cetera, we have very, very little clinical trial guidance that tells us how to decongest individuals when they're hospitalized with swelling and heart failure and a lot of these individuals can be quite ill, and we have some clinical trial data, but largely, we have a lot of negative studies or inconclusive studies in this space.

So certainly, what drew me to this trial was definitely that context, and obviously, based on the mechanistic data with SGLT2 inhibitors, I think one of the natural questions, which Christian addresses, is that we know that up front, they do augment natriuresis. So I think it's very compelling to marry those two together because this is what many of us that use these medications regularly have been asking is whether or not they would have some efficacy in that regard, and then another thing that caught my eye and me as a cardiorenal investigator was, just as Christian highlighted, was we have a clinical trial that randomly assigned individuals, really that were ill and many of whom were not stabilized within 12 hours of presentation, and we're talking about patients that are coming into the hospital at all times during the day in and I think that's very remarkable that we have something with standard...

We have a study with standardized assessments where we're really trying to ask a very practical, pragmatic question, which is do these therapies lower the sodium balance in individuals with decompensated heart failure, and I think what's important is largely, we've got a lot of medications that supplement loop diuretics, which are the class of drugs that the majority of us use, and we have a lot of other therapies that we use that really have very little data or poor data that guide us such as thiazide diuretics, carbonic and hydrase inhibitors, mineralocorticoid receptor antagonists, and so here, we have a clinical trial that asks a question that's on many people's minds.

And then we do have very compelling, at least short term pragmatic and mechanistic data that does tell us that these individuals do have a greater natriuretic effect when empagliflozin is used as an adjunct to standardized loop diuretic therapy. So it's a very practical clinical question, and I think what's very important, and we could debate probably all day about the implications of GFR change and kidney function change while we're decongesting somebody with diuretics, but I think what's reassuring to all the clinicians is we really didn't see an effect on kidney function despite a greater natriuretic effect or enhanced diuretic effect, if you will, with the use of empagliflozin.

Dr. Greg Hundley:          

Very nice. Well, thank you, Justin. Listeners, now we have an editorialist and as you know, editorialists really help us put the scientific presentation of an original manuscript into the perspective of really the global theme of a topic, and we have Stefan Anker from Berlin, and Stefan, can you describe for us how do we put these two manuscripts and results that we've heard about really in the context now of moving forward with the use of SGLT2 inhibitors in the management of patients with acute decompensated heart failure?

Dr. Stefan Anker:           

Thank you so much. Really, I think these two papers, on the one hand, enhance our certainty about early use, and on the other hand, possibly show us that there might be even more to achieve by, on the one hand, moving even earlier with the application of SGLT2 inhibitors or possibly consider the higher dose. Now let's take one step back. These drugs were developed in type two diabetes and the first successful trial was the [inaudible 00:25:42] outcome trial. Many people have forgotten that this trial tested two doses and not only one, the 10 and the 25 milligram dose, and of course, with the success for improving kidney outcomes and heart failure hospitalization outcomes, we move forward into these two specialist areas, on the one hand, broadening it to the non-diabetic communities, but on the other end, narrowing it by focusing on the 10 milligram dose regardless of whether there is [inaudible 00:26:12].

And we basically now learn A, to use these drugs even earlier than we did in the big trials and we can now be sure to start their use in the hospital, and if you take the average change in quality of life results seen, you actually get a better result for the patient on quality of life when you start earlier than when you start late in the ambulatory studies where basically, in the chronic setting, maybe you have one and a half to two points difference. Here, you now have four and a half points in the study shown by Mikhail, and of course, it's also good to know that you can start this in any type of patient, regardless of their quality of life. The impact study from Christian, they basically moved it now even earlier, moving into the hospital space is possible based on EMPULSE. Moving it into the acute admission space is at least a consideration now based on what Christian here has shown.

And he is actually addressing the one question I hear very often in my presentations about SGLT2 inhibitors, what about this 25 milligram dose? Is there a place for this in cardiology as well, and a possible place is shown here, not only that this is a safe thing to do, but also you get urinary output. Of course, we may in the future, want to see this compared, directly compared to the 10 milligram dose, but of course, the world is not created in one day, but needs more than one and so really, I think these two studies, on the one hand, address an important issue, when to start using them. On the other hand, show us a little bit of a glimpse to the future.

Dr. Greg Hundley:          

Very nice, Stefan, and listeners, we get to take advantage of having these authors, editors, and editorialists together and ask them what they see as the next study to be performed in this sort of sphere of research. So Mikhail, we'll start with you. In 30 seconds or less, what do you see as the next study to be performed in this arena of research?

Dr. Mikhail Kosiborod:  

I think, Greg, what we've learned recently, including from the EMPULSE trial, we have this population of patients in a hospital with heart failure's a huge issue as Justin mentioned, and until recently, we had very little [inaudible 00:28:31] for them beyond the usual kind of decongestion with loop diuretics and trying to make them feel better, but you look at outcome data. It really was a dearth of effective therapies that have meaningful impact on important outcomes. Now that's changing, SGLT2 inhibitors is one example. There are some other recent examples in this patient population, like a firm HF and iron deficient patients with heart failure.

But the bottom line is it's no longer kind of a desert, if you will, of positive trials. We now have something we can do and I think what this proves is that we need to actually invest more, both in terms of resources and time to really do what we we're being able to do in other areas of heart failure and those patients with chronic, half and half where we can start developing pillars of therapy that can actually truly improve outcomes with this patient population and there is a lot going on that makes me optimistic that's going to be the case in the coming years.

Dr. Greg Hundley:          

Very nice. And Brendan?

Dr. Brendan Everett:     

Well, I think both trials mentioned today really pushed our understanding of this population forward. I think the biggest clinical question that I face when I'm caring for these patients is that we have four, at least, guideline directed therapies, right? We have beta blockers, we have ARBs, ACE inhibitors and ARNIs. We have mineral receptor antagonists and we have SGLT2 inhibitors. So which do we use in what order and how do we start them, and what kind of parameters do we use to guide us if we're limited either by renal function or by blood pressure or by some other factor.

And we often, if not always, have one of those constraints that we're dealing with and so I would say the next step for me is trying to sort out which of these therapies and what order ought to be our highest priority for patients with acute decompensated heart failure as we move quickly from the acute decongestion stage towards discharge and a chronic therapy that will then be followed as an outpatient over the ensuing days and months.

Dr. Greg Hundley:          

Very nice. And Christian.

Dr. Christian Schulze:    

Thank you again, and Brandon pointed out very nicely. I mean, we have good evidence now for chronic heart failure treatment. We have the four columns of heart failure medical therapy. Questions that remain open is what do we do with all these patients that are now guideline medicated, come to the hospital with an acute decompensation? Should we carry on with the medication? Should we terminate and in particular, should be carry on with full dose, 50% dose of SGLT2 inhibitors, and the next question is, what dose should we use, in fact, for SGLT2 inhibitors? Is it in group effects or is sotagliflozin comparable to empagliflozin, and then is there a role for a step by scheme that we initially have in high dose therapy that we then downgrade to 10 milligrams on the chronic heart failure treatments, and then of course, quality of life is very important. We should ask this question also in this patient population that is early on treated, do we see benefits that carry on in the outpatient setting and do we see an effect of early treatment on long term benefits?

Dr. Greg Hundley:          

Justin?

Dr. Justin Grodin:           

Well, I would have to agree with all of my colleagues here on this call. I think all have raised really good points, but I think one very simple, and I'll echo some of Brendan's statements, but one very simple question is we know that when we decongest people and initiate a negative salt balance in the hospital for decompensated heart failure, we cause neurohormonal activation and there are a lot of downstream untoward effects from chronic decongestive therapies, and I think one of the more compelling things is we still yet have defined what is the best way to decongest individuals with swelling or volume overload in the hospital. Here, we have compelling studies with SGLT2 inhibitors for quality of life and really, the way patients feel.

And this is really what's important to them, and then something very pragmatic to clinicians and let's make people pee more, but I think one of the compelling questions, and I don't know if it will be answered, is we have a lot of choices for supplemental therapies and different diuretic strategies when patients come in the hospital for decompensated heart failure, and I do think that these studies do move the needle with SGLT2 inhibitors. I think that's abundantly clear, but we still don't know what is the best way to dry out my patient or make my patient pee so that they feel better, but I do think that these studies do at least set the stage that there's some compelling advantages to SGLT2 inhibitors.

Dr. Greg Hundley:          

And then lastly, Stefan.

Dr. Stefan Anker:           

Thank you. Besides the detailed points mentioned by many, and Christian, totally support 25 versus 10 milligram, how long 25 milligram, if at all in the future. Besides this, I'm interested in the big picture question. So what about the post myocardial infarct congestion/heart failure situation, and there will be two trials in the next 18 to 24 months that report on this, and my pet kind of area is actually to treat heart failure where nobody thinks it is heart failure, and what I mean is for instance, advanced cancer patients, cardiac wasting cardiomyopathy. So the heart failure in sick cancer patients, and indeed, we are planning to do exactly that now in a study focusing on hospice care patients to really improve the quality of life, the very thing focus here on the EMPULSE trial.

Dr. Greg Hundley:          

Well, listeners, we want to thank our authors, Dr. Mikhail Kosiborod from Mid America Heart Institute in University of Missouri, and Christian Shults from the University Hospital in Jena, Germany. Also, our associate editors, Dr. Brendan Everett from Brigham and Women's Hospital in Boston, and Dr. Justin Grodin from University of Texas Southwestern in Dallas, Texas, and also, our editorialist, Dr. Stefan Anker from Charité in Berlin, Germany for bringing us these two manuscripts pertaining to two randomized clinical trials regarding the administration of the SGLT2 inhibitor, empagliflozin in acute heart failure, demonstrating first, marked improvement in heart failure symptoms and health related quality of life.

And second, in those with estimated GFRs greater than 30 mls per minute, an augmentation of natriuresis in the setting of the co-administration of diuretics without deterioration in renal function. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join Associate Editors Mercedes Carnethon and Karol Watson, as well as Guest Editor Fatima Rodriguez as they present the 2nd annual Disparities Issue. Then join Rishi Wadhera and Ashley Kyalwazi as they discuss their article "Disparities in Cardiovascular Mortality Between Black and White Adults in the United States, 1999 to 2019."

Dr. Mercedes Carnethon:

Well, good day listeners. I'm Mercedes Carnethon, and I'm joined by my fellow editors, Karol Watson, and Fatima Rodriguez, Associate Editor and Guest Editor for Circulation. And we'd like to welcome you to Circulation on the Run, for our second annual disparities issue. We have a lot of articles to discuss today, many of which we'll summarize, but we encourage you to access the issue and read the articles. First off, Fatima, I believe you have a paper to discuss.

Dr. Fatima Rodriguez:

Sure thing, Merci. My first paper is a thought provoking article by Nilay Shah, and co-authors from Northwestern University, that examine factors associated with the racial gap in premature cardiovascular disease.

Dr. Fatima Rodriguez:

This study used data from a well-known cardiac cohort, that aims to identify factors that begin in young adulthood and predict the development of future coronary artery risk. The objective of this study was to examine the relative contributions of clinical versus social factors, in explaining the persistent black/white gap in premature cardiovascular disease. After following around 5,000 black and white study participants for a median of 34 years, black men and women had a higher risk of premature cardiovascular disease. After controlling for multi-level individual and neighborhood level factors measured in young adulthood, the racial differences in premature cardiovascular disease were attenuated.

Dr. Fatima Rodriguez:

The authors found that the greater contributors to this racial disparity were not only clinical factors, but also neighborhood and socioeconomic factors. The relative explanatory power of each of these factors varied by men and women. This is really noteworthy, since we spent so much of our time in clinical medicine, focusing on identifying and managing traditional risk factors. But in reality, these structural factors and inequities are critically important to address, and contribute to differences in clinical risk factors downstream.

Dr. Mercedes Carnethon:

Thank you so much, Fatima. That was a really excellent summary. And now, I'm turning to you, Karol. I'd love to hear what you're going to be talking about today.

Dr. Karol Watson:

I'd like to discuss the paper, Association of Neighborhood Level Material Deprivation with Atrial Fibrillation Care in a Single-Payer Healthcare System Population Based Cohort Study. This is by Dr. Abdel-Qadir and colleagues.

Dr. Karol Watson:

So in this study, the author sought to determine whether there was an association between neighborhood material deprivation, by that we mean, inability to attain the basic needs of life and clinical outcomes, in individuals with atrial fibrillation. The kicker here is, they did this in an area with universal healthcare. So they wanted to see, if you took away the differences between the ability to see a physician or get your drugs paid for, if you would see any disparities.

Dr. Karol Watson:

So they performed a population based cohort study, individuals over the age of 66 years of age with atrial fibrillation, in the Canadian province of Ontario. They have universal healthcare there, and full drug coverage for anyone over 65. The primary exposure was neighborhood material deprivation. That's a metric used to estimate the inability to attain basic material needs, like healthy foods, safe housing. Neighborhoods were categorized by quintile, from the least deprived, quintile one, to the most deprived, quintile five. They find that, among about 350,000 individuals with atrial fibrillation, their mean age was 79, and about half of them were women. Those in the most deprived neighborhoods, quintile five, had a higher prevalence of cardiovascular risk factors and non-cardiovascular work comorbidity, relative to those who were in the least deprived areas.

Dr. Karol Watson:

Even after adjusting for all the confounders, they found that those in the most deprived neighborhoods had higher hazards of death, stroke, heart failure, and bleeding, relative to those in the least deprived neighborhoods. They also found that, despite having universal healthcare and drug coverage, those in the most deprived neighborhoods were less likely to visit a cardiologist, less likely to receive rhythm control intervention, such as ablation, and have worse outcomes.

Dr. Karol Watson:

And then, the accompanying editorial by Utibe Essien, he reminds us that intervening only on traditional markers of access, like health insurance and drug costs, may not be sufficient to achieve health equity. We have to address all of the structural needs that make people unable to get good help. Further, he points out that, the association between atrial fibrillation and neighborhood deprivation is very likely true with other cardiovascular conditions, as well.

Dr. Karol Watson:

So, Merci and Fatima, this just reminds us again, that addressing all the social determinants of health are necessary to achieve the best health outcomes.

Dr. Mercedes Carnethon:

Thanks so much, Karol. I really appreciate that summary of that important piece, focusing on a different domain of disparity. My first paper is an excellent piece, led by one of my favorite other associate editors at Circulation, Dr. Wendy Post, from Johns Hopkins University. And I see a familiar name on here. That's yours, Karol. You two are joined by an all-star list of authors, to describe race and ethnic differences in all-cause in cardiovascular mortality, in the multi-ethnic study of atherosclerosis.

Dr. Mercedes Carnethon:

MESA is a longitudinal cohort study that launched in 2000, and recruited just over 6,800 adults who identified as black, white, Hispanic, and Chinese. While the study participants were initially free from cardiovascular disease, over an average of 16 years of follow up, 364 participants died from cardiovascular disease. There are a number of novel findings in this paper that led our editor-in-chief to select it as his pick of the issue.

Dr. Mercedes Carnethon:

The finding that really stands out to me is, how much of an influence the social determinants of health had on black versus white disparities in cardiovascular mortality. In fact, after adjusting for socioeconomic status, the disparities were nearly eliminated. Other critically important findings are that, the oft described Hispanic paradox of lower cardiovascular mortality in Hispanics, as compared with white adults, was demonstrated in this population. And finally, we have longitudinal data on Asians living in the United States. Asian participants in MESA had similar rates of cardiovascular disease mortality as their white counterparts. There's so much to learn in this well designed cohort study, and so many hypotheses about how social determinants and structural racism influence the disparities that we see.

Dr. Mercedes Carnethon:

So Fatima, I'd like to turn to you next. What else do you have to share?

Dr. Fatima Rodriguez:

Thank you, Merci. My second paper is a research letter for my home institution of Stanford University, led by my colleague, Dr. Shoa Clarke, discussing how race and ethnicity stratification for polygenic risk course, may mask disparities among Hispanic individuals.

Dr. Fatima Rodriguez:

This study used data from the Million Veteran Program, to determine how self-identified race and ethnicity impact the performance of polygenic risk scores in predicting coronary artery disease.

Dr. Fatima Rodriguez:

The investigators found, that the current polygenic risk scores predict coronary artery disease similarly well in Hispanic and non-Hispanic white individuals. However, what I found most interesting, is that there was so much more heterogeneity among Hispanic individuals as measured by K-Means clustering, than among non-Hispanic white individuals. And this study really confirms that there is much more heterogeneity within populations than between populations. And this is particularly true as we think of the extreme diversity of Hispanic populations. Lumping Hispanic populations into one category, may mask important differences in cardiovascular risk prediction outcomes, and even the notions of the Hispanic paradox that you just discussed, Merci.

Dr. Mercedes Carnethon:

I appreciate you bringing that up again, because there are so many different nuances to the observations that we see in these studies. But I'll keep moving, because we have an embarrassment of riches in this wonderful issue. So Karol I'll turn back to you.

Dr. Karol Watson:

Thanks, Merci. The next paper I'd like to discuss, is an On My Mind piece by Peter Liu and colleagues, and they entitle it, Achieving Health Equities in the Indigenous Peoples of Canada, Learnings Adaptable for Diverse Populations. Now the author's note that, lessons learned about addressing health disparities from indigenous peoples in Canada, can offer a lot of new lessons for other populations where there are similar disparities. They begin by offering historical perspective, and they say that, most of the health to disparities for the indigenous populations originate from early colonization, in dismantling of the sociocultural economic educational and health foundations, the indigenous communities had historically.

Dr. Karol Watson:

It's true that, that is true in a number of different countries. This is data from Canada, but we can see similar things in the United States. With the recognition of the historical and ongoing social health inequities, the Canadian government initiated what they call, the Truth and Reconciliation Commission, to recommend a path towards reconciliation, to create best practices for engaging indigenous populations.

Dr. Karol Watson:

For instance, in Canada, any health research or implementation program, requires the direct engagement of indigenous communities and their elders. They have to try to develop culturally safe environment, including what they say, quote unquote, anti-racism and cultural safety education for all, both indigenous and non-indigenous populations. They want to really respect community values, customs and traditions, including the access to traditional foods, and healing practices, and the support from elders. So they really are making it a very important point, that cultural sensitivity is absolutely critical to engaging these populations. You want to jointly collect data whenever available, to track progress and outcomes. And they offer many examples of successful programs developed using these principles, such as the Diabetes and My Nation program, in British Columbia, or the mobile diabetic telehealth clinic.

Dr. Karol Watson:

They offer discussion of future initiatives as well, that can help other communities in Canada. Such as, there's an initiative addressing hypertension in the Chinese population in Canada.

Dr. Karol Watson:

So this thoughtful paper, really looks at disparities in unique populations in Canada. More importantly, it offers potential roadmaps for other populations, solutions to address longstanding legacies of racism and colonialism.

Dr. Mercedes Carnethon:

Thank you so much, Karol, for that description from our neighbors from the north.

Dr. Mercedes Carnethon:

My second paper is really relevant during this hot month of July, in much of the United States and the upper hemisphere. And that's because Sameed Khatana and colleagues from the University of Pennsylvania, discuss how extreme heat is associated with higher cardiovascular mortality. For those of us who welcome the heat of summer and the opportunity to get out from behind our desks and exposed to some vitamin D, Khatana and colleagues reviewed county level daily data on temperature, and linked those data with mortality rates.

Dr. Mercedes Carnethon:

But before I summarize the findings, I invite you to California based cardiologists to join me in Chicago, where extreme heat is really only a problem for about 30 days a year. The authors found that between 2008 and 2017, when the heat index was above 90 degrees Fahrenheit, or 32.2 degrees Celsius, there was a significantly higher monthly cardiovascular mortality rate. In total, extreme heat was associated with nearly 6,000 additional deaths from cardiovascular disease. And sadly, black adults, older adults, and men, bore the greatest burden of mortality rates from extreme heat. So, we can all take lessons from that.

Dr. Mercedes Carnethon:

But turning to you now, Fatima.

Dr. Fatima Rodriguez:

Thanks so much, Merci. I'm from Florida, so I can definitely relate to the issues of extreme heat, but I'm very happy for the perfect year round weather here in Northern California.

Dr. Fatima Rodriguez:

My third paper is led by Dr. Zubair (and Chikwe) and colleagues from Cedar Sinai, and it describes changes in outcomes by race, in children listed for heart transplantation in the United States. I won't give all the details, but this research letter really nicely summarizes how the 2016 Pediatric Heart Allocation Policy revisions may have inadvertently widened health disparities between white and non-white children. This article touches on the difference between equality and equity, even in the most well-intentioned national policies. And I invite our listeners to read the full details in this special Circulation edition.

Dr. Mercedes Carnethon:

Thanks Fatima. Karol.

Dr. Karol Watson:

The next paper I'd like to discuss, is a community based cluster randomized pilot trial, of a cardiovascular mobile health intervention, preliminary findings of the FAITH! Trial, from LaPrincess Brewer and colleagues from the Mayo Clinic.

Dr. Karol Watson:

So it's well known that African Americans have suboptimal cardiovascular health metrics, such as less regular physical activity, suboptimal blood pressure levels, suboptimal diets. So the authors of this study hypothesize, that developing a mobile health intervention, in partnership with trusted institutions, such as, African American churches, might be an effective means to promote cardiovascular health in African American patients. So using a community based participatory research approach, they develop the FAITH! trial. FAITH stands for Fostering African American Improvement in Total Cardiovascular Health. The manuscript in this issue reports, feasibility and preliminary efficacy findings from this refined community informed mobile health intervention, using the FAITH! App, developed by the investigators.

Dr. Karol Watson:

They performed a cluster randomized control trial. Participants from 16 different churches in the Rochester, Minnesota and Minneapolis St. Paul, Minnesota areas. The clusters were randomized to receive the FAITH! App, that was the intervention group, or were assigned to a delayed intervention program. The 10 week intervention feature culturally relative and sensitive information modules, focused on American Heart Association's Life's Simple 7. Primary outcomes were changes in the mean Life Simple 7 score, from baseline to six months post intervention. They enrolled 85 participants, mean age was 52, and about 71% were female.

Dr. Karol Watson:

At baseline, the mean Life Simple 7 score was 6.8, and 44% of the individuals were characterized as being in poor cardiovascular health. The mean Life Simple 7 score of the intervention group, after the end of the intervention, increased by 1.9 points. In the control comparator group, it only increased by 0.7 point. Highly statistically significant, with P value of less than 0.0001 at six months.

Dr. Karol Watson:

Now this FAITH! Trial demonstrated preliminary findings, that suggest that a culturally sensitive and mobile health lifestyle intervention could be efficacious, promoting ideal cardiovascular health among African Americans. I think what's so important about this is that, they partnered with a very trusted group, the churches, and getting buy-in to a community that has had many reasons not to trust in the past, I think is critically important.

Dr. Mercedes Carnethon:

Well, thank you so much, Karol. My third paper is an original research investigation by Anoop Shah and colleagues from the University of Edinburgh, arguing that socioeconomic deprivation is an unrecognized risk factor for cardiovascular disease.

Dr. Mercedes Carnethon:

In their study, the authors evaluated how risk scores, with and without indicators of socioeconomic deprivation, performed in a population study in Scotland, the Generation Scotland: the Scottish Family Health Study, of over 15,000 adults. Again, I won't give away all the details, so that I keep our listeners excited to read the article, but all risk scores aren't created equally. And the observed versus expected number of events varied, based on whether the risk score included socioeconomic indicators or not. Further, the performance of the risk scores varied, based on the degree of deprivation that participants were currently experiencing. It's a thought provoking piece, that may challenge us to reconsider how we identify risks for cardiovascular disease in the population.

Dr. Mercedes Carnethon:

And I'm turning to you now, Fatima.

Dr. Fatima Rodriguez:

Sure thing, Merci. My last paper is led by Dr. Anna Krawisz, and is looking at how differences in comorbidities explain racial disparities in peripheral vascular interventions. This study used Medicare fee for service data from 2016 to 2018, to examine risks of death and major amputation, one year following peripheral endovascular intervention. They found that, black Medicare beneficiaries had higher population level need for peripheral endovascular interventions, and that black race was associated with adverse events following these interventions. However, after adjusting for the higher prevalence of comorbidity, such as diabetes, hypertension, and chronic kidney disease in black populations, this observation was eliminated. Again, like a common theme in many of the articles we've discussed today, this is to suggest, that moving upstream to reduce risk factors is really critical to eliminate disparities in cardiovascular disease outcomes. And this includes the understudy disease of peripheral arterial disease. Black adults were also less likely to be treated with guideline directed medical therapies in this study.

Dr. Mercedes Carnethon:

Well, thank you so much, Karol and Fatima, for your wonderful summaries of all of the excellent pieces in this issue.

Dr. Karol Watson:

And I'd like to thank all of the fantastic investigators who submitted their really fantastic work, so that we could produce this issue. And really, keep them coming. We thank you for this.

Dr. Mercedes Carnethon:

Well, thank you. So now we'll transition to our feature discussion with Drs. Wadhera and Kyalwazi, from Beth Israel Deaconess Medical Center, and the Harvard Medical School.

Dr. Mercedes Carnethon:

Welcome to this episode of Circulation on the Run podcast. I'm really pleased to host this feature discussion. My name is Mercedes Carnethon, from the Northwestern University Feinberg School of Medicine. And I'm pleased to have with us today, Drs. Ashley Kyalwazi and Rishi Wadhera from Beth Israel Deaconess, and the Harvard Medical School. And they shared with us a really important piece of work for our disparities issue, that is describing disparities in cardiovascular mortality, between black and white adults in the United States from 1999 to 2019. First of all, I really want to thank you both for submitting your important work to circulation.

Dr. Rishi Wadhera:

Thanks so much Mercedes, and thanks for the opportunity to submit and revise our manuscript.

Ms. Ashley Kyalwazi:

Thanks so much for having us.

Dr. Mercedes Carnethon:

Wonderful. I'd like to start out with you Rishi. Tell our listeners about the objectives of your study, and what your motivation was for carrying out this work.

Dr. Rishi Wadhera:

Well, I think it's been well established that, black adults are disproportionately impacted by cardiovascular disease, and experience worse cardiovascular outcomes, due to systemic inequities and structural racism. And so, the goal of our study was really, to perform a comprehensive national evaluation of how age adjusted cardiovascular mortality rates have changed for black adults, compared with white adults, over the past two decades in the United States, with a focus on some key subgroups, like younger adults and women.

Dr. Rishi Wadhera:

In addition, because we know that the neighborhood community or environment in which you live in the US, has an immense influence on cardiovascular health, we also examine changes in cardiovascular mortality for black and white adults by geographic region, rurality, and neighborhood racial segregation. And our primary objective was really, to understand whether disparities in cardiovascular outcomes between black and white adults improved, worsened, or didn't change, from 1999 to 2019.

Dr. Rishi Wadhera:

And there are some reasons to think we might have made progress in narrowing the mortality gap between these groups over this time period. There have been substantial improvements in preventative care and treatments for cardiovascular disease over the past two decades. And the expansion of insurance coverage under the Affordable Care Act, led to increases in access to care, cardiovascular risk factor screening and treatment, particularly, for black adults. At the same time, we know that, black adults were disproportionately affected by the economic recession of 2008, and experienced worsening poverty, job loss, and wealth loss, all of which are inextricably tied to cardiovascular health, and more broadly, health. And so that was our interest in really exploring how disparities in cardiovascular mortality have changed amongst black and white adults between 1999 and 2019.

Dr. Mercedes Carnethon:

Thank you so much for that summary. It's really nice to have these sort of pieces that really outline for us a lot of data, and across a number of different domains. Because it allows us really, a chance to think about those data, and how we can use those data in order to help improve health.

Dr. Mercedes Carnethon:

So tell me a little bit, Ashley, about what your study found.

Ms. Ashley Kyalwazi:

Absolutely. Yeah. So in the United States, overall, we found that age adjusted cardiovascular mortality rates declined for both populations, so both black and white adults, by around 40% from 1999 to 2019. So encouraging declines across the country. We found that these patterns were similar for both women and men, when we stratified by gender, over the 20 year period. While mortality rates declined in all regions, we still did find disparities when we stratified by age. So between the younger and older black women, versus younger and older black men, we found that, younger black men and black women were dying at higher rates, and were at increased risk of death from cardiovascular mortality, compared to younger white women and men, respectively. But we also found that black women and men living in rural areas consistently experienced highest mortality rates. And then finally, black adults living in higher areas of residential racial segregation, and compared to those living in low to moderate areas of residential racial segregation had higher mortality rates, as well.

Dr. Mercedes Carnethon:

Wow, this is a lot. And it's really describing a lot of disparities across multiple domains that we can easily measure. Which aspects of these results in your work did you find the most surprising, Ashley?

Ms. Ashley Kyalwazi:

Yeah, I was intrigued, I think overall, by just the gaps. I was very encouraged by, I think, the declines over time. On an absolute scale, the country has made a lot of progress, in terms of reducing cardiovascular mortality rates for both groups. But still, by the end of the study period, there were notable gaps between black adults and white adults. Particularly, between black, younger women and white, younger women, we see that by the end of the study period, black, younger women still remain over two times the risk of death from cardiovascular disease than younger white women. Which I think, leaves something to be desired from a public health and health policy standpoint, with regards to how we're going to kind of decrease these disparities.

Dr. Mercedes Carnethon:

I wanted to follow up on that point. Why do you think you see such disparities between black and white younger women? I love the opportunity of the podcast to allow authors a chance to speculate, beyond what they would do in the paper.

Ms. Ashley Kyalwazi:

Absolutely. I think that, there are a lot of great efforts on a national scale right now, to kind of address the disparities between black and white women. The Association of Black Cardiologists, for example, had a whole paper out about ways to really target and provide preventative measures for black women. So for example, working with communities, where there's a high proportion of black women, to figure out what community based research looks like. Engaging with churches, different types of methods, to really understand the barriers that black women face towards obtaining preventative care.

Ms. Ashley Kyalwazi:

I think the disparities that we are seeing, could potentially parallel well known and documented disparities in maternal health outcomes. So I think, from a perspective of preventative care, really thinking about, what are the barriers to healthy cardiovascular profiles for black women pre and postnatally, to ensure that their cardiovascular health is an actionable before and after the pregnancy?

Ms. Ashley Kyalwazi:

And then I think, broadly, the challenges that black women face, mirror the challenges of black adults, plus the additions of like social stressors, things that we looked at in this study neighborhood residential racial segregation, access to healthcare, and all of those things kind of contribute to the profile that black women face, in terms of being often, the heads of their households as well, and carrying on a lot of different societal challenges.

Dr. Mercedes Carnethon:

Thank you so much for that. I really appreciate that.

Dr. Mercedes Carnethon:

As I read the paper, one of the findings that I found the most surprising, and it was challenging for me to understand, is that while the absolute difference in rates was declining, or getting smaller over time, between black and white men and women, the rate ratios remained elevated across the course of time. I think, these concepts can be a little challenging to understand, not just to me, but to others as well. That when one measure of effect is showing progress, but another is still reporting a disparity.

Dr. Mercedes Carnethon:

Rishi, could you explain for our listeners, how we can see progress on one metric, but still find a mortality rate ratio that's 1.3 times higher in black, as compared with white men, for example?

Dr. Rishi Wadhera:

Thanks for that really important question, Mercedes. Just to summarize, we presented two outcomes that compared cardiovascular deaths among black and white adults in our paper, absolute rate differences, and then separately, rate ratios. And I think, both measures provide important complementary insights. I think that, understanding the absolute rate difference in cardiovascular deaths is critically important from a public health perspective, because it characterizes excess deaths experienced by black adults, compared with white adults. The fact that the absolute rate difference in cardiovascular death has narrowed over the past two decades between these groups is positive news. In contrast, the rate ratio provides us with important insights on the relative difference, or disparity or gap, between black and white adults.

Dr. Rishi Wadhera:

So again, both are important, both provide sort of synergistic and complimentary insights. And just to sort of cement that, as an example, you were talking to Ashley earlier, about some of the patterns we noticed amongst younger black women and white women. The absolute rate difference in cardiovascular deaths between younger black women, compared to younger white women, decrease from 91 per 100,000 in 1999, to about 56 per 100,000 in 2019. And that's good progress. However, our rate ratio analysis indicated that, still in 2019, young black women were 2.3 times more likely to die of cardiovascular causes than young white women. Highlighting that, we still have a lot of work to do, to address disparities between these groups. Some of which, Ashley already talked about.

Dr. Mercedes Carnethon:

Thank you so much for that excellent explanation. I know it's certainly, I find it alarming to hear, but then I remember I'm actually not young anymore. So maybe this doesn't apply to me quite as much. But no, I appreciate the explanation.

Dr. Mercedes Carnethon:

So your report was really unique, in that you studied these disparities, as we discussed, across a number of domains, age, geography, even racial residential segregation. Whereas, the pronounced disparities have been reported in a few of the other domains that you studied. I'm really interested in hearing more about racial residential segregation. I think, a lot of people don't fully understand what the concept is, and the ways in which racial residential segregation may contribute to higher rates of cardiovascular death among blacks.

Dr. Mercedes Carnethon:

Ashley, would you mind explaining to us first, what racial residential segregation is? And then really, how it would contribute to higher rates of cardiovascular death?

Ms. Ashley Kyalwazi:

Yeah, absolutely. So in its simplest terms, racial residential segregation is just the physical separation of two or more groups by race and/or ethnicity into different neighborhoods. What gets tricky is, like the long history within the United States of how we got to this point, where you see numerous degrees of segregation across the country. Residential racial segregation in the United States dates back to policies pre World War II, that resulted in kind of discriminatory banking practices and policies. For example, reverse red lining and gentrification, much of which the extent still exists today. And that's what we see kind of, I think, in our results when we looked at high versus low to moderate areas of residential racial segregation, and how those kind of track onto the trends that we see in cardiovascular mortality over time.

Ms. Ashley Kyalwazi:

The residential racial segregation impacts almost every aspect of life. You can imagine where you live, we know definitely impact, for example, your zip code can impact health outcomes. We've seen individual's cardiovascular health kind of trend with something as simple as your zip code. Where you live really does impact your, for example, access to affordable housing, health insurance, where your primary care physician is, whether or not you even have one. What that trip looks like to see your primary care physician, is it hours on end, and unrealistic to get to, or is it just around the corner?

Ms. Ashley Kyalwazi:

Educational opportunities, which leads to income, which we know is linked to cardiovascular disease employment in all of these aspects. Even access to green space. In some metropolitan areas that are more segregated, we see that, black adults, for example, have less access to green space, and numerous studies have shown that, that does impact overall health, but then also, from a cardiovascular disease perspective as well. So I think that, given that we know that lack of access to all of these key determinants can adversely affect cardiovascular mortality, and just general cardiovascular health, I think is very interesting that we found that, there was this link between high residential racial segregation and cardiovascular mortality. That we definitely can look into more, and understand kind of in more detail, that the mechanisms at play and ways to intervene.

Dr. Rishi Wadhera:

And just to layer onto and reinforce Ashley's really excellent answer to that question. We know that black adults are more likely to live in disadvantaged neighborhoods, because of the intentionally racist policies that were put in place many decades ago, that Ashley described so well. And black communities and segregated communities, as Ashley mentioned, are less likely to have access to primary care, high quality hospital care, and green spaces, but also, pharmacies and healthy foods. And we also know, there's a lot of empirical work that's shown that black communities, disproportionately experience psychosocial stressors, trauma.

Dr. Rishi Wadhera:

Also, these communities are disproportionately exposed to climate change, such as extreme heat. There was a recent paper that extreme heat has been linked to increases in cardiovascular mortality, and disproportionately affects black communities. These communities are also disproportionately exposed to pollution. All of these things we know are linked to cardiovascular health, and represent the effects of again, intentionally racist policies that were put into place many decades ago, the effects of which still persists today. Which will require equally intentional policies that aim to dismantle these longstanding effects, if we hope to make progress in advancing health equity, and specifically, cardiovascular health equity.

Dr. Mercedes Carnethon:

I appreciate the facility with which the two of you address the multiple complex contributors to cardiovascular health. It's even more impressive coming from two clinicians. So I really appreciate you taking the time to explain this. And this is where I really like the opportunity to open up and say, what more do you want your clinical peers to know about? For example, how does this affect the day to day encounters that you have in clinic with black patients, and other patients who've been traditionally underrepresented? How do you hope your clinical peers will use this information to promote cardiovascular health equity? And I'll open it up to either of you to respond.

Ms. Ashley Kyalwazi:

Yeah, I can get on that one. I think that, the disparities that our paper highlights, really requires a multisystem level approach to tackling, from public health to public policy. But I think at a provider level, to your question, Mercedes, physicians must be able to, I think at first, read the data and understand that these disparities exist.

Ms. Ashley Kyalwazi:

If there's no insight with regards to the risk profiles, that simply black women and black men have, because of systemic racism, because of these inequities, then I think, we're already kind of steps behind where we need to be. So recognizing disparities in cardiovascular disease burden for black men and women, prioritizing education on cardiovascular risk. A lot of the conditions are preventable with appropriate access to care and education around these topics. And so, providing education about the signs and symptoms of heart disease and treatment options for black men and women. Recognizing the history of medical mistreatment for black adults in this country. And really, tailoring the approach towards the individual who comes into the office, who might have very valid reasons for hesitating to take a medication, or a lot of questions that need time and consideration.

Ms. Ashley Kyalwazi:

At a research level, I think, more data and resources should be spent on studying risk prevention and treatment for cardiovascular disease in black adults, and really, developing more community based models, that really get at the specific interventions that work within black communities, that are culturally specific, that are targeted and relevant, for the populations that we're talking about.

Ms. Ashley Kyalwazi:

I think finally, and I'll let Rishi chime in, I think, this is shockingly low level of racial and ethnic representation in the field of cardiology as a whole. And we know that, diversity in healthcare can improve health outcomes. So from a cardiology perspective, I think, training the next generation of black young men and women to take up their seats at the table, and really advocate for some of these issues, alongside individuals who are already doing great work, would be essential towards reducing disparities that we see. And so all of the above, I think, I would encourage for my colleagues.

Dr. Mercedes Carnethon:

Thank you so much. Rishi, any final thoughts?

Dr. Rishi Wadhera:

No, I'll just add onto Ashley's again, really outstanding response that, this is a tension we face when we see patients in cardiology clinic all the time. I think, awareness about disparities, and the multiple factors that contribute to disparities in cardiovascular health, particularly, as it relates to race and ethnicity, are increasingly being recognized as they should be.

Dr. Rishi Wadhera:

And one of the challenges, how much can clinicians do within the bounds of hospital walls? We can make sure that we get patients the treatments they need. We can make sure we screen patients appropriately. But we know, as we've discussed, that so many factors beyond hospital walls, like widening income inequality, that's disproportionately affected black adults, and has been worsening over the last several decades. Widening educational inequality, that again, disproportionately affects black adults, and has been worsening over decades, also affect how. So I think, thinking about how clinicians, researchers, and policy makers, can work together to address some of these challenges, issues, and broader social determinants of health, that also exist outside our clinical practice, or hospital walls, will be really, really important, if we are serious about advancing health equity in this country.

Dr. Rishi Wadhera:

I don't think, we can operate in silos anymore. In the clinical world, in the research world, in the policy making world, we need more researchers and clinicians to have a seat at the table when it comes to policy making, individuals who understand how all of these complex factors are inextricably tied to one another, so that we can seek and implement solutions that advance cardiovascular health.

Dr. Mercedes Carnethon:

Thank you so much. The insights that we've gotten, from not only your written work, but even more importantly, this opportunity to speak with you today, and share with our readership, have just been invaluable. And I really appreciate the amount of time that you spent, in preparing the manuscript, and really contextualizing the findings with us today, as well as in writing. So thank you so much for contributing this really important work to our annual disparities issue.

Dr. Rishi Wadhera:

Thank you so much, Mercedes. We really appreciate all the time you and the Circulation team took to make the manuscript stronger.

Ms. Ashley Kyalwazi:

Thank you so much for having us. It was truly an honor to have this conversation and to submit our work.

Dr. Mercedes Carnethon:

Well, thank you.

Dr. Mercedes Carnethon:

That wraps up our feature discussion for this episode of Circulation on the Run podcast. I'm Mercedes Carnethon, from Northwestern University, Associate Editor and guest editor of the disparities issues. So thank you so much.

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors, or of the American Heart Association. For more, please visit hajournals.org.

This week, please join author Ambarish Pandey and Editorialist Linda Peterson as they discuss the article "Frailty Status Modifies the Efficacy of Exercise Training Among Patients with Chronic Heart Failure and Reduced Ejection Fraction: An Analysis from the HF-ACTION Trial" and the editorial "Heart Failure With Reduced Ejection Fraction (HFrEF): ‘The Importance of Being Frail.’"

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature article, Heart Failure Reduced Ejection Fraction in Evaluating the Efficacy of Exercise Training. But guess what? It appears it may be more efficacious in those that have high Frailty Index scores, as opposed to those that may not. But before we get to our feature discussion, let's grab a cup of coffee and go through some of the other articles in the issue. Would you like to go first?

Dr. Carolyn Lam:

I would love to, and this first paper is one that defines epigenetic biomarkers of lifelong cardiovascular health exposure and really contributes to our understanding of their roles in cardiovascular disease development. First though, a little quiz for Greg. So, Greg, what does DNA methylation mean to you?

Dr. Greg Hundley:

Well, Carolyn, DNA methylation. So, what I understand is these methyl groups get involved with our DNA and actually affect change over time that leads to phenotypic expression of, maybe, new traits. But I don't know. Maybe I'm not quite up to date.

Dr. Carolyn Lam:

Oh, you're perfect. Indeed, DNA methylation is a widely characterized epigenetic modification, which means exactly as you said. It's a regulatory modification to our DNA induced by environmental exposures and can affect gene expression. And this is the topic of today's paper by Doctors Zheng, Hou, and Lloyd-Jones from Northwestern University Feinberg School of Medicine and their colleagues. So, what they did is they studied blood DNA methylation at over 840,000 methylation markers measured twice over five years in participants of the CARDIA study. Epigenome-wide association analyses on a clinical cumulative cardiovascular health score were then performed in both CARDIA and compared in the Framingham Heart Study.

Dr. Carolyn Lam:

The authors identified 45 midlife DNA methylation markers associated with clinical cardiovascular health metrics, such as body mass index, blood pressure, blood glucose, and total cholesterol longitudinally measured since young adulthood. The methylation markers were located in genes involved in lipid metabolism, insulin secretion, and cytokine production, which could not be fully attributed to genetic factors. So, they proposed and validated in summary a methylation-based risk score to promote a personalized cardiovascular disease risk evaluation beyond traditional cardiovascular risk factors.

Dr. Greg Hundley:

Oh, wow, Carolyn. Interesting, a methylation-based risk score to promote personalized cardiovascular disease risk evaluation. Wow! That's really exciting.

Dr. Greg Hundley:

Well, I'm going to go to the world of preclinical science, and just like last week where we had a really nice article on myocardial regeneration, this week, we've got another. And so, Carolyn, early neonates of both large and small mammals are able to regenerate the myocardium through cardiomyocyte proliferation for only a very short period after birth. This myocardial regenerative capacity declines in parallel with withdrawal of cardiomyocytes from the cell cycle in the first few postnatal days. No mammalian species examined to date has been found capable of a meaningful regenerative response to myocardial injury later than one week after birth.

Dr. Carolyn Lam:

Interesting. Now, I see that these investigators worked with possums. Could you tell me why they did that, and what did they find, Greg?

Dr. Greg Hundley:

Right, Carolyn. So, this work was led by Dr. Wataru Kimura from the RIKEN Center for Biosystems Dynamic Research and their colleagues. The reason they studied possums, so the marsupial possum maintains cardiomyocyte proliferation and a capacity for myocardial regeneration for at least two weeks after birth. Remember we stated before, all the other mammalian species, it's only one week after birth. So, this appears to be the longest postnatal duration of such a capacity among mammals examined to date, and AMP kinase signaling was implicated as an evolutionary conserved regulator of mammalian postnatal cardiomyocyte proliferation.

Dr. Greg Hundley:

And they additionally found that in a separate mouse experiment, the authors noted that the pharmacological inhibition of AMP kinase signaling was sufficient to extend the postnatal window of cardiomyocyte proliferation in neonatal mice, so really exciting work in the area of cardiomyocyte regeneration.

Dr. Carolyn Lam:

Wow, indeed! And I've learned now about possums. Thank you, Greg.

Dr. Carolyn Lam:

So, Greg, have you ever asked yourself, what is the frequency, penetrance, and variable expressivity of dilated cardiomyopathy-associated gene variants in the general population? Well, guess what? This next paper addresses just that in more than 18,600 UK Biobank participants who had undergone whole-genome sequencing, ECG, and cardiovascular magnetic resonance imaging.

Dr. Greg Hundley:

Wow, Carolyn, another really interesting study from the UK Biobank. So, what did they find?

Dr. Carolyn Lam:

So, this study is from Dr. Chahal from the Center for Inherited Cardiovascular Diseases Wellspan Health in Lancaster, Pennsylvania and colleagues, and they found that approximately one in six of adults with putative pathogenic variants in dilated cardiomyopathy genes exhibited early dilated cardiomyopathy features potentially associated with the genotype. And it's most commonly manifesting with arrhythmias in the absence of substantial ventricular dilation or dysfunction.

Dr. Carolyn Lam:

Among individuals with putative pathogenic dilated cardiomyopathy gene variants, ECG or CMR-detected early features were nearly four times more common than clinically manifest dilated cardiomyopathy or early features. Over 90% of subjects with these gene variants in dilated cardiomyopathy-associated genes did not have a prior history of dilated cardiomyopathy, and the overall clinical or subclinical penetrance of dilated cardiomyopathy-associated single pathogenic variants was highly variable between genes ranging from zero to 67%. And so, in conclusion, a genotype-first screening approach for dilated cardiomyopathy using a large genetic panel is currently not suitable in the general population due to incomplete understanding of the genetic architecture and reduced penetrance of the associated genes.

Dr. Greg Hundley:

Very nicely said, Carolyn. Wow! Well, let's take a look and see what's in the mailbag. And first, there's a Research Letter from Professor Huguenard entitled, “Frequency of Screening Detected Intracranial Aneurysms in Patients With Loeys-Dietz Syndrome.” And our own Bridget Kuehn has a really nice piece on Cardiology News.

Dr. Carolyn Lam:

Nice. There's also an On My Mind paper by Dr. Sattar, McGuire, and Gill entitled, “High-Circulating Triglycerides Are Most Commonly a Marker of Ectopic Fat Accumulation: Connecting the Clues to Advanced Lifestyle Interventions,” and an exchange of letters between Dr. Groothof and myself, Dr. Lam, regarding my article on “Efpeglenatide and Clinical Outcomes With and Without Concomitant SGLT-2 Inhibition in Type 2 Diabetes: An Exploratory Analysis of the AMPLITUDE-O Trial.”

Dr. Carolyn Lam:

Ah, that was awesome. Well, thanks, Greg. I am so excited to get to the future discussion that you queued us on so well, frailty in heart failure with reduced ejection fraction. Here we go.

Dr. Greg Hundley:

You bet.

Dr. Greg Hundley:

Welcome, listeners, to this July 12th, 2022 feature discussion. And we have with us today, Dr. Ambarish Pandey from University of Texas Southwestern Medical Center in Dallas, Texas, and Dr. Linda Peterson, an editorialist for this article from Washington University in St. Louis. Welcome to you both. Well, Ambarish, We're going to start with you. Could you describe for us basically the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address?

Dr. Ambarish Pandey:

Thanks, Greg, for having me on this, and thanks to Circulation for publishing our article. Yeah, I think the premise for this study stems from the longstanding known benefit of exercise training in patients with heart failure with reduced ejection fraction. Now, that was shown in the HF-ACTION trial, where individuals with chronic stable heart failure with reduced ejection fraction underwent exercise training, and there was demonstrated benefit in quality of life and adjusted analyses. There was a protocol-specified adjusted analysis that did demonstrate improvement in some of the key primary endpoint.

Dr. Ambarish Pandey:

Based on these results, CMS has approved exercise training and cardiac rehabilitation in patients with chronic stable heart failure with reduced ejection fraction. However, despite this mandate from CMS and generally well-accepted benefits of exercise training in heart failure with reduced ejection fraction, the uptake of exercise training has been pretty low, and there's a lot of heterogeneity in the improvement in outcomes that is associated with exercise training.

Dr. Ambarish Pandey:

So, we wanted to see whether frailty, which is a well-characterized syndrome of reduced physiologic reserve and impaired homeostatic tolerance to stressors and is common in patients with HFrEF, we wanted to see how frailty modifies the beneficial effects of exercise training in HFrEF. And based on the existing literature and some of the prior works we have done, we hypothesized that individuals who are frail and who have more functional impairments are going to have more targets for improvement in their functional status and thus would be more likely to benefit from exercise training. And we looked at this in the HF-ACTION trial itself and using the Rockwood Frailty Index and the difference in primary outcome and treatment effect of exercise among frail and non-frail individuals.

Dr. Greg Hundley:

Very interesting, so really sort of a look back in HF-ACTION data. Describe a little bit more for us that study design, and then specifically, what was the study population that you used to test your hypothesis?

Dr. Ambarish Pandey:

Right. So HF-ACTION was a randomized control trial multi-centered that was sponsored by NHLBI and was conducted in the early 2000s and basically focused on chronic stable patients with heart failure with reduced ejection fraction who have not had a hospitalization in the past six weeks and have ejection fraction less than 35% and class II to IV. And these participants were randomized in one-to-one fashion to getting aerobic exercise training followed by some home-based exercise versus the usual care.

Dr. Ambarish Pandey:

And in our study, what we looked at was we looked at the effect modification by baseline frailty status on the treatment effect of exercise training. So, we calculated the frailty index, which is a well-established measure of frailty using a Rockwood Index Model, and we stratified patients by frail versus non-frail status based on a Frailty Index cut-off of 0.21, such that higher index identifies more frail participants. And then, we looked at how the treatment benefit of exercise training on different outcomes was differential across the frail and non-frail strata. We looked at qualitative interaction, and we also looked at the Frailty Index, so the continuous variable to assess the benefits of exercise across the spectrum of frailty in the study population.

Dr. Greg Hundley:

And so, before we get to your study results, how many patients were in your study? Give us an idea of what was the range in age, and then also the composition of sex? How many men? How many women?

Dr. Ambarish Pandey:

Right, so this is really important because that's addressed to the generalizability of the study. So, the study included around a little over 2,100 participants. The mean age was 59 years. 28% were women, and 32% were self-reported black individuals with chronic stable heart failure. That was the demographic distribution. The age was slightly younger than what you've commonly see in observational studies with heart failure, and that is largely because the study recruited patients who were able to do exercise training and were able to do exercise tests with peak VO2 and peak VO2 peak excess capacity assessment at baseline and follow-up. So, that kind of selected for a slightly younger population.

Dr. Greg Hundley:

Very nice. And so, what were your study results?

Dr. Ambarish Pandey:

So our study results are, indeed, pretty interesting. We identified that around 60% of patients with chronic stable heart failure with reduced ejection fraction who were in the trial were actually frail based on the Rockwood Frailty Index Model. And we observed that among the study participants, the exercise training was associated with significant improvement in the primary composite endpoint of all-cause hospitalization or death in frail participants, but not in the non-frail or less fail participants. And there was a significant treatment interaction, such that baseline frailty modified the treatment effect of exercise training for the primary composite endpoint.

Dr. Ambarish Pandey:

Now, this was largely driven by a significant reduction in all-cause hospitalization among frail individuals who underwent exercise training, and not so much by an effect on mortality. And we did not see a significant difference in the mortality component of the primary composite endpoint across frail versus non-frail status participants. So, in a nutshell, baseline frailty did modify the treatment effect, largely driven by substantial reduction in the risk of all-cause hospitalization among frail participants more than non-frail participants.

Dr. Greg Hundley:

And before we get to Linda in her interpretation of your study, Ambarish, did you see the same effects in frail men, in frail women? And also, what about in individuals that might be a little older versus those that were perhaps younger?

Dr. Ambarish Pandey:

That's a really important question, and we were a little bit limited to do further subgroups because we are dealing with around, I think, 2,000 participants and we had frail, non-frail, and we did not do a further subgroup stratification by sex or by age. The age range was rather narrow. It's 58 years plus/minus 13 years, so we didn't really have a lot of older individuals above 75, something like what REHAB-HF Trial has shown in the news, a recent trial.

Dr. Ambarish Pandey:

We couldn't address the question of whether the effect modification was further modified by sex or age, so I think that's the two-level interaction. But I think that is something that would be interesting to test perhaps in a pool analysis of multiple exercise training studies, which is something we are considering.

Dr. Greg Hundley:

Thank you. Well, listeners, now we're going to turn to our editorialist, Dr. Linda Peterson, from Washington University in St. Louis, and, Linda, very provocative results here, heart failure reduced ejection fraction. And certainly, we like to go to things like cardiac rehab, but we're hearing this it seemed to make a difference if you were frail versus not frail.

Dr. Linda Peterson:

Right, I think that's an important distinction here in this article as Ambarish has so eloquently put forth, and it's especially important because other articles have shown in looking at the PARADIGM-HF Study and ATMOSPHERE it appears that one out of two patients with HFrEF are actually frail. And so, the magnitude of these findings and the importance of these findings is highlighted by that study. And this frequency of frailty is roughly double that of community-dwelling adults who are over age 90, so we're thinking of frailty usually as much older adults, but in HF-ACTION, actually, the patients' average age was 60 in the patients with HFrEF.

Dr. Linda Peterson:

So, there's almost an accelerated aging phenotype we're seeing here in a large proportion of the patients who have HFrEF. I think this has an enormous impact on a lot of the patients that we're seeing with HFrEF, and we should be alerted to looking for frailty and potentially screening for frailty. And I think another highlight of this study is that it points out the importance of frailty because frail patients have a 50% higher risk of hospitalization and death, according to some other studies, particularly one by Faray and their group and also by Yang and their group.

Dr. Linda Peterson:

And so, it highlights the importance of getting patients who are frail with HFrEF into cardiac rehab or getting them some sort of aerobic exercise training. But paradoxically, frailty is also associated with a lower likelihood of those particular patients on getting into cardiac rehab and also getting on goal-directed medical therapy. And that was shown by Phil Ades and his group. So, I think the importance of these findings by Ambarish and his group are to be commended, and they're very important for a large proportion of our patients with HFrEF.

Dr. Greg Hundley:

Very nice. Well, let's turn back to Ambarish, and then follow up with Linda. Ambarish, what do you see as the next study that should be performed in follow-up to your study?

Dr. Ambarish Pandey:

I think that's a great question. And I think we are just beginning to realize the magnitude of impact that frailty has in the care of patients with heart failure. And this goes across the spectrum of ejection fraction, both HFpEF or heart failure with preserved ejection fraction and heart failure with reduced ejection fraction. Indeed, the burden of frailty is higher in patients with heart failure with preserved ejection fraction, and they are more of the accelerated aging phenotype.

Dr. Ambarish Pandey:

And I think the next study basically should look at a targeted approach to exercise training or category of intervention among patients who are most likely to benefit from it, which would be patients who have a high frailty burden or patients who have HFpEF. I think they go hand in hand when it comes to frailty and HFpEF. So, I think that's the next study to do is to see to what extent we can actually identify and target exercise training in the highest risk individuals who are most likely to benefit from it because that subset of highest modifiable risk is indeed identified by frailty and when you look at other subtypes by HFpEF which has a lot of high frailty burden.

Dr. Greg Hundley:

And, Linda, from your perspective, what do you see as the next study to be performed in this sphere of research?

Dr. Linda Peterson:

Yeah, I think this study really provides a springboard for future studies in HFrEF, in particular. One, what hospital interventions can be done in patients to get them moving more, and really assess is there a possibility of different types of exercises to get patients less frail even while they're in the hospital when they're enroute to going home? And then also, how do we have different mechanisms by which we can get more patients into cardiac rehab? Clearly, our national average of getting patients who qualify for cardiac rehab, which is a class I indication is 20% at best, and the aim from the AHA is 70%.

Dr. Linda Peterson:

There's a big gap there, so interventions looking at implementation and getting patients to cardiac rehab or looking at other types of aerobic exercise training, such as home-based cardiac rehab for patients who don't have a cardiac rehab center next to them, I think the field is wide open for different studies to springboard off of these findings.

Dr. Greg Hundley:

Very nice. Well, listeners, we want to thank Dr. Ambarish Pandey from University of Texas Southwestern Medical Center in Dallas, Texas, and our editorialist, Dr. Linda Peterson, from Washington University in St. Louis, for bringing us this research study, highlighting that among patients with chronic stable heart failure and reduced ejection fraction, that baseline frailty modified the treatment effect of aerobic exercise training with a greater reduction in the risk of all-cause hospitalization.

Dr. Greg Hundley:

Well, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week on the run.

Speaker 5:

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Fabian Eichelmann and Associate Editor Svati Shah as they discuss the article "Deep Lipidomics in Human Plasma: Cardiometabolic Disease Risk and Effect of Dietary Fat Modulation."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor Director at the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, we are going to get into the world of lipidomics and understand how some lipid metabolites may be more predictive of cardiovascular events above and beyond the conventional serum lipoproteins, like HDL and LDL. But before we get to that, how about we grab a cup of coffee and start with some of the other articles in the issue? Would you like to go first?

Dr. Carolyn Lam:

Sure thing. This first paper is about the basilar artery. Have you ever heard the analogy that the basilar artery is the neurologists' equivalent of our cardiologists' left main coronary artery? Well put, isn't it? Well, that's from the editorial that accompanies this paper, but basically, occlusion of either artery can be fatal without rapid re-perfusion. So that's why the basal artery is the neurologists' left main coronary artery. Re-perfusion therapies for acute basilar artery occlusion include thrombolysis or mechanical endovascular thrombectomy.

Dr. Carolyn Lam:

In today's issue, Professor Hu from University of Science and Technology of China, and Professor Nogueira from University of Pittsburgh School of Medicine in the US, these are the co-corresponding authors, and their colleagues, reported the outcome of the attention registry of more than 2000 patients with acute basilar artery occlusion who enrolled prospectively and consecutively at 48 sites in China from 2017 to 2021, and followed for the primary outcome of a favorable neurological functional outcome defined as a modified Rankin score of zero to three at 90 days.

Dr. Greg Hundley:

Wow, Carolyn, I love that analogy. So the basilar artery is kind of similar in the brain to the left main coronary artery in the heart. Whoa, what did they find here?

Dr. Carolyn Lam:

So, in this nationally representative observational study, the authors found a significant association between endovascular thrombectomy and better functional outcomes and survival at 90 days in patients with acute basilar artery occlusion, and this was compared to chemical thrombolysis. Now, notably, this relationship was modified by the baseline NIH stroke scale. Specifically, patients with baseline NIH stroke scale of 10 or more had an increased rate of favorable outcome when treated with endovascular thrombectomy, whereas no significant beneficial effect was seen in patients with baseline NIH stroke scores of less than 10. Now, all this is discussed in a beautiful editorial by Dr. Hankey, entitled, "Endovascular therapy for acute basilar artery occlusion."

Dr. Greg Hundley:

Oh, beautifully stated, Carolyn. What a great article. But guess what, Carolyn? I've got a quiz for you.

Dr. Carolyn Lam:

Uh-oh.

Dr. Greg Hundley:

This one's open answer, so it's not multiple choice. Can you name a unique feature of zebra fish pertinent to the study of cardiovascular disease?

Dr. Carolyn Lam:

Okay. Watch me hedge there because, first of all, I'm a daughter of a zoologist. So my dad would have a heart attack if I couldn't say something about the zebra fish. So, what I do know is the zebra fish is an excellent animal model for genetic studies of heart generation, basically development. So, there must be something really cool there about how we can observe that.

Dr. Greg Hundley:

Excellent, Carolyn. So very well done. As you know, and your dad knows, certain non-mammalian species like zebra fish, have an elevated capacity for innate heart regeneration. Now, understanding how heart regeneration occurs in these contexts can help illuminate cellular molecular events that can be targets for heart failure prevention or treatment, your area of expertise. The epicardium, the mesothelial tissue layer that encompasses the heart, is a dynamic structure that is essential for cardiac regeneration in zebra fish, and these authors, led by Dr. Jinhu Wang from Emory University performed single cell RNA sequencing and identified seven epicardial cell clusters in adult zebra fish, three of which displayed enhanced cell numbers during regeneration.

Dr. Carolyn Lam:

Oh, interesting, Greg. So did these cell clusters provide some clues that could be applied clinically?

Dr. Greg Hundley:

Yes. Carolyn. So these authors identified that these subsets of epicardial cells emerge in post embryonic, zebra fish and sponsor regions of active cardio myogenesis during cardiac growth and regeneration. And as the heart achieves its mature structure, these cells facilitate extracellular matrix hyaluronic acid deposition to support formation of the compact muscle layer of the ventricle. These cells associate with the function of the hyaluron and proteoglycan link protein 1 or HAPLN1 paralogue in production and organization of hyaluronic acid containing matrix in cardiac injury sites and thereby enable normal cardiomyocyte proliferation and muscle generation. And so Carolyn, potentially in the future targeting hyaluronic acid regulation by manipulation of HAPLN1 in human epicardial cells could potentially modulate cardiac repair after myocardial infarction.

Dr. Carolyn Lam:

Well, thanks, Greg. That was awesome. Well, the next paper I want to tell you about is one in which a novel ECG based machine learning approach was used to determine and predict multiple structural heart conditions. So the authors led by Dr. Chen from Department of Translational Data Science and Informatics at the Geisinger Health System in Danville, Pennsylvania. So these colleagues hypothesized that a composite model would yield higher prevalence and positive predictive value to facilitate meaningful recommendations for echocardiography.

Dr. Greg Hundley:

Oh wow, Carolyn. Machine learning, it's just emerging everywhere these days. So don't we need a large data set to do this?

Dr. Carolyn Lam:

Absolutely, and listen to how large this is. So using more than 2.2 million ECGs linked to electronic health records and echocardiography reports from almost 500,000 adults between 1984 and 2021, the authors trained machine learning models to predict the presence or absence of any of seven echo confirmed diseases within a year, and the composite model and the composite label that they used included moderate or severe valve disease and reduced ejection fraction. So their composite recommend model where reco is E-C-H-O we used age, sex ECG traces, and had an area under the receive operating curve of 0.91 and a positive predictive value of 42% at 90% sensitivity with a composite label prevalence of 17.9%. Whereas the individual disease models had area under curve ranging from 0.86 to 0.93 and lower positive predictive values from about 1% to 31%.

Dr. Carolyn Lam:

So in summary, they showed that an ECG based machine learning model using a composite endpoint can identify a high risk population for having undiagnosed clinically significant structural heart disease while outperforming the single disease models and improving practical utility with higher positive predictive values. So this approach may facilitate targeted screening with echo to improve under diagnosis of structural heart disease.

Dr. Greg Hundley:

Wow, Carolyn, really great article from the world of machine learning. Well, how about we jump to some of the other articles in the issue and I can go first. There are two Research Letters. The first Research Letter comes from Professor Adlam entitled "Pregnancy and Spontaneous Coronary Artery Dissection Lessons from Survivors and Nonsurvivors." And our own Dr. Joe Hill, our Editor-in-Chief also has a Research Letter entitled “Impaired AMP Kinase Signaling in HFpEF Associated Atrial Fibrillation.”

Dr. Carolyn Lam:

Wow, what an issue filled with great stuff. There's an AHA update by Dr. Churchwell on promoting nutrition security through policies and programs. And there are highlights from the circulation family of journals by our own Molly Klemarczyk, now known as Molly Robbins. I'd love to tell you a little bit about it. The association of new onset AF with cardiovascular outcomes in patients hospitalized with COVID-19 are described in Circ Arrhythmia, and EP. Rates of cardiovascular and cerebral vascular disease mortality among Asian subgroups are presented in Circ CV, Quality and Outcomes. Blood pressure and glycemic control are presented in patients with heart failure in Circ Heart failure. The associations of atrial update with technetium 99 pyrophosphate scans for transthyretin amyloid cardiomyopathy with incident atrial fibrillation and possibly earlier diagnosis of amyloid is presented in Circ Cardiovascular Imaging.

Dr. Carolyn Lam:

And finally the outcomes associated with larger burdens of residual thrombus after aspiration thrombectomy for STEMI are presented in Circ CV Interventions. Isn't that cool? And finally, we've got an On My Mind paper by Dr. Arany on “It’s Time to Offer Genetic Testing to Women with Peripartum Cardiopathy”. So that wraps it up, Greg. Let's go to our feature discussion, shall we?

Dr. Greg Hundley:

You bet.

Dr. Greg Hundley:

Welcome listeners to this feature discussion on July 5th, and we are very fortunate today. We have with us Dr. Fabian Eichelmann from the German Institute of Human Nutrition in Potsdam, Germany, and our own associate editor, Dr. Svati Shah from Duke University in Durham, North Carolina. Welcome to you both. Fabian, we're going to start with you. Can you describe for us some of the background information that went into the preparation of your study and what was the hypothesis that you wanted to address?

Dr. Fabian Eichelmann :

Yeah, sure. So first of all, thanks for the invitation to speak here. So this project was basically comes from a collaboration between us and a group in Redding, UK and we are part of a consortium called FAME, which is short for fatty acid metabolism. And there, we are interested in the health effects of fatty acid metabolism in general. And in this paper that we did, this was particularly cardiometabolic diseases. And I think this is no surprise that we look at lipid metabolism in this context, because there's so many really now also causal factors, lipoproteins, total triglycerides for specific cardiometabolic outcomes. So this is the reason why we wanted to look at it. And through this collaboration, we were also able to harness the potential from two different study designs that I probably will go into later, but which really gave us an opportunity to really generate I think, quite interesting insights.

Dr. Greg Hundley:

Very nice. And so what was that hypothesis?

Dr. Fabian Eichelmann:

So the hypothesis was that since the lipid metabolism has formally only been mostly in the clinic, at least been measured by lipoproteins and total triglycerides, for example, but the lipidome of plasma, for example, is really rich. It's really heterogeneous and it contains many different lipid classes and different fatty acids. And through novel technologies and in this case, lipidomics, you can really dive in really deeply and look at this in a specific manner. And then the idea was to really look at this and potentially identify lipids that would be associated or could surface as biomarkers for cardiometabolic diseases and at the same time, if those lipids were also sensitive to a dietary intervention that really tried to modulate the dietary intake of a fat.

Dr. Greg Hundley:

Very nice. And so how did you set this up? What was your study design and what was your study population?

Dr. Fabian Eichelmann:

So we had two different study populations for this. So the first one was the EPIC-Potsdam, which is a cohort study, a large scale cohort study here in Potsdam, which started in the nineties. And there, we basically associated baseline concentrations of these lipid measurements with later on occurring incident cardio metabolic outcomes. And in this case, this was type two diabetes and primary CVD and CVD in our case meant myocardial infarction and stroke. And we did that we checked which lipids would be statistically significantly associated after multiple testing with at least one of these outcomes. And then we took those lipids further into intervention trial, which is called the DIVAS trial in Redding, as I said, UK. And there, they had basically a dietary intervention trial that really wanted to assess if the change in the fatty acid proportions in the diet affects the lipids. So there we had the lipidomics measurements at baseline and after four months, and then we compared three different trials to each other.

Dr. Greg Hundley:

Very nice. And so how many patients did you include and who were these patients? Men and women? And did they have, for example, prior cardiovascular disease?

Dr. Fabian Eichelmann:

So in EPIC-Potsdam, that's a population based cohort study. All of the participants were drawn from the registries and invited. So these were apparently healthy people. And in those we did these association analyses and those we used the design, which is a case cohort design, which is a sub sample of the whole cohort, which is a really effective way and efficient way of analyzing biomarker projects. And there we had in total 1,262 control participants, and then later on additionally, a 775 type two diabetics and 551 CVD cases. In the DIVAS trial, that was a trial where participants also men and women, which was also the case in EPIC-Potsdam were invited, and they were at a higher risk of at the higher cardiovascular disease risk, which was measured by score, but they didn't have any prior cardiovascular diseases. And those were 113 participants that were randomized to one of these diets.

Dr. Greg Hundley:

Right. So it sounds like two studies. One, a large case control study and looking at different plasma lipid concentrations in two separate groups. And then the second was a randomized trial, a smaller trial of 113 individuals looking at a dietary intervention. So with that established, tell us your study results.

Dr. Fabian Eichelmann:

Yeah. So in the first step, as I said, where we associated lip concentrations to later occurring disease, we found from the 282 lipids that we looked at, 69 were really associated to at least one of these outcomes. And interesting here we saw that only eight were associated to both outcomes and 49 were specific to cardiovascular disease and 12 for specific to type two diabetes. And from those 69, we found 19 were also sensitive to the dietary intervention, and what was really striking here was that of these 19, 17 were perfectly in agreement with a suggested beneficial effect, meaning that those lipids that were associated in the EPIC-Potsdam studies on the cohort study with a higher disease risk were reduced by these diets or in the opposite direction, we saw those lipids that were associated with lower risk were increased by these diets. So this was quite a striking observation there.

Dr. Greg Hundley:

So it sounds like from the lipidomics analysis, there was a construct of certain blood lipid markers that were associated with cardiovascular events, and then in your randomized trial, you were able to modify those by different dietary interventions?

Dr. Fabian Eichelmann:

Exactly.

Dr. Greg Hundley:

So listeners, now we're going to turn to our own associate editor, Dr. Svati Shah. And Svati, you see many papers come across your desk. What attracted you to this particular paper and how do we put this study's results in the context with other studies that have been published in really the sphere of lipidomics research?

Dr. Svati Shah:

Yeah. Thank you, Greg. I just want to point out that this is a really elegant translational study. I think these papers can be very complicated to understand, and I think the authors did a fantastic job of really laying out how you can combine cutting edge what we call omics, using these cutting edge technologies, but applying them to human cohorts with a very strong clinical lens. So it's not just what do we learn about biology, but also what do we learn about biomarkers that might be relevant to how we take care of patients? And that's really one of the biggest things I loved about this study is sort of, you get to have your cake and eat it too. You get to learn about biology, but with a very strong clinical lens towards identifying clinically relevant biomarkers. I think another really important strength of this study, which differentiates it is this sort of use of really cutting edge lipidomics.

Dr. Svati Shah:

So this is a subset of omics where we're really looking at these granular lipid classes. And some of the clinicians might say, well, we measure cholesterol, why is this different? And you know, Greg, really what lipidomics allows us is a much more granular snapshot of these complex lipid species that are only grossly captured by the cholesterol levels that we would measure normally if we were seeing a patient in clinic. So to be able to get this really granular snapshot of what is happening to lipid biology and how it might relate to cardiovascular events, diabetes, I think is really important. And finally, I think the coolest part about this study is, in other studies we always have a little bit of a hard time with what we call confounders. And what does that mean? That means there may be other things for why you're seeing these biomarkers associated with your disease and those might be uncaptured things, things that you didn't measure in this study. And we call that residual confounding.

Dr. Svati Shah:

And I think the authors in this study, not only statistically adjusted for those potential confounders, but also importantly, the DIVAS study, where they took the biomarkers that they found from EPIC-Potsdam and said, do they change with the dietary intervention? And in fact, they did find that many of these lipid, these granular lipid species improved, meaning they went in the proper direction in terms of your health with a diet that was higher in unsaturated fats. So really proving not only the potential biology of the benefit of diets enriched in unsaturated fats, but also that these particular biomarkers are modifiable, so they're able to be changed even in this case within 16 weeks with just a dietary intervention. So to me that really was just a beautifully laid out study that highlights really what translational omics and these biomarker studies can do as we think about the clinical care of patients.

Dr. Greg Hundley:

Very nice. And so it sounds like listeners, moving beyond the lipoproteins, LDL, maybe total cholesterol and these granular lipid species cholesterol esters, free fatty acids, fingo-lipids, glycerophospholipid, et cetera, that's what we were studying in this particular manuscript. So, well, let's turn back to Fabian. And Fabian, what do you see is the next study to really be performed in this sphere of research?

Dr. Fabian Eichelmann:

I think what would be really interesting and what would really kind of prove what we saw is if you could find a way that an intervention, be it like a drug intervention and not diet because we looked at dietary intervention, that kind of shows the same as we saw, but also that really specifically only alters these lipids and how obviously not really feasible, but if that would be going on for a long enough period, if you also saw these effects that we now saw after four months would also affect the health outcomes instead of just only these proxies.

Dr. Greg Hundley:

Very nice. And Svati, how about you? What do you see as the next study that might be informative in this sphere of research?

Dr. Svati Shah:

Yeah. Great question, Greg. I mean, to me, I really think about this gap that we have in actually translating these findings in how we take care of patients. So again, really provocative results here. We have really significant P values, strong effect sizes, biomarkers that are modifiable, but in the paper they show that it adds on top of a clinical model, so what we might use as clinicians in the clinic that these biomarkers may help on top of what we already know about patients. But we really need to implement these findings and study that implementation for how this might in a real world setting actually change outcomes in patients and how we can actually help explain to clinicians how these results might be beneficial for clinical care.

Dr. Svati Shah:

So on top of what Fabian already said, I think really implementation science is a huge gap in how we take these translational omics discoveries and use them in support of improving patient care. We have lots to learn about these lipid biomarkers and lots more discovery science that can be done. As Fabian said, can we find drugs that might beneficially modified these lipid subspecies? But again, I think this gap in implementation science is really important.

Dr. Greg Hundley:

Very nice. Well listeners, we want to thank Dr. Fabian Eichelmann from the German Institute of Human Nutrition in Potsdam, Germany, and our own associate editor, Dr. Svati Shah from Duke University in Durham, North Carolina for bringing us these really provocative results, highlighting the identification of several lipids and their association with cardiometabolic disease risk. And then also nested within the same paper, a subset of individuals undergoing a randomized clinical trial demonstrating benefit by a dietary fat intervention, and there possibly supporting the substitution of dietary saturated fatty acids with unsaturated fatty acids perhaps as a potential tool for primary disease prevention.

Dr. Greg Hundley:

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week's special podcast features the CardioNerds. Join Maryjane Farr, Vanessa Blumer, and M. Trejeeve (Tre) Martyn as they interview Amit Goyal and Daniel Ambinder, who started the Cardio Nerds podcast, website, and learning resources.

Dr. Maryjane Farr:

Welcome, everybody, to Circulation on the Run. My name is Maryjane Farr from UT Southwestern, and here we have an opportunity to take a week from Circulation on the Run and let our social media editors take over and do an interview of their choice. To welcome both two of our social media editors, first, Vanessa Blumer, who is going to be doing her postgraduate year seven in Cleveland Clinic, in advanced heart failure, and Trey Martin, who is a newly-minted faculty member in heart failure and amyloidosis and population health at the Cleveland Clinic. And they've chosen to interview Dan Ambinder and Amit Goyal of CardioNerds.

Dr. M. Trejeeve (Tre) Martyn:

So, thanks to Vanessa and to Dr. Farr for setting this up, and thanks for Amit and Dan for being here. Really excited to talk to you guys. The first thing I want to start off with is to get a little bit of an origin story about CardioNerds. And if you could tell us how you got started and how this all came to be, I think the listeners would be interested to hear that.

Dr. Daniel Ambinder:

Thank you so much, Trey, and it is really great to be here and nice to meet you. This is Dan. So, the origins of CardioNerds actually began early 2019. One of our mentors put us together, Dr. Reza Manesh, who's one of the co-founders of Clinical Problem Solvers, and thought that we should be thinking about potentially starting a podcast. And that definitely lit the spark and is it going to be something that's worthwhile pursuing?

Dr. Daniel Ambinder:

And so, we said to ourselves, at rounds we could teach five people at Noon conference, maybe we could reach out to 20 and to 40 people, but maybe with a podcast, we could reach 500 people at a time and that would be something that would be really worthwhile. So let's just sit down, create a script and start from there. And we created the first episode, aortic stenosis, and we did the recording and we just loved that process. And after that, we said, "This is worth it." So we made a couple more episodes-

Dr. Amit Goyal:

Hey, I'm just going to chime in here real quick. This is Amit. And I'll start off by saying, thank you so much for this invitation and what a joy it is to be doing this with two people who we respect so much, Vanessa and Trey. The process of creating this podcast and education, we learned so much. And it was so much fun that we decided why don't we just give it a shot and trial it by creating maybe three, maybe four episodes and seeing how it goes from there. So that was a backstory.

Dr. M. Trejeeve (Tre) Martyn:

I was curious how you guys thought about initially getting traction. Because that, I think, is the really challenging part and how you thought about getting listenership for your podcast and expanding. And was it focusing on the product, obviously? But I was curious how you, because now you have, you guys have this gravitational pull of prominent faculty and trainees that want to work with you, but how did you get there, and what was the strategy in doing that?

Dr. Amit Goyal:

I'll say that, initially, like Dan said, that we went out with the idea of just giving it a shot, seeing if it fit with our schedules, seeing if we enjoy the process and if there was enough of a need and a desire for this. And so, we said, why don't we create a short number of episodes? And if we could get 500 listeners, that would be the biggest audience that we have individually reached. And before you knew it, the 500 per episode turned into 5,000 per episode.

Dr. Amit Goyal:

And we realized that, even without actively and very deliberately trying to promote this, there was already a need and a desire for this. There was a niche that we were filling that we hadn't realized. The value of asynchronous medical education for people within or people who are interested in the care of patients with cardiovascular illness. So I think that's one. I think that's one takeaway, that there is value for open access, asynchronous education that is high quality.

Dr. Amit Goyal:

I think from there, our next big major pivot was well into COVID-19 when ACGME and the bodies decided that we should have virtual recruitment. This is when, enter Dr. Nosheen Reza, who was the chair of ACC FIT section at the time. And she messaged us on Twitter early afternoon, one day, saying, hey, is there maybe a way we could potentially use social media and the growth that cardio nurses has already had up until that point to maybe help connect residents with programs, ACGME accredited cardiology program, to have their fellows present a case, use one of their experts to provide an editorial expert commentary and then had the program director have a message for the applicants.

Dr. Amit Goyal:

And in discussing the case, the fellows would also talk about the program. And what that did was, I think, internally for us, it helps us realize that this just made it so much, the quality of the content and the breadth of the content, the depth of content just skyrocketed, right? I mean, we had fellows bring us cases of preeclampsia and bicuspid aortic valve, aortic stenosis with pregnancy. I mean, it was just, it was incredible that CardioNerds wasn't just about what we wanted, it was very rapidly turning into a communal entity that other people could take pride of. And so, that became really important to us.

Dr. Daniel Ambinder:

Yes. And I'll just add, again, as Amit's explained is, it happened sequentially. But it was actually a pivotal moment, right before the CardioNerds case report series was launched, where things were feeling stale. We definitely love to teach, there's no doubt about it, and that is a huge part of this. But there was a certain point where we were teaching and we just felt like there needs to be something more.

Dr. Vanessa Blumer:

Thank you so much, Dan and Amit. I mean, I think everything that you do, this is Vanessa. I think everything that you guys do, it's so inspiring for, I think, all generations, right? I think it's inspiring for future generations, but I think you guys inspire people at all levels. When you think about CardioNerds, what is your purpose? What drives you? What is your motivation? What do you think is your ultimate, why?

Dr. Daniel Ambinder:

While we had this passion to educate, that is not necessarily the why. And all of a sudden, as soon as we took off, there was multiple opportunities and multiple things dragging us in different directions. And we immediately sought out our mentor, Dr. Sanjay Desai, who is our program director at the Osler Medical Residency, and he said, "You got to find out your why right away." So, now our why includes to create and disseminate education, promote diversity, equity, inclusion, foster wellness, and humanity in the field of cardiology and in life, and provide mentorship and sponsorship and invigorating a love of cardiovascular medicine and science. Choices were easy. We can just say, "Does this fit the rubric of our mission? Is this an opportunity that we want to pursue? Is this something that's going to enhance this mission?"

Dr. Amit Goyal:

Putting words to a mission was extremely helpful for us. And actually, part of that conversation we're having at that time was around diversity and inclusion, because that's when Sanjay was saying you have to define what your organization stands for and what is a mission, and who are the people that are going to represent these cardiology fellowship training programs, in the eyes of residents who are thinking about a field in cardiology, and how deliberate we want to be about asking program directors to be cognizant about representing diversity in the fellows that they have representing the programs. And so, around these discussions, that's when Sanjay said, okay, there are a lot of things that you can do with CardioNerds, but before you do that, figure out what is your goal and how every action fits into that goal.

Dr. M. Trejeeve (Tre) Martyn:

Thanks, Amit. So, keeping that mission that you described in mind, what do you think is the ultimate goal of CardioNerds? Or, I guess I should say, where do you see CardioNerds being in five to 10 years? I know that's far out and some of the days you're just trying to get through the day you have in front of you. But if you could envision a future and, in the structure or the mission, keeping that in mind, where do you see CardioNerds in five years, let's say?

Dr. Amit Goyal:

Yeah, thanks, Trey. That is such an important question and a very difficult question to answer. I will say that things have evolved so quickly. And so, I think our one challenge that we talk about that we don't know how to resolve just yet is how to build CardioNerds in a way that's scalable, that outlives us. How do we make CardioNerds go beyond us? And that's Dan and I, but also everyone else within CardioNerds, a generation later. How do you maintain CardioNerds?

Dr. Amit Goyal:

And I think the logistic part of that is probably not that hard to figure out, right? You need admin support, you need resources, you need to delegate, you need leadership structure, but how do you grow it and have it outlive you in a way that still continues within the ethos of how you started it, within that mission, within the goals that you set it out to? And I think that's really something that we have to figure out, but that's going to be probably a deliberate way of how we grow it and how people grow into a leadership structure within it, how we design the programs. So I think that that part of the growth depends on the actions and the decisions we make today.

Dr. Daniel Ambinder:

Yeah. I definitely agree with all of that. And just to be brief, I just reiterate, CardioNerds is really for the people and what people want changes. And so, we're always listening and we're getting tons of feedback. And as the network grows, people are coming to us with projects and ideas, and we always try to find people that are just really passionate about what they want to do and give them a space to do it and try to give them as many resources and mentorship and sponsorship as we can, and then get out of the way. And so, that has already been a great recipe for a lot of different outpouchings and outgrowths of CardioNerds that really, again, goes back to the entire mission. And so, it's almost really hard to predict what will happen in five to 10 years, but we are ready and listening and looking to see what we can help the community with and vice versa.

Dr. Vanessa Blumer:

Thank you so much, Dan. And I mean, these answers have been fascinating, honestly. This interview, in general, has just been so enlightening. Dan, I think you touched on the point of democratizing cardiovascular education, which I think is, or should be, one of the highlights of this interview. Can you maybe touch a little bit more on this? And we talked about the why, can you talk about the how and see how you see this moving forward?

Dr. Daniel Ambinder:

Yeah. Thanks so much, Vanessa. We agree, democratization of cardiovascular education, what does that even mean? But what we mean by that is that why should somebody, somewhere off in a distant country, not have the ability to take care of their patients in the most topnotch way, because they may not have had the exposure to a particular part of cardiovascular education? Breaking down some of the formal barriers between levels of trainees, so, for example, CardioNerds' journal club really encompasses that.

Dr. Daniel Ambinder:

Once a month, our CardioNerds Academy, which you haven't talked about, puts on an amazing show. It's really a way where journal club hits Twitter in a traditional format, same process of discussing the article, but in the Twitter format. So it allows for this amazing group of, usually hundreds of people, honestly, to come together and discuss. And what's so amazing is that the scientific community has really gotten on board. So we often have authors of the papers that we're discussing join the actual Twitter club.

Dr. Daniel Ambinder:

And then we have medical students that are asking questions of the authors and this amazing engagement between multi-levels of education coming together. There are certainly ways that some, I wouldn't say the barriers, there are certain ways that these things can be helpful, like traditional learning and formats like that, but sometimes not. And so, we aim to be constructively destructive in terms of that way. And that's what we've done with democratization of cardiovascular education.

Dr. Amit Goyal:

If I might just add, then when we think about democratizing cardiovascular education, it's both for the learner, in terms of making high-quality education available and accessible, but also for the educators, right? I had a conversation with a mentee when he was a resident, and he called me and said, "Amit, I want to be an interventional cardiologist, but I also want to be a medical educator. How does that work?". And the fact that he was asking that is, for me, a problem, right?

Dr. Amit Goyal:

I've had this conversation with Dr. Katie Berlacher, who was also a medical educator, but is a cardiologist. Why does there seem to be strain between becoming a medical educator and becoming a cardiologist, right? That's not there for hospitalist medicine and other fields. So that's part of the reason we really enjoy having all sorts of trainees and faculty come on and teach on the show and be deliberate about how they want to teach on the show.

Dr. M. Trejeeve (Tre) Martyn:

Thanks a lot, Amit and Dan. In some ways, it sounds like you guys have been able to democratize another area other than education, which is clinical trials. And I wanted to get your perspective and hear a little bit more about the CardioNerds Clinical Trials Network. It really seems like an amazing program you guys have set up.

Dr. Amit Goyal:

It all goes back to the mission, but the origins of that is, Dr. Starling, he was a pretty early adopter for CardioNerds. He was a part of our very early heart failure series back in early 2020. And he was such a great supporter and source of encouragement and mentorship for so long. And Trey, I know you understand this, and Vanessa, you too, but he, for one reason or another, he brought up CardioNerds at a meeting about PARAGLIDE-HF. And I think present were Dr. Eugene Braunwald, who's part of the steering committee and Dr. Robert Mentz, who is the lead principal investigator, began recruiting around the time of COVID-19, affecting recruitment for a lot of trials. Lot of challenge there that I think we can all understand at this point.

Dr. Amit Goyal:

And we said, "Okay, well, not sure. We haven't thought about clinical trials, but why don't we think about it and get back to you?" So then, we said, okay, well, what's the core strength of CardioNerds? It's the people, right? After we did the CNCI recruitment series, hosting fellowship training programs, we realized that that worked out really well, because brilliant fellows from all these different programs came and elevated the education. So we established the Healy Honor Roll, after Dr. Bernadine Healy, of training programs who are part of the honor roll by nominating a FIT ambassador, a fellow and training ambassador, who's interested in education.

Dr. Amit Goyal:

We said, okay, well, why don't we just extrapolate that to a clinical trial? Instead of fellowship training programs, it would be trial sites that have training programs affiliated with them. Instead of a program director nominating a FIT ambassador for education, it would be the site PI nominating a FIT trialist for recruitment. But how would that fit as part of the mission? Well, with the Healy Honor Roll, with the academy, with everything else, hosting people on the podcast, it's always been, how do we pair content creation with personal and professional development?

Dr. Amit Goyal:

So, with a clinical trials network, the question was, how do we pair equitable trial enrollment with FIT personal and professional development? How do we meaningfully engage the fellows in the conduct of clinical trials, but also meaningfully help develop their interest in clinical trials and academic careers? How do we equip them with important skills and knowledge in the space? So we created a curriculum that's related to career development and equitable enrollment. And then, also, how do we make sure that they have, and deliberately, they have networking and mentorship as part of this?

Dr. Amit Goyal:

Since then, after we got all the fellows involved, the impact has been absolutely amazing. Because there are two goals here, right? There's equitable recruitment and there's fellow development. And just by having these meetings, by having the curriculum, the fellows are already engaged. So at the very minimum, half the mission is working out really well. But what about the other half, and that's equitable recruitment. So I will say from the time of the first FIT-recruited patient up until June 2nd, okay? So, that's February 8 to June 2nd, we account for 16% of all trial sites, but 49% of patients enrolled.

Dr. Amit Goyal:

Of the patients that we have enrolled, 54% are women compared to 47% for the non-CardioNerds sites. And 80% are BIPOC, or Black, Indigenous and people of color populations, compared to 19% for patients not enrolled by CardioNerds fellows. So, the impact there is, I think it's flooring, honestly. It is earth shattering and we are all amazed by it. And part of the question has been, can this be consistent, right? Is this a fluke? But since, when we had 30 patients enrolled, then we had 35 patients enrolled, we had 40 patients enrolled, these numbers had stayed relatively consistent.

Dr. Amit Goyal:

The question now is why? How is it that we've been so effective in disproportionately recruiting patients who had been historically underrepresented? And that's a very important question that we are really excited to dive deep into the data and try to understand. So our plans with Rob Mentz and the rest of the people who really made this possible is to really look at the numbers in terms of recruitment.

Dr. M. Trejeeve (Tre) Martyn:

That's really amazing, guys. And I have to applaud you on the vision to do that, and then to think about how to meet your mission, and then also to meet an unmet need that is... Because clinical trial enrollment, when you go through it, it's always slower than you hope. And this is such a great way to light that, to one, ignite a new generation into how to do clinical trials on the ground floor, but then also to increase the diversity of enrollment is amazing and you guys should be applauded for that.

Dr. Vanessa Blumer:

I also want to congratulate the both of you. Thank you. You guys are trailblazers and definitely are changing the world for all of us and making it a better place. So, we're so proud of you. We have to wrap up, so maybe just one last question before we go. So, maybe a two-part question, or you can choose to answer one or the other. But what do you guys feel most proud of? And what do you guys think has been the most important lesson that you have learned in the CardioNerds journey so far?

Dr. Daniel Ambinder:

Thanks, Vanessa. It definitely always helps to emphasize this. We really started this right before COVID. We had no idea COVID-19 would hit. And, really, the whole world was lurched into this virtual space. And there was always the hashtag, in real life? Is this even real life? And there was a sense that maybe it wasn't. And when we went to ACC and we met our people in person, and relationships were, not like they were just starting, but they had been ongoing for years. We really, really felt that this is something so real, and that is the lesson of CardioNerds. The lesson of CardioNerds is that the cardiovascular community is a real cohesive, beautiful community, and there's a lot of CardioNerds out there that embrace their nerdom when it comes to cardiology.

Dr. Amit Goyal:

I think in terms of what I'm taking away from this journey and what I'm going to keep relying on, the lessons I'm going to keep relying on, are one, is just find something you love and lean in. Right? I mean, when we first started telling people, "Oh, we're going to make a podcast and, hey, by the way, we're going to call the CardioNerds," the reactions we were getting from people, people we deeply respect and look to for advice and for role models, there were a lot of people who said, "Oh, that's great. It's so nice to have a hobby, but what are you going to do during your research block?" Right. That's great.

Dr. Amit Goyal:

But I think the reason why we've been able to stick with it is because we found something that we genuinely love to do. And so, I think that's really, whatever it is for you, that's really important. I think the second thing that's been extremely important for us is to surround yourself by people who inspire you, who push you, who will advise you, who make you want to be better. And that's people who are senior to you, people who are your peers, people who are junior to you, right? Because you can get as much inspiration from somebody who's 10 years your junior as you can from somebody who's 10 years your senior.

Dr. Amit Goyal:

I know I've taken a lot of inspiration from Vanessa and Trey and have relied on both of you for advice. I remember Vanessa, I think I had a very, a specific conversation about the clinical trials program when it was just a burgeoning idea way back when. And if number two is to take inspiration, take advice, take mentorship, number three is give. To flip that around and try to just give yourself and make yourself available to as many people around you, because that's how you build a community and that's how you give back and thank the people who give to you.

Dr. Maryjane Farr:

Okay, great. So, thank you. Thanks all of you. Four contemporaries who are leading the way into the future of cardiovascular medicine, science, and education. So, on behalf of Circulation on the Run, we have been so delighted and honored for you to spend some time with us, have a podcast about the podcasters. But you're not just podcasters, this is a real and amazing and innovative platform, and we are so excited to see where you go next. Any final, last words from Trey and Vanessa or Amit and Dan?

Dr. Vanessa Blumer:

Thank you so much to Circulation on the Run and Dr. Farr for this opportunity. Amit, Dan, like always, it's such a pleasure. I learn so much from you every single time that I get the opportunity to interact with the both of you and you are an inspiration to all of us. So thank you so much for this platform.

Dr. M. Trejeeve (Tre) Martyn:

Thanks to Dr. Farr for Circulation on the Run, for this platform, Amit and Dan for taking the time out of their evening to be here, Vanessa, for joining me in Cleveland. And I would say that you guys, the CardioNerds founders, you're an inspiration that you don't necessarily have to wait to make an impact.

Dr. Amit Goyal:

Yes. Thank you so much. I don't even know what to say. I'm speechless. I'll say that, for Dan and I, we're still just a couple of nerds. I do my recordings in my attic, Dan's in his home office. I think if you, we're still besides ourselves with disbelief that we are a topic of conversation for a platform like Circulation on the Run. It is absolutely a privilege and an honor for us. And so, I think all I can do is just say thank you so much, and then to Dr. Farr for the invitation to have this conversation for Circulation, and Dr. Hill for giving us this platform. I think this is just such a... Again, we are speechless. Thank you. Thank you so much.

Dr. Daniel Ambinder:

I'm equally as speechless and this podcast, Circ on the Run, really reminds me of my earlier roots, reaching out of my own institution, because it was a Circ social media team that first gave me a great glimpse at what happens outside of the institution that I had been training at for many, many years. And to see how the sausage is made, in terms of how research is vetted and undergoes a strict peer review, was really amazing. And I had the opportunity of meeting Dr. Hill and also being part of the team as COVID was revving up and Circulation had to... We're getting bombarded with all these COVID-related articles. And there was just a very important understanding that what gets published is going to be really, really important.

Dr. Daniel Ambinder:

So, watching that from the sidelines, under the mentorship of Dr. Amit Kara, just seeing how that happened, gave me such an important understanding that what you put out into the world, whether you're Circulation or writing a personal tweet or putting something out on CardioNerds is just really important and treat it as if it's something that's going to be there forever. And I learned so much about collaboration and I also learned so much about podcasting, because of Circ on the Run, it was actually the first podcast I was on and I don't like to listen to that very often. So thank you so much. This is such an honor to bring this full circle and come back and join you all.

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Roderick Tung, editorialist William Stevenson, and Associate Editor Sami Viskin as they discuss the article "First-Line Catheter Ablation of Monomorphic Ventricular Tachycardia in Cardiomyopathy Concurrent with Defibrillator Implantation: The PAUSE-SCD Randomized Trial" and the editorial "Can Early Ablation of Ventricular Tachycardia Improve Survival?"

Dr. Greg Hundley:          

Welcome listeners to this June 21st, 2022 issue of Circulation on the Run. And I'm Dr. Greg Hundley, associate editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Listeners, what a very interesting forum that we're going to have in this session today with Dr. Rod Tung, bringing us an article from first line catheter ablation of monomorphic ventricular tachycardia in cardiomyopathy with concurrent defibrillator implantation. Some results from the Pause sudden cardiac death randomized clinical trial.

This article is really interesting because it is collecting data from multiple centers from multiple countries in Asia. But before we get to that article, why don't we grab a cup of coffee and go through some of the other articles in the issue? Well, the first is entitled cardiovascular magnetic resonance for rejection surveillance after cardiac transplantation. And it comes to us from Dr. Jim Pouliopoulos from the Victor Chang Cardiac Research Institute. In this study, CMR based multiparametric mapping was initially assessed in a prospective cross-sectional fashion to establish agreement between cardiovascular magnetic resonance and endomyocardially based measures of cardiac rejection and determine the CMR cutoff values between various cardiac rejection grades.

Then after that, a prospective randomized noninferiority pilot study was undertaken in adult orthotopic heart transplant recipients who were randomized at four weeks post orthotopic heart transplant to either CMR or endomyocardially based rejection surveillance. And clinical endpoints were also assessed at 52 weeks. And so listeners, what did this investigative team find? Well, despite similarities in immunosuppression requirements, kidney function and mortality between the groups, the rates of hospitalization and the rates of infection were lower in the CMR group.

On 15 occasions, patients that were randomized to the CMR arm underwent endomyocardial biopsy for clarification or logistic reasons, representing a 94% reduction in the requirement for endomyocardially based surveillance. And so listeners, a noninvasive CMR based surveillance strategy for evidence of rejection in the first year after orthotopic heart transplantation is feasible. And interesting, listeners, these results really suggest the possibility for further studies to confirm whether CMR and perhaps in combination with other modalities could be used to survey orthotopic heart transplant patients for acute rejection without necessarily having to undergo endomycardial biopsy. There's an excellent editorial by Dr. Jim Fang from the University of Utah who also reviewed this paper.

Well, listeners, let's next turn to the world of preclinical science. And this paper comes to us from professor Simon Sedej from Medical University of Graz. It involves the insulin and insulin growth factor one or IGF-1 pathway. And that is known as a key regulator of cellular metabolism and aging. Now, although its inhibition promotes longevity across species, the effect of attenuated IGF-1 signaling on cardiac imaging really remains controversial. So what did the authors find? Well, they found that cardiomyocyte IGF-1R over expression in mice resulted in physiological hypertrophy and superior cardiac function in early life, but led to accelerated cardiac aging, heart failure and reduced lifespan in late life. Mechanistically, increased cardiomyocyte IGF-1R signaling accentuated cardiac dysfunction by reducing autophagy and mitochondrial oxidative capacity at old age, and therefore clinically pharmacologic inhibition of cardiac IGF-1R signaling in late life could suppress the age related deterioration of cardiac performance and perhaps increase lifespan. And therefore age should be considered as a major outcome determinant in future clinical trials, testing IGF-1R P13K inhibitors for cardiac benefits.

Well listeners, what is our next study? And this study is somewhat related to our feature discussion, which we'll get to in a few minutes. It's from Dr. Paolo Della Bella from San Rafael Hospital, and it is a two phase prospective multicenter randomized clinical trial that was performed to evaluate the benefit of ablation after first implantable cardiovert defibrillator, or ICD shock. And patients with ischemic or nonischemic dilated cardiomyopathy and primary or secondary prevention indication for ICD were enrolled in an initial observational phase until first appropriate shock. And that was phase A of the study. Then afterwards, they were re-consented and patients were randomly assigned in a one-to-one fashion in the second phase or phase B to immediate ablation. That's within two months from shock delivery or continuation of standard therapy.

And the primary endpoint of the study was a composite of death from any cause or hospitalization for worsening heart failure. And amiodarone intake was not allowed except for documented atrial tac-arrhythmias. So listeners, what were the results from this trial? Well, ventricular tachycardia ablation after first appropriate shock was associated with a reduced risk of the combined endpoint of death or worsening heart failure for hospitalization, lower mortality and fewer ICD shocks. And these findings therefore provide support for considering ventricular tachycardia ablation after the first ICD shock.

Now this study and the feature which will be coming up in a few minutes is nicely reviewed in an editorial from Bill Stevenson at Vanderbilt University. Well listeners, what other articles are in this issue? Well, from the mail bag, we have a research letter from Professor Solomon entitled Health Status Trajectories Before and after hospitalization for Heart Failure. Also, there is a second research letter from Professor Eikelboom entitled Rivaroxaban 2.5 Milligrams Twice Daily Plus Aspirin Reduces Venous Thromboembolism in Patients with Chronic Atherosclerosis. And then next there's an ECG challenge from Professor Rosenfeld entitled Around and Around, a Wide Complex Tachycardia.

Well listeners, what a great series of articles. And now we're going to get on and visit with Rod Tung, Sami Biskin and Bill Stevenson to evaluate first line catheter ablation of monomorphic ventricular tachycardia in cardiomyopathy, concurrent with defibrillator implantation.

Well, listeners, welcome to this June 21st feature discussion. And we're very fortunate today to have with us Dr. Roderick Tung from the University of Arizona in Phoenix. We also have our own associate editor, Dr. Sami Viskin from Tel Aviv Medical Center in Tel Aviv, Israel, and Dr. Bill Stevenson from Vanderbilt University in Nashville, Tennessee. Welcome gentlemen. Well, Roderick, we're going to start with you. Rod, can you describe for us some of the background information that went into the construct of your study and what was the hypothesis that you wanted to address?

Dr. Roderick Tung:         

Well, thank you, Greg, Pause is really the culmination of a lot of personal academic and cultural exchanges between many Asian centers and particularly in China. In terms of exchanges, where we would go across overseas, do a lot of different VT cases. And this all started in about 2013. And at that point in time, I was struck by a lot of differences that we were seeing, particularly whenever they wanted us to do a case, it tended to be a nonischemic etiology patient, and they always wanted to see some sort of epicardial procedure. And these are the ones that are enriched for epicardial substrates. As many listeners know, the ischemics tend to have more endocardially based scars. And that's why epicardial BT ablation is typically reserved for those that either have failed endocardial or those ARVC patients or non-ischemic cardiomyopathy.

So that was the first thing, is there's a paucity of ischemic cardiomyopathy in Asia, which is still inexplicable. The second thing that was really interesting in my observations going to Asia was that the defibrillator penetration and adoption is not widespread like it is in America. And in a very Amero-centric view, we always think that, oh, well, everything else is a departure from a standard of care. Well, when you look at 1.4 billion people, that's a really significant population at risk for sudden death that's not being treated the same way that we typically see it in a lot of Western cultures. So I felt like it was a perfect fertile grounds for clinical exploration. And that's really where Pause was born, is to be able to look at the impact of catheter ablation and ICD therapies on the risk of sudden death. And that's really how the trial began.

Dr. Greg Hundley:          

And what was the hypothesis, Rod, that you wanted to address?

Dr. Roderick Tung:         

Well, when we started designing Pause in 2014, 2015, there had only been two prior trials that were published and that was Smashed VT in New England Journal. And then there was VTAC by Karlheinz Cook in Lancet. So really the hypothesis was to be able to assess whether preemptive or first line catheter ablation at the time of defibrillator implantation, which is not what we do in the US, we usually wait till there's therapies, if that decreases the composite endpoint of recurrent VT cardiovascular hospitalization mortality.

Dr. Greg Hundley:          

Very nice. And so describe for us, Rod, your study population, and then the design that you use to address the hypothesis.

Dr. Roderick Tung:         

So this was a randomized controlled trial, multicenter across 11 centers in China, Korea, Japan, Taiwan. These were really well respected and regarded academic centers. I do want to give a shout out to many of them, Kyoko Sojima, who trained with Bill Stevenson, wrote so many seminal papers in VT. In Japan, Akid Nogogami who really was charged with and responsible for opacity some of the mechanisms of particular VT, then there's Yao Yin in Beijing who's done great work in atrial fibrillation, cardiac neuroablation. Ming Long Chen, Chan Yang Jeng. So some really great names, and it was done over 11 centers, one to one randomization between control, which was just ICD, and the active arm was ICD with catheter ablation within 90 days of the ICD implantation.

Dr. Greg Hundley:          

And how many patients, and then what were your study results?

Dr. Roderick Tung:         

So we ended up with 121 patients that were randomized, 61 versus 60, 180 were eligible and screened. And what was really also different about this trial compared to others is that we involved a non-randomized registry. Those were patients that refused to be randomized, and most typically didn't want to have a defibrillator. And that's where the cultural differences of ICD acceptance are different. For two reasons. Number one, physicians actually don't truly believe a lot of the defibrillator data is relevant to non ischemics in Asia and the Asian population. So there's actually a little bit of an academic barrier of generalizing historical ICD data to Asia, which I observed with a lot of the physicians.

And number two, patients sometimes don't want that technology in there, and they have different ideas of sudden death. So these patients were actually put into a registry and followed prospectively with catheter ablation alone without background ICD therapy. And that's very unique because the amount of data that has been prospectively followed for ablation sans ICD therapy is very few. So that was 47 in the registry. And there was 121 that was one to one randomized.

Dr. Greg Hundley:          

And what did you find?

Dr. Roderick Tung:         

Well, we found that those that underwent concomitant ablation with their ICD implantation that presented with monomorphic VT had a lower rate of the composite triple endpoint of VT recurrence, cardiovascular hospitalization, and death. This was largely driven by a nearly 20% absolute risk reduction in VT recurrence. There was a 4% absolute risk reduction in cardiovascular hospitalization, but this is not significant. And mortality rates were low. It was seven and 8% in those arms. So one of the things that we were hoping to get to was actually looking at mortality, but I think this is challenging with background ICD therapy there. And number two, it's challenging because mortality rates are lower in non-ischemic cardiomyopathy. And that's because they don't have the concomitant comorbidities of peripheral vascular disease, coronary artery disease, older age, cetera. So we actually had a pretty low rate of mortality, which we were hoping to get to, but that wasn't able to be assessed in this because of the low rates.

Dr. Greg Hundley:          

Very nice. Well, now listeners, we're going to turn to our own associate editor, Dr. Sami Biskin. And Sami, many papers come across your desk. What attracted you to this particular study?

Dr. Sami Viskin:

Well, we need to better define what is the optimal timing for VT ablation in patients with the organic heart disease. As we have seen many patients that are referred too late for ablation, where they already have an arrhythmic storm and recurrent shocks. And on the other hand, we have seen studies like the Berlin Study from Cook that fail to show any benefit on endpoints like heart failure or mortality. So the study by Tung arrived shortly after the different study by Paolo Della Bella, the PARTITA study, that was also studying patients at an earlier stage. So in the Partita study, they were studying patients at the time of the first ICD shock. And then Rod came with this study where he studied patients at the time of ICD implantation.

Now, usually authors ask to get an executive review of their article. In this occasion, we as the editors, we saw the opportunity and asked Rod to submit his paper as fast as possible and made the correction as soon as possible so we could get the two papers dealing with early VT ablation in the same issue with an invited editorial by Dr. Stevenson so we could put everything in context.

Dr. Greg Hundley:          

Very nice. Well, Bill, Sami has set you up very nicely here. And as the editorialist, help us put these results from Rod into the context of what we know already today in this sphere of investigation pertaining to VT shocks, defibrillator implantation.

Dr. William Stevenson: 

Yeah. So first I want to congratulate Rod on a very important study. It has been so difficult to conduct randomized trials of VT ablation and intervention, and to be able to bring this to fruition and internationally in Asia is really quite an accomplishment. We definitely need more information that guides us as to when VT ablation should be performed in people who have defibrillators and are having spontaneous episodes of VT. And we know that in patients with ischemic heart disease, with coronary artery disease, post infarct VTs, that catheter ablation can reduce the episodes of recurrent VT and reduce shocks from VT. And this is a very important quality of life issue for patients with defibrillators. But we haven't really had good data, certainly not randomized multicenter data in other patient populations. And we still are grappling with, does a reduction in VT episodes improve other outcome measures?

Does it really improve quality of life? Does it reduce hospitalizations? Does it translate to a reduction in mortality? And so Rod's study, one of the strengths of it being in Asia is that there were a lot of patients who had non-ischemic causes of heart disease. And more than a third of patients had arrhythmogenic right ventricular cardiomyopathy, and his study makes it clear that those patients really benefit substantially with a reduction in VT episodes. And that overall, VT episodes are reduced in all three of the subgroups of different diseases, the ARVC and the ischemics and the non ischemics that were included in the trial. But I think it's worth digging in a little more to the non-ischemics, because they did not seem to receive the benefit that the arrhythmogenic right ventricular cardiomyopathy and the ischemic cardiomyopathy patients received. So that the efficacy was largely driven by the benefit in the ischemics and the ARVC patients.

So one of the important considerations I think is when you're in your office with a patient who has a defibrillator and has had episodes of VT, and you're considering does this patient need a VT ablation? I think that if they've got ischemic cardiomyopathy, this data strongly supports that approach. If they've got arrhythmogenic right ventricular cardiomyopathy, again, ablation is very likely to reduce their episodes of VT/ for the non-ischemic group, which is about a third of the patient population that Rod studied, the data are less convincing in that group. And we know that's a harder group to achieve success with, with ablation. So we'll definitely want more data in that group. And I'm looking forward to some of the more detailed and sub-study sorts of analyses that I'm sure Rod is planning.

Dr. Greg Hundley:          

Very nice, Bill. Well, listeners, and Bill you've teed it up nicely to really sort of circle back through each of you and ask, what is the next study to be performed in this space? So we'll start with Rod and then Sami, and then finish up with you, Bill. So Rod, what is the next study that you see needs to be performed really in follow up to yours?

Dr. Roderick Tung:         

Well, we're thinking Pause too might be a nice just ARVC study alone, because again, inexplicably, there's a very high incidence of ARVC in Asia, and I was always taught that this was a disease from the Veneto region of Italy. And that might not be the case, or there's a lot of sarcoid mimicking of it as ARVC and undiagnosed. But we're thinking about a Pause too being an ARVC study, maybe without background I,CD therapy with background ICD therapy, this might provide justification for that. Because again, those in the registry did quite well, but that's because they were younger and had ARVC and normal LV function. So that might be a nice area to explore worldwide. And then lastly, just to put things in perspective for the Circ listeners, you need 8,400 patients in paradigm to show benefit mortality and heart failure hospitalization for an ARNI. Right? For IRNESTO.

We're talking about 120 patient studies when we talk about VT ablation, with these very complex ablation trials. So I think we just need larger trials. And the hard thing for us as VT ablation centers is we often will get patients that have had recurrent VT after a failed procedure. So it's hard to come by these that are very early, but I think we need 500 patient studies, a thousand patient studies. And also for the listeners, it's very hard to show mortality reduction with a background ICD therapy. And that's the problem, is that ICD is so effective as an abortive treatment that it's very hard to show reduction and mortality. You'd have to show it in terms of heart failure.

Dr. Greg Hundley:          

Very nice, Rod. And Sami, what would you like to add?

Dr. Sami Viskin:

Oh, obviously the last word on the optimal timing of VT ablation is not out there. And we need more studies to really define when is the appropriate time for the VT ablation. That's what we need.

Dr. Greg Hundley:          

Very good. And Bill?

Dr. William Stevenson: 

Yeah, I agree with Sami. And with rod, we need larger studies to assess the benefit, to really help guide our clinical decision making that can get at quality of life issues as well as the mortality and cardiovascular hospitalization issues in even more detail. But this is a wonderful first initial step into the ischemic, non-ischemic and ARVC populations.

Dr. Greg Hundley:          

Very nice. Well listeners, we want to thank Dr. Rod Tung from university of Arizona, Phoenix, Dr. Sami Viskin from the Tel Aviv Medical Center in Tel Aviv, Israel, and Dr. Bill Stevenson from Vanderbilt University in Nashville, Tennessee, for bringing us this study that highlighting among patients, particularly with ARVC in an ischemic cardiomyopathy from Asia across multiple centers in different countries that early catheter ablation performed at the time of ICD implantation really reduced the composite primary outcome of VT recurrence, cardiovascular hospitalization, or death. And these findings were really nicely driven by a reduction in the ICD therapies. Well, on behalf of Carolyn and myself, I want to wish you a great week and we will catch you next week, on the run.

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Christan Mueller, editorialist Christopher deFilippi, and Associate Editor Torbjørn Omland as they discuss the research article "Skeletal Muscle Disorders: A Non-cardiac Source of Cardiac Troponin T" and the editorial "Skeletal Muscle Disorders: A Non-cardiac Source of Cardiac Troponin T."

Dr. Greg Hundley:

Welcome, listeners, to this June 14, 2022, version of Circulation on the Run. I am Dr. Greg Hundley, associate editor and director of Poly Heart Center at VCU Health in Richmond, Virginia. This week I don't have my good friend Carolyn with me, but we will grab a cup of coffee and work through several of the articles in the issue.

Dr. Greg Hundley:

Well, first, I want to tell you about the feature discussion today, and we're going to interview with Christian Mueller and talk about the utility of cardiac troponin T and its association with an elevation in those individuals with skeletal muscle disorders, but, before we get to that, let's go through some of the other articles in this issue.

Dr. Greg Hundley:

Listeners, the first study comes to us from Professor Haidong Kan from Fudan university. These investigators conducted a time stratified, case crossover study among 1,292,000 acute coronary syndrome patients from 2,239 hospitals across 318 Chinese cities between January 1 of 2015 and September 30 of 2020 to determine the associations between sub-daily or hourly levels of criteria air pollutants with the onset of an acute coronary syndrome.

Dr. Greg Hundley:

Now, hourly concentrations of fine particulate matter, coarse particular matter, nitrogen dioxide, sulfur dioxide, carbon monoxide and ozone were collected, and the hourly onset data of acute coronary syndrome and its subtypes including ST segment elevation myocardial infarction, non-ST segment elevation myocardial infarction and unstable angina were obtained.

Dr. Greg Hundley:

Listeners, what did the investigators find? Well, their results indicated that transient exposure to the air pollutants of fine particulate matter, nitrogen dioxide, sulfur dioxide, and carbon monoxide, but not coarse particular matter or ozone may trigger the onset of acute coronary syndrome even at concentrations below the World Health Organization Air Quality Guidelines. Now, greater magnitude of associations were observed among patients that were older than 65 years in age or those without a history of smoking or chronic cardiorespiratory diseases and those in the cold seasons.

Dr. Greg Hundley:

Listeners, next, we're going to move from the study of air pollution to the world of preclinical science. Listeners, this study comes to us from Dr. Ming-Hui Zou from Georgia State University. Indoleamine 2,3-dioxygenase 1 or IDO1 is the rate limiting enzyme for tryptophan metabolism. IDO1 malfunction is involved in the pathogenesis of atherosclerosis, and vascular smooth muscle cells with an osteogenic phenotype promote calcification and features of plaque instability, but it remains unclear whether aberrant IDO1-regulated tryptophan metabolism causes vascular smooth muscle cell osteogenic reprogramming and arterial calcification.

Dr. Greg Hundley:

Listeners, what did this study find? Well, this investigative team and their results revealed the previously unrecognized protective role of IDO1 in arterial calcification in that vascular smooth muscle cells defective of IDO1 result in enhanced runt-related transcription factor 2 and ectopic calcium deposition in plaques. In contrast, administration of kynurenine via intraperitoneal injection markedly delayed the progression of intimal calcification in parallel with decreased RUNX2 expression.

Dr. Greg Hundley:

Also, listeners, the authors found that patients with coronary artery calcification have abnormal tryptophan metabolism, and serum IDO1 activity was inversely associated with calcification development in clinical settings, so, listeners, what are the clinical implications here? Well, this work reveals a protective role for IDO1 in mitigating arterial intimal calcification through kynurenine production and then, secondly, developing interventions toward the IDO1 kynurenine RUNX2 access may prevent the pathogenesis of arteriosclerotic complications.

Dr. Greg Hundley:

Well, listeners, a really interesting article, and now let's turn our attention to some of the other articles in the issue. Well, first, there's a Research Letter from Professor Modarai entitled “A Higher Incidence of Chromosomal Aberrations in Operators Performing a Large Volume of Endovascular Procedures,” and then, also, there is an AHA Update from our exiting AHA president who addresses “What Does the American Heart Association Do (and How Can You Help)?” Well, now, listeners, let's turn now to our feature related to a discussion of the utility of troponin T as well as troponin I in those with skeletal muscle disorders that may also present with acute coronary syndromes.

Dr. Greg Hundley:

Welcome, listeners, to this June 14 issue, and we're very excited today. We have with us Dr. Christian Mueller from the University Heart Center at Basel, Switzerland, Dr. Torbjorn Omland from the University of Oslo in Oslo, Norway, and Dr. Chris deFilippi from Inova Heart and Vascular Institute in Falls Church, Virginia.

Dr. Greg Hundley:

Welcome, gentlemen, and, Christian, we'll start with you. Could you describe for us some of the background information that went into your study, and what was the hypothesis that you wanted to address?

Dr. Christian Mueller:

Thank you very much for giving me the opportunity in this podcast to discuss our study with you and together with Torbjorn and Chris, who both contributed so enormously to the field with their own research. It's about cardiac troponin, cardiac troponin, an essential pillar in our early diagnosis of myocardial infarction. In this specific study, we tried to address possible non-cardiac causes of cardiac troponin T. In our clinical practice, we use and guidelines recommend both cardiac troponin T and I more or less as equivalent in providing identical information and, when going back from the clinical practice to biology, we have learned that, the troponin complex, that it is composed of three isoforms, T, I, and C.

Dr. Christian Mueller:

While they are very similar in their function, they are distinct regarding amino acid sequence in configuration in cardiac and skeletal muscle. As the cardiac form, of course, is the one that we are interested in, cardiac-specific assays have been developed both for cardiac troponin T and cardiac troponin I. As with any other tests in medicine, they are very good, but they may have limitations, and the specific questions that we had set for this study is whether skeletal muscle disease might be non-cardiac source for cardiac troponin T as measured in blood, therefore, with the possible harm of having false positive increases that could lead to a misdiagnosis of acute myocardial infarction.

Dr. Greg Hundley:

Very nice. We're trying to understand the utility of cardiac troponin T measures in those individuals that may have concomitant skeletal muscle disorders. Christian, what was your study population, and describe for us your study design?

Dr. Christian Mueller:

Our study had two components, a clinical component and a translational component. The clinical component included 211 consecutive patients that presented with active and chronic muscle symptoms to a workup either with a rheumatologist or a neurologist or internal medicine specialist, so more or less elective workup for muscle, skeletal muscle symptoms, to have a population that is broad and reflects all possible skeletal muscle disorders, their possible impact on cardiac troponin T concentration.

Dr. Christian Mueller:

In this population, we quantified cardiac involvement as this is common in some of these musculoskeletal disorders to be either major, minor or are not. They're according to patient history, according to … ECG and cardiac imaging, and we did the measurement of high sensitivity cardiac troponin using the high sensitivity cardiac troponin T assays used all over the world and three high sensitivity cardiac troponin I assays to look for mismatches, the percentage of patients that might have elevated T concentration, but not I as a possible sign that the T might be from the muscle, not the heart, particularly in those patients that didn't have any imaging evidence of cardiac involvement, and then we correlated the amount of high sensitivity cardiac troponin T with the amount of muscle injury as quantified by CK.

Dr. Christian Mueller:

In the translational part, those patients who have received a skeletal muscle biopsy with quantified by differential gene expression, the MRNA of the cardiac isoform of cardiac troponin T as well as of I in those patients who had the biopsy and matched it and compared it to controls to see whether the cardiac isoform would be upregulated in those with the cases of skeletal muscle disease.

Dr. Greg Hundley:

Very nice, and so, Christian, was this one single measurement at one point in time or did you have a series of measures over time?

Dr. Christian Mueller:

In fact, this is a large, ongoing project where patients will receive followup appointments. The current study reports the first phase versus single measurement at a single time point was performed.

Dr. Greg Hundley:

Very good. Christian, what did you find?

Dr. Christian Mueller:

We first found that even in those patients with active skeletal muscle disease, cardiac troponin T still reflected the presence of cardiac disease. Those patients with severe cardiac disease did have significantly higher concentration than those patients with mild or with no cardiac disease. That was the good thing. However, the more challenging one for this biomarker in this setting is that high sensitivity cardiac troponin T was significantly higher in these patients as compared to controls. We had the chance to have a couple of thousand controls from another study that presented with non-cardiac chest and no skeletal muscle disease and, while high sensitivity troponin I concentrations were similar, cardiac troponin T was elevated, resulting in a much higher prevalence of elevated T concentration versus elevated I concentration and corresponding mismatches in these patients.

Dr. Christian Mueller:

In the second part, we were able to show that there was a significant correlation between high sensitively cardiac troponin T with CK quantifying somehow muscle damage while this was not seen in the correlation with high sensitivity I, and that signaled that some of the systemic cardiac troponin T concentration seems to be derived from the muscle. It was confirmed in the translational part of the study in which the differential gene expression showed an eightfold over-expression of cardiac troponin T in skeletal muscle biopsies of those patients with disease, so with active skeletal muscle disease. This … expression correlated with disease activity, a pathological score that quantifies the extent of damage in the skeletal muscle history and correlated with the high sensitivity cardiac troponin T plasma concentration measured with the immunoassay.

Dr. Greg Hundley:

Very nice. Listeners, it sounds as if, in patients with skeletal muscle disorders, Christian's team observed an elevation in cardiac troponin T, but not necessarily cardiac troponin I, and you've got mechanistic understanding from the biopsies where you see this cardiac troponin T expression in the damaged skeletal muscles. Well, Torbjorn, you have many papers come across your desk. What attracted you to this particular paper?

Torbjorn Omland:

Thank you, Greg. I think, in general, when I receive papers from circulation, there are three main criteria I consider. The first is whether this is an interesting research question and then, second, whether the study is well-designed and the third is whether they're in themselves are novel, robust and interesting with potential clinical implications.

Torbjorn Omland:

For this specific papers, I must say it seemed to me to fulfill all these criteria and that it would be able to bring this field forward. The study of re-expression of troponin T in skeletal muscle is not entirely novel because it has been done in small samples, but mainly with rare and neuromuscular diseases previously, but this study broadened that or generalized that to a much more clinically relevant population. The clinical implications also seemed to be much greater than what has been reported by previous papers.

Dr. Greg Hundley:

Very nice. Listeners, we have in addition to Dr. Omland, we have another expert with us today, Dr. Chris deFilippi, really in the area of biomarkers particularly as they pertain to cardiac injury.

Dr. Greg Hundley:

Chris, now turning to you, how do we put the context of the results today really with the broader scope of what we have learned about cardiac troponin I and cardiac troponin T and then their use in diagnosing acute ischemic syndromes or even forecasting future cardiovascular events down the road?

Dr. Christopher deFilippi:

Thank you, Greg, and thank you Circulation for inviting me to participate in this podcast and to write this editorial. First, Christian, this was a terrific paper and one that was probably great to review during the pandemic because, as I spent a good Sunday peeling back layers of the onion and reiterating what Torbjorn said, this paper makes a tremendous contribution where there already was some knowledge to maybe the expression of the cardiac specific troponin T and skeletal muscle, but there's something there for everyone just to get the takeaway message, but for those who really want to delve in, there are supplemental tables that contribute a huge amount of nuance and detail that I think will help guide researchers in the future in maybe how to optimally use cardiac troponin T and troponin I both in the evaluation for acute myocardial infarction and then in a variety of chronic conditions, so first putting this in context of how you would evaluate patients with acute myocardial infarction, and that's the predominant indication for measuring a high sensitivity troponin T or troponin I.

Dr. Christopher deFilippi:

As Christian in an earlier study has shown and others have shown, actually, the correlation between a high sensitive troponin I by a variety of commercial assays. Troponin T is really pretty good. I think in one study from Christian's group, it was measured at 0.89. Now, the issue that's relevant is more around the edges. People who come in with just a low elevation and, as Christian pointed out and colleagues pointed out in the paper, using the ESC algorithm, a number of those patients would have qualified for myocardial infarction with the skeletal myopathies particularly the myositis or the non-inflammatory myopathy. If there is an index of suspicion for these disorders I think particularly around the cutoff for troponin T, one has to be cautious. Whether one can actually look at serial changes and try to differentiate that way I think is an open question. It may be.

Dr. Christopher deFilippi:

I think the other thing that gets quite interesting for me in an area that we've delved in over the past decade is the use of high sensitive troponin T or troponin I as a measure of chronic injury that's been codified in the fourth universal definition of MI published four years ago to identify individuals at risk. These can be individuals who are living in the community without known cardiovascular disease or actually without, perhaps, a lot of other comorbidities other than advanced age, for example, who an elevated troponin I or troponin I can be indicative of an increased risk for incident heart failure over the next five to 10 years. It can be patients with other chronic comorbidities.

Dr. Christopher deFilippi:

Actually, what drew me to this paper and thinking along these lines was a paper that Torbjorn had published back in 2013 where, using the key study which are individuals who have chronic ischemic heart disease without heart failure, he measured both troponin I and troponin T and found there was quite a discordance. There, we're looking at … value of about 0.4 and found that troponin I was a great predictor for the risk of coronary heart disease event and an acute myocardial infarction in the future, but T was not, but both T and I were good predictors of incident heart failure in the future.

Dr. Christopher deFilippi:

Other investigators, the … investigators, investigators from Scotland have also found this discordance between I and T in chronic ambulatory populations with or without comorbidities, and so it opens an interesting question in individuals with maybe conditions of pre-frailty or frailty or some element of sarcopenia, subclinical skeletal muscle disease. Does this cause this discordance? Ultimately, we know particularly with heart failure, with preserved ejection fraction, it is a systemic disorder, and measures of skeletal muscle disease may be relevant in ultimately determining who's going to have symptomatic heart failure.

Dr. Christopher deFilippi:

I think it really opens things wide open potentially to further investigation. Is this modifiable? Is it through intervention simply like physical activity? Could you see changes in cardiac troponin T that may be reflecting cardiovascular changes and skeletal muscle changes, but maybe not so much with I, and does this have relevant prognostic implications? I think I was really excited about it based on the defined pragmatic findings with respect to evaluating patients for myocardial infarction who have these underlying skeletal muscle diseases, but also implications, what this might mean in chronic disease populations as well.

Dr. Greg Hundley:

Very nice. Well, Chris, you've led us really to our next series of questions, and maybe we'll circle back with each of you, first, Christian. What do you see, Christian, as the next study to be performed in this space?

Dr. Christian Mueller:

I think the next study should address two aspects. The first one is I think we already, with the current population have found that skeletal muscle disease includes various pathologies, and as indicated by Torbjorn, the cardiac troponin T re-expression seems to be at least of our current understanding limited to the two groups of myositis and the muscular dystrophies, whereas the other skeletal muscular disorders at least in those that we have currently investigated did not seem affected. However, we were limited by the number of patients in this subgroup, and so for sure need a larger population to cover all aspects or all classifications of skeletal muscle disease in more detail.

Dr. Christian Mueller:

The second point that I'd like to highlight is the followup and to look for cardiac events and to look for cardiac changes, functional or anatomical changes in cardiac imaging, because it still may be that some of the T that is more commonly seen in this patient, that the majority of this is derived from the heart, so it's not a black and white, it's only from the muscle or only from the heart. It's still possible that some of the higher concentration of T found in these patients, as in many of the skeletal muscle systemic disorders, they have cardiac involvement which may not be identifiable by current imaging techniques at the first visit. This may become apparent during followup, and so these studies will help us to get a better quantitative understanding, so ideally to understand is it just a tiny amount, I don't know, 10, 20% of the systemic T concentration that is derived from the muscle? Then it would have a very different clinical implication as compared to if, I don't know, more than 50% of the systemic concentration would be derived from the skeletal muscle rather than the heart.

Dr. Greg Hundley:

Very nice. Torbjorn, I would like to turn to you. What do you see as the next study to be performed in this space?

Torbjorn Omland:

Oh, I agree with Christian that the serial assessment of changes of disease activity versus troponin changes would be very interesting to study in more detail and also correlate that to changes, for instance, by cardiac MRI if you can see whether there are actually correlations there. Long-term prognostic implications of skeletal muscle derived cardio troponin is another subject, and then, finally, I think that we do need to know even more accurately what is the impact of these alterations on the diagnostic workup in the acute coronary syndrome setting. Is it really a clinically important confounder? I think studies that could address that will be important.

Dr. Greg Hundley:

Very nice, and then finally Chris, and, Chris, I want to add just another question. Just from my listening to this, if I'm trying to identify someone with an acute ischemic syndrome and then they may also have an underlying skeletal muscle disorder, both Christian was talking about inflammation, but you brought in frailty and things of that nature. Should we really then turn clinically to measuring cardiac troponin I in this setting when we're trying to rule out, for example, acute myocardial infarction?

Dr. Christopher deFilippi:

Yeah. I don't want to overstate that. I mean, Christian's work and others have shown actually a high sensitive troponin T and a variety of different high sensitive troponin Is in a very heterogeneous chest pain population have been equivalent, looking at receiver operator curves area under the curbs, and so they're probably our people at the margins where this will make a difference, but it should be. Listeners should be reassured at this point because troponin T is a very common assay that it's still quite efficacious and accurate for the diagnosis of acute myocardial infarction from what we know, and a lot of Christian's work has identified this.

Dr. Christopher deFilippi:

Again, moving into the more chronic disease population outside the evaluation of acute myocardial infarction, maybe where we can use it as a differentiator, it could be helpful in some instances to look at interventions. Earlier work has shown in just small numbers of patients have been published, but patients with hypothyroidism, patients with statin-induced skeletal myopathies, the treatment of these has actually led to a decrease in high sensitive troponin I corresponding with decreases in CK, so there may be opportunities for lifestyle interventions like physical activity, and you could see that response and whether that has prognostic implications. This could be of interest for future research.

Dr. Greg Hundley:

Very nice. Well, listeners, what an incredible discussion today. We want to thank Dr. Christian Mueller from University Heart Center in Basel, Switzerland, Dr. Torbjorn Omland from the University of Oslo in Oslo, Norway, and also Dr. Chris deFilippi from the Inova Heart and Vascular Institute in Falls Church, Virginia, for really helping us understand that in patients... from this research, that in patients with active chronic skeletal muscle disorders, elevations in cardiac troponin T are common and may not be related to cardiac disease. These elevations were not observed in those with assessment of cardiac troponin I and, coming back to in the case of cardiac troponin T based on this wonderful biopsy work, the elevations of the troponin T appear related to re-expression of troponin T and skeletal muscle.

Dr. Greg Hundley:

Well, listeners, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week on the run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit aha journals.org.

This week, please join author Ratika Parkash and Editorialist Sean D. Pokorney as they discuss the article "Randomized Ablation-Based Rhythm-Control Versus Rate-Control Trial in Patients with Heart Failure and Atrial Fibrillation: Results from the RAFT-AF trial" and the editorial "The Evidence Builds for Catheter Ablation for Atrial Fibrillation and Heart Failure."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor, from the National Heart Centre and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature discussion, oh, so exciting. We enter the month of June, and it pertains to heart failure and atrial fibrillation. And we are going to learn a little bit more from the RAFT-AF trial, involving randomizing patients to ablation and rhythm control, as opposed to just settling for rate control for patients with AFib. But before we do that, how about we grab a cup of coffee and start with some of the other articles in the issue? Would you like to go first?

Dr. Carolyn Lam:

I absolutely would. And I will start by asking everyone a question. Could a single high-sensitivity cardiac troponin T level, below the limit of detection of six nanograms per liter, exclude an acute myocardial infarction? Well, you are going to find out because, remember that data for excluding AMI with a single high-sensitivity cardiac troponin level relies largely on the limit of detection, which is really a threshold of five nanograms per liter, which cannot be reported in the United States, per the FDA, because there, only the lowest reportable concentration is allowed, which is the limit of quantitation of six nanograms per liter.

Dr. Carolyn Lam:

So, today's authors Dr. Sandoval from Mayo Clinic and colleagues, very cleverly sought to determine whether a single high-sensitivity cardiac troponin T level below the limit of quantitation of six nanograms per liter could indeed identify patients at low risk for AMI.

Dr. Greg Hundley:

Very interesting, Carolyn. So we have the limit of quantitation and then the limit of detection. This is really intriguing. And of course, cardiac troponin T, as cardiologists, we receive a lot of requests for consults on this. So, what did this study find, Carolyn?

Dr. Carolyn Lam:

A total of over 85,000 patients were first evaluated in the CV data marked biomarker cohort, amongst which 29% had a baseline high-sensitivity cardiac troponin T level below this limit of quantitation of six nanograms per liter. Among 11,962 patients with this baseline high-sensitivity cardiac troponin below six nanogram per liter and serial measurements, only 1.2% developed acute myocardial injury, resulting in a negative predictive value of 98.8% and a sensitivity of 99.6%.

Dr. Carolyn Lam:

In an adjudicated cohort, among those with a non-ischemic electrocardiogram, only 0.2% had myocardial infarction or death at 30 days. So in summary, Greg, this is the largest study evaluating a single high-sensitivity cardiac troponin T level below this limit of quantitation of six nanograms per liter to identify patients at low risk for AMI.

Dr. Carolyn Lam:

And indeed, the present study demonstrates that a single high-sensitivity cardiac troponin level below six nanogram per litter is a safe and rapid method to identify a substantial number of patients at very low risk for acute myocardial injury and infarction.

Dr. Greg Hundley:

Oh wow, Carolyn, really informative study. Well, Carolyn, my next study comes from the world of preclinical science. And Carolyn, vascular smooth muscle cell phenotypic switching contributes to cardiovascular diseases. And epigenetic regulation is emerging as a key regulatory mechanism with the methylcytosine dioxygenase Tet2, acting as a master regulator of the smooth muscle cell phenotype.

Dr. Greg Hundley:

The histone acetyltransferases, HATs p300, and CBP are highly homologous and often considered to be interchangeable. And their roles in smooth muscle cell phenotypic regulation are not known. So Carolyn, these authors led by Dr. Kathleen Martin from Yale University School of Medicine assessed the roles of p300 and CBP in human vascular smooth muscle cells with knockdown in inducible, smooth muscle specific knockout mice, and in samples of human intimal hyperplasia.

Dr. Carolyn Lam:

Cool, Greg. So what did they find?

Dr. Greg Hundley:

Right, Carolyn. So, they found that p300 and CBP serve non-redundant and opposing function in vascular smooth muscle cell phenotypic switching and coordinately regulate chromatin modifications through distinct functional interactions with Tet2 or HDACs. And Carolyn, targeting specific histone acetyltransferases therefore may hold therapeutic promise for future cardiovascular disease interventions.

Dr. Carolyn Lam:

Oh, that's great, Greg. Well, to round it all up, there are some other papers in today's issue. There's a Research Letter from Professor Zhang, entitled “Single Nucleus Transcriptomics: Apical Resection in Newborn Pigs Extends the Time-Window of Cardiomyocyte Proliferation and Myocardial Regeneration.” There's also a Research Letter from Dr. Vaduganathan, entitled “Estimating the Benefits of Combination Medical Therapy in Heart Failure with Mildly Reduced and Preserved Ejection Fraction.” Ah, that's such a cool issue. Now, let's go on to our feature discussion. Shall we, Greg?

Dr. Greg Hundley:

You bet, and learn a little bit more about rhythm versus rate control in patients with heart failure and atrial fibrillation.

Dr. Carolyn Lam:

Our feature discussion today is about the long-awaited results of the RAFT-AF trial, and that is the randomized ablation-based rhythm control versus rate control trial in patients with heart failure and atrial fibrillation. Thank you so much, Dr. Ratika Parkash for joining us today as the first and corresponding author from Queen Elizabeth II Health Sciences Center in Canada, as well as Dr. Sean Pokorney, the editorialist from Duke University.

Dr. Carolyn Lam:

I am so, so excited to be discussing this paper. I really meant it. You know, as a heart failure cardiologist, we've been waiting for these results and trying to understand everything in context. So maybe, Ratika, could you please start off by telling us about the RAFT-AF trial and what you found?

Dr. Ratika Parkash:

Thank you, Carolyn. I'm happy to be able to talk about this study on behalf of the RAFT-AF investigators and my co-PI, Dr. Anthony Tang. So the trial... First of all, the rationale for the study, I think many of us, as heart failure or heart rhythm specialists, understand that in the past, we've done many trials looking at rate versus rhythm control, the AFFIRM trial being the largest, and then of course, specifically in heart failure patients, the AF-CHF trial, both of which were negative in reducing cardiovascular events and mortality in patients with or without heart failure, in terms of a rate to rhythm control.

Dr. Ratika Parkash:

One of the issues with those trials is that the form of rhythm control was antiarrhythmic drugs. So we have learned that catheter ablation is superior to antiarrhythmic drugs in maintaining sinus rhythm. And based on that premise, we decided to go forward with the RAFT-AF study.

Dr. Carolyn Lam:

That's great, Ratika, so thanks. And what were the results?

Dr. Ratika Parkash:

The main finding, so the primary outcome of the study was mortality and heart failure events. Heart failure events was defined as a heart failure hospitalization or any escalation of heart failure therapy that was done in the outpatient settings, including the use of intravenous Lasix in an emergency department setting.

Dr. Ratika Parkash:

So the main findings were that ablation-based rhythm control was not statistically significant in reducing mortality and heart failure events over rate control in patients with atrial fibrillation and heart failure. The study included patients both with preserved ejection fraction, as well as reduced eject fraction. And we did stratify based on ejection fraction at the entry point into the trial. The hazard ratio was 0.71 and the 95% confidence interval just crossed unity, ranging from 0.49 to 1.03 with a P value of 0.066.

Dr. Carolyn Lam:

Oh, ouch. So, thank you. And again, truly, congratulations on a very, very important trial. Sean, I said it before, I'll say it again, really, really loved your editorial. Could you put these findings in the context of... Maybe, start with even the most recent guidelines, the 2022 ACC/AHA/HFSA heart failure guidelines, which I believe gives catheter ablation a class 2A recommendation. Maybe, start from there, and how does this fall in place?

Dr. Sean Pokorney:

Yeah, no, absolutely. I think, first of all, it's a really important trial and it's great to have this additional data. I do think, as you said, that it's important to understand the context. We now have several recent guidelines that have commented on the role of catheter ablation in patients with heart failure.

Dr. Sean Pokorney:

You mentioned the most recent heart failure guidelines. We also have additional AFib guidelines and we have the 2019 AHA/ACC/HRS guidelines for atrial fibrillation that give catheter ablation a 2B recommendation in patients who have heart failure, to potentially lower mortality and reduce hospitalization. And it has a 2A indication in the 2020 ESC guidelines. And we're currently undergoing some revisions of the guidelines for atrial fibrillation, and there'll be new guidelines around atrial fibrillation coming out from AHA/ACC/HRS in the coming years. And so that will also be helpful, I think, to incorporate some of this additional data.

Sean Pokorney:

When you really look at the guidelines and see what's driving the guidelines, there are several trials now that are really driving the guidelines. And so I think, looking back on the data, we have the AATAC trial, which was a trial of 203 patients that looked at ablation versus amiodarone. And we have the CASTLE-AF trial, which had 363 patients in it and was looking at atrial fibrillation in patients with heart failure with reduced ejection fraction and defibrillators.

Dr. Sean Pokorney:

And when you put that data into context, the AATAC trial did find lower rates of death and hospitalization as a secondary outcome, and CASTLE-AF did identify a reduction in heart failure hospitalizations and death. At the three year follow-up, there was a statistically significant reduction, although the event number was lower than the previously sort of calculated target sample size.

Dr. Sean Pokorney:

And so in aggregate, these trials do show a modest evidence of benefit for clinical outcomes in this population. And that's where adding more data is really critical.

Dr. Carolyn Lam:

That's so true. And actually, Ratika, is there any plan for some meta-analysis or sort of adding the data? And if you could, also speak to, the trial was interrupted at some point, so how that may have impacted things as well.

Dr. Ratika Parkash:

Those are important questions. So, first of all, there is a planned longer term follow-up for the study, to look at whether or not following these patients out beyond our meeting follow-up of 37 months, it will actually produce a different result than what we observed in the current findings.

Dr. Ratika Parkash:

I think a meta-analysis is obviously going to show benefit for ablation-based rhythm control, based on the data that Sean had just described. One of the things that we'd need to keep in mind is that this trial, the RAFT-AF study really enrolled patients who were suitable for either ablation-based rhythm control or rate control. So it wasn't a study that looked at rhythm control only.

Dr. Ratika Parkash:

So, the CASTLE-AF trial had essentially two rhythm control arms. The medical therapy arm was, was amiodarone in that trial, versus catheter ablation. So patients could get rhythm control in both. And so, the types of patients that would've gotten into CASTLE-AF were different than the patients in our trial, even when you look at the reduced ejection fraction patients.

Dr. Ratika Parkash:

Having said that, our curves, when you look at the reduced ejection fraction group in our study does mirror what was observed in CASTLE-AF. So, even if a patient is not deteriorating initially with rate control, it appears that over time they begin to deteriorate. And that's what all of these trials have shown, is that patients do better with ablation-based rhythm control, the best form of sinus rhythm maintenance that we have.

Dr. Ratika Parkash:

And it takes time for them to deteriorate and it takes time to accrue those events. And this is evident in all trials of atrial fibrillation. You either need a very large sample size, like 15,000 patients, to look at heart failure in a short period of time, or you follow them longer, so that you can accrue those events.

Dr. Ratika Parkash:

In terms of the stopping of the trial, certainly, had we reached the sample size of 600, which was the intended sample size after recalculation during the study from 1000 down to 600, I believe we would have reached a positive outcome. But again, we hope that our longer term follow-up might shed some light on that. The interruption of the study was based on the DSMC decision and certainly could have affected the power of the study.

Dr. Ratika Parkash:

We have to remember that the other possibilities are that ablation-based rhythm control is not superior to rate control. And as someone who is pro-ablation, it's difficult to say that, but we see hints of benefit and we have to recognize that.

Dr. Ratika Parkash:

The other issue is that the secondary endpoints in our trial were all significant, as overall, it doesn't matter which group you looked at, NT-proBNP, six-minute walk test, quality of life, both for heart failure and atrial fibrillation, as well as ejection fraction, were all improved. And for many of the studies that have been done previously, those were the primary endpoints of those studies.

Dr. Ratika Parkash:

The idea of whether ablation-based rhythm control reduces heart failure per se, is from our study, purely from our study, we can't be a hundred percent certain. There's definitely a hint of clinical benefit there. From all the secondary endpoints, which are the current guidelines, is what they indicate ablation should be done for, is to improve quality of life. Our study was certainly supportive of that.

Dr. Carolyn Lam:

You know, Sean, I especially appreciated your discussion of these issues, the early stopping of the trial, the secondary endpoints. Could you know, share some of those thoughts?

Dr. Sean Pokorney:

I think it's really an important topic. I think that, again, as Ratika said, part of why this trial is so important is that many of the previous trials that have been published and many of the data sets have really looked at rhythm control versus rhythm control in this population, even including the analysis from CABANA, which included almost 780 patients from CABANA that had heart failure. And in that population, they did show a reduction in the composite primary endpoint of death, disabling stroke, serious bleeding, or cardiac arrest. And again, CABANA was, as well, a study of rhythm control with ablation versus medical therapy, most patients getting rhythm control in that medical therapy arm.

Dr. Sean Pokorney:

And so this data really is additive. I think that one of the challenges is always, how do we make sure to get the most information out of a clinical trial once we commit patients to that scientific process? And I think here, at least in retrospect, it's obviously unfortunate that the trial was stopped early. I think that more data would certainly be helpful.

Dr. Sean Pokorney:

I appreciate the fact that longer term data may help solve that gap and close that gap a little bit. I think that, I guess, it'd be interesting to hear from Ratika a little bit more about the process that was involved with interaction with the DSMC and stopping the trial.

Dr. Ratika Parkash:

Yeah. Thanks, Sean. That also is a very good question. The DSMC really evaluated the data, evaluated the progress of the trial, back in 2017. It had been six years since we'd started the study. The data they had, in fact, did not show any benefit to ablation-based rhythm control over rate control at the time. So the follow-up period at the time was around two years.

Dr. Ratika Parkash:

And again, if you look at our Kaplan-Meier curves, you can understand why they would have made that decision at the time, based on 363 patients for the data that was available to them. They had a futility index that they looked at. it was calculated. The cutoff for stopping of the study was 0.8, and it was 0.81. So, there was a 19% chance that the study was going to show any benefit. And based on that, plus the progress of the trial, they made a decision to stop the study.

Dr. Sean Pokorney:

Yeah. I think it's really important when we look at these decisions, that there was example when we talk about this in the editorial as well with the ISIS-2 trial, where early on in the data, ISIS-2 was a trial looking at aspirin versus placebo. And basically in that trial, when you looked early on at the events that were accumulating, there was really roughly no difference between aspirin and placebo. And ultimately, that trial became positive and was a really critical trial. And if it had been stopped at that point for futility, we wouldn't have had some really critical data.

Dr. Sean Pokorney:

So, it's always a challenging decision. And obviously, the decisions are trying to be made in the best interest of the patients. Here, it just shows how important this additional follow-up data is for this trial, for RAFT in particular. And ultimately, it'll be interesting to see, as you mentioned, as we add additional long-term follow-up, how that will affect the results.

Dr. Ratika Parkash:

Absolutely. So, we hope that our additional follow-up is of benefit to clarifying our results. The unfortunate issue, I agree, was the stopping of the study, but we do trust our DSMCs. We have them for a reason and they perform an important function. So, we have to pay attention of course, to how they see things and evaluate the... at the time.

Dr. Ratika Parkash:

The other thing we should keep in context is that ablation for those, that time period, is not the same as it is today. Our safety has improved. You may have noticed that there were some adverse events in the study with ablation, and we would expect it to actually be lower, but in this day and age, but at the time, contact force wasn't available.

Dr. Ratika Parkash:

There were some tools and techniques that we now have at our disposal, improved mapping systems and so on, that allow us to do a safer and more efficacious job. But even in the context of that, our sinus rhythm maintenance was almost 80 to 90% for patients that you wouldn't normally expect to have that much sinus rhythm.

Dr. Sean Pokorney:

Yeah. I think that's a really critical point. You made a lot of really important points there, actually. Obviously, the vision of the field of electrophysiology is shifting, as you mentioned. And with data from EAST-AFNET 4, we're really shifting towards earlier rhythm control, as well as additional ablation trials attest, stop AFib or stop AF.

Dr. Sean Pokorney:

So again, there have been several studies that have shown the benefits of earlier rhythm control, EAST-AFNET 4, I think, being obviously one of the most relevant, looking at addressing atrial fibrillation of population of patients who've been diagnosed within the last year, and showing that there was a benefit to rhythm control, although the majority of rhythm control in that study was antiarrhythmic medications.

Dr. Sean Pokorney:

I think in the heart failure population, the challenge with rhythm control is that we're a lot more limited in terms of the medical therapies that are available for these patients. And I think that's where ablation really plays in a more important role, because not only have you shown that it seems to be efficacious in this patient population, with a really high rate of rhythm control, but in a lot of these patients, it's often a safer alternative than antiarrhythmic therapy.

Dr. Ratika Parkash:

Absolutely. And we've already shown that amiodarone is ineffective in this population, in AF-CHF. So, using that drug does not seem to be, in a population that could go for an ablation, the appropriate approach.

Dr. Sean Pokorney:

Yeah. And as well, I think that's important. And when you look back at data from SCD-HeFT as well, there were some concerns with safety signals of amiodarone in patients with heart failure as well, from that study, again, likely related to the side effects of the medication itself.

Dr. Sean Pokorney:

So again, it is a complex patient population in terms of decision-making and management. And I do think, again, we talked a lot about the trial being stopped earlier than we would've ideally liked. I still think that the data that you guys produced is really important and critical and additive. Again, we're consistently seeing these modest treatment effects across multiple studies. And the fact that all the studies are pointing in the same direction is very reassuring.

Dr. Ratika Parkash:

Yeah. I was just going to comment on some of the points that Sean had raised, with respect to early rhythm control and the concept of atrial substrate, and how advanced atrial substrate with a negative remodeling effect in patients with heart failure or prolonged atrial fibrillation may not necessarily be in our patient's benefits to then try to intervene, and trying to get these patients early would be useful.

Dr. Ratika Parkash:

So in RAFT-AF, patients did not have to fail an antiarrhythmic drug in order to get into the study. So that, again, critical, very much along the lines of EAST-AFNET and EARLY-AF, which was also published, demonstrating benefit for early intervention.

Dr. Carolyn Lam:

Wow. Just, thank you so much, both of you. That was such a rich discussion, really, really unpacking very, very important elements of the trial, not just the trial results, but also the implications of what happens with trial conduct and execution and so on.

Dr. Carolyn Lam:

Again, thank you so much Ratika, for publishing this very important paper in circulation, Sean, for your beautiful editorial that put it all in context, the audience for listening today. From Greg and I, you've been listening to circulation on the run. Thank you for joining us today, and don't forget to tune in again next week.

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, please visit AHAJournals.org.

This week, please join author Ronald Goldberg, Editorialist Hertzel Gerstein, and Guest Editor Rury Holman as we discuss the article "Effects of Long-term Metformin and Lifestyle Interventions on Cardiovascular Events in the Diabetes Prevention Program and Its Outcome Study" and the editorial "Shouldn't Preventing Type 2 Diabetes Also Prevent Its Long-Term Consequences?"

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-host. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Centre and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Today. Oh, this feature discussion involves the glance of diabetes. Truly this interview, I felt like I was sitting among gurus and just learning so much about diabetes, the history and the whole topic is about long term metformin and lifestyle interventions on cardiovascular events in the Diabetes Prevention Program and its outcome study. Now, way more than that, we discussed. You have to have to listen. But okay, before that, let's summarize today's issue for our listeners. Shall we, Greg?

Dr. Greg Hundley:

You bet Carolyn. So the first paper that I've got to discuss today really comes to us from the world of interventional cardiology and it's led by Dr. William Fearon from Stanford University Medical Center. Well, Carolyn previous studies have shown quality of life improves after coronary artery revascularization, more so after coronary artery bypass grafting than after PCI. Now this study aimed to evaluate the impact of fractional flow reserve guidance, and current generation zotarolimus drug-eluting stents on quality of life after PCI compared with CABG.

Dr. Greg Hundley:

Now the study emanates from fractional flow reserve versus angiography for multi vessel evaluation or the fame three trial. And Carolyn, that's a multicenter international trial that included 1500 patients with three vessel coronary artery disease who were randomly assigned to either CABG or FFR guided PCI. Now, what did they assess? So quality of life was measured using the European Quality of life Five Dimensions. And we're going to abbreviate that EQ-5D questionnaire baseline, one, and then 12 months following the procedure. Also, Canadian cardiovascular class angina grade and working status were assessed at the same time points, and then also an additional time point in six months. And the primary objective was to compare the EQ-5D summary index at 12 months, and secondary endpoints included angina grade and work status.

Dr. Carolyn Lam:

Ooh, interesting Greg. So quality of life in the theme three trial. All right. So what did they find?

Dr. Greg Hundley:

Right, Carolyn. So the EQ-5D, so that... European Quality of life Five Dimensions summary index at 12 months did not differ between the PCI and CABG groups, but the trajectory over the 12 months at the one month time interval between PCI and CABG did differ. Now, the proportion of patients with the Canadian cardiovascular class or CCS2 or greater angina 12 months was 6.2% versus 3.1% respectively in the PCI group compared with the CABG group. Additionally, a greater percentage of younger patients, so those less than 65 years old were working at 12 months in the PCI group compared with the CABG group. So in summary, Carolyn, in the fame three trial, quality of life after fractional flow reserve guided PCI with current generation DS compared with CABG was similar in one year. And the rate of significant angina was low in both groups and not significantly different. However, the trajectory of improvement in quality of life was significantly better with PCI as was working status in those less than 65 years old.

Dr. Carolyn Lam:

Wow. Thanks Greg. Hey, guess what? It's time for Greg quiz. The next paper is about the Chocolate Touch Study. So, Greg, is this about, A, the benefits of eating chocolate? B, the benefits of chocolate mud baths? Or C, the benefits of a second generation drug coated balloon?

Dr. Greg Hundley:

So, Carolyn, I just have one question. Where in the world do we get the benefits of chocolate mud bath? I don't think that's right. I do love eating chocolate, but I am going to go with the benefits of the second generation drug coated balloon.

Dr. Carolyn Lam:

Yeah, yeah, yeah. I made it easy for you. All right. So first generation drug coated balloons have significantly reduced the rate of restenosis compared to balloon angioplasty alone. However, high rates of bailout stenting and dissections persist. The chocolate touch drug coated balloon is a nitinol constrained balloon designed to reduce acute vessel trauma and inhibit neointima formation and restenosis, so you were right, Greg. In today's study led by Dr. Shishehbor, from University Hospital's Harrington Heart and Vascular Institute at Cleveland, Ohio. They studied 313 patients with claudication or ischemic rest pain, and superficial femoral or popliteal disease. And randomized them one to one to the chocolate touch or Lutonix Drug Coated Balloon at 34 sites in the United States, Europe and New Zealand. The primary efficacy endpoint was drug coated balloon success defined as primary patency at 12 months. The primary safety endpoint was freedom from major adverse events at 12 months. A composite of target limb related death, major amputations, or reintervention. Both primary endpoints was assessed for non-inferiority and have met sequential superiority testing for efficacy was pre-specified.

Dr. Greg Hundley:

Interesting, Carolyn. So this nitinol constrained balloon designed to reduce acute vessel trauma. So, what were the results of this study?

Dr. Carolyn Lam:

So in this trial, the second generation chocolate touch drug coated balloon met both non-inferiority endpoints for efficacy and safety. And was more effective than the Lutonix Drug Coated Balloon at 12 months for the treatment of femoral popliteal disease. Cool, huh?

Dr. Greg Hundley:

Very interesting. Great summary, Carolyn. So Carolyn, my next paper comes to us from the world of preclinical science. And the impact of three dimensional chromatin topology on transcriptional dysregulation and pathogenesis in human dilated cardiomyopathy remains elusive. And so these authors led by Professor Lei Jiang from Guangdong Provincial People's Hospital, and Guangdong Academy of Medical Science, generated a compendium of 3D epigenome and transcriptome maps from 101 biobank human dilated cardiomyopathy, and non-filing heart tissues and mouse models to further interrogate the key transcription factor implicated in 3D chromatin organization, and transcriptional regulation in dilated cardiomyopathy pathogenesis.

Dr. Carolyn Lam:

Oh, wow. Sounds like a lot of work. What did they find, Greg?

Dr. Greg Hundley:

Right, Carolyn. So they found that enhancer promoter connectomes are extensively rewired in human dilated cardiomyopathy, which reside in pre accessible chromatin size and also hand one drives the rewiring of enhancer promoter connectome to induce dilated cardiomyopathy pathogenesis.

Dr. Carolyn Lam:

Okay, Greg. So what are the clinical implications?

Dr. Greg Hundley:

Right, Carolyn. So first, dilated cardiomyopathy enriched enhancer promoter loops identified in this study could be developed as novel 3D genomic biomarkers for dilated cardiomyopathy. And then second Carolyn, targeting hand one might be used as a novel approach for therapeutic intervention in patients with dilated cardiomyopathy.

Dr. Carolyn Lam:

Oh, nice. Greg. Well, also in today's issue, there's an On My Mind paper by Dr. Brook, entitled, “The Doctor is Out, New Tactics and Soldiers For our Losing Battle against Hypertension.” In another paper, we have Molly Klemarczyk bringing us highlights from the Circulation Family of Journals.

Dr. Greg Hundley:

Right, Carolyn. And also from the mailbag, there's a Research Letter from Professor Baggish, entitled, “Cardiovascular Outcomes in Collegiate Athletes, Following SARS-CoV-2 Infection: The 1-Year Follow Up From the Outcomes Registry for Cardiac Condition in Athletes.” Well, Carolyn, how about now we get onto that feature discussion and learn a little bit more about the long term metformin and lifestyle interventions on cardiovascular events in the Diabetes Prevention Program.

Dr. Carolyn Lam:

Hold on to your seats, everyone. Here we go. We know that lifestyle intervention and metformin have been shown to prevent diabetes. However, what is their efficacy in preventing the cardiovascular disease associated with diabetes development? Well, guess what? We're going to have data on that through today's feature paper and what a star crowd I'm talking to today. We have Dr. Ron Goldberg and he's a first end corresponding author from the University of Miami Diabetes Research Institute. We have the editorialist Dr. Hertzel Gerstein from McMaster University Population Health Research Institute. And a guest editor for this paper, Dr. Rury Holman from University of Oxford. I have to admit I'm starstruck. You gentlemen have totally defined the field. I cannot wait to learn more, but shall we start with you, Dr. Goldberg? Could you tell us a little bit more about your paper, what you did, what'd you found?

Dr. Ronald Goldberg:

So the background is that the Diabetes Prevention Program started in 1996 was a Diabetes Prevention Program to test the effects of intensive lifestyle intervention versus metformin, versus placebo on the prevention of diabetes in over 3000 individuals with impaired glucose tolerance, a form of prediabetes. And after demonstrating the efficacy of those interventions over about three years, we went on to do a follow up study in which the metformin group continued to receive it. Everybody got lifestyle because it worked so effectively. And we are now reporting after a further 18 years of follow up on the question of whether these interventions, now 21 years later, had any effect on cardiovascular outcomes. The background to that of course, is that people with prediabetes have a somewhat increased risk for heart disease and that rate increases as diabetes develops, particularly with severity of hyperglycemia and duration of diabetes. So, that was the study and we're now reporting on whether these interventions had a significant effect on the major cardiovascular.

Dr. Carolyn Lam:

Well, first Dr. Goldberg, congratulations on the foresight to get the informed consent and to plan ahead to be able to get these valuable data. But because I know this is going to be a critical point later. Could you tell us a little bit about the completeness of follow up and perhaps surveillance for outcomes before you share the results?

Dr. Ronald Goldberg:

Absolutely. So, 86% of the original randomized group of participants agreed to continue with a follow up study, so there was a loss at that point. And then of course, over 18 years of follow up, there's going to be a further loss. Some due to death and some due to loss to follow up. But despite that, I would say the group that entered the follow up study, we were able to maintain follow up in 85%.

Dr. Carolyn Lam:

Fantastic. And the results?

Dr. Ronald Goldberg:

The findings were that we found no significant effect of either of the two active interventions on our primary cardiovascular outcome, which was nonfatal myocardial infarction, stroke and fatal cardiovascular disease. We also had an extended outcome with more events in it, and similarly found no significant benefit or harm from either of those two intervention.

Dr. Carolyn Lam:

Oh, I love that paper. What a great, great, perhaps surprising conclusion that Dr. Gerstein loved the title of your editorial, you crystallize it. Shouldn't preventing type two diabetes also prevent long term consequences? So please tell us what was your thoughts when you saw this paper and how you frame it?

Dr. Hertzel Gerstein:

Thanks very much, Carolyn. And first of all, I was very impressed by the extensive amount of work and analysis done by Dr. Goldberg and his team. I thought that it's wonderful to see this sort of long term follow up. I've had the privilege in the past of speaking together with the DPP team on their trial and in their long term follow up. And I continue to be impressed by the extensive amounts of work and data collected and a rigor and academic value of the analysis. So, that was my very first impression and obviously it's a pleasure to write on this. I think the findings are clearly important and they both highlight the importance of long-term follow up as well as highlight the difficulties of long-term follow up in a study like this.

Dr. Hertzel Gerstein:

So this was a study done in a trial, originally done in a fairly young cohort of individuals who had very low risk for cardiovascular events. And over their 18 year follow up that Dr. Goldberg Ron described, the actual annual event rate for the primary outcome was 0.6% per year in that ballpark. Now, anybody... I've had the privilege as Ron Avery of doing many cardiovascular trials and we all know that we would never start a trial recruiting people with an event rate of 0.5% per year, 0.6% per year, because we would have to recruit 30,000 people and follow them for seven years in order to accrue enough events to be able to detect a clinically relevant benefit of the therapy. So because of this low event rate, the advantage was the long term follow up, the 26th year, I think it was in the end follow up. No, it was a 21 year median follow up period, because of the long follow up, you get a little bit away from the advantage of the low event rate.

Dr. Hertzel Gerstein:

But even then, over the course of the 21 years, there were only about 310 first cardiovascular events and most cardiovascular outcomes trials, for instance, we need close to at least a 1000, 500 to a 1000 is what we like to see. So that being said, it's perhaps not surprising that we didn't see a benefit of diabetes prevention because even if diabetes reduces the risk of a cardiovascular event by a quarter, by 25%, there would've only been a 50, 50 chance of detecting that with this particular cohort of people.

Dr. Hertzel Gerstein:

So I would say that the most conservative assumption is that diabetes prevention doesn't reduce the event rate by 25% or less or 30, but it's certainly... pardon me, by 25% or more, it could reduce it by 20%, 15% we would not have detected at all, or Ron would not have detected and his team would not have detected it with this thing. So I think that to me is the most important caveat in interpreting this does not mean that diabetes prevention has no effect on cardiovascular outcomes.

Dr. Hertzel Gerstein:

It means that diabetes prevention doesn't have a moderate or smaller effect. So, that's I think the most important message to take and as is even mentioned in the paper by Ron and the team is that there has been at least one diabetes prevention trial conducted in China many, many years ago that showed clearly that people who were randomly assigned to the diabetes prevention arm, 26 years later did have lower cardiovascular events and even death than people who were in the control arm. So, I think this adds to the story but it's clearly like everything, not the final word in this, but it certainly adds a lot of important data.

Dr. Carolyn Lam:

Oh, I would love to hear Dr. Goldberg's response to that. But before that, Dr. Holman, could I ask you to weigh in as well?

Dr. Rury Holman:

Yes. Sure. So, I agree with Hertzel that this is underpowered, but this is a question I've long wanted to see the answer to. And I congratulate Ron and his team for actually doing the work. All major studies should have long term follow up. People should be consented for life so that we can answer these questions. And Hertzel even though the power is perhaps minimal, we still need to do this analysis.

Dr. Rury Holman:

And if there had been a dramatic result, then we'd have all been very excited. I think one of the issues... one, if I could just bring it up, you mentioned the look ahead study in your discussion as being a negative dietary intervention. But I have a slightly different take on that. When you look at that paper in detail, what you see is that the people in the usual care group forgot quite a lot more risk factor reduction medications, and that's because their usual care physicians spotted the fact that their risk factor levels were higher than in the intensive care group, of course it was blinded at that point. But there's a whole point here is, in your paper you show an increase in the statin proportion, which is higher in the placebo group compared with the metformin and your intensive lifestyle, significantly so for the lifestyle one. So I'm just wondering whether even the low power was further blunted by the drop in effects of these other medications.

Dr. Ronald Goldberg:

Thanks very much for those comments guys, I think they're spot on. Let me first respond Hertzel with my thoughts on this, and then go over to your point, Rury. I think it's really interesting to look back over time and realize how much medical management has changed. And that goes right to your point, Rury, that doing a clinical trial like this where the primary care physicians are informed about what we're doing, what... communicated with on a regular basis, particularly when their patients develop diabetes, it just heightens the entire level of medical management. And I think you're absolutely right, but it's interesting to see what's happened to cardiovascular disease over the last 25 years, both in the general population and in the prediabetic population, the risk of cardiovascular disease has gone down. And then on top of that, we've got this very intensive cardio prevention intervention by primary care physicians, with high rates of statin usage, high rates of any hypertensive treatment, even the placebo group to your question, really lost weight.

Dr. Ronald Goldberg:

And they knew full well what was... and this was a very hands on type of study where our participants were really followed now for all these years, really became integrated with the research team. And so everybody knew what everybody else was doing. And so I'm sure the placebo effect was very strong, but I think nevertheless... Oh, and the last point I wanted to make was of course, the severity of the diabetes, even though 60% are developed diabetes, the severity of the diabetes was relatively mild. Even in those who developed diabetes, we know their average A1C was only about 6.7. And so I think that has a lot to do with blunting the acceleration effect of diabetes on cardiovascular disease. So, I think all of these factors contributed together to produce a negative result. But I think an important message, nevertheless.

Dr. Hertzel Gerstein:

I can highlight that point, that Ron was saying is that if diabetes prevention is going to prevent cardiovascular outcomes, it's going to do that because of a difference in glycemic exposure. The diabetes is by definition a disease of an elevated blood sugar. So if diabetes prevention prevents cardio, it means that the blood sugar's going to be lower than it would otherwise be. So if there's very little difference over the long term follow up in blood sugar because of co-intervention and therapy of all the treatment groups, then that would eliminate a lot of the benefits of diabetes prevention, because these are patients who are in this trial, who are being scrutinized even more than they would be if they were out there free range without being involved in any follow up. So, that's a spot on point. Rury, you wanted to comment.

Dr. Rury Holman:

Yeah. So, Hertzel just to expand on that. Obviously the glycemic impact on macrovascular disease is relatively modest compared to the impact on microvascular disease, which of course is what we all saw originally with type 2 diabetes. In fact, in KPDS35, when we looked or calculated what 1% reduction in A1C would do, it would only reduce stroke or MI by about 12 to 14%. So it's quite a shallow slope if you like. And your point is spot on is if that glucose levels are kept low by good treatment and good management role tell us about the great team they have. Then there was no room for a glycemic impact in this particular study. It's another question, whether you think metformin acts by different mechanisms to reduce cardiovascular disease, that's another question I had for Ron that he might like to address, is if there was a magic effect of metformin, why didn't we see that?

Dr. Ronald Goldberg:

And that's a really interesting question, Rury, because you may be aware that we published a paper a few years ago on our assessment of coronary calcification in a subgroup, in about 60% of the population who agreed to do this and who were eligible. And interestingly found that metformin did was accompanied by a reduction in the prevalence of coronary calcium in men, not women.

Dr. Ron Goldberg:

And the effect was actually when we did subgroup analysis, we found it was particularly strong in young men. And actually that gave us some sense of optimism that we might see something when we came to actual events. And of course, as you all know, metformin has beneficial effects on several cardiovascular risk factors. And so the question is whether there is some effect of metformin that might yet be identified, a coronary calcium after all is a surrogate of events and may take time, or it may be that... And we are really interested in the idea that both prediabetes and diabetes are heterogeneous. There's more and more interest in looking at subgroups of individuals who may be more predisposed. And it may be that metformin might have beneficial effects in some of those subgroups.

Dr. Hertzel Gerstein:

But also remember on the other hand, there was a lot of co-intervention with metformin in all groups after the trial was over. So all groups were offered metformin, et cetera. So even if metformin had an effect, it could have easily been washed out by the exposure of all the other groups to metformin during follow up. But Ron, you also touched on both the hope and the frustration too, because if we start thinking about subgroups, we can always think of subgroups. Yeah. But then the problem with subgroups is you have a study, let's say you have a cohort study with 7,000 or 10,000 people and it followed for five years and, oh, well the effect isn't in all 10,000, it's only in 20% of them. So now you have a study of 2000 people, that's not enough to detect an effect in a subgroup.

Dr. Hertzel Gerstein:

So, subgroups just eat away at power in an exponential, not a linear way, so that you just rapidly lose any ability to detect anything. And so, yes, this is going to work in people with these three snips on this gene, in this subpopulation. Good luck, that's the difficulty and the challenge of... We need to find sometimes better or more efficient ways of identifying outcome protective therapies, because we can't keep drilling into some groups because we just don't have the resources to find it really. I don't know what other people feel about that, but.

Dr. Carolyn Lam:

I'm personally so enjoying this conversation as I know the audience is and we covered a lot. I'm sure everyone wants to pick up the paper and the editorial. Now, we talked about being underpowered for the number of studies. We talked about profitable dilution of things like statins, antihypertensive agents, even the crossover of potential treatment in the placebo arm and so on. And then we started talking about, or is it the how you got there and the drug that was used. And here, please don't shoot me, but I just know I have the answers on behalf of everyone else's thinking it. What do you say of people who go, "Well, it's because it's metformin. What if it was an SGLT2 inhibitor? What if it was a GLP-1 receptor agonist?" And as you know, a lot of people say those would in spite of the effect on glucose.

Dr. Hertzel Gerstein:

I can quickly jump in. It's very clear. We've learned this in the last 10 years, is that there are glucose lowering drugs and there are glucose lowering drugs with benefits. And the GLP-1 receptor agonist and the SGLT2 inhibitors are glucose lowering drugs with benefits. They lower glucose, but they seem to have a separate cardioprotective effect. And with the SGLT2 inhibitors that cardioprotective effect does not seem to be related to the glucose lowering. There are a few meta regression analyses that suggest that with the GLP-1 receptor agonist, part of the cardioprotective effect is related to glucose lowering and part is not. And clearly mediation analysis with some of the trials have shown the same thing with the GLP-1 receptor agonist, not really with the SGLT2 inhibitors. So, maybe, that's my spin on this.

Dr. Carolyn Lam:

Dr. Holman.

Dr. Rury Holman:

Yeah. I was going to echo what Hertzel said in that regard, these other agents do have multiple effects. They change weight, they change blood pressure. And so other risk factors are brought into play other than glucose lowerings. We've already agreed, glucose lowering impact on cardiovascular disease is quite modest. I'd rather have it than not, but it wouldn't be my primary way to treat cardiovascular disease. And coming back to Ron's study, which is crucial today, the issue here is whether we could untangle an impact particularly of metformin, which has been foundation drug for type 2 diabetes for so long.

Dr. Rury Holman:

But clearly within the dataset we have here, underpowered it is. There are no clear messages in that respect, which is disappointing, but it doesn't mean that there isn't an effect. With longer follow up, with more data than you might see it. When the study... I'm coming for you Hertzel, was stopped for futility then the hazard ratio has changed, that often the way, not for the right way, but it's often what happens when you stop studies. I wondered if you wanted to comment on that aspect, because I know it's something that you've talked a lot about.

Dr. Carolyn Lam:

Dr. Gerstein. Did you want to?

Dr. Hertzel Gerstein:

I agree with what Rury said. I think the point you're making Rury goes back to power, and the ability to have enough people and enough events to detect and effect and that's clearly true, so...

Dr. Carolyn Lam:

Well, I hate to be the one to break the party up, but we have gone over time and intentionally so, there's just so much learning here. But Dr. Goldberg, could I give you the last say please? What do you think is the important clinical take home message of your paper?

Dr. Ron Goldberg:

Well, I think that the fact that we demonstrated that our study has been able to maintain really low levels of cardiovascular risk factors, low levels of A1C, even though that likely contributed to the negative finding still leaves the physician where the recognition that it is important to identify individuals with prediabetes to Institute Diabetes Prevention Programs, because I think it's entirely possible as I said earlier, and we've begun to identify them, subgroups of individuals who do progress more rapidly and who do warrant a more effective treatment, which would come from an early intervention program.

Dr. Carolyn Lam:

Wow. Thank you so, so much for that. Thank you so much. All three gentlemen for this amazing discussion. Well, audience, you heard it right here on Circulation on the Run from Greg and I thank you for joining us today and don't forget to tune in again next week.

Speaker 6:

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Sanjiv Shah, Editorialist Evangelos Michelakis, and Associate Editor Justin Ezekowitz as they discuss the article "Latent Pulmonary Vascular Disease May Alter the Response to Therapeutic Atrial Shunt Device in Heart Failure" and Editorial "Atrial Shunt Devices in Patients with Heart Failure and Preserved or Mildly Reduced Ejection Fraction and the Pulmonary Circulation: Promises and Concerns."

Dr. Carolyn Lam:

Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from The National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health, in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, I love today's featured article. It's all about heart failure with mildly reduced and preserved ejection fraction, talking about device therapy and the response to therapeutic atrial shunt device. Now, this is a very interesting discussion of how specifically selecting patients based on latent pulmonary vascular disease may hold some answers, but we're going to keep everyone hanging here. You've got to, got to listen to the discussion. But first, we'd like to tell you about some of the papers in today's issue. And I think Greg, you've got one to start us with, right?

Dr. Greg Hundley:

Absolutely. Carolyn, thank you so much. Well, this first paper comes from Dr. Eliot Peyster from the University of Pennsylvania. And Carolyn, the aim of this study was to leverage computational methods for analyzing digital pathology images from routine endomyocardial biopsies, to develop a precision medicine tool for predicting cardiac allograft vasculopathy, years before overt clinical presentation.

Dr. Carolyn Lam:

Ooh, interesting. Again, precision tools. So what did they find?

Dr. Greg Hundley:

Right, Carolyn. So there was a clinical predictive model that achieved modest performance on the independent test set, with area under the receiver operating curve of 0.7. But interestingly, a histopath- predictive model for predicting cardiac allograft rejection achieved good performance, with an area under the receiver operating curve of 0.8. Most importantly, however, a model, incorporating both clinical and histopathologic features, achieved excellent predictive performance, with an area under the receiver operating curve of 0.93.

Dr. Greg Hundley:

So in summary, Carolyn, these authors found that prediction of future cardiac allograft vasculopathy development is greatly improved by incorporation of computationally extracted histologic features. Their results suggest morphologic details, contained within regularly obtained biopsy tissue, have the potential to enhance precision and personalization of treatment plans for post heart transplant patients.

Dr. Carolyn Lam:

Aw, that's cool. Makes so much sense, but yet so novel. Thanks.

Dr. Carolyn Lam:

Well, for the paper I want to talk about, we are going to talk about dapagliflozin. Now we know the SGLT-2 inhibitor, dapagliflozin, improved heart failure and kidney outcomes in patients with Type two diabetes with or at high risk for cardiovascular disease, in the DECLARE–TIMI 58 trial. In the current paper, authors, led by Dr. Wiviott from the TIMI study group, aimed to analyze the efficacy and safety of dapagliflozin stratified, according to baseline systolic blood pressure.

Dr. Greg Hundley:

Ah, so an interesting question, since SGLT-2 inhibitors are known to reduce blood pressure. And given the concerns regarding the safety of SGLT-2 inhibitors, in patients with low to normal systolic blood pressure. So Carolyn, what did they find?

Dr. Carolyn Lam:

Nicely put Greg. So in patients with type two diabetes with, or at high risk of, atherosclerotic cardiovascular disease, dapagliflozin reduced the risk for heart failure hospitalizations and renal outcomes, regardless of baseline systolic blood pressure, with no difference in benefit for reduction in heart failure or renal outcomes, among patients with blood pressure from the normal range, all the way to severe hypertension. Moreover, there appeared to be no difference in adverse events of volume depletion, acute kidney injury, or amputations, across the levels of baseline blood pressure. So these results indicate that dapagliflozin provides important cardiorenal benefits in patients with Type two diabetes at high risk, the independent of baseline blood pressure.

Dr. Greg Hundley:

Oh, very nice, Carolyn. Well, my next paper comes to us from the world of preclinical science, and it's from professor Jeffrey Towbin and colleagues, at Le Bonheur Children's Hospital. So Carolyn, as we know, arrhythmogenic cardiomyopathy is an inherited genetic disorder of desmosomal dysfunction, and plakophilin-2 has been reported to be the most common disease causing gene when mutation is positive. Now in the early concealed phase, the arrhythmogenic cardiomyopathy heart is at high risk of sudden cardiac death before cardiac remodeling occurs, due to mis-targeted ion channels and altered calcium handling. However, the results of pathogenic plakophilin-2 variants on myocyte contraction in arrhythmogenic cardiomyopathy pathogenesis, really remains unknown. So Carolyn, these authors studied the outcomes of a human truncating variant of plakophilin-2 on myocyte contraction, using a novel knock-in mouse model, as well as evaluation of human subjects.

Dr. Carolyn Lam:

Oh, interesting. So what were the results from this plakophilin-2 knock-in mouse model?

Dr. Greg Hundley:

Right, Carolyn. So serial echocardiography, a plakophilin-2 heterozygous mice revealed progressive failure of the right ventricle, but not the left ventricle, in animals older than three months of age. Now next, adrenergic stimulation enhanced the susceptibility of plakophilin-2 heterozygous hearts to tachyarrhythmia and sudden cardiac death. Contractility assessment of isolated myocytes demonstrated progressively reduced plakophilin-2 heterozygous RV cardiomyocyte function, consistent with right ventricular failure, measured by echocardiography.

Dr. Greg Hundley:

And the next, Western blotting of plakophilin-2 right ventricular homogenates revealed a 40% decrease in actin. In contrast, plakophilin-2 heterozygous left ventricular myocytes had normal contraction and actin expression.

Dr. Greg Hundley:

And finally, Carolyn, Western blotting of cardiac biopsies revealed actin expression was 40% decreased in the right ventricles of end stage arrhythmogenic cardiomyopathy patients. So in conclusion, Carolyn, during the early concealed phase of arrhythmogenic cardiomyopathy, reduced actin expression drives loss of RV myocyte contraction, and that contributes to progressive RV dysfunction.

Dr. Carolyn Lam:

Wow. Thanks, Greg. Well, also in today's issue, there's an exchange of letters among Drs. Whitman, Ibrahim, and Løfgren, regarding physics at the heart of the matter, referring to the article, “Anterior–Lateral Versus Anterior–Posterior Electrode Position for Cardioverting Atrial Fibrillation.”

Dr. Greg Hundley:

Right Carolyn. And also in the mail bag, there's an On My Mind piece, from Professor Taegtmeyer, entitled, “The 2022 Beijing Winter Olympics, The Spotlight On Cardiac Metabolism.”

Dr. Greg Hundley:

Well, how about we get onto that feature article, and learn a little bit more about atrial shunts, and how they may be helpful in heart failure with preserved ejection fraction?

Dr. Carolyn Lam:

Ooh, can't wait.

Dr. Greg Hundley:

Well, listeners, we have a very interesting feature discussion today related to hemodynamics pertaining to interatrial shunt devices, in those with and without pulmonary hypertension. And we have, gosh, a repertoire of speakers today. We have Dr. Sanjiv Shah, from Northwestern University in Chicago, Dr. Evangelos Michelakis, from Edmonton Alberta, and our own associate editor, Dr. Justin Ezekowitz, also from Edmonton Alberta.

Dr. Greg Hundley:

Well, Sanjiv, we're going to start with you. Describe for us, some of the background pertaining to your study, and what was the hypothesis that you wanted to address?

Dr. Sanjiv Shah:

Great. Thanks, Greg. Thanks for having me today. Well, the background of our study is that, it was a subgroup analysis, or a secondary analysis, of the REDUCE LAP-HF II trial. Now this trial has been in the making for over 12 years, almost 13 years. It started out as an idea that was David Celermajer. David is a pediatric cardiologist in Australia, who had this idea that, in mitral stenosis patients, it's well known that, if there's a concomitant secundum ASD, a congenital secundum ASD, in these patients with mitral stenosis do better. They have a way to unload the left atrium, and distribute that blood to the systemic veins and the right atrium, the right side of the heart. And so could this be helpful in quote, diastolic, heart failure or HFpEF?

Dr. Sanjiv Shah:

And so, I started working with him about 12 years ago. This started out as a concept. It was studied in animal models, and then in humans, in open label studies, and then, in a first randomized controlled trial. Where we showed, that an intraatrial shunt device, an iatrogenic ASD, so to speak, put in humans with heart failure with risk preserved EF, results in a lowering of exercise pulmonary capillary wedge pressure. And so based on that data, we designed a pivotal trial, a Phase III trial, the largest trial of its kind, of heart failure with preserved and mildly reduced ejection fraction, to see if interatrial shunt device would improve outcomes. And we published that trial earlier this year in the Lancet. Unfortunately, it was a totally neutral trial. And when you have a neutral trial in any condition, but as we see often in HFpEF, the question is, was it neutral overall? Or was there a subgroup that benefited? And what we found in that trial was that, there were three predefined subgroups that came out that seemed like there was a difference.

Dr. Sanjiv Shah:

First, there was a sex difference. Women did better. Men did worse with the device. Then, there was right atrial volume. Those with bigger right atrial volumes did worse. If you had a smaller right atrial volume, you did better. But the most significant interaction and subgroup was exercise pulmonary artery systolic pressure.

Dr. Sanjiv Shah:

If the pulmonary artery systolic pressure was greater than 70 at 20 Watts of exercise, so just with a little bit of exercise, those patients did worse. And if PA pressure stayed low, the patients did better. And so we sought to further explore this to say, "Okay, what's exactly going on?" In a post hoc analysis, what's going on with the pulmonary vasculature during exercise, and how does that differentiate how patients potentially respond to the device? And that's what we hope to figure out.

Dr. Sanjiv Shah:

We hypothesize, that if exercise pulmonary vasculature resistance is lower, then the shunt can actually work, and blood can flow from the left to the right, into the lungs, and the right heart doesn't get too overloaded. And we know, that the normal response of the pulmonary vasculature is to vasodilate with exercise. And so, if patients had retained that response, the ability to do that, that they may benefit. And so, we sought to figure that out with this subgroup analysis.

Dr. Greg Hundley:

Sanjiv, it sounds like a really elegant, well thought out hypothesis. So what was your study design? And describe your study population.

Dr. Sanjiv Shah:

Yeah. This was a randomized controlled trial. And so this was 626 patients enrolled at 89 centers across the world. And it was really, heart failure with mildly reduced, so an EF of greater than 40, or preserved EF, and 93% of them had HFpEF. And what was unique about this trial is that we, this is the first trial really, that confirmed that these patients actually had heart failure, with mildly reduced or preserved ejection fraction. Most trials say, well, you have to have an elevated BNP, and you have to have some sign of structural heart disease, and maybe, a history of heart failure hospitalization. In this trial, every single patient had to undergo rigorous noninvasive echocardiography. And then, on top of that, they had to undergo exercise invasive hemodynamic testing. And people thought that it wasn't possible for 626 patients, but we did it. And every single patient had had an exercise pulmonary capillary wedge pressure greater than, or equal to, 25. And so this really was HFpEF. So it's a randomized trial.

Dr. Sanjiv Shah:

And then, beyond that, we did a subgroup analysis. So we looked on various subgroups, focusing on exercise PVR, and we really looked to see the effect on three outcomes. Number one, a hierarchical endpoint, a combination of cardiovascular death, ischemic nonfatal stroke, recurrent heart failure hospitalizations, and the KCCQ. And then the other two outcomes were just the individual recurrent heart failure hospitalizations, and the KCCQ. We looked at all of these, and tried to figure out if there are certain subgroups that benefit.

Dr. Greg Hundley:

Great detail. So Sanjiv, what did you find?

Dr. Sanjiv Shah:

Well, we found that, there's this group of patients, that during exercise, the pulmonary vascular resistance at peak exercise stays above 1.74 Wood units. Now that seems like an arbitrary number, but in fact, in older individuals that are healthy, when you exercise them, the PVR upper limit, the exercise PVR upper limit, is about 1.8. So we're right about the upper limit of where the PVR should be. And if it was above that, the patients actually did worse with the shunt device. They had a lot more heart failure hospitalizations. Their KCCQ got worse, didn't benefit. And if they were below that threshold, meaning they were, sort of compliant pulmonary vasculature, and it stayed compliant, or they vasodilated effectively with exercise, then they benefited from the device. And what we call this concept of exercise-induced pulmonary vasoconstriction, or inability to vasodilate, is latent pulmonary vascular disease.

Dr. Sanjiv Shah:

And so, if you have that latent pulmonary vascular disease, your win ratio is 0.6. That means you do worse. And if you don't have this pulmonary, this latent pulmonary vascular disease, your win ratio is 1.31. And that means, you do better with the device. And we saw very similar findings with the KCCQ. We saw similar findings with the recurrent heart failure hospitalizations.

Dr. Sanjiv Shah:

And the final thing is, we found that, we looked at various other subgroups, and it turned out that if there was no latent pulmonary vascular disease and no history of pacemaker, which we found was kind of associated with sex and right atrial volume, those patients, for about 50% of the group, actually did the best. And that was what we called, the responder subgroup.

Dr. Greg Hundley:

Thank you, Sanjiv. Well, listeners, we're going to turn now to our associate editor, Justin Ezekowitz. And Justin, you have many papers come across your desk. What attracted you to this particular manuscript?

Dr. Justin Ezekowitz:

So Greg, this paper kind of stood out for a number of different reasons, as I sent you. You're to be congratulated for a variety of reasons. But the number one is, pursuing the data from a neutral trial overall, to understand who might benefit and who might be harmed from a pretty novel device and way to treat patients in such a scale, that's not being done like this before. So it stands out by just the magnitude of number of right heart catheterizations, number of patients enrolled, number of procedures done. And all of those things really lead to us to be able to understand the area much better than I think we can in a human population.

Dr. Justin Ezekowitz:

Where this sits with other devices that are very similar, is hard to really know, if all devices are going to be the same or different, but your population is quite unique is if they're not all end stage, but they're sick enough to get into your trials. So there's this population we treat actively. And I wondered if you could touch on that continuous nature. And so for readers, there's this beautiful figure, which shows a continuous nature of exercise PVR. And I wonder if you could touch on that. Is this mid group, the group that we should target for our future therapies like this, or this needs further study?

Dr. Sanjiv Shah:

Well, I think it needs further study. I think the listeners should be aware that this is a post hoc analysis. We did pre-specify exercise PA pressure. This is one trial. But it makes a lot of sense, pathophysiologically. What we're doing here is we're shunting this excessive LA, overloaded LA, shunting the blood from the LA to the RA and into the pulmonary vasculature. Well, if that pulmonary vasculature can't accept that increased flow, the patient's not going to do well. And how can we simulate that? Well, we can simulate it with exercise. As the patient's pedaling on the bike, on the cath lab table, there's increasing blood flow to the pulmonary vasculature, and we're seeing what happens with the pulmonary vasculature. Does it vasodilate, does it not? And so, I think that's why we were excited about this finding.

Dr. Sanjiv Shah:

I do think that, there are at least seven other companies making shunt devices, interatrial shunt devices or therapies. And I do think, they need to pay attention to this and really look at this. Not all trials are doing exercise and basic hemodynamics, that needs to be done, I think. So it'll be really interesting to see.

Dr. Sanjiv Shah:

Now, one thing I will say is that, and I've written about this, this is a really interesting trial. Because the BNPs were lower, and so you would think, okay, these are patients that are less sick. And yet, their heart failure hospitalization rate was at least one and a half times higher than pharma Phase III trials. KCCQ was way lower, like 30 points lower. So there are these patients out there that are really sick, and they're the ones that I think, are where their life, their sort of quality of life, their outcomes, are being driven by the HFpEF. And that's what we found in this trial.

Dr. Greg Hundley:

Very nice. Well, listeners, let's turn now to our editorialist, Dr. Evangelos Michelakis. And Evangelos, two questions. How do we put the results of this substudy, really in the context of the main trial? And then secondly, do you have any, with your expertise in endothelial function, and understanding the mechanisms of pulmonary hypertension, can you describe what you think might be operative as a mechanism here, and why Sanjiv observed these positive results in some patients?

Dr. Evangelos Michelakis:

Thank you. So the first point is that, I have to also repeat, that it was a remarkable achievement to do all this right heart catheterization on a treadmill in the cath lab. It's a very complex procedure. And it is, they have to be congratulated, the authors, for actually doing this. There is no question that, like Sanjiv said, ongoing trials for future trials will need to include the hemodynamics in the trials, before and after the procedure.

Dr. Evangelos Michelakis:

So another important thing is that, the authors brought up this, they called it latent pulmonary hypertension, we could call it latent pulmonary hypertension, or probably, early pulmonary hypertension, as an entity. Now that entity, it's newer in the heart failure field. It's not that old in the PIH, the pulmonary interior hypertension field, since it used to be in the guidelines for this disease, that exercise pulmonary hypertension was a diagnostic criterion for that. Because the idea is that, exercise pulmonary hypertension reflects early pulmonary hypertension. So you needed to intervene with therapies early.

Dr. Evangelos Michelakis:

Now, I'm not sure that this is a fact. But it is very likely that these patients, in Sanjiv's trial, that had the early, that had the sort of enhanced response with exercise, did have at least, endothelial dysfunction in the pulmonary arteries. Not only because this population has a number of endothelial risk factors, diabetes, smoking, you name it. But also, there are newer problems like SNPs polymorphism mutations, that will recognize more into the pulmonary arterial hypertension field, to be more unique to the pulmonary circulation.

Dr. Evangelos Michelakis:

But the reason I say that is that, the reason that you dilate with exercise, is mostly because of your pulmonary arterial endothelial cells, secreting vasodilatory factors. And also, allowing previously closed capillaries to open up with increased flow. However, the problem is that, if you have pulmonary arterial endothelial cells in vitro, and you expose them to high flow, like in this case, you can actually change their identity. Turn them into cells that are not endothelial cells anymore, are proliferative pro-inflammatory, and they can actually cause structural pulmonary circulation damage.

Dr. Evangelos Michelakis:

Also, there are animal models and people working in PAH and ASD, where they've shown that, if you have, if you're given endothelial toxin in animals, and then, you do an aortocaval shunt, then you get really severe pulmonary hypertension with structural disease, that is not even reversible if you remove the shunt.

Dr. Evangelos Michelakis:

So from this trial, the conclusion that patients with pulmonary hypertension should not get the device, is very clear. And probably, the ones with exercise pulmonary hypertension. My theoretical concern is, for those that don't have exercise pulmonary hypertension, or those that do have it, could they get worse after a number of years, and have structural pulmonary vascular disease? And unfortunately, we didn't have a follow up right heart catheterization to prove that, whether this is right or wrong. Which is a thing, is the most important thing to do in the future. So mimic the protocol for this trial from now on, but also add a follow up right heart catheterization, perhaps not just in a year, but longer. In other words, enough time to allow the structural pulmonary remodeling get established, but also, affect the right ventricle, these things don't. So maybe in a few years. It's a very demanding thing for these protocols, but I think, that's what needs to be done before we say this device can actually be beneficial for those patients, or for some patients, or not hurt others.

Dr. Greg Hundley:

Very nice. And so, a great segue, Evangelos, into what we think the next studies may need to be performed in this particular sphere of research.

Dr. Greg Hundley:

So Sanjiv, in just 30 seconds, could you share your thoughts first, and then we'll circulate back to Justin, and then finish up with Evangelos. Sanjiv?

Dr. Sanjiv Shah:

Yeah. I think the key thing is, to do a confirmatory trial. And that's what we're aiming for, is to do a confirmatory randomized sham-controlled trial, but focus in on these patients with an exercise peak PVR of less than 1.75, around there. And I think, that'll help answer the question. The Qp/Qs we get with this device is 1.2 to 1.3. So I don't think it's a high flow. And we actually have open label studies, where we've gone out to three years, with repeat invasive hemodynamic testing, echocardiograms, and we've had patients who've been implanted for seven years. We're not seeing, at least at that point, any sort of worsening of pulmonary vascular disease, or RV function, or anything like that. And so, it remains to be seen.

Dr. Sanjiv Shah:

The last thing I'll say, which I think is provocative, in the field of HFpEF, all pulmonary vasodilator drugs have failed. And though, we only measure pulmonary vascular resistance at rest. And what we saw in this trial, is that some patients have a high PVR and it comes down. Some people have a PVR that stays low, and is low and stays low. Some people have a low PVR and it goes up. You know? So I think what we need to think about in the field of PH‐HFpEF, is more exercise genotyping, to determine what's the dynamic exercise PVR? And maybe, those with exercise elevation of pulmonary vascular resistance are the ones that respond to pulmonary vasodilators. So that's another thing that I think we can think about taking away from this trial.

Dr. Greg Hundley:

Thank you, Sanjiv. Justin.

Dr. Justin Ezekowitz:

Yeah. So my thoughts are mimicking Sanjiv's. But one of the things that we desperately need is, ways in which we can noninvasively assess the exercise PVR, so that we can think about the large scale interventions that might come down the road, if interventions such as this work well. Because the noninvasive scans will really help us look at broader populations. Those are, that don't make it into trials, and those that aren't traditionally in our studies of HFpEF. So I think, that's another area where we can really grow the field, and then, grow our knowledge.

Dr. Greg Hundley:

Very nice. And Evangelos.

Dr. Evangelos Michelakis:

So, yes. Of course, like everybody said, we need trials that will have a follow up right heart catheterization, at least address, if not both, like the investigators did. But because the big question is, are these patients having an earlier stage pulmonary hypertension or not? These patients that the authors called, latent pulmonary hypertension, we need to phenotype more their endothelial cells, or their disease. And in the absence of biopsies, the only way we could do that, is perhaps, with molecular imaging, or at least, in some small populations. Or with analyzing pulmonary arterial endothelial cells in the blood, and their molecular phenotype, to see if they are a distinct group, which I suspect they may be. So further genotyping of this exercise induced pulmonary hypertension in this population, will be important as well.

Dr. Greg Hundley:

Thank you. Well, listeners, we've had a great discussion today, from Dr. Sanjiv Shah, from Northwestern University in Chicago, our editorialist, Dr. Evangelos Michelakis, from Edmonton, Alberta, and our own associate editor, Dr. Justin Ezekowitz from Edmonton, who brought us this study, demonstrating that in patients with heart failure and preserved ejection fraction, or heart failure and mildly reduced ejection fraction, the presence of pulmonary vascular disease, uncovered by invasive hemodynamic exercise testing, identifies patients who may worsen with atrial shunt therapy. Whereas, those without pulmonary vascular disease may, at least in the short term, benefit. And of course, as Evangelos has pointed out, the long term findings really warrant further study.

Dr. Greg Hundley:

Well listeners, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week on the Run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors, or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author David Kandzari and Associate Editor Wanpen Vongpatanasin as they discuss the article "Effect of Alcohol-Mediated Renal Denervation on Blood Pressure in the Presence of Antihypertensive Medications: Primary Results From the TARGET BP I Randomized Clinical Trial."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240607.177703

This week, please join author Andrew Stokes as he and Greg Hundley discuss the Research Letter "E-Cigarette Use and Risk of Cardiovascular Disease: A Longitudinal Analysis of the PATH Study (2013–2019)."

Dr. Greg Hundley:

Well, listeners, welcome to this May 17th issue of Circulation on the Run. And I am Dr. Greg Hundley, associate editor, director of the poly heart center at VCU Health in Richmond, Virginia. And this week, Carolyn is away out on vacation and we are going to go through the summaries together. We have a great feature today on e-cigarette use and the risk of cardiovascular disease. But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue? And the first one comes to us from the world of clinical science and Dr. Jiaqi Huang from the National Cancer Institute. Listeners, the objective of this study was to examine overall and cause-specific mortality in relation to dietary and serum cholesterol, as well as egg consumption through the prospective analysis of 27,000 men in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention or ATBC Study, and also a systematic review and meta-analysis of several other cohort studies.

Dr. Greg Hundley:

So, what did the investigators find? Well, first, based on 482,000 person-years of follow-up, the authors identified 22,000 deaths, including 9,110 deaths from cardiovascular disease. Now, greater dietary cholesterol and egg consumption were associated with increased risk of overall and cardiovascular disease mortality. Now, second, from the meta-analysis component of the study, overall consumption of one additional 50-gram egg per day was associated with an increased cardiovascular disease risk with a pooled relative risk of 1.04 with a higher risk of cardiovascular disease among those from us cohorts where their pooled relative risk ratio was 1.88, a borderline higher cardiovascular disease risk in European cohorts with a pooled relative risk of 1.05, but not an increased cardiovascular disease risk in the Asian cohorts. So, the results from this study, which includes an updated meta-analysis, suggest that there is support for restricted consumption of dietary cholesterol as really a means to improve long-term health and longevity.

Dr. Greg Hundley:

Well, let's go to our next article. So, in this next study, we are going to move from cholesterol risk now to salt substitution. And this article comes to us from Professor Maoyi Tian from the Harbin Medical University. Listeners, the Salt Substitute and Stroke Study, or SSaSS is a five-year cluster randomized controlled trial and demonstrated that replacing regular salt with a reduced sodium added or potassium salt substitute reduced the risk of stroke, major cardiovascular events, and premature death among individuals with prior stroke or uncontrolled high blood pressure that lived in rural China. So, this particular study, a substudy, assessed the cost-effectiveness profile of this particular intervention.

Dr. Greg Hundley:

So, listeners, what did the study find? Well, there was a mean follow-up of 20,995 participants that was conducted a little over four years, and over the period, replacing regular salt with salt substitute reduced the risk of stroke by 14% and the salt substitute group had on average 0.054 more quality-adjusted life years per person. The average costs were lower in the salt substitute group, and this intervention was dominant. That is better outcomes at a lower cost for prevention of stroke as well as for quality-adjusted life-years gained. Now, interestingly sensitivity analyses showed that these conclusions were robust except when the price of the salt substitute was increased to the median and highest market prices identified in China. The salt substitute intervention had a 95% probability of being cost-saving and a greater than 99.9% probability of being cost-effective. A really interesting article.

Dr. Greg Hundley:

Well, now, let's turn our attention to the world of population science. And in this study, these authors led by Dr. Steven Lubitz from Massachusetts General Hospital performed a Genome-Wide Association Study or GWAS of the QT corrected interval among 84,630 United Kingdom Biobank participants. And they created a polygenic risk score. Now, among 26,976 participants with whole-genome sequencing and electrocardiogram data in the Trans-Omics for Precision Medicine or TOPMed program, they identified 160 carriers of punitive pathogenic, rare variants in 10 genes known to be associated with the QT interval.

Dr. Greg Hundley:

So, the authors here examined the QTC corrected associations with the polygenic risk score and with rare variants from the TOPMed cohort. So, what did they find? They found 54 independent loci by GWAS in the UK Biobank. 21 loci were novel of which 12 were replicated in TOPMed. The polygenic risk score comprising over a million common variants was significantly associated with the QTC in TOPMed, and carriers of punitive pathogenic rare variants had longer QTC intervals than non-carriers. Now, 23.7% of individuals with a QT corrected of greater than 480 milliseconds carried either a monogenic rare variant or had a polygenic risk score in the top decile. 3.4% for monogenic and 21% for the top decile of the polygenic risk score.

Dr. Greg Hundley:

So, listeners, the findings of this study indicate that the QTC duration in the population is influenced by both rare variants in genes, underlying cardiac repolarization and polygenic risk, with a sizeable additional contribution from polygenic risk. And therefore, comprehensive assessment of the genetic determinants of QTC prolongation should include incorporation of both polygenic and monogenic risk.

Dr. Greg Hundley:

Well, listeners, let's turn our attention to the world of preclinical science. And this next article comes to us from Professor Junbo Ge from the Department of Cardiology in Zhongshan Hospital in Fudan University. Well, listeners, after myocardial infarction, cardiac resident macrophages, which are self-maintaining in that they originate from embryonic hematopoiesis are responsible for the efficient clearance and degradation of apoptotic cardiomyocytes. And that process is called efferocytosis. Now, efferocytosis is required for inflammation resolution and tissue repair. However, the underlying molecular mechanisms of this process really remain unknown.

Dr. Greg Hundley:

So, as such, listeners, these authors sought to identify the mechanisms of the continued clearance and degradation of phagolysosomal cargo by cardiac resident macrophages during myocardial infarction. Well, what did Dr. Ge and colleagues find? Several things. First, they identified legumine as a gene specifically expressed by cardiac resident macrophages, and legumine deficiency resulted in a considerable exacerbation in cardiac function, accompanied with the accumulation of apoptotic cardiomyocytes and a reduced index of in-vivo efferocytosis in the border area of infarcts. Furthermore, the formation of LC3 to dependent phagosome around secondary encountered apoptotic cardiomyocytes was disabled. In addition, legumine deficiency increased infiltration of MHC to high CCR2+ macrophages, and the enhancement of recruitment of MHC to low CCR2+ monocytes with downregulation of anti-inflammatory mediators, such as IL10 and TGF-beta, and upregulation of pro-inflammatory mediators, including interleukin-1-beta, Tumor Necrosis Factor alpha, IL6, and IFN-gamma.

Dr. Greg Hundley:

So, listeners, in summary, the results of this study directly link efferocytosis to wound healing in the heart and identify legumine as a significant link between acute inflammation resolution and cardiac function after infarction. Well, listeners, also in this issue, we have a wonderful On My Mind feature from Professor Camlet entitled “A Role for the Vascular Endothelium in Post-Acute COVID-19.” Well, next, we're going to head to our feature article on e-cigarette use and the risk of cardiovascular disease.

Dr. Greg Hundley:

Well, listeners, welcome to our feature discussion today. A very interesting topic. E-cigarette use and the risk of cardiovascular disease. And we have with us today the senior author of this particular manuscript, Dr. Andrew Stokes from the Boston University School of Public Health in Boston, Massachusetts. Welcome, Andrew. Andrew, to get started, can you describe some of the background information pertaining to your study and what was the hypothesis that you wanted to address?

Dr. Andrew Stokes:

Absolutely, and thank you for having me on the podcast. Despite the increasing popularity of electronic cigarettes, the long-term health effects of habitual e-cigarette use remain unclear. Most of the studies that have been conducted to date are either cross-sectional or they pertain to small clinical samples. The goal of the present study was to develop a longitudinal design to see if e-cigarette use at a point in time was linked to cardiovascular events over a multi-year follow-up period.

Dr. Greg Hundley:

Very nice. So, your specific hypothesis really pertained to e-cigarette use, correct?

Dr. Andrew Stokes:

That's right. As a novel product, information on e-cigarette use and its health effects is lacking, and so our goal was to see if e-cigarette use was associated with the incidence of clinical events.

Dr. Greg Hundley:

And so, can you describe for us your study population and your study design?

Dr. Andrew Stokes:

Absolutely. Data come from the Population Assessment of Tobacco and Health Study or the PATH Study, which is a nationally representative cohort study of the non-institutionalized population containing five annual waves of self-reported data collected between 2013 and 2019. The initial sample included over 30,000 US adults ages 18 years and older with oversampling of tobacco users. We excluded respondents who were lost to follow-up or who had a previous diagnosis of CVD or were missing baseline exposure information. Ultimately, we ended up with a sample of just over 20,000 individuals.

Dr. Greg Hundley:

Very nice. And so, what were your study results?

Dr. Andrew Stokes:

So, we had several key findings. One key finding was that, compared to people who only smoke cigarettes, people who smoke both traditional cigarettes and used e-cigarettes had no significant reduction in risk for heart attack, heart failure, or stroke, nor any cardiovascular disease outcome. This is significant because many e-cigarette users use both e-cigarettes and cigarettes in combination. Very few move to exclusive e-cigarette use. Additionally, we found that those who do move to e-cigarette use exclusively though, representing a very small fraction of the cohort, had some evidence of reduction in cardiovascular harm. However, these results for exclusive e-cigarette users were not statistically significant, indicating that additional studies with longer follow-up will be required before we can make any definitive conclusions about this group.

Dr. Greg Hundley:

Very nice. And did you notice any discrepancy in your results between either men versus women or between individuals that were younger in age versus those that may say be 50 years or older?

Dr. Andrew Stokes:

I think both sources of effect modification will be valuable directions for future research. Unfortunately, samples of e-cigarette users are quite small and incident events over follow-up are quite limited. Therefore, the present study did not pursue or explore these types of stratifications.

Dr. Greg Hundley:

Very good. So, sounds like more research to come forward. Well, Andrew, how do we put your results really in the context with other studies evaluating the harmful effects of e-cigarettes?

Dr. Andrew Stokes:

Of course. So, we know from toxicological studies that there are many constituents of e-cigarette aerosols that are concerning and have substantial toxicity. We know that the inhalation of e-cigarette aerosols among young healthy adults induce inflammation and oxidative stress. Population-based studies from cross-sectional data sources also suggest evidence of harm. What's needed are more longitudinal studies with longer follow-up periods and more incidence events so we can really parse this risk and identify the magnitude of these harms. Finally, we also need to understand better whether there's any harm reduction potential associated with e-cigarette use. E-cigarettes are currently not an FDA-approved cessation product. Therefore, we do not recommend their use despite preliminary evidence of potential harm reduction. We'll need further evidence before we can make any such conclusions.

Dr. Greg Hundley:

And Andrew, describe for us, and you've started to already, what series of studies are needed next to be performed in this sphere of research?

Dr. Andrew Stokes:

Right. So, it's difficult to really identify definitively the effects of e-cigarette use in the absence of randomized control trials. However, we can use observational data with target trial approaches to emulate the clinical trial that we would like to do if we were able to. So, the next step is really to look at transitions across products between cigarette and e-cigarette use and to associate those who switch products, such as from e-cigarettes to cigarettes or vice versa, to see if those switches are associated with any harm or harm reduction.

Dr. Greg Hundley:

Very good. Any specific racial or ethnic groups or even social determinants of health that may need to be targeted with some of these future studies?

Dr. Andrew Stokes:

That's a great question. So, what we know so far from preliminary research is that some groups are more likely to switch to e-cigarettes than other groups. Particularly among current combustible cigarette users, the rates of switching do vary by race and ethnicity. Thus, we need further research to understand why these patterns differ across subgroups and what their implications may be for health.

Dr. Greg Hundley:

Do you foresee any difficulty in trying to enroll participants from those other groups as you plan these studies moving forward?

Dr. Andrew Stokes:

The advantage of the current research design is that we're using a large secondary data set of survey participants who are enrolled in the Population Assessment of Tobacco and Health study. Therefore, we are not enrolling patients ourselves and the response rates are quite high in these surveys.

Dr. Greg Hundley:

Well, Andrew, we hear that some of the inhalants that are mixed with the inhaled nicotine can be flavors and perhaps have been approved by the FDA for consumption in the GI tract where, whatever these additives are, you would think might be broken down by the digestive system. But if they're inhaled and get into the lung tissue and the parenchyma, the alveoli, et cetera, do they perhaps have harmful effects that maybe we're not aware of?

Dr. Andrew Stokes:

Absolutely. E-cigarettes come in thousands of characterizing flavors including sweet flavors, tobacco flavors, and many other miscellaneous flavors. As we saw with the outbreak of lung injury associated with the use of e-cigarettes in 2019, inhaling flavors can have health effects that are unanticipated based on research in the GI tract, and therefore, as a next step in this research, we really need more work to investigate how different flavors are associated with the incidence of clinical events, whether cardiovascular or pulmonary conditions.

Dr. Greg Hundley:

Very nice. Well, listeners, we want to thank Dr. Andrew Stokes from the Boston University School of Health for bringing us this data from the PATH study, suggesting that combining smoking with e-cigarette use does not reduce cardiovascular events and that quitting both products is needed to ensure overall cardiovascular disease risk reduction.

Dr. Greg Hundley:

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join Guest Host Mercedes Carnethon and Author Brendon Neuen as they discuss the article "Sodium-Glucose Cotransporter 2 Inhibitors and Risk of Hyperkalemia in People With Type 2 Diabetes: A Meta-Analysis of Individual Participant Data from Randomized, Controlled Trials."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, this week's feature paper is on one of my favorite topics, SGLT2 inhibitors. And this time, looking at their association with the risk of hyperkalemia in people with type-two diabetes. Now this is something we've all been waiting to look at. It's a meta-analysis of individual participant data from randomized controlled trials, so a very important, clinically applicable discussion coming right up. But first, I'm actually going to talk to you about text messages.

Dr. Greg Hundley:

Wow, Carolyn. I can't wait to hear about this article.

Dr. Carolyn Lam:

Well, specifically the TEXTMEDS randomized clinical trial, which is our first paper today. It is a trial that examined the effectiveness of text-message delivered cardiac education and support on medication adherence following an acute coronary syndrome.

Dr. Carolyn Lam:

This is from Dr. Clara Chow from University of Sydney and her colleagues, who performed a single blind multi-center randomized controlled trial of post-ACS patients across 18 rural and urban centers and three time zones in Australia. The control group received usual care, and the intervention group additionally received multiple motivational and supportive weekly text messages on medications, and healthy lifestyle, with the opportunity for two-way communication.

Dr. Greg Hundley:

Wow, Carolyn. So text messaging to facilitate medication adherence. I can't wait to hear. So what did they find?

Dr. Carolyn Lam:

I think the design, it's such a neat study. However, the study found no significant impact on the primary outcome of medication adherence at six and 12 months, nor on LDL cholesterol or blood pressure.

Dr. Carolyn Lam:

However, intervention participants were more likely to achieve a normal body mass index and to eat guideline-recommended servings of fruit and vegetables. Qualitative analysis demonstrated a high level of acceptability, utility in being a unified source of information, high program engagement, and emotional support, especially during times of uncertainty.

Dr. Greg Hundley:

Interesting, Carolyn. Sounds like an impact on diet, so what did we learn from this study?

Dr. Carolyn Lam:

Well, customized and personalized text message-based prevention programs are indeed a scalable and low-cost means of delivering consistent education and support to patients following hospitalization for ACS. So this study shows it's feasible. The lack of impact, however, on medical adherence, though with better adherence to healthy lifestyle practices, suggests that maybe external factors, such as cost, may strongly influence medical adherence. These need to be addressed, in addition to education programs, to improve medical adherence. But all of this is discussed in a beautiful editorial entitled, "Opportunities and Challenges of Mobile Health Tools to Promote Health Behaviors" by Drs. Sharma and Avram.

Dr. Greg Hundley:

Very nice. Carolyn, what a great summary. Well, my paper comes to us from Professor Mario Delmar from New York University School of Medicine, and Carolyn, exercise training as well as catecholaminergic stimulation increases the incidence of arrhythmic events in patients affected with arrhythmogenic right ventricular cardiomyopathy or ARVC, and this correlates with plakophilin-2 mutations. Now, Carolyn, separate data show that reduced abundance of plakophilin-2 leads to dysregulation of intracellular calcium homeostasis, and Carolyn, these authors studied the relation between exercise and or catecholaminergic stimulation, intracellular calcium homeostasis, and arrhythmogenesis in plakophilin-2 deficient murine hearts.

Dr. Carolyn Lam:

Ooh. So what were the effects?

Dr. Greg Hundley:

Right, Carolyn. For training, the mice underwent 75 minutes of treadmill running once per day, five days each week, for six weeks. And the authors observed that exercise disproportionately affected calcium intracellular homeostasis in plakifilin-2 deficient hearts, in a manner facilitated by stimulation of intracellular, beta-adrenergic receptors or hyper-phosphorylation of phospholamban.

Dr. Greg Hundley:

Now these cellular changes created a pro-arrhythmogenic state that can be mitigated by plakophilin receptor blockade. Additionally, Carolyn, these authors' data unveiled an arrhythmogenic mechanism for exercise-induced or catecholaminergic life-threatening arrhythmias in the setting of a deficit in plakophilin-2. They suggest that membrane-permeable beta blockers are potentially more efficient for ARVC patients.

Dr. Greg Hundley:

And also they highlight the potential for ryanodine-receptor channel blockers as treatment for the control of heart rhythm in this population at risk, and propose that plakophilin dependent and phospholamban-dependent, ARVC-related arrhythmias have a common mechanism.

Dr. Carolyn Lam:

Wow, thanks again, Greg. That was really, really a nice explanation. Well, for this next original paper, it looks at the question of the association between major bleeding and non-major clinically relevant bleeding, with subsequent mortality in hospitalized patients, and authors did this by exploring this relationship in the MAGELLAN and MARINER trials of extended thrombo-prophylaxis in hospitalized medical patients.

Dr. Greg Hundley:

Wow. Carolyn. I can't quite remember, and maybe for our listeners, remind us of the design of the MAGELLAN and the MARINER trials.

Dr. Carolyn Lam:

These trials evaluated, whether rivaroxaban compared with enoxaparin or placebo, could prevent venous thromboembolism without increased bleeding. The authors, led by Dr. Spyropoulos from the Feinstein Institute of Medical Research in New York, hypothesized that patients with major bleeding, but not those with non-major clinically relevant bleeding, would be at an increased risk of all-cause mortality. So Greg, would you like to guess what they found?

Dr. Greg Hundley:

Oh, Carolyn, you've put me on the spot here. I'm not sure.

Dr. Carolyn Lam:

Maybe just, did the authors get it right or wrong? Just....

Dr. Greg Hundley:

I'm saying, they got it right.

Dr. Carolyn Lam:

Oh, always clever. They found that compared to patients with no bleeding, the risk of all-cause mortality for patient with non-major clinically relevant bleeding was not increased in MARINER, but was increased in MAGELLAN. Major bleeding, however, was associated with a higher incidence of all-cause mortality in both studies, while trivial bleeding was not associated with mortality in either study. These results really inform the risk benefit calculus of extended thromboprophylaxis in medically ill patients.

Dr. Greg Hundley:

Wow. Carolyn, great presentation. We've got some other articles in this issue. And let me tell you about two that I have. First is a Research Letter from Professor Frankel entitled "Trends in Opioid Use after Cardiac-Implantable Electronic Device Procedures in the United States, between the years of 2004 and 2020." And Tracy Hampton, from the National Association of Science Writers, presents some very recent news in the world of cardiology.

Dr. Carolyn Lam:

Nice. Well, there's an exchange of letters as well between Drs. Yang and Nagareddy regarding the article "Retention of NLP3 Inflammasome-Primed Neutrophils in the Bone Marrow is Essential for Myocardial Infarction-Induced Granulopoiesis." And finally, in the Editor’s Page, a nice piece from Drs. Joe Hill, Darren McGuire, and James de Lemos on “Circulation: Best Papers, 2021.” Gosh, really, really nice issue. Now let's go on, though, to the feature discussion, yeah?

Dr. Greg Hundley:

You bet.

Dr. Mercedes Carnethon:

Welcome to this episode of Circulation on the Run podcast. My name is Mercedes Carnethon, one of the associate editors, and I'm a professor of preventive medicine at the Northwestern University Feinberg school of Medicine. I'm really excited today to have a guest with us. Dr. Brendon Neuen, who has shared with us his really outstanding research on SGLT2 inhibitors and the risk of hyperkalemia in people with type-two diabetes, a meta-analysis. So welcome to our podcast today, Brendon.

Dr. Brendon Neuen:

Thanks very much for having me Mercedes. It's a real pleasure to be here.

Dr. Mercedes Carnethon:

Well, thank you for joining us. We're really pleased that you chose Circulation to share with us your really important findings. Can you tell us a little bit about the rationale for your study and how you carried out your work?

Dr. Brendon Neuen:

Yeah, absolutely. So we know that in people with diabetes and people with CKD, hyperkalemia is a common occurrence, and it's a problem for two reasons as you'd be aware. Firstly, it is associated with cardiac dysrhythmias and secondly, perhaps at least as importantly, it limits the optimal use of treatments that reduce kidney disease progression and heart failure events. So that is, agents that block the renin angiotensin aldosterone system.

Dr. Brendon Neuen:

We now know, and we've got robust evidence from large outcome trials, that SGLT2 inhibitors reduce the risk of heart failure and kidney disease progression in people with and without diabetes, but we haven't really, up and until now, systematically evaluated their effect on potassium outcomes, particularly hyperkalemia. And so we set out to assess whether these agents affect serum potassium levels and alter the risk of hyperkalemia as well as hypokalemia.

Dr. Mercedes Carnethon:

Thank you. That sounds like a really excellent and well needed study, given how much we've heard within the field about the benefits of SGLT2 inhibitors. It's nice to see a careful evaluation of what some of the considerations are in their use. So tell us a little bit about how you carried out this study and what you ultimately found.

Dr. Brendon Neuen:

What we did was, we identified clinical trials that enrolled people with type two diabetes at high cardiovascular risk or with chronic kidney disease. And what we did is, we approached the investigators of each of these trials and asked them to collaborate on a large meta-analysis using individual participant data.

Dr. Brendon Neuen:

What that allowed us to do was, then, standardize across all of the trials of different outcome definitions, and allowed us to assess the effective SGLT2 inhibitors on a primary outcome of time to first serum potassium greater than or equal to six, defined as serious hyperkalemia, as well as hypokalemia, investigator-reported hyperkalemia events, and a range of other potassium-related outcomes in a broad population, including people with chronic kidney disease, people with heart failure, and people using different concomitant medications, such as diuretics and MRAs in the background.

Dr. Mercedes Carnethon:

So thank you, Brendon, for the explanation of the use of the meta-analytic design and the entry criteria of type-two diabetes and chronic kidney disease. Can you tell us, what were the outcomes across these studies?

Dr. Brendon Neuen:

The primary outcome we evaluated was time to first serious hyperkalemia, defined as a serum potassium greater than or equal to six, as well as a range of other potassium-related outcomes, including investigator reported hyperkalemia, change in potassium over time, as well as hypokalemia, defined as a serum potassium less than 3.5.

Dr. Brendon Neuen:

What we found was that overall SGLT2 inhibitors reduce the risk of serious hyperkalemia by about 16%. And that effect was consistent across the agents within the class, and across different subpopulations and trials. This effect was supported by a 20% risk reduction in investigator-reported hyperemia events and importantly, there was no difference in risk of hypokalemia, that is a serum potassium less than 3.5, between SGLT2-treated and placebo-treated participants.

Dr. Mercedes Carnethon:

Thank you for that summary. You know, one of the very impressive aspects of this clinical trial is certainly the size and the number of participants. Brendon, I was really struck by your description of the consistency of findings across the subgroups. And in particular, when I reviewed the findings in the paper, I noticed that serious hyperkalemia was higher in those with poorer kidney function. Did you find that surprising?

Dr. Brendon Neuen:

From clinical practice, we know that one of the major determinants of hyperkalemia risk is kidney function. It's a major problem that we run into in people with more advanced CKD. And what that means is that for people with more advanced chronic kidney disease, who are at high risk of hyperkalemia, the absolute benefits of SGLT2 inhibition on hyperkalemia risk are likely greater in these individuals, because they're at high risk of this outcome.

Dr. Brendon Neuen:

Other patients who might be at increased risk of hyperkalemia include those with heart failure or those taking mineralocorticoid receptor antagonists at baseline. And so you'd expect that if the relative effects are consistent across many subgroups, then the absolute risk reductions are likely to be larger in people taking MRAs or people with more advanced CKD.

Dr. Mercedes Carnethon:

Thank you so much for summarizing the importance of these findings and what they mean for our clinical audience. It's wonderful to have this sort of information from a meta-analysis because it allows us large sample sizes, where we can do things like you describe, such as describing subgroup effects.

Dr. Mercedes Carnethon:

It also presents us with very robust evidence that can be taken into clinical practice for our clinical audience to use. Based on what you found, how do you anticipate that these findings can be used by our clinicians?

Dr. Brendon Neuen:

Well, thanks, Mercedes. I think the reduction in risk of hyperkalemia that is observed in these data suggests that SGLT2 inhibitors might enable better use of other proven therapies that reduce cardio-renal risk in people with chronic kidney disease and people with heart failure. We all know that in treating these high risk patients, hyperkalemia is a problem. And by reducing the risk of hyperkalemia with SGLT2 inhibitors, it might enable better use of renin angiotensin system blockade and mineralocorticoid receptor antagonists in people with chronic kidney disease and heart failure.

Dr. Mercedes Carnethon:

So you've provided a really excellent overall summary of the impact of these finding for clinical practice and the possible next steps. I wanted to end on a note of asking you what surprised you about these findings that might lead to further future investigations.

Dr. Brendon Neuen:

Thanks, Mercedes. I think that's a really interesting question. What was somewhat surprising, but also reassuring, was the consistency of the treatment effect on hyperkalemia, regardless of how we defined it, whether that was defined based on investigator-reported hyperkalemia events or central laboratory-measured serum, potassium levels, the treatment effect was very consistent. And I think that gives us some confidence about the robustness of these findings and their application to clinical practice.

Dr. Mercedes Carnethon:

Well, thank you so much, Brendon. I have really enjoyed this discussion with you today and this really important paper that is describing an important safety outcome for SGLT2 inhibitors in patients with type two diabetes. And again, I really want to thank you for sharing your excellent work with us here at Circulation. I anticipate that our readership, when they leave this podcast and pick up their journals, will be thrilled to read about all of the details about the excellent work that you and your team have carried out. So thank you very much for joining us today.

Dr. Brendon Neuen:

Thanks very much for having me, Mercedes. It was a real pleasure.

Dr. Mercedes Carnethon:

Thank you, and thank you again to our audience for joining us for this episode of Circulation on the Run.

Speaker 5:

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Guest Host Mercedes Carnethon, Author Brian Bergmark, and Associate Editor Parag Joshi as they discuss the article “Effect of Vupanorsen on Non–High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70.”

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-host. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center in Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well Carolyn, this week's feature, non-high density lipoprotein cholesterol levels in statin treated patients with elevated cholesterol. We're going to hear from the TRANSLATE-TIMI 70 study. But before we get to that, how about we grab a cup of coffee and discuss some of the other articles in the issue? Would you like to go first?

Dr. Carolyn Lam:

I would. And by the way, that feature is going to be all exciting. It was discussed at the American College of Cardiology. But okay, how about from cholesterol to vitamins? Let's start with the Greg quiz. Greg, which vitamins have been associated with arterial calcification? Is it A, B, C, D, E?

Dr. Greg Hundley:

I'm going to pick E and K.

Dr. Carolyn Lam:

You’re smart. Indeed. Vitamin K2, also known as menaquinone-7 is the most effective co-factor for the carboxylation of proteins involved in the inhibition of arterial calcification. Furthermore, combined low vitamin K and low vitamin D have been associated with increased all-cause mortality risk. And so, today's paper is from Dr. Diederichsen from Odense University Hospital in Denmark and colleagues really present the first double-blind, randomized controlled trial to test whether vitamin K2, a drug-targeting processes of calcification in addition to vitamin D, could slow the progression of aortic valve calcification and stenosis. So, in a randomized double-blind multicenter trial, men from the community with an aortic valve calcium score above 300 arbitrary units on cardiac non-contrast CT were randomized to daily treatment with 720 micrograms of vitamin K2 plus 25 micrograms of vitamin D or matching placebo for 24 months. And the primary outcome was the change in aortic valve calcium score.

Dr. Greg Hundley:

Carolyn, so menaquinone-7 and aortic valve score. So, what were the results?

Dr. Carolyn Lam:

Menaquinone-7 had no major effect on the progression of aortic valve calcification as assessed by CT or echo. High-dose menaquinone-7 was, however, safe and well tolerated. Now, some limitations is that this external validity is limited to men aged 65 to 74 with aortic valve calcification scores of greater or equals to 300 arbitrary units. Thus, caution is needed if we extrapolate these findings and other pathways need to be explored in order to identify an effective therapy for this unmet clinical need.

Dr. Greg Hundley:

Wow, very nice Carolyn. Well, my first article comes to us from Dr. Michael Laflamme from the University Health Network. And Carolyn, human pluripotent stem cell-derived cardiomyocytes or hPSC-CMs exhibit promise for application in cardiac regeneration, but their translational potential is limited by an immature phenotype. So Carolyn, this research team hypothesized that large scale manufacturing of mature hPSC-CMs could be achieved via culture on polydimethylsiloxane, and we're going to call that PDMS, lined roller bottles and that the transplantation of these cells would mediate better structural and functional outcomes then with conventional immature hPSC-CMs populations.

Dr. Carolyn Lam:

Oh, that's neat, Greg. So, what did they find?

Dr. Greg Hundley:

Right, Carolyn. So, these authors demonstrated the economic generation of greater than one times 10 to the eighth mature hPSC-CMs per PDMS line roller bottle. And compared to their counterparts, PDMS matured hPSC-CMs exhibited increased cardiac gene expression and more mature structural and functional properties in vitro. More importantly, intracardiac graphs formed with PDMS matured myocytes showed greatly enhanced structured alignment, better host graft electromechanical integration, less pro arrhythmic behavior, and greater beneficial effects on contractile function. So in summary, Carolyn, this team describes practical methods for the scale generation of mature human pluripotent stem cell-derived cardiomyocytes and provide the first evidence that the transplantation of more mature cardiomyocytes yields better outcomes in vivo. And there's a wonderful editorial by Professor Murray entitled Flexing Their Muscles: Maturation of Stems Cell-Derived Cardiomyocytes on Elastomeric Substrates to Enhance Cardiac Repair.

Dr. Carolyn Lam:

Wow! That's really significant. Thank you, Greg. Well, the next paper is the largest genome-wide association meta-analysis of plasma ACE2 levels in over 28,000 individuals. And this is from Dr. Xia Chen from Fudan University and Dr. James Wilson from University of Edinburgh in UK, and their colleagues. And guess what, it focuses on severe acute respiratory syndrome coronavirus 2, the etiologic agent of COVID 19. And we know that that enters human cells using the ACE2 protein as a receptor. ACE2 is thus key to the infection and treatment of the coronavirus. ACE2 is highly expressed in the heart, respiratory and gastrointestinal tracts, playing important regulatory roles in the cardiovascular and other biologic systems.

Dr. Greg Hundley:

Wow, Carolyn. ACE2, and also a very important topic here with SARS-COVID-2. So, what did they find?

Dr. Carolyn Lam:

First, the overall heritability of ACE2 level is 16% of which 30% can be explained by 10 protein quantitative trait loci identified in this study. ACE2 level is genetically correlated with both COVID-19 and cardiovascular. Elevated ACE2 levels show a causal relationship with COVID-19 severity, hospitalization and infection as shown by Mendelian randomization analyses. ACE2 regulatory variants are enriched on DNA methylation sites in immune cells.

Dr. Greg Hundley:

Wow, Carolyn. So, elevated ACE2 and a causal relationship with COVID-19 severity. So tell us, what are the clinical applications of this really nice study?

Dr. Carolyn Lam:

The causal evidence of ACE2 suggests that pharmacological inhibition of circulating ACE2 may be a promising approach for treating COVID-19 or its comorbidities. Transcription factors that play essential roles in ACE2 generation could provide alternative paths to pharmacological modulation of ACE2 plasma levels. The genetic correlations between ACE2 and both COVID-19 and cardiovascular disease imply that the cardiovascular complications seen in COVID-19 patients may be intrinsic to the disease and mechanically or/and mechanistically-driven by ACE2. Isn't that neat?

Dr. Greg Hundley:

You bet, Carolyn. Boy, what an exciting issue. And we've got other articles in this issue.

Dr. Carolyn Lam:

Yeah. Now, let me start this time. There's an exchange of letters between Drs. Duan and Chang regarding the article “Therapeutic Exon Skipping Through a CRISPR-Guided Cytidine Deaminase Rescues Dystrophic Cardiomyopathy in Vivo.” There's a Perspective piece by Dr. Morris, “The Updated Heart Failure Guidelines: Time for a Refresh.” Love that piece! There's an AHA Update piece (AHA President’s Page) by Dr. Elkin on The Road to Equity in Brain Health, and ECG challenge by Dr. Kolominsky, Electrical Extremists in a Critically ill Patient, and an On My Mind Paper by Dr. Paulus entitled “Border Disputes Between Heart Failure Phenotypes.”

Dr. Greg Hundley:

Wow, Carolyn. And I've got two Research Letters. The first from Professor Groeneveld entitled “Prevalence of Short-Coupled Ventricular Fibrillation in a Large Cohort of Dutch Idiopathic Ventricular Fibrillation Patients.” And then a second Research Letter from Professor Yamashita entitled “Single Cell RNA Sequence Reveals a Distinct Immune Landscape of Myeloid Cells in Coronary Culprit Plaques Causing Acute Coronary Syndrome.” Well Carolyn, now, we get to go onto our feature, vupanorsen on non-high-density lipoprotein cholesterol levels and catching up with TIMI 70.

Dr. Carolyn Lam:

Let's go.

Dr. Mercedes Carnethon:

So, good morning listeners. I'm really pleased to invite you to this episode of our Circulation on the Run podcast. For those of you who don't hear me often, I'm stepping in as a guest host today. My name is Mercedes Carnahan from the Northwestern University Feinberg School of Medicine. And I'm really excited to be joined today by Dr. Brian Bergmark, and associate editor, Dr. Parag Joshi. And we will have today Dr. Bergmark discussing his new article published with us on the effects of vupanorsen on non-HDL cholesterol levels in the TRANSLATE-TIMI 70 trial. We're really thrilled to have you with us here today, Brian, to talk about the really important findings coming from this trial. So to start us off, just tell us, what did you find?

Dr. Brian Bergmark:

Great. Thank you so much. It's really a pleasure to be here and I'm grateful for the opportunity. So, in the big picture, despite numerous agents to reduce lipid-mediated cardiovascular risk, obviously, residual risk remains and there are novel targets to address that risk. One of them is angiopoietin-like 3, which is a protein made in the liver. Angiopoietin-like 3 or ANGPTL3 inhibits lipoprotein lipases among other lipases, and thereby interferes with metabolism of triglyceride-rich lipoproteins. And so, the idea here was that if ANGPTL3 could be inhibited that LPL or lipoprotein lipase function could be augmented and metabolism of these lipoproteins could be augmented. And so, what we did is we took patients with an elevated non-HDL cholesterol, at least 100 milligrams per deciliter, and elevated triglycerides, 150 to 500 milligrams per deciliter, and randomized them to placebo or one of seven doses of vupanorsen, which is an antisense oligonucleotide, which inhibits the synthesis of ANGPTL3 in the liver. We then follow them to see what the impact was on their non-HDL cholesterol, as well as other lipid parameters through 24 weeks.

Dr. Mercedes Carnethon:

Thank you so much. It's a wonderful design, and I'm really excited to hear a little bit more about what you found.

Dr. Brian Bergmark:

Great. So, the primary endpoint was the change in non-HDL cholesterol from baseline to 24 weeks. And we did find that all vupanorsen regimens reduced non-HDL cholesterol in a statistically significant manner. The magnitude of that effect was up to 27.7% in one of the dose arms or about 28%. We also saw a statistically significant reductions in the target ANGPTL3 up to about a 95% reduction in the highest dose arm, as well as statistically significant reductions in triglycerides at all of the dose regimens. The effect on LDL cholesterol and on apolipoprotein B or apo B was variable across regimens and only statistically significant in a few of the dose arms. We also found several safety signals. One, there appeared to be higher rates of injection site reactions in the skin at higher total monthly doses. We also found higher rates of elevation in liver enzymes, AST and ALT at higher total monthly doses. And we also found significant increases in hepatic fat fraction or the fat content of the liver at higher total monthly doses.

Dr. Brian Bergmark:

In the end, we found that while statistically significant, the magnitude of the reduction in non-HDL cholesterol was modest as was the reduction in apo B. And so, the goal here was to find a dose that might have a reduction of a magnitude that would be clinically meaningful for cardiovascular risk reduction. We were underwhelmed by the magnitude of that reduction, and then it was paired with these safety signals, which if there's interest, we could get into more detail in our thinking about why those occurred, what the implications are, but suffice it to say that there were medically meaningful safety concerns paired with a modest reduction in non-HDL cholesterol.

Dr. Mercedes Carnethon:

Thank you for that excellent summary. Before I turn it over to the associate editor, I read this with great interest, and in particular, looking at one of the first figures in the paper, which is demonstrating the adjusted change at 24 weeks across different doses and based on how frequently the doses were given the four week as compared with the two week. And one thing that really stood out to me was the clear dose response with the four week regimens with the higher doses appearing to demonstrate the greatest reductions but a less clear signal with the two week regimens. Do you have any hypotheses about why these patterns appeared so different?

Dr. Brian Bergmark:

Yeah. It's a great question. So, the responsiveness of this is something of interest here I think. So, if you look at the effect of the drug on its target, ANGPTL3, there is a very clear dose response, so there's no doubt that higher doses were impacting the target ANGPTL3 to a greater extent. So, one of the most direct effects would be on triglycerides, one of the most direct lipid effects, and that appears pretty close to a dose response relationship within each of these frequencies of administration. But once you start getting to non-HDL cholesterol, it starts to break down a bit. And is it simply because of random chance or is there actually something distinct going on with how the lipids are being metabolized?

Dr. Brian Bergmark:

That is something we are diving into. So, the hope would be that we actually reduce apo B, the number of these actually circulating lipoproteins as has been demonstrated with the monoclonal antibody. It's possible that with this other different mechanism in the antibody, this antisense oligonucleotide, perhaps, we're simply shifting the content of these lipoprotein molecules and decreasing the triglyceride content but not actually meaningfully modifying the amount of apo B, LDL cholesterol. And that might be part of what we're seeing with the more muted relationship between dose and the effect on non-HDL cholesterol. I don't know for certain we are diving into this a bit more with other lipid fractions, et cetera.

Dr. Mercedes Carnethon:

Oh, well, thank you so much for that explanation. I know that a number of people, this was extremely well received when shared at the recent American College of Cardiology meetings, and so I was really thrilled to find that this was appearing in the journal circulation. So Parag, I'm really interested in hearing your perspectives on why we knew that this was certainly a priority paper for us.

Dr. Parag Joshi:

Yeah. Let me first start, Brian, congratulations. Fantastic work. And we were excited to receive the paper. I think really hard to pull off trials right now or in the last couple years, so kudos to you. And I echo the sentiments from Mercedes. This is great work. Really important space, the residual risk space I think is very important of course and is critical to moving forward with improving cardiovascular health. So, one of the big picture questions and as we get to this triglyceride-rich lipoprotein lowering space, certainly, there's strong associations with residual risk, but can we impact that risk? And here, we're starting to explore that. And I think when you think of the lipoprotein space, many of us are interested in what is the effect on these lipoproteins as opposed to the cholesterol content or the triglyceride content. And non-HDL cholesterol or apo B, clearly, the better, stronger markers for that risk, so we were really excited to see this paper.

Dr. Parag Joshi:

And as Brian mentioned, unfortunately, not the strongest impact here on those measures. And I want to dive into that a little more because I think that carries significant implications for the space, and I'd love to hear your thoughts on that. But overall, really fantastic work. I think my first question really is around the apo B aspect of this and the less than anticipated lowering of those levels. You hinted at this in terms of, is this shuffling cholesterol and triglycerides across particles, or do you think this could be the mechanism by which this happens through ANGPTL3? You do inhibit the levels quite a bit. Did we just miss that... Is this not the right target? What do you think?

Dr. Brian Bergmark:

Yeah, it's a great question. I do think the target itself holds great promise. Obviously, a monoclonal antibody against this same target results in major reductions in apo B, LDL cholesterol, and the latter through a mechanism that is not really known but is not dependent on the LDL receptor, and therefore has real clinical utility that's approved for people with familial homozygous hypercholesterolemia. Beyond that, of course, in genetic studies, there's a clear association with loss of function in the ANGPTL3 gene and lower levels of all of these lipids, lower rates of coronary artery disease, et cetera.

Dr. Brian Bergmark:

So, I think it's not that this pathway is not promising and actually already being taken advantage of, I think it's that this particular agent acting through this mechanism was not able to achieve a necessary efficacy with reasonable safety. Some genetic data suggests that there is not actually a dose response between a reduction or loss of function in ANGPTL3 and reduction in apo B or lower levels of apo B and non-HDL cholesterol, but it really requires your complete elimination of ANGPTL3 function, which is probably, likely achieved with the monoclonal antibody. And so, even though we had quite large reductions with the antisense oligonucleotide, perhaps, we just didn't cross that threshold that's needed to modify the lipid panel in the way that would've been clinically meaningful.

Dr. Parag Joshi:

Yeah. I think that's fantastic as you allude to with evolocumab and the impact that has on apo B levels. I didn't think of it as a threshold effect, but that makes a lot of sense as maybe that just getting to that tipping point is where the issue is here. In terms of the liver signal, what were your thoughts on that? And is that something that we should expect to see in ASOs or do you think it's specific to this compound?

Dr. Brian Bergmark:

Yeah, I don't know. That was unexpected. Right, there are two liver signals and it's unclear how related they are. One is the inflammation of the liver as indicated by the elevation in enzymes, and then the other is the fat accumulation. So with respect to the fact, if anything, genetic data suggests perhaps loss of function in ANGPTL3 might result in lower rates of hepatic steatosis. In animal models, the antisense oligonucleotide reduces liver fat, and so there's, there was promise going into this that this could actually be beneficial for non-alcoholic fatty liver disease. And additionally, there's not data to suggest that the monoclonal antibody increases liver fat. So, there's not a lot to support this as being an on-target effect that by inhibiting ANGPTL3, by that pathway, the liver fat was increased. So, I think a reasonable person might wonder whether this was an off-target effect of the drug.

Dr. Brian Bergmark:

By what mechanism that occurred, I don't know, what the implications would be for other related agents, I don't know. And then similarly, the liver enzyme elevations, is that related to this? I'm not exactly sure, but also unexpected and I think off-target. But that sort of intrinsic to this mechanism of hepatic targeting, is this something we need to be worried about for other agents in this class or not? I don't know. Obviously, we can't answer that from this single study. We are going to dive into it a bit more to try to overlay patients with hepatic fat accumulation, liver enzymes, et cetera. Of course, both of those happen more at higher doses. How much we can really parse this? I'm not sure yet.

Dr. Parag Joshi:

Yeah. That's really fascinating. I think the appeal of this paper to the circulation audience is that you have a really exciting novel target and pathway to explore here but somewhat divergent results from what's existing in this space. And I think that raises a lot of questions, really interesting questions going forward for this space. For the ANGPTL3 pathway, what do you see there coming down the line or what are your thoughts on that going forward for this target and ways to approach risk related to it?

Dr. Brian Bergmark:

Yeah. Great. Thank you. Yeah. No, so I agree. I think moving into this other end of the spectrum of triglyceride-rich lipoproteins, et cetera, I think this is where we're headed and this is why we do the trial. We weren't expecting these things that's why you do this experiment, and this is what we found. So now, where do we go from here? So there are, of course, other ways beyond the monoclonal antibody of targeting ANGPTL3 specifically. There's siRNA, there is gene therapy being investigated. So, I think all of them hold an great promise. And of course, we will need to see as those therapies move along what the actual trials show. And then there are, of course, other pathways that are of interest, APOC3, for instance. So, I think there's a lot more in this space that's coming down the line.

Dr. Parag Joshi:

Yeah, absolutely. I think it's a really exciting space, and we're really happy to get this paper as one piece of that whole puzzle. So, thank you.

Dr. Mercedes Carnethon:

Yes. And I echo that as well. And as a methodologist myself, I'm always really pleased to see such well-designed studies. I think this was sophisticated in many aspects in testing different dosing and different timing of the dosing. And also, I'm really impressed by your inclusion criteria, particularly when I noted that 44% of the participants were female, and that you reported those stratum-specific effects. I just had a final question as we wrap up. You acknowledge a nominally significant interaction by sex and I see, for example, that it appears that the magnitude is larger possibly in the relatively smaller subset of females as compared with males. Is this something to pay attention to or do you think this is just some type of an artifact related to greater variability because the group is smaller?

Dr. Brian Bergmark:

Yeah, it's a good question. So, this is the burning question. We had no a priority reason to suspect that biologically and we are not adjusting for multiple testing in the key value of 0.04. So just to put my money down, I would say, I would guess it's random chance. We found it. It's worthy of looking into a bit more. There were, of course, the important implications for other drugs, et cetera. So, I think it's worth diving into as we will, but are we likely to uncover some biological difference? I doubt it. I wouldn't guess. There are other subgroups where I think at least upfront, you might expect there could be a difference. So, there are thoughts about insulin's effect on LPL. Could diabetes status have an interaction with the drug? I think though not statistically significant, it's also something worth looking into that group and the subfractions of the lipid panel and all of that stuff. So, I think it's all worth looking into but cautiously with the constraints.

Dr. Mercedes Carnethon:

Well, thank you so much for that explanation. And I've really enjoyed this discussion with you today, Brian, and you, Parag. I've certainly learned a lot and I'm really excited to see this excellent work coming out in the journal circulation. So, thank you very much for your time this morning and thank you to our listeners. Wrapping up this episode of Circulation on the Run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Vasan Ramachandran and Associate Editor Mercedes Carnethon as they discuss the article "Temporal Trends in the Remaining Lifetime Risk of Cardiovascular Disease Among Middle-Aged Adults Across 6 Decades: The Framingham Study."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center in Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, I'm so excited about today's feature paper. You see, I trained at the Framingham Heart Study and today's feature paper talks about the temporal trends in the remaining lifetime risk of cardiovascular disease among middle aged adults across six decades in the Framingham Heart Study. Truly a landmark study and a discussion nobody wants to miss. But first, let's talk about the other papers in today's issue, and I understand that you've got one ready.

Dr. Greg Hundley:

You bet Carolyn. I'll get started first. Thank you. So my first paper comes from Dr. Daniel Mark from Duke University and it refers to the ISCHEMIA trial.

Dr. Carolyn Lam:

Ooh, could you please first remind us what is the ISCHEMIA trial and are you presenting a substudy, is that correct?

Dr. Greg Hundley:

Right, Carolyn. So the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches, or ISCHEMIA, compared an initial invasive strategy with an initial conservative strategy in 5,179 participants with chronic coronary disease and moderate or severe ischemia. And this sub study of the ischemia research program included a comprehensive quality of life analysis.

Dr. Carolyn Lam:

So very interesting. What did they find Greg?

Dr. Greg Hundley:

Right, Carolyn. So this study included 1,819 participants. 907 in the invasive, 912 in the conservative. And collected a battery of disease specific and generic quality of life instruments by structured interviews at baseline. And then at three, 12, 24 and 36 months post randomization, and then finally at study closeout. Now Carolyn, these assessments included an angina related quality of life assessment from the 19 item Seattle Angina Questionnaire, a generic health status assessment, an assessment of depressive symptoms, and for North American patients, cardiac functional status from the Duke Activity Status Index, or DASI. In this study, Carolyn, in terms of results, the median age was 67 years and about 20% were women and about 16% were nonwhite. So Carolyn, getting to the results. The estimated mean difference for the SAQ 19 summary score favored invasive therapy. And remember the SAQ 19 was the Seattle Angina Questionnaire.

Dr. Greg Hundley:

Next, no differences were observed in patients with rare or absent baseline angina. Next, among patients with more frequent angina baseline, those randomized to invasive had a mean point higher score on the SAQ 19 summary score than the conservative approach, with consistent effects across all of the SAQ subscales including physical limitations, angina frequency and quality of life health perceptions. For the DASI, and remember DASI refers to the Duke Activity Status Index, no difference was estimated overall by treatment. But in patients with baseline marked angina, DASI scores were higher for the interventional arm. Whereas patients with rare or absent baseline angina showed really no treatment related differences.

Dr. Carolyn Lam:

Oh, okay. So a lot of results. What's the take-home message, Greg?

Dr. Greg Hundley:

Right, Carolyn. Glad you asked. So in the ISCHEMIA comprehensive quality of life substudy, patients with more frequent baseline angina reported greater improvements in the symptom physical functioning and psychological wellbeing dimensions of quality of life when treated with an invasive strategy. Whereas patients who had rare or absent angina baseline reported no consistent treatment related quality of life differences.

Dr. Carolyn Lam:

Wow. Thank you, Greg. Very interesting indeed. Now from angina to now cholesterol. Now, cholesterol guidelines typically prioritize primary prevention statin therapy based on 10 year risk of cardiovascular disease. Now the advent of generic pricing may in fact justify expansion of statin eligibility. Moreover, 10 year risk may not be the optimal approach for statin prioritization. So these issues were looked at in this next paper by authors led by Dr. Kohli Lynch from Northwestern University and colleagues who estimated the cost effectiveness of expanding preventive statin eligibility, and evaluated novel approaches to prioritization from a Scottish health sector perspective. A computer simulation model predicted long term health and cost outcomes in Scottish adults, age 40 years or more.

Dr. Greg Hundley:

So Carolyn, what did they find?

Dr. Carolyn Lam:

The advent of generic pricing has rendered preventive statin therapy cost effective for many adults. Absolute risk reduction guided statin therapy, which is based on 10 year cardiovascular disease risk and non HDL cholesterol levels, is cost effective and would improve population health. Whereas age stratified risk thresholds were more expensive and less effective than alternative approaches to statin prioritization. So guidelines committees may need to expand statin eligibility and consider new ways to allocate statins based on absolute risk reduction rather than 10 year risk thresholds.

Dr. Greg Hundley:

Very nice Carolyn. Always important, new information regarding statin therapy. Well Carolyn, my next paper comes to us from the world of preclinical science. And Carolyn, as you know, the regenerative capacity of the heart after myocardial infarction is limited. And these authors led by Dr. Tamer Mohamed from University of Louisville previously showed that ectopic introduction of Cdk1, CyclinB1 and Cdk4, CyclinD1 complexes and we'll refer to those now as 4F, promoted cardiomyocyte proliferation in 15 to 20% of infected cardiomyocytes in vitro and in vivo and improved cardiac function after MI in mice. So Carolyn, in this study using temporal single cell RNA sequencing, the investigative team aimed to identify the necessary reprogramming stages during the forced cardiomyocyte proliferation with 4F on a single cell basis. And also using rat and pig models of ischemic heart failure, they aim to start the first preclinical testing to introduce 4F gene therapy as a candidate for the treatment of ischemia induced heart failure.

Dr. Carolyn Lam:

Oh, wow Greg. So what did they find?

Dr. Greg Hundley:

Several things, Carolyn. First, temporal bulk and single cell RNA sequencing and further biochemical validations of mature HIPS cardiomyocytes treated with either LAcZ or 4F adenoviruses revealed full cell cycle reprogramming in 15% of the cardiomyocyte population at 48 hours post-infection with 4F. Which was mainly associated with sarcomere disassembly and metabolic reprogramming. Second Carolyn, transient overexpression of 4F specifically in cardiomyocytes was achieved using a polycistronic non-integrating lentivirus encoding the 4F with each driven by a TNNT2 promoter entitled TNNT2-4F polycistronic-NIL. Now this TNNT2-4F polycistronic-NIL or control virus was injected intra myocardial one week after MI in rats, so 10 per group, and pigs, six to seven per group.

Dr. Greg Hundley:

And four weeks post-injection the TNNT2-4F polycistronic-NIL treated animals showed significant improvement in left ventricular injection fraction and scar size compared with the control virus treated animals. And four months after treatment, the rats that received TNNT2-4F polycistronic-NIL still showed a sustained improvement in cardiac function without obvious development of cardiac arrhythmias or systemic tumorigenesis. And so Carolyn this study advances concepts related to myocellular regeneration by providing mechanistic insights into the process of forced cardiomyocyte proliferation and advances the clinical feasibility of this approach by minimizing the oncogenic potential of the cell factors, thanks to the use of a novel transient and cardiomyocyte specific viral construct.

Dr. Carolyn Lam:

Wow. What a rich study. Thanks so much, Greg.

Dr. Greg Hundley:

Well, Carolyn, how about if we see what else and what other articles are in this issue. And maybe I'll go first. So there's a research letter from Dr. Wu entitled Modeling Effects of Immunosuppressive Drugs on Human Hearts Using IPSC Derived Cardiac Organoids and Single Cell RNA Sequencing. Carolyn, there's an EKG challenge from Dr. Yarmohammadi, entitled “Fast and Furious, A Case of Group Beating in Cardiomyopathy.” And then finally from Dr. Tulloch, a really nice Perspective entitled “The Social Robots are Coming, Preparing For a New Wave of Virtual Care in Cardiovascular Medicine.

Dr. Carolyn Lam:

Oh, how interesting. Well, also in the mail back is an exchange of letters of among Drs. Lakkireddy, Dhruva, Natale, and Price regarding Amplatzer Amulet Left Atrial Appendage Occluder versus Watchman Device for stroke prophylaxis, a randomized control trial. All right. Thank you so much, Greg. Shall we go on to our feature discussion now?

Dr. Greg Hundley:

You bey. Welcome listeners to our feature discussion today. And we're so fortunate we have with us today, Dr. Vasan Ramachandran from Boston University and our own Associate Editor, Dr. Mercedes Carnethon from Northwestern University in Chicago. Welcome to you both. And Vasan, let's start with you. Could you describe for us some of the background information pertaining to your study and what was the hypothesis that you wanted to address?

Dr. Vasan Ramachandran:

Thank you, Greg, first of all for having me. So we know two facts. One is that heart disease and stroke disease death rates and incidents are declining over the last six decades in the United States. Juxtapose against that is also the observation that there is rising incidence of obesity and overweight, and also a rising burden of diabetes. There are a lot of advances in our ability to treat high blood pressure, high cholesterol, as well as high blood sugar. So we wanted to ask the question, given the historic trends in control awareness of risk factors and their control, interrupted by this escalating burden of obesity, overweight, and diabetes, what is the lived experiences of people over time in terms of the risk of developing heart disease or stroke using a metric we call as the remaining lifetime risk of developing heart disease or stroke.

Dr. Greg Hundley:

The hypothesis you wanted to address?

Dr. Vasan Ramachandran:

The hypothesis we wanted to address was that perhaps the decline in the incidence of heart disease and stroke may have decreased over time given the escalating burden of overweight, obesity and diabetes.

Dr. Greg Hundley:

Very nice. And can you describe for us your study population and your study design?

Dr. Vasan Ramachandran:

Thank you, Greg. So the Framingham Heart Study is one of the oldest running epidemiological studies in the world. We have multiple cohorts. The study began in 1948 with the original cohort, the offspring cohort enrolled in 1971, third generation cohort in 2002, and two minoritized cohorts in the 1990s and 2002. So we have an observation period of different cohorts over a six decade period. So we asked the question, if you were a participant in the Framingham study between 1960 and 1979 and then 1980 to 1999, and then 2000 to 2018, what was your lifetime risk of experiencing a heart disease or stroke in the three different time periods? Is it going down, is it steady or is it going up?

Dr. Greg Hundley:

Very nice. And so, Vasan, describe your study results.

Dr. Vasan Ramachandran:

Look, what we found was if you look at the first, the 20 year period from 1960 to 1979, and compare that with the latest, which is 2000 to 2018, in the initial time period, the lifetime risk of developing heart disease or stroke in a man was pretty high. It was about one in two. And that for a woman was about one in three. So when you come to the latest epoch, what we find that the risk of one in two men had dropped to about one in three men in the latest decade. For women, the risk declined from what was one in three in the earlier epoch to one in four. So approximately there was about a 36% reduction in the lifetime probability of developing heart disease or stroke across the six decade period of observation.

Dr. Greg Hundley:

Very nice. And so help us a little bit, put the context of your results into what that might mean for us today as we are managing patients with atherosclerotic disease.

Dr. Vasan Ramachandran:

Yes, Greg. What it means is that the permeation of the advances in science in terms of the screening of risk factors, awareness of risk factors, medications to lower these risk factors effectively, the clinical trials that have given us these new medications, they may have translated into a reduction in risk over time. That the lived experience of people in the later decades is better in terms of having a lower risk of heart disease or stroke as the consequence of multiple advances that have happened in heart disease and stroke.

Dr. Greg Hundley:

Well, thank you so much Vasan. Well listeners, now we're going to turn to our Associate Editor, Mercy Carnethon. And Mercy, you have many papers come across your desk. What attracted you to this particular paper and how do you put these results really in the context of other science pertaining to risk associated with populations that may have atherosclerotic cardiovascular disease?

Dr. Mercedes Carnethon:

Thanks so much for that question, Greg. And again, Vasan, I really thank you and your team for bringing forth such outstanding research. You know, as cardiovascular disease epidemiologists, we were all raised and taught that what we know about risk factors for cardiovascular disease are based on the Framingham cohort. And so I was really excited to see this very comprehensive piece of work that characterized what the Framingham study has identified and also leverages the unique characteristics of a study that started in 1948.

Dr. Mercedes Carnethon:

So, you know, we're almost 75 years in and actually has the ability that cross sectional studies don't have to look over longer periods of time at risk. And you know, when we think about papers that excite us, that we really want to feature in circulation, they are papers that teach us something new. And I will say there were aspects of this work that confirmed what I had heard but had not seen using empirical data. Namely that the remaining lifetime risks for developing cardiovascular disease were going down over time, and they were going down secondary to better management and recognition of the risk factors that the Framingham cohort study had really been instrumental in identifying in the first place.

Dr. Mercedes Carnethon:

There were surprising elements of the paper. The surprising elements being that I think as you brought up earlier, we were concerned that risk factors that were on the rise, such as obesity, were threatening these increases in life expectancy. And it was really nice to see that the findings held, even in the face of rising risk factors. And just to summarize, what I really like about this piece when we situate it within circulation, where we are addressing clinical treatment factors, where we're also featuring clinical trials and even other epidemiologic studies, is that your work identifies for us the overall context in which the clinicians who read the journal are thinking about managing patients and where we're going. It highlights our successes, but it also really brings up what we need to do next. And I look forward to hearing from you about where you think this may be headed.

Dr. Greg Hundley:

Well, Mercy, you're teeing us up for that next question. Vasan, what do you think is the next study or studies that need to be performed in this space?

Dr. Vasan Ramachandran:

Thank you, Greg and Mercy, for your kind comments. Like I shared, this is a success story for a predominantly white population in the Northeast. We are very much aware about the heterogeneity and the geographic variation in heart disease burden in our country. So one of the success stories interpretation might be this represents the upper bound. What can happen to a population that is compliant with screening of risk factors, awareness of risk factors, treatment and healthcare access. I think the next set of studies should broaden the study population to bring in additional populations that are more diverse, that are also followed up over a period of time to assess and put the current observations in the appropriate context. Do we see similar findings longitudinally in other cohorts with non-white participants? Is it different, is their lived experience different? If so, why? And that could inform us how we can reach the success story and replicate it across the entirety of our country.

Dr. Greg Hundley:

And Mercy, do you have anything to add?

Dr. Mercedes Carnethon:

I do. You know, I really like that focus on broadening to whom these results are applicable. We've undergone a lot of shifts within our country and also around the world. You know, circulation, we have a worldwide readership. I would love to see this sort of work replicated across different countries to the extent that we have the data to do so, recognizing that limitation. But I'd love to see work focus on comparing how these things change in low income countries, middle income and high income countries, so that we can really think about resource allocation and find strategies to try to replicate the successes that we are seeing based on the data from the Framingham heart and offspring studies.

Dr. Greg Hundley:

Excellent. Well listeners, we really appreciate the opportunity to get together today with Dr. Vasan Ramachandran from Boston University and our own Associate Editor, Dr. Mercedes Carnethon from Northwestern University in Chicago. And really appreciate them for bringing us these epidemiologic data from the Framingham cohort, indicating that over the past decades, mean life expectancy increased and the remaining lifetime risk of atherosclerotic cardiovascular disease decreased across individuals in the cohort, even after accounting for increasing incidences of other cardiovascular risk factors like obesity and smoking. Well on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.

Dr. Greg Hundley

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Andrew Chapman and Guest Editor Harvey White as they discuss the article "Coronary Artery and Cardiac Disease in Patients With Type 2 Myocardial Infarction: A Prospective Cohort Study."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Greg Hundley:

Well, Carolyn, this week's feature on April 19th refers to coronary artery and cardiac disease in patients with type two myocardial infarction. And we will have more to learn about that, but how about we grab a cup of coffee and get started with some of the other articles in the issues.

Dr. Carolyn Lam:

Please? You first.

Dr. Greg Hundley:

Thanks Carolyn. So Carolyn, this team investigated the observational and causal associations of 90 cardiovascular proteins, which were measured using affinity based proteomic assays to estimate their association with incident heart failure. And so to accomplish this, the team, led by Dr. Thomas Lumbers from University College of London, utilized a fixed effect meta-analysis of four population-based studies comprising a total of 3,000 plus participants with 732 heart failure events. Now, the causal effects of heart failure associated proteins were then investigated by Mendelian randomization using CIS protein, quantitative loci, genetic instruments identified from genome-wide association studies or GWAS and over 30,000 individuals.

Dr. Carolyn Lam:

Wow! Big study, important stuff. So what did they find?

Dr. Greg Hundley:

Right Carolyn, several things. So 44 of 90 proteins were positively associated with the risk of incident heart failure. Now, among these eight proteins had evidence of a causal association with heart failure that was robust to multiverse sensitivity analysis. Higher CSF1, Galectin-3 and KIM-1 or kidney injury molecule one were positively associated with the risk of heart failure, whereas higher adrenomedullin chitinase-3 like-protein-1, cathepsin L1, and fibroblast growth factor 23, and matrix metalloproteinase 12 were protective. And so Carolyn in summary, the team identified 44 circulating proteins that were associated with incident heart failure of which eight showed evidence of a causal relationship, and seven were identified as being drugable, including adrenomedullin, which represents a particularly promising drug target.

Dr. Greg Hundley:

Additionally, Carolyn, this is a really interesting study as the teams approach demonstrates a tractable roadmap for the triangulation of population genomic and proteomic data for the prioritization of therapeutic targets for complex human diseases.

Dr Carolyn Lam:

Wow! Super cool. Yeah, indeed the methodology is significant there too. Thanks Greg. Well, this next paper deals with hypertrophic cardiomyopathy and we know that familial hypertrophic cardiomyopathy is the most common inherited cardiac disease and is typically caused by mutations in genes encoding sarcomeric proteins that regulate cardiac contractility. But how exactly is the dysregulated sarcomeric force production sensed and how does that lead to pathological remodeling?

Dr. Carolyn Lam:

Well, today's authors and they are Dr. Qyang from Yale University School of Medicine and colleagues gained insights from a severe phenotype of an individual with hypertrophic cardiomyopathy and a second genetic alteration in a sarcomeric mechanosensing protein. They derived cardiomyocytes from patient specific induced pluripotent stem cells and developed robust, engineered heart tissues to study human cardiac mechanobiology at both cellular and tissue levels. They further used computational modeling for muscle contraction and rescue of disease phenotype via gene editing and pharmacological interventions to identify a new mechanotransduction pathway in hypertrophic cardiomyopathy.

Dr. Greg Hundley:

Wow, Carolyn! Tell us more about this new pathway.

Dr. Carolyn Lam:

The study presents a novel biomechanical mechanism by which enhanced myofilament contractile force generation due to sarcomeric mutations, destabilize the muscle limb protein Z-disc mechanosensory complex, and this leads to disinhibition of calcineurin nuclear factor of activated T-cells or NFAT signaling and consequently leads to hypertrophy. Normalization of hypercontractile force in proband cardiomyocytes either with gene editing approaches or with ectomyosin crossbridge inhibitor mavacamten, resulted in an increase in Muscle Lim Protein levels, a decrease in that calcineurin and fat activity and a rescue from the hypertrophic cardiomyopathy defects.

Dr. Carolyn Lam:

The authors provided evidence that the common Muscle Lim Protein W4R variant is an important modifier that worsens the disease severity of hypertrophic cardiomyopathy, but alone does not appear sufficient to cause disease. All in all, these data established a foundation for developing innovative mechanism-based treatments for hypertrophic cardiomyopathy that stabilize the Z-disc Muscle Lim Protein mechanosensory complex.

Dr. Greg Hundley:

Oh, wow Carolyn! What a really nice mechanistic study and important new information too. Well, Carolyn, my next paper comes to us from Dr. Anthony Rosenzweig, Massachusetts General Hospital at the Harvard Medical School and Carolyn the LV myocardium increases in mass in response to pathological as well as physiological stimuli. The former or pathologic hypertrophy, often proceeds cardiomyocyte loss and heart failure. The latter or physiologic, paradoxically protects the heart enhances cardiomyogenesis. The mechanisms underlying these differences remain incompletely understood. Now, while long non-encoding RNAs are important in cardiac development and disease associated with pathologic hypertrophy, less is known about their roles in physiologic hypertrophy or cardiomyogenesis.

Dr Carolyn Lam:

Oh, interesting! So what did these authors find about link RNAs and physiologic hypertrophy?

Dr Greg Hundley:

Right, Carolyn. So in this study of mice, the authors identified exercise regulated cardiac link RNAs termed lncExACT and lncExACT1 was evolutionarily conserved and decreased in exercised hearts, but increased in experimental heart failure. Cardiac lncExACT1 over expression caused pathological hypertrophy and heart failure while lncExACT1 inhibition induced physiologic hypertrophy and cardiomyogenesis protecting against cardiac fibrosis and dysfunction.

Dr. Greg Hundley:

Now, lncExACT1 functioned by regulating microRNA 222 calcineurine signaling, and Hippo/Yap1 signaling through DCHS2. Cardiomyocyte DCH2 over expression in zebra fish induced pathological hypertrophy and impaired cardiac regeneration promoting scarring after this injury. In contrast mirroring DCH2 deletion, induced physiological hypertrophy and promoted cardiomyogenesis.

Dr. Carolyn Lam:

Oh, wow, Greg! Okay. Could you wrap it up for us? What's the take home message?

Dr. Greg Hundley:

You bet, Carolyn. These studies identify that lncExACT1 DCHS2 is a novel pathway regulating cardiac hypertrophy and cardiomyogenesis. lncExACT1 DCHS2 acts as a master switch, toggling the heart between physiological and pathological growth to determine functional outcomes, providing a potentially tractable therapeutic target for harnessing the benefits of exercise.

Dr Carolyn Lam:

Oh, thank you, Greg. Well, also in this issue is an In-Depth paper by Dr. Luesebrink on “Percutaneous Transvalvular Micro Exhale Flow Pump Support in Cardiology.” There's a Research Letter by Dr. Shekhar on “Age and Racial or Ethnic Disparities in Pediatric Out-of-Hospital Cardiac Arrest.”

Dr. Greg Hundley:

Right, Carolyn. Well, Carolyn from the mailbag, we have a Letter to the Editor from Dr. Gronda entitled “The Failing Heart and SGLT2 inhibitor Renal Effects: Are They Mutually Engaged in Business?” We also have from Dr. Viskin, an ECG challenge entitled “Sinus Node Dysfunction with a Nice Twist.” And finally, Carolyn, there's a Perspective piece from Dr. Schulman entitled “The Price and Quality of the Generic Pharmaceutical Market.” Well, how about at Carolyn we get on our feature discussion involving type two myocardial infarction.

Dr. Carolyn Lam:

Yay! Let's go.

Dr. Greg Hundley:

Well, listeners, welcome to our feature discussion on this April 19th and we have with us today, Dr. Andrew Chapman from Edinburg, Scotland and Dr. Harvey White from Auckland, New Zealand. Welcome gentlemen. And we'll start with you, Andrew. First, could you describe for us some of the background information that went into the preparation of your study?

Dr Andrew Chapman:

Good morning and good evening and thank you very much for the invitation. So type two myocardial infarction is an interesting diagnosis. It was first introduced in around 2007 in recognition that patients could have heart injury when they were in hospital with other problems that led to an imbalance in myocardial oxygen supply, or an unmet need in myocardial oxygen demand, without the presence of atherothrombotic coronary artery disease. We don't know a great deal about these patients.

Dr. Andrew Chapman:

There have been a number of observational cohort studies, including from ourselves in Scotland, which have demonstrated the outcomes for this patient group are poor. We know only around one-third of patients with type two MI, survive to five years after diagnosis. And we also know, and previously demonstrated from patients in Scotland that those with underlying coronary artery disease actually had the worst outcomes and were at increased risk of future myocardial infarction events due to plaque rupture. So we hypothesized that patients with type two myocardial infarction may have failed a physiological stress test due to another illness and we wanted to investigate what the prevalence of underlying coronary artery disease and/or structural heart disease was, using a panel of different imaging modalities.

Dr. Greg Hundley:

And so Andrew tell us the hypothesis that you wanted to address?

Dr. Andrew Chapman:

So we believed that observational evidence suggested that coronary artery disease was important in patients with type two myocardial infarction and we felt that this was increasing their susceptibility to these events. Our primary hypothesis was that the majority of patients with type two myocardial infarction would have underlying coronary artery disease, which was previously quiescent undetected.

Dr. Greg Hundley:

Tell us a little bit about the study design and the study population that you use to answer this question.

Dr. Andrew Chapman:

Demand MI is to our knowledge, the first prospective observational cohort study in which patients who were in hospital with evidence of myocardial injury, so a raised cardiac troponin, were screened for the presence of supplier demand imbalance and the clinical diagnosis of type two MI. Now, in those patients that we were able to recruit, we did obviously have important exclusion criteria, but we designed a series of different investigations depending on individual patient risk factors and the appropriateness of such, but the primary goal was to undertake coronary angiography, ideally using an invasive coronary angiogram, which would allow us to undertake additional testing, such as plaque imaging and pressure wire study, to look for the functional consequences of stenosis. In those not fit for an invasive angiogram, we undertook CT coronary angiography. And in all patients we undertook structural imaging and we aimed to do cardiac MRI in all. Due to the coronavirus pandemic and for other reasons, we used echocardiography where MRI was not available.

Dr. Greg Hundley:

And so the total number of subjects here was how many?

Dr. Andrew Chapman:

We recruited 100 patients with a clinical diagnosis of type two myocardial infarction.

Dr. Greg Hundley:

Very good. And so now, Andrew, what were your results?

Dr. Andrew Chapman:

It's a really fascinating study, obviously, in my opinion. So we recruited 100 patients with a clinical diagnosis of type two myocardial infarction who had evidence of supplier demand and balance, a raised cardiac troponin concentration and evidence of symptoms and/or signs of myocardial ischemia. So in line with the universal definition criteria. Of 100 patients after undertaking coronary imaging, we reclassified the diagnosis in seven.

Dr. Andrew Chapman:

In five patients, we found that there was evidence of either plaque rupture or a stent thrombosis. And in two patients, we found evidence of myocarditis and stress cardiomyopathy respectively. The first principle finding is that actually despite careful characterization and really detailed screening, we were correct in 93 of 100 patients and we got the diagnosis wrong in seven. The principle hypothesis related to the prevalence of coronary artery disease and this was, as alluded to, undertaking with invasive and noninvasive imaging. But overall, the prevalence of coronary artery disease was 68% of those with type two myocardial infarction and this was obstructive in 30%.

Dr. Andrew Chapman:

We also undertook structural imaging as mentioned. We observed evidence of left ventricular systolic dysfunction in 34% of patients, of around a third, and perhaps most surprisingly, although we had a clear diagnosis of myocardial infarction in these patients, we only found imaging evidence of in part pattern late gadolinium enhancement, which is considered the gold standard for its diagnosis of myocardial infarction. We only observed that in 42%, which raises some interesting questions.

Dr. Andrew Chapman:

One of the principle clinical findings of the study is that these underlying conditions of coronary artery disease and left ventricular impairment, both of which are readily treatable with secondary prevention. These conditions were previously unrecognized in 60% of patients and only one-third were on appropriate evidence-based treatment, which gives me some cause for optimism, that there may be a role here for targeted treatment, which could plausibly, plausibly impact on outcomes.

Dr. Greg Hundley:

And Andrew, just a clarification point, maybe a subgroup analysis, any differences in your findings in regarding men versus women?

Dr. Andrew Chapman:

Excellent question. And in most studies of type two myocardial infarction, it's thought that this condition is more prevalent in women than men, but undoubtedly in all observational cohorts, there is selection bias as you will only diagnose a type two myocardial infarction if a clinician requests to test troponin in the first place. In our study, interestingly, we recruited more men than women. We had 56% men and we did not find any differences by sex in our analysis.

Dr. Greg Hundley:

Well listeners, what an excellent description from Dr. Chapman. A very interesting study. And we now want to turn to one of our editors, guest editors, Dr. Harvey White, and Harvey, we want to thank you for your work here with us at the American Heart Association and Circulation, and you receive many articles to review. What attracted you to this particular article and how do we put in context, these results with others that have been published pertaining to type two myocardial infarction?

Dr. Harvey White:

Thanks, Greg, it's a pleasure to work for Circulation. This paper is very close to my heart because I introduced the typing system in 2007 and it had minimal support and people said, "Why do we need a typing system? We've got killer class and Canadian class and you've done a troponin release system as well". And people stood up and then I laid out the type one plaque rupture. We know the pathophysiology and we know the treatment. Type two, I'd worked on beta blockers, supply and demand and I thought we should define the pathophysiology and define the treatment. That's 2007, which is 15, 16 years ago. And Andrew's paper is really lovely. As I said, it's close to my heart and he inches things forward. I've written an editorial, which I call "Zooming in on the enigmas of type two MI" and enigma means mystery or it's unclear, uncertain.

Dr. Harvey White:

And that's for sure we don't have full support for the diagnosis. It's become very practical, used in clinical trials and clinically, but we don't know how to manage it and we don't know how to define the groups. Andrew and colleague study is very nice. It's prospective and it has set out to define the coronary artery disease. I've tried for about 10 years to subdivide type two and to those without coronary disease and those with coronary disease. And you could also have a type C, which hasn't been investigated or unknown. And Andrew has answered one of the enigmas and it's really interesting. Large proportion, normal coronary arteries, diagnosis was changed a little bit based on the finding of thrombus. We're challenged with that finding because all MIs have thrombus at PM and really type one should be ruptured plaque. But Andrew changed the diagnosis in a few where one was an OTC, a marvelous case with marvelous pictures, changed the diagnosis. So I like the study and I like the findings. Thanks.

Dr. Greg Hundley:

Very nice. Well, Andrew, what a perspective and listeners getting just to listen to Dr. White is really quite exciting for me. Andrew, what do you see as the next study to be performed in this sphere of research?

Dr. Andrew Chapman:

I think we've gone some way to provide some insights into the underlying pathophysiology of this condition and these coexistent conditions of coronary artery disease and left ventricular impairment, which might increase an individual's susceptibility to a type two myocardial infarction. The question is what can we do about it and does targeted treatment with secondary prevention therapies for coronary disease and treatment for heart failure left ventricular impairment, does that improve outcomes?

Dr. Andrew Chapman:

The next study for me is clear. The next study for me, needs to be a randomized controlled trial, whereby patients with type two myocardial infarction are randomized to current best practice or risk stratification by a cardiologist with an interest in this condition, followed by targeted investigation for coronary disease and LV impairment and thereafter treatment as appropriate. This will be a trial of a complex intervention. I'm very grateful that we've received funding in Scotland already for this pilot phase of this trial, which we've called Targets Type Two and we'll begin recruitment for that trial in August of this year.

Dr. Andrew Chapman:

I must acknowledge colleagues in this area are looking at coronary disease and type two myocardial infraction. Professor Derek Chew is leading a study called Act Two, which is already recruiting and that will also provide invaluable information as to the prevalence of coronary disease and the potential benefits of treatment of that coronary disease in patients with this condition.

Dr. Greg Hundley:

And Harvey. How about your, what is your perspective in terms of the next series of studies perhaps that need to be performed in this space?

Dr. Harvey White:

There's a number and I like very much, Andrew's suggestion. The study that we're doing is randomizing to angiography or not angiography working with Derek Chew. I think all patients with MI should have coronary angiography. It's simple, it takes about 10 minutes. There's obviously some contraindications, but the information as Andrew has pointed out is really so useful. He found dissection, he found an embolus. Normal coronary arteries that in my view changes the management. Whether you should do an angiogram is very important. Randomization to various treatments. That's important. I would like to get more information about the objective evidence of type two MI, the criteria for low hemoglobin, shortness of breath, low blood pressure, high blood pressure, and so forth. There's a lot to do. As Andrew pointed out, the outcome may be worse than type one that's becoming more common and I think these studies will be very, very important.

Dr. Greg Hundley:

Very nice well listeners. We want to thank Dr Andrew Chapman as lead investigator and Dr Harvey White as guest editor for bringing us this study using advanced imaging of patients with type two myocardial infarction, which identified coronary artery disease in two-thirds and left ventricular dysfunction in one-third, and also highlighting that unrecognized and untreated coronary or cardiac disease occurs in many patients with type two MI and gives us pause for thought on a series of studies that may be performed in the future.

Dr. Greg Hundley:

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.

Dr. Greg Hundley:

This program is copyright of the American heart association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit AHAjournals.org.

This week, please join author Enrico Ammirati and Guest Editor Stephane Heymans as they discuss the article "Prevalence, Characteristics, and Outcomes of COVID-19–Associated Acute Myocarditis."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-host. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

 Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature on this April 12, we are going to review COVID-19–associated acute myocarditis, looking at the prevalence and the outcomes. But before we get to that feature discussion, how about we grab a cup of coffee and discuss some of the other articles in the issue, and maybe there could be a quiz in there somewhere.

Dr. Carolyn Lam:

Oh, yikes.

 Dr. Greg Hundley:

But before we get to that quiz, Carolyn, would you like to go first?

Dr. Carolyn Lam:

I would, and we're starting with a topic that we rarely talk about, it's about neurodevelopmental impairment. We know that it's common in children with congenital heart disease, yet postnatal variables explain only 30% of the variance in outcomes. To explore whether the antecedence for neuro development disabilities might begin in utero, these authors, led by Dr. Rollins from Boston Children's Hospital and Harvard Medical School, analyzed whether fetal brain volume predicted subsequent neuro development outcome in children with congenital heart disease. To do this, the authors studied fetuses with isolated congenital heart disease and social demographically comparable healthy controlled fetuses, all undergoing fetal brain MRI and two year neurodevelopmental evaluation.

 Dr. Greg Hundley:

Ah, Carolyn, wonderful, interesting article that we're taking on here in Circulation. What did this group find?

Dr. Carolyn Lam:

In children with congenital heart disease, a smaller total brain volume on fetal MRI correlated with worse neurodevelopmental outcome at two years of age, across all domains of development and adaptive function. A predictive model, including total brain volume, along with sociodemographic and medical data, accounted for up to 45% of the variance in neurodevelopmental outcome within the congenital heart disease group. Fetal brain volume was the most consistent predictor of outcomes across neurodevelopmental domains compared with other sociodemographic and medical or surgical variables.

 Dr. Greg Hundley:

Very nice, Carolyn. Well, my first paper comes to us from the world of preclinical science. Okay, Carolyn, we're going to start it with the infamous Carolyn's quiz. Here we go.

Dr. Carolyn Lam:

Wait a minute, we should put a rule here, no quizzes on preclinical basic science, especially stuff we can't pronounce.

 Dr. Greg Hundley:

Ah, yes, but seems to me, there's a heart failure expert on the team. Always remember, you can phone a friend because we have our wonderful Augie Rivera, our production manager, who is available and you can call on him at any time. Okay, here's the quiz, is Cam Kinase II helpful to cure or harmful to exacerbate heart disease?

Dr. Carolyn Lam:

Oh goodness, Greg. Okay. Cam Kinase II, I know it's Calcium-calmodulin Kinase II. I know there are different isoforms, and I'm cheating here a bit because last week we talked about targeting CaM Kinase II in heart disease. I'm going to guess harmful, I'm going to guess dealing with something with calcium overload, but I'm sure there's more to the story.

 Dr. Greg Hundley:

Carolyn, getting onto to the article, cardiac ischemia-reperfusion injury really has emerged as an important therapeutic target for ischemic heart disease, the leading cause, as we know, of morbidity and mortality worldwide. Currently, there is no effective therapy for reducing ischemia-reperfusion injury. Calcium II Calmodulin dependent Kinase II, or CaM Kinase II plays, a pivotal role in the pathogenesis of severe heart conditions, including ischemia-reperfusion injury. Therefore, pharmacological inhibition of CaM Kinase II could be an important strategy in the protection against myocardial damage and cardiac diseases. But to date, however, there is no drug targeting CaM Kinase II for the clinical therapy of heart disease. Furthermore, currently, there is no selective inhibitor of CaM Kinase II Delta, the major CaM Kinase II isoform, in the heart.

Dr. Carolyn Lam:

Wow. What did the authors do?

 Dr. Greg Hundley:

Okay, Carolyn. A small molecule kinase inhibitor library, and a high throughput screening system for kinase activity of CaM Kinase II Delta9, the most abundant CaM Kinase II Delta splice variant in the human heart, were used to screen for CaM Kinase II Delta inhibitors. Using cultured neonatal rat ventricular myocytes and human embryonic stem cell derived cardiomyocytes, as well as in vivo mouse models, in conjunction with myocardial injury induced by ischemia-reperfusion or hypoxia-reoxygenation and CaM Kinase II Delta9 over expression, this team, led by Professor Yan Zhang, from Peking University, sought to investigate the protection of Hesperidin against cardiomyocyte death and cardiac diseases.

Dr. Carolyn Lam:

Oh, wow. Please tell us, so what happened?

 Dr. Greg Hundley:

Right, Carolyn. Several important findings. First, Hesperidin, the Aurora B kinase inhibitor, with antitumor activity in vitro directly bound to CaM Kinase II Delta and specifically blocked its activation in an ATP competitive manner. Second, Carolyn, functionally, Hesperidin ameliorated both ischemia-reperfusion and over express CaM Kinase II Delta9 induced cardiomyocyte death, myocardial damage, and heart failure in both rodents and human embryonic stem cell derived cardiomyocytes. And then, finally, Carolyn, in an in vivo BALB/C nude mouse model, with xenografted tumors of human cancer cells, Hesperidin delayed tumor growth without inducing cardiomyocyte death or cardiac injury.

Dr. Carolyn Lam:

Wow. Goodness, Greg, that's impressive. Okay, what's the take home message?

 Dr. Greg Hundley:

Well, Carolyn, these results suggest that Hesperidin is a specific small molecule inhibitor of CaM Kinase II Delta with dual functions of cardioprotective and antitumor effects. These findings not only suggests that Hesperidin is a promising leading compound for clinical therapy of cardiac ischemia-reperfusion injury, and heart failure, but also could provide a strategy for the joint therapy of cancer and cardiovascular disease caused by anti-cancer treatment.

Dr. Carolyn Lam:

Wow, Greg, that is an amazing summary. Thank you. Well, for my last paper, I'd like to tell you about a study in which authors led by Dr. Lubo Zhang from Loma Linda University in California, and the colleagues, tested the hypothesis that microRNA-210 protects the heart from myocardial ischemia-reperfusion injury by controlling mitochondrial bio energetics and reactive oxygen species flux. Myocardial infarction in an acute setting of ischemia-reperfusion was examined via comparing loss versus gain of function experiments in microRNA-210 deficient and wall type mice.

 Dr. Greg Hundley:

Ah, Carolyn, another really interesting paper from the world of preclinical science. What were the results here?

Dr. Carolyn Lam:

MicroRNA-210 deficiency induced an ischemic sensitive phenotype and exaggerated acute myocardial infarction and cardiac dysfunction after MI in males in a gender dependent pattern in a murine model of myocardial infarction. The study identified a novel mechanism of MicroRNA-210 targeting mitochondrial glycerol-3-phosphate dehydrogenase in controlling mitochondrial energy metabolism, and reactive oxygen species flux, and improving cardiac function in the setting of acute ischemic-reperfusion injury. Thus, the present findings reveal new insights into the mechanisms and therapeutic targets for treatment of ischemic heart disease.

 Dr. Greg Hundley:

Oh, beautiful descriptions, Carolyn. Well, my next papers come from the mail bag, and there is a great Research Letter from Professor Downing entitled “Critical Illness Among Patients Hospitalized With Acute COVID-19 With and Without Congenital Heart Defects.” Carolyn, there's a second Research Letter from Professor Zhao entitled “Dual Genetic Lineage Tracing Reveals Capillary to Artery Formation in the Adult Heart.”

Dr. Carolyn Lam:

Nice. There's also an On My Mind paper by Dr. Mintz on “Prioritizing Quad Therapy and the Path Forward in Guideline-Directed Medical Therapy for Patients with Heart Failure with Reduced Ejection Fraction.” Cool, Greg, thank you. Now, let's go to our feature discussion, shall we?

 Dr. Greg Hundley:

You bet. To learn more about the prevalence and outcomes in COVID-19–associated acute myocarditis.

Dr. Carolyn Lam:

Acute myocarditis is thought to be a rare cardiovascular complication of COVID-19, or is it? Well, we have minimal data available in case reports, but really not a large scale study until today's issue and today's feature paper, which really aims to look at the prevalence, baseline characteristics, in hospital management and outcomes for patients with COVID-19–associated acute myocarditis.

Dr. Carolyn Lam:

I'm so pleased to have the first author with us, Dr. Enrico Ammirati from Niguarda Hospital in Milano, Italy, as well as our guest editor, Dr. Stephane Heymans from Maastricht University Medical Center in The Netherlands. Welcome, gentlemen. Enrico, thank you, thank you, thank you for this very important study. Could you please tell us what you did and what you found?

Dr. Enrico Ammirati:

Carolyn, it's a pleasure to be here with you and Stephane. We performed, let's say, large study on myocarditis associated with the COVID-19. That is a multicenter study, including 23 centers in the United States and in Europe. The senior author is Professor Marco [Metra], from Brasia, and the co first author is Dr. Laura Lupi, again, from Brasia. What we have done was to better characterize the prevalence of in-hospital myocarditis among the patients hospitalized with the COVID-19 diagnosis.

Dr. Enrico Ammirati:

And then, we tried to describe the outcome and the clinical characteristic at presentation. First of all, we define the myocarditis as a definitive or probable. That was based on the presence of cardiac magnetic resonance imaging consistent with myocarditis plus increase in troponin plus presence of symptoms that are compatible with an acute myocarditis. Alternatively, the patients must have a positive endomyocardial biopsy.

Dr. Enrico Ammirati:

The first result was that among more than 56,000 patients hospitalized in these hospitals, the rough prevalence of myocarditis was around 2.4 among 1000 hospitalized patients. The second main message was that the prognosis, we divided the population, we spitted the population in two groups. Patients with an ongoing and concurrent pneumonia and patient with myocarditis, but without evidence on CT of pneumonia. What we have found it was that among 57% of cases of COVID patients, you can have a myocarditis without pneumonia. So this is an interesting and new finding, and we compare the clinical characteristic of this patient comparing with the patient with the pneumonia. And we found that generally patient with pneumonia were older comparing with the patient with the isolated myocarditis and the prognosis of patients was worse comparing with the patient with just myocarditis.

Dr. Enrico Ammirati:

The outcome was around, overall, the outcome of this population that had median age of 38 year was an incidence of 6% of death. And if we look at the patient with the concurrent pneumonia, the outcome was worse. Then we have other findings that are of potential interest. And that is, for instance, that in 55% of patients, corticosteroids were used, and that is consistent with the idea that corticosteroids can work in this setting. We have also data on the presence of such Coronavirus, two in the heart, in patient that undergo vital search. And it was just in 21% of cases that underwent genome research in the myocardium. So I would say that these are the main findings of this research.

Dr. Carolyn Lam:

Oh, wow. First of all, heartfelt congratulations more than fifth, almost 57,000 hospitalized patients with COVID-19 and 23 hospitals across us and Europe. Stefan, you really appreciate that you served as guest editor here. Could you tell us some of your initial reactions, put the findings in context, perhaps?

Dr. Stephane Heymans:

Yes, yes. For sure. Enrico, indeed, I would like to concur with this congratulations on this beautiful study. It's a lot of work to collect this data and also to try to distinguish myocarditis from all other possible cause of cardiac injury. When I first saw this data, I think, oh, how difficult should be to make a diagnosis of myocarditis. And, of course, increased troponins are often seen in those COVID-19 hospitalized patients. Cardiac MRI is quite a specific for any non-ischemic myopathy. Yeah, I was wondering, so are these cardiac MRI images suggestive of acute myocarditis, but a really specific, sensitive enough to make a definite accurate diagnosis of COVID 19 related myocarditis, or could also be severe illness related to COVID-19 sepsis of pneumonia, give similar images on cardiac MRI?

Dr. Enrico Ammirati:

Stephane, this is a very good point. We haven't studied so in detail the cardiac injury in patients with the viral pneumonia, with the other viruses, so we cannot say that this kind of cardiac involvement is specific for such Coronavirus too. But what I can say is that this population is a population of highly likely acute myocarditis because if you look at simple clinical characteristics, and you can find that the median age is 38 years. This is the first reassuring a clinical characteristic because if we compare with the age of the population, of the laboratory registry of acute myocarditis we published in 2018 in Circulation, the media age was 36.

Dr. Enrico Ammirati:

Then, another point in support of our finding is that in the end, we have both present of edema and positive LG in patients with consistent myocarditis on magnetic resonance imaging. So, I know that probably edema can be associated with either other form of myocardial injury that are not necessary so specific for myocarditis. But if you look at troponin increase in this population, the median increase was 55 folds above the upper reference limit, so it was not just a small increase. It was a huge increase in troponin.

Dr. Enrico Ammirati:

Specifically, in patients that were above 45 years, we have a confirmation that was no coronary artery disease associated, to assure the readers that likely these are myocarditis. But as you said, we cannot be 100% sure about that. And you mentioned an important point, we cannot say that, also, in other form of viral disease, we can have a myocardial injury that can be very similar to myocarditis.

Dr. Stephane Heymans:

Yes. Thank you so much for your clear answer. It just underscores how sick a COVID-19 can make you because the numbers you're getting is two [in] 1000, you would say, okay, that's a small number, but still, there's so many more patients with a cardiac injury related to COVID-19. Indeed, to put it into context, so common viral myocarditis occurs in one to 10, 100,000, so the COVID-19 related myocarditis is up to 100 times more with your numbers. And of course, the common viral myocarditis, it's at the same age, similar age around 36, means a young, relatively young age.

Dr. Stephane Heymans:

Indeed, this COVID-19 is probably a trigger in immune and maybe genetic susceptible, young persons had to get myocarditis upon COVID-19 disease. Whereas, the COVID-19 vaccination related myocarditis, which is getting much more media attention, at least, previous months, only occurs in one to five in 100,000 people. And those patients are completely recover and transplant free. Survival is over 99%. To put it in context, it's still quite severe at this COVID-19 related myocarditis.

Dr. Carolyn Lam:

Thank you so much. Stephane.

Dr. Enrico Ammirati:

Can I add some comments? First of all, we have to say that these patients that died with myocarditis associated with the COVID-19, died to complication related to ECMO. For instance, we had a patient with a brain hemorrhage, and we had one patient who had a complication related septic shock. So, myocarditis can be something on top of a severe disease. We have a condition that is as background that is quite severe, and we a further complication related to myocarditis, so what we have seen is that, generally, even comparing with the previous Lombardy Registry I referred before the outcome of this patient was worse. Of course, it's very difficult to compare studies that have been performed in different centers during a different time period. But, of course, if you think that most of viral myocarditis are secondary to cold or flu, so the background condition is really mild.

Dr. Enrico Ammirati:

The main focus is the myocarditis. While in this patient, we have a subpopulation where you have in a great proportion of them, a severe myocarditis associated with a pneumonia. So you have the double component and that can explain why this patient had a worse outcome. Referring to them, vaccination, my thought is that for the first time we have a large vaccine campaign in this range of age, between 15 and 30 years or 35 years, that is the population at higher risk for myocarditis, where we do not generally perform large campaign for vaccination.

Dr. Enrico Ammirati:

In the end, it can be that we have seen more myocarditis related to vaccination because it was the first time that we vaccinate this kind of population. We have seen something similar with a smallpox vaccination in the military population. And that's the case because for other reason, that are not really related to the health reason, we vaccinated a high-risk population for myocarditis by itself. And we found that smallpox is more associated with myocarditis. Probably, there are, as you said, genetics per count that can explain in some patients an increase risk of myocarditis, but that can be possible that is there is also hormonal or epigenetics phenomena that can explain the higher risk in this population for myocarditis, both for COVID related or for vaccine related.

Dr. Stephane Heymans:

Ah, yeah. Enrico, could you remind me, was this incident of prevalence of COVID-19 myocarditis more prevalent in male patients compared to female when correcting for the background numbers?

Dr. Enrico Ammirati:

In our population, the main population was exactly was about 60%. There was just a slight increase in the number of cases in the male population, but it was not such a large prevalence as you expect in, let's say, uncomplicated myocarditis, where you can find an 80% of male prevalence or in vaccine.

Dr. Stephane Heymans:

Indeed. In the common or the vaccine related myocarditis, it's mainly young male, hetero sex, hormonal factors are being involved, so probably, as you say, these COVID-19 patients have a change in their immune background. And some of those, might some of those also have already background cardiomyopathy or myocarditis, maybe cardiomyopathy, that was not known yet. And then with the COVID-19 might have developed a clinical myocarditis/cardiomyopathy.

Dr. Enrico Ammirati:

When we look at the endostolic diameter of the left ventricle, I can say that the diameter was in the normal range, so that can support the idea that generate this patient did not have a previous dilated cardiomyopathy, but I cannot say that this patient had a known dilated cardiomyopathy before this event.

Dr. Carolyn Lam:

You know, once in a while, Augie, I get to do some of these interviews, and it just takes off on its own. And I love it. And there's nothing I need to do except to sit and listen, and to be grateful that you are publishing this and having such a lovely discussion on this podcast. Thank you, both of you. And, if I could, just very quickly, do you have any take home clinical messages now, from what you've seen, for someone who may be managing one of these COVID-19 patients and suspecting anything?

Dr. Enrico Ammirati:

Can I add that, in the end, what I can, say based on this research, is that likely myocarditis associated with COVID-19 is worse compared with myocarditis associated to vaccine. So even if we see that probably the prevalence is, again, high year with COVID-19, but the most important point is that it's even worse with myocarditis is associated with COVID-19 comparing with the vaccine, so please get the vaccination.

Dr. Carolyn Lam:

Thank you. And you've been listening to Circulation on the Run. From Greg and I, thank you for joining us today. I'm sure you're so grateful, and have learned so much, as I have. And don't forget to tune in again, next week.

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join author Zdenka Pausova and Associate Editor Svati Shah as they discuss the article "Circulating Metabolome and White Matter Hyperintensities in Women and Men."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your cohosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, have you ever wondered what white matter hyperintensities in a brain are made of? Well, guess what? The feature discussion is going to give us a little clue. Believe it or not from the circulating metabolome, interesting, huh? Well, I'm going to keep you in suspense, as we first discuss other papers in the issue. And I want to go first, may I?

Dr. Greg Hundley:

Absolutely, but let's all grab a cup of coffee.

Dr. Carolyn Lam:

All right. You got yours. And here goes. This first paper reviews the results of endovascular aneurysm repair in patients from the Japanese Committee for Stent Graft Management registry, to determine the significance of persistent type II endoleak and the risk of late adverse events, including aneurysm sac enlargement.

Dr. Greg Hundley:

Ah, Carolyn, a very clinically relevant question. So what did this study show?

Dr. Carolyn Lam:

Of more than 17,000 patients who underwent endovascular aneurysm repair for abdominal aortic aneurysm from 2006 to 2015, 29% had persistent type II endoleak. The cumulative incidence rates of abdominal aortic aneurysm related mortality, rupture, sac enlargement, and reintervention were higher in patients with persistent type II endoleak. Specifically, the cumulative incidence rates of rupture and abdominal aortic aneurysm related mortality increased to 2% at 10 year follow up, which is dissimilar to the previously reported frequency of only about 1%. Cox regression analysis revealed older age, female sex, proximal neck diameter, and chronic kidney disease as independent, positive correlates of sac enlargement.

Dr. Carolyn Lam:

So these wonderful results are from Dr. Hitoshi Matsuda and colleagues from the National Cerebral and Cardiovascular Center in Osaka Japan, and really suggests that persistent type II endoleaks are not always benign.

Dr. Greg Hundley:

Beautiful summary, Carolyn. Well, my paper comes from the world of pre-clinical science. And Carolyn, in most eukaryotic cells, the mitochondrial DNA is uniparenterally transmitted and present in multiple copies derived from the clonal expansion of maternally inherited mitochondrial DNA. All copies are therefore, nearly identical or, as we would call homoplasmic.

Dr. Greg Hundley:

Now Carolyn, the presence of more than one mitochondrial DNA variant in the same cytoplasm can arise naturally or as a result from new medical technologies aimed at preventing mitochondrial genetic diseases and improving fertility. The latter is called divergent non-pathological mitochondrial DNA heteroplasmy, or DNPH.

Dr. Greg Hundley:

Now Carolyn, these investigators led by Professor Jose Enriquez from the Centro Nacional de Investigaciones Cardiovasculares hypothesized that DNPH is maladaptive and usually prevented by the cell.

Dr. Carolyn Lam:

Wow, that's really interesting, investigations from the world of preclinical science. What did the investigators find?

Dr. Greg Hundley:

Right, Carolyn. So, the investigative team engineered and characterized divergent non-pathological mitochondrial DNA heteroplasmy, or DNPH, as we've talked about before, mice throughout their lifespan. The authors found that DNPH impair mitochondrial function with profound consequences in critical tissues that did not resolve heteroplasmy, particularly within cardiac and skeletal muscle. Progressive metabolic stress in these tissues led to severe pathology results, including pulmonary hypertension and heart failure, skeletal muscle wasting, frailty, and premature death. And finally, Carolyn, symptom severity was strongly modulated by the nuclear context.

Dr. Greg Hundley:

So in conclusion, Carolyn, these findings suggest that medical interventions that could generate divergent non-pathological mitochondrial DNA heteroplasmy, or DNPH, so to address potential incompatibility between donor and recipient mitochondrial DNA.

Dr. Carolyn Lam:

Oh wow. That is fascinating. Well guess what? My next paper is also about mitochondria, but this time looking at the role of the mitochondrial calcium uniporter. So we know that calcium is a key regulator of energy metabolism and impaired calcium homostasis damages mitochondria, resulting in cardiomyocyte death, pathological hypertrophy, and heart failure.

Dr. Carolyn Lam:

This study by Dr. Wang from University of Washington and colleagues investigated the regulation and the role of the mitochondrial calcium uniporter in chronic stress induced pathological cardiac remodeling. In a series of elegant experiments in the mitochondrial calcium uniporter knockout or transgenic mice infused with isoproteronol, the authors found that the mitochondrial calcium uniporter is up regulated in the stressed heart to orchestrate mitochondria sarcoplasmic reticulum, and cytosolic calcium handling, preventing cytosolic calcium overload induced cardiomyocyte death.

Dr. Carolyn Lam:

Lack of mitochondrial calcium uniporter mediated mitochondrial calcium uptake is detrimental. Whereas, transgenic over expression is beneficial to the heart during chronic beta adrenergic stimulation. The nuclear translocation of calcium/ calmodulin kinase II delta beta via calcineurin mediated dephosphorylation of serine 332 activates CAMP response element binding protein to promote mitochondrial calcium uniporter gene expression in adult cardiomyocytes.

Dr. Greg Hundley:

Well, Carolyn, what's the take home here? What are the clinical implications?

Dr. Carolyn Lam:

Ah, thought you might ask. Well, this study indicates that enhancing mitochondrial calcium uptake could be a new approach to prevent chronic beta adrenergic stimulation induced heart remodeling. Targeting this cam kinase two delta beta KREB mitochondrial calcium uniporter pathway could be a therapeutic option for pathologic cardiac remodeling associated with chronic adrenergic stress.

Dr. Greg Hundley:

Excellent description, Carolyn, and thank you for walking us through that wonderful paper. Well, we've got some other papers in the issue and from the mail bag, Professor Lusis has a Research Letter entitled Identification of DNA Damage Repair Enzyme, ASK II as Causal for Heart Failure with Preserved Ejection Fraction. And Carolyn there's a cardiovascular case series from Professor Barrett entitled, “The Unrepairable Infant Mitral Valve, an Unexpected Case of Decompensated Heart Failure.”

Dr. Carolyn Lam:

Interesting. There's an exchange of letters between Doctors Matrougui and Wang regarding the article, “Integrated Stress Response Couples Mitochondrial Protein Translation with Oxidative Stress Control” and a Perspective piece by Dr. Fatkin on “Fishing for Links between Omega-3 Fatty Acids and Atrial Fibrillation.” Wow. Super cool. Greg, let's go on now to a feature discussion, shall we?

Dr. Greg Hundley:

You bet.

Dr. Carolyn Lam:

For our feature discussion today, we are talking about white matter hyperintensities. Now that's the most common brain imaging marker of small vessel disease. That may be known, but there's a lot more to it. For example, what are they made of? Well, you're going to so enjoy today's feature paper, and I'm so proud to have the corresponding author with us, Dr. Zdenka Pausova from Hospital for Sick Kids in Toronto, Canada, as well as our associate editor, Dr. Svati Shah from Duke University. So welcome ladies. And Zdenka, if I could start with, could you explain the rationale for your study and what you did?

Dr. Zdenka Pausova:

Yeah. Thank you. Thank you for having me. Well, we were thinking that it is important to know what the metabolic variables that associate with white matter hyperintensities might be, simply because we know that there are other studies that have shown that whatever circulates in blood is in some way related to brain health. For example, different lipids associated with Alzheimer Disease, cognitive functioning and with structural properties of the brain. So we were wondering what the metabolics that are associated with white matter hyperintensities might be, simply because we would like to know a little bit more about the pathogenesis of the disease, because that's what metabolomic profiling can provide. And also if one can identify biomarkers that potentially could be used in the clinical setting.

Dr. Carolyn Lam:

Wow. Thank you. And Zdenka, this may be a very basic question, but we hear a lot about the metabolome and sometimes it's not very clear what metabolome profiling actually is. And could you just say a little bit about the technique and your study population and then your findings? Thanks.

Dr. Zdenka Pausova:

Yes. Sure. So we actually studied over 9,000 individuals from eight different population based studies and all of those individuals had metabolomic assays done with two main platforms. It's mass spectrometry and nuclear magnetic spectroscopy. Mostly these platforms are actually commercially available and altogether across all platforms, there were over 2,200 different metabolites. And from those we could study about 1200 that we had at least in two populations. And what the metabolites are, these are different metabolites of lipids, sugar, proteins, amino acids that people put on those platforms or that designers put on the platforms, in order to test some of their hypotheses, that they were actually these metabolites of interest for different sorts of diseases, including cardiovascular and cerebrovascular disease.

Dr. Carolyn Lam:

Wow. So this is really large scale, massive, big data, if I may, and if I'm not wrong, it's the first large scale study to identify circulating metabolomic measures associated with white matter hyperintensities. So could you please summarize the main findings?

Dr. Zdenka Pausova:

Well, overall we actually found that there were 416 metabolites that were nominally associated with white matter hyperintensities, but as it is in epidemiology, you have to correct for multiple comparisons. So when we did DR correction, there were only 30 variables associated with white matter hyperintensities. And when we wanted to check whether those associations are independent of the risk factors for white matter hyperintensities, such as hypertension, type two diabetes, smoking, obesity, we actually ended up with seven markers, seven metabolites that were significantly associated in the fully adjust model.

Dr. Zdenka Pausova:

And the main one was actually a derivative of amino acid hydroxyphenol that probably is a marker of ischemia in the brain. And what actually I am coming to is, and one of the main findings was, that many of those metabolites were associated with white matter hyperintensities in a sex specific manner. That is that they were detected in the pool sample, but essentially the signal came from only one of the sexes. And so this one that was the most significant was detected only in males essentially, and not really in females.

Dr. Zdenka Pausova:

And that I think is an interesting, one of the most interesting findings that we can expect that there are really sex specific pathways, biochemical pathways, that accompany white matter hyperintensities.

Dr. Carolyn Lam:

Wow. Zdenka, thank you so much. I have to bring Svati in right now to share some perspective, Svati, especially to put these findings into context, please.

Dr. Svati Shah:

Yes. Dr. Pausova, really wonderful paper. This is an incredible study, if you think about it. The largest scale study that really is trying to understand metabolic by biomarkers, but the biomarkers actually tell us about the potential biology of what's going on with these white matter hyperintensities. We know that these hyperintensities in the brain are associated with increased risk of stroke, increased risk of cognitive decline, but we don't really understand stand what the risk factors are. There's been some studies suggesting that there's genetic risk factors, but this is really the first large scale study to say, "Hey, what's in the blood that we can measure?" And just to be clear, these technologies are measuring these biomarkers that are very, very, very low levels in the blood, really granular snapshot of what's going on with the human being.

Dr. Svati Shah:

And by looking at these blood markers that the authors were able to find biomarkers that are associated with these brain abnormalities, but really highlighting some of the important biology as Dr. Pausova started to talk about. So I think what it gets us to is we get to have our cake and eat it too. We get to learn about biomarkers that might have clinical utility, but we also have discovered, they've discovered new biology that could lead to new therapies, for example, and a better understanding of the mechanisms of why some people develop these hyperintensities as they age. And some people do not.

Dr. Carolyn Lam:

Wow, Svati, you put that so eloquently and just to put it out there for everyone, that significant metabolite hydroxyphenol pyruvate explain 14% of the variants of white matter hyperintensity volumes in males. Whereas, the proportion of variants explained by hypertension is only 1% or type two diabetes is only 1 to 3%, or smoking is even less than 0.1%. So this is, as you said, Svati, it's a significant discovery as well. Zdenka, though, how do we apply this clinically?

Dr. Zdenka Pausova:

Well, it could be a marker that is measured in circulation and it is a marker that can be measured in blood and can indicate early stages of white matter hyperintensities. But I think before we get there, it would be of high value to actually carry out some longitudinal studies, because it would be really interesting to know if it is an early marker before the white matter hyperintensities extent is enlarged. And so that would one thing. But other than that, I think if that would be the case, we can just measure it in blood and see how predictable it is.

Dr. Carolyn Lam:

Can I ask what about the women? Did anything predict it in women?

Dr. Zdenka Pausova:

That's a good question. There was only actually one variable. To our surprise, only one variable that was significantly associated with white matter hyperintensities in women. And it is really surprising because the sample size was the same. The extent, the volume of white matter hyperintensities was quite similar. They were of similar age, similar adiposity. So there were no huge differences, yet we could not actually detect too many metabolized associated with white matter hyperintensities in women. Really surprising. And I don't have a good answer for it now.

Dr. Carolyn Lam:

Wow. Thank you. Svati, did you have further thoughts on the clinical applications and implications of these tremendous data?

Dr. Svati Shah:

Yeah. I think the ability to have a biomarker as Dr. Pausova nicely articulated that would potentially prevent people from having to get an MRI. And we would be able to identify people hopefully at an earlier stage in the process. In this lovely study, they were looking at biomarkers in people who already had the hyperintensities. I think the next step as Dr. Pausova outlined to be able to identify whether these predict high risk people who will develop them in the future and then try to target therapies. A potential advance in precision medicine in the neurologic space, that we could use this biomarker to say, "You need this particular medication."

Dr. Svati Shah:

Some of the biomarkers that Dr. Pausova's group discovered were actually just cholesterol measures. So maybe we need to be instituting more aggressive cholesterol therapies in these patients who are at high risk. I'm not saying we can do that yet, but these provocative results suggest that this could lead to a more personalized approach to high risk individuals who may have consequences and develop these white matter hyperintensities.

Dr. Carolyn Lam:

And Zdenka, did you have anything to add to that?

Dr. Zdenka Pausova:

Perhaps one interesting aspect of the study that I actually was nicely surprised at the end of the study that the markers, one could the different lipids or the different derivatives of amino acids, the literature provided actually a possible pathways, how those could be involved in the development of white matter hyperintensities. Some of them actually, we could possibly link to impairment of myelination of a neuronal axons, or actually the axons themselves could be the metabolized could reflect damage of those axons.

Dr. Zdenka Pausova:

And also, one suspicious pathway or one pathway that is suspected to be big part of the development of white matter hyperintensities is the disruption of blood brain barrier and some of the markers could be actually linked to that vascular dysfunction.

Dr. Carolyn Lam:

Aw, that's wonderful. Thank you so much, Zdenka, for publishing this beautiful work with us in Circulation. And thank you, Svati, for taking this paper through and inviting this beautiful editorial. In fact, it quite summarizes our discussion. It's entitled, What Turns White Matter White? Metabolic Clues to the Origin of Age-Related White Matter Hyperintensities and it's by Dr. Eric Smith from University of Calgary and I invite everyone to read this.

Dr. Carolyn Lam:

So thank you once again for joining us today on Circulation on the Run. From Greg and I, it's been wonderful having you. Don't forget to join us again next week.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, join authors Steven Lubitz and Associate Editor Mark Link as they discuss the article "Screening for Atrial Fibrillation in Older Adults at Primary Care Visits: VITAL-AF Randomized Controlled Trial."

Dr. Carolyn Lam:            

Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass of the journal and its editors. We're your co-hosts. I'm Dr.  Carolyn Nam, Associate Editor from the National Heart Center in Duke National University of Singapore.

Dr. Greg Hundley:          

And I'm Dr. Greg Huntley, Associate Editor, Director of the Pauley Heart Center from VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:            

Well, guess what we have for the featured discussion today, Greg. It's about screening for atrial fibrillation in older adults at primary care visits. Very, very important topic. And what we'll be looking at is the vital AF randomized control trial. Ooh, we're going to keep everyone in suspense here as we carry on and discuss today's papers. Can I start?

Dr. Greg Hundley:          

Absolutely.

Dr. Carolyn Lam:            

Alright. This first paper is about infective endocarditis. Now, we know that cardiac surgery often represents the only treatment option in patients with infective endocarditis. However, infective endocarditis surgery may lead to a sudden release of inflammatory mediators, which is associated with the severity of postoperative organ dysfunction. So, authors Dr. Doesnst from Friedrich Schiller University of Jena in Germany, and colleagues, decided to investigate the impact of hemo absorption during infective endocarditis surgery on post-operative organ dysfunction.

This multicenter, randomized, non-blinded controlled trial assigned 288 patients undergoing cardiac surgery for infective endocarditis to hemo absorption, which is integration of cytosorb to the cardiopulmonary bypass or control. The primary outcome was defined as the difference between the mean total postoperative sequential organ failure assessment score, calculated maximally to the ninth postoperative day, and the difference with the basal score. Secondary outcomes were 30 day mortality, durations of mechanical ventilation, basal presser and renal replacement therapy. Cytokines were also measured in the first 50 patients.

Dr. Greg Hundley:          

Interesting study, Carolyn. Wow. So, what are the results?

Dr. Carolyn Lam:            

Yes, this trial involved a lot of work and results showed, however, that there was a failure to demonstrate a reduction in postoperative organ dysfunction, 30 day mortality, or any of the clinically relevant secondary outcomes through intraoperative hemo absorption. Although hemo absorption reduced plasma cytokines at the end of cardiopulmonary bypass, there was no difference in any of the clinically relevant outcomes.

Dr. Greg Hundley:          

Great description, Carolyn. Well, my first paper comes to us from the world of preclinical science. And Carolyn, the ascending thoracic aorta, site of aneurysm formation, is populated by a mosaic of medial and adventitial cells that are embryonically derived from either the second heart field, or the cardiac neural crest. Second heart field derives cells, populate areas that coincide with the spatial specificity of thoracic aortopathies that are often associated with aneurysms. And so, this study, led by Dr. Alan Daugherty, from the University of Kentucky. Its purpose was to determine whether and how second heart field derived cells contribute to as sending aortopathies.

Dr. Carolyn Lam:            

Wow, an important topic, Greg. What did the authors find?

Dr. Greg Hundley:          

Okay. So, Carolyn, first, ascending aortic pathologies were examined in patients with sporadic thoracic aortopathies and angiotensin 2 infused mice. And so, the investigators found several things. First, second heart field derived smooth muscle cells and fibroblasts associate with angiotensin 2 induced aortic pathologies. Second, angiotensin 2 induced a distinct fibroblast sub-cluster that was less abundant for messenger RNAs related to major extracellular components and TGF beta-ligands and receptors, but more abundant for proliferative genes.

Third, TGFBR2 deletion in second heart field derived cells were embryonically lethal, with significant dilatation of the outflow tract in the mice. And finally, second heart field specific deletion of LRP1 led to aortic pathologies in mice, supporting the importance of second heart field derived cells in maintaining ascending aortic wall integrity.

Dr. Carolyn Lam:            

Wow. Could you just sum up the clinical implications for us, Greg?

Dr. Greg Hundley:          

Well, Carolyn, I knew you were going to ask me that. So, these results indicate that heterogeneity of the embryonic origins of smooth muscle cells and fibroblasts contributes to complex mechanisms of vasculopathy formation, which should be considered when investigating the pathogenesis of thoracic aortopathies.

Dr. Carolyn Lam:            

Wow, thanks Greg. Well, my next study is also a translational study, and this one provides a deeper understanding of insulin regulation of cholesterol metabolism, and its disruption in type one diabetes. So, this is from Dr. Biddinger from Children's Hospital Boston and colleagues. In order to define the mechanisms by which insulin controls plasma cholesterol levels, the authors knocked down the insulin receptor, FOXO1, and the key bioacid synthesis enzyme, CYP8B1, in mice. They measured bioacid composition, cholesterol absorption, and plasma cholesterol. In parallel, they measured markers of cholesterol absorption and synthesis in humans with type one diabetes treated with ezetimibe and statins in a double blind crossover study.

Dr. Greg Hundley:          

Oh, wow, Carolyn. So, experiments in both animal models and in human subjects. So, what did they find?

Dr. Carolyn Lam:            

Insulin, by inhibiting FOXO1 in the liver, reduces 12 alpha hydroxylated bio acids, reduces cholesterol absorption and reduces plasma cholesterol levels. Thus, type one diabetes leads to a unique set of derangement in cholesterol metabolism with increased absorption rather than increased synthesis. These derangements are reversed by ezetemibe, which is a cholesterol absorption inhibitor, but not simvastatin, which is a cholesterol emphasis inhibitor. So, taken together, these data suggest that a personalized approach to lipid lowering in type one diabetes may be more effective, and highlight the need for further studies specifically in this group of patients.

Dr. Greg Hundley:          

Nice, Carolyn. Well, we've got some other really interesting or articles in the issue. And first, from the mail bag, there's a Research Letter from Professor Bers, entitled "Empagliflozin Reverses Late Sodium Current Enhancement and Cardiomyocyte Proarrhythmia in a Translational Murray Model of Heart Failure with Preserved Ejection Fraction." Carolyn, there's another research letter from Professor Shu entitled, "Activation Of INKY Cells at the Maternal Fetal Interface that Predisposes Offspring to Cardiac Injury." Also, there's a really nice, in depth article entitled, "Takasubo Syndrome Pathophysiology Emerging in Concepts and Clinical Implications." And it's from Dr. Trisha Singh.

Dr. Carolyn Lam:            

Nice. We also have an ECG challenge by Dr. Mugnai on “A Tachycardia in Disguise” and a Perspective piece by Dr. Alexander on “Equipoise in Clinical Trials: Enough Uncertainty [but] in Whose Opinion?” Isn't that interesting? Wow, thanks, Greg. Now, though, let's go on to this super exciting feature discussion on screening for atrial fibrillation in older adults' primary care.

Dr. Greg Hundley:          

You bet.

Well, listeners, we are here for the feature discussion, now, on this March 29th issue. And we have with us Dr. Steve Lubitz, from Mass General and Boston, and our own associate editor, Dr. Mark Link, from University of Texas Southwestern Medical Center in Dallas, Texas. Welcome, gentlemen.

So, Steve, we're going to start with you. Can you describe for us some of the background information that went into the construct of your study, and then what was the hypothesis that you wanted to address?

Dr. Steven Lubitz:           

Sure. Well, thanks for the opportunity to talk with you today about our work. So, as we know, AFib is a common and more bitter arrhythmia. And the first manifestation of AFib can be stroke in a substantial number of individuals. Strokes from atrial fibrillation or debilitating, but they can be prevented using oral anticoagulants if we know who has atrial fibrillation.

But atrial fibrillation can be a symptomatic and it's possible, therefore, that screening pre-AFib could lead to new diagnoses and ultimately improve outcome by enabling stroke prevention. Point of care screening for AFib has been embraced by some guidelines for individuals age 65 or older, such as those in Europe, and mobile technology has now evolved and enables rapid mask screening using handheld ECGs, single lead ECGs, which obviates the need and expense of performing 12-lead ECGs to screen for AFib.

Nevertheless, though, some guidelines have suggested that data are insufficient to recommend screening AFib using ECGs, such as those from the United States Preventative Services Task Force. We tested whether screening individuals age 65 or older at the time of a primary care clinic visit using a single lead ECG would lead to an increased rate of detection of AFib in contemporary United States practices.

Dr. Greg Hundley:          

Very nice. And so, maybe describe for us this task force, and also what was your study design and, again, your study population?

Dr. Steven Lubitz:           

Sure. So, specifically our study design, we performed a cluster randomized control trial in which primary care practice clinics were randomized to the screening intervention or to usual care, and patients aged 65 or older arriving for a primary care visit with their provider were eligible for participation. Patients were offered screening by practiced medical assistants at the time of their vital sign assessments, and screening was performed, if they consented, within a live core cardio mobile single ECG device, which was affixed to an iPad and stationed in the clinic.

The results of the screening were made available to the providers at the time of the visit, and then the provider was able to make any and all decisions about subsequent management, confirmation or treatment. The primary outcome was a new diagnosis of Afib made in the medical record at one year following the start of the screening intervention, and the outcome was ascertained using the electronic health record and then manually adjudicated. We powered the study to detect a difference of nearly 0.5% in the rate of atrial fibrillation diagnoses at 12 months between the screening and usual care arms.

Dr. Greg Hundley:          

And how many patients did you enroll? And then what were your study results?

Dr. Steven Lubitz:           

Well, eight practices were randomized to the screening arm and eight practices to the usual care arm. And in total, that equated to about 15000 patients without a history of atrial fibrillation in the screening arm and 15000 patients in the control arm without a history of atrial fibrillation. The mean age was about 74, about 60% were female, 82% were white. And the mean chad-vad score was 3.4.

We observed several main findings. The first is that, of the individuals in the screening arm, 91% were screened at least once. And this is the largest point of care screening study to date. The rate of screening in the intervention arm was substantially greater than any other contemporary trial, point of care, single ECG screening. We think that high rate of compliance with the intervention reflects patient enthusiasm for screening and a widespread feasibility of incorporating single ECGs into the routine vital sign practice workflow.

Secondly, the primary endpoint, however, incidence of new AFib diagnoses at 12 months, was 1.72% in the screening arm, and 1.59% in the usual care arm, which equates to a risk difference of .13%. That was not statistically significant in the overall sample. We observed a substantial difference in new AFib diagnoses among those aged 85 or older in pre-specified subgroup analyses, 5.56% in the screening arm and 3.76% in usual care arm, which corresponds to a risk difference of 1.8%, where a number needed a screen of about 55, raising the possibility that point of care single ECG screening among the oldest and highest risk individuals might be effective. But this finding warrants future study.

Third, we observed a shift in the location of diagnosis. So, they fit with a higher likelihood of diagnosis at a primary care practice encounter in the screening arm, as compared to the usual care arm, which is as expected. And the implications on downstream management pathways, cost of care, other downstream work flows is unknown at the moment.

And lastly, we observed it in anticoagulation use was high, even among those with AFib diagnosed in the screening arm, which is a reassuring finding, suggesting that clinicians recognized that AF detected using this single lead point of care screening is likely to represent high burden, persistent AF that carries a substantial risk of stroke.

Dr. Greg Hundley:          

Very nice. Well, Mark, I know you review many papers for us here at Circulation. What attracted you to this particular paper?

Dr. Mark Link:   

This issue of point of care screening for AFib is a very hot topic. We all know that clinically diagnosed AFib carries with it a high risk of stroke, but what we don't know is incidentally found Afib, or nonclinically found Afib, what does that mean? This was one of the largest, if not actually the largest, study of point of care screening. And the i-cors are a very accurate device, or reasonably accurate device. So, we thought it's an important contribution to the literature. I think it surprised the authors, as well as us, there wasn't a difference in the diagnosis of AFib between the two arms. I think all of us would've expected to see that. But we're still learning a lot about point of care screening, and we're not to the point where we know what to do yet.

Dr. Greg Hundley:          

And Mark, what are some of your thought? Steve raised the point that, in that subgroup, greater than age 85, any additional insights there?

Dr. Mark Link:   

Yeah. I think that, if you can enrich your group with people that are more likely to have AFib, and the older you get, the more likely you are to have AFib, you are more likely to find Afib. But then treating people over age 85 also becomes a little bit riskier, with both anticoagulants and antirhythmic drugs and ablation.

Dr. Greg Hundley:          

Great points. Well, Steve, coming back to you, what do you see as the next study to be performed, really, in this sphere of research?

Dr. Steven Lubitz:           

Thanks. I think I proposed two additional lines of inquiry. At first, I think our hypothesis generating observation to the point of care screening with a single EDCG can lead to higher rates of AFib detection among the oldest individuals, age 85 or older, with a small number needed to screen warrants, replication, and the downstream implications of that on stroke and bleeding merit further evaluation.

I think secondly, given the proliferation of wearable technology, future studies should examine the effectiveness of detecting perccismal atrial fibrillation for preventing downstream adverse events, including stroke. This point of care screening is likely to detect the highest burden persistent forms of atrial fibrillation in contrast to some of the wearable technology, like consumer wearable technology, that might detect paroxysmal atrial fibrillation, more commonly.

Dr. Greg Hundley:          

Ah, great point. And Mark, how about you? Anything to add? What future study do you see needs to be performed in this space?

Dr. Mark Link:   

It's clear from a number of studies that the longer that you monitor someone, the more likely you are to get a diagnosis of AFib. And that's pretty clear. This was a 30 second monitor. We have a number of studies that have shown two week and ILS monitoring is far more likely to get a diagnosis of AFib. But what we don't know is, if making that diagnosis of AFib makes any difference on ultimate outcomes. That's the studies that we need to see, is does treatment of incidentally found AFib improve clinical care.

Dr. Greg Hundley:          

Very good. Well, listeners, we want to thank Dr. Steve Lubitz from Mass General in Boston, and also Dr. Mark Link from UT Southwestern in Dallas, bringing us results from this study indicating that screening for atrial fibrillation using a single lead EKG at a primary care visit did not affect new atrial fibrillation diagnoses among those that were aged 65 years or older. There was, perhaps, a difference in those aged greater than 85 years, but more research is to come in that space. And, of course, looking for peroxisomal AFib with handheld devices is another area you yet to be investigated.

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week, On the Run.

Dr. Greg Hundley:          

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, join authors Maryjane Farr and Josef Stehlik as they discuss their Perspective article "Heart Xenotransplant: A Door That Is Finally Opening."

Dr. Carolyn Lam:

Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center in Duke National University of Singapore.

Dr. Greg Hundley:

And I'm, Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center, at VCU Health in Richmond, Virginia.

Dr. Greg Hundley:

Well, Carolyn, this week's feature, very interesting, xenotransplantation, where organs from other species are transplanted into humans. And it's a perspective piece. And so, we're going to get a weighted conversation from two different individuals that have a different perspective on the topic.

Dr. Greg Hundley:

But, before we get to that, how about we grab a cup of coffee, and start with some of the other articles in the issue? Would you like to go first?

Dr. Carolyn Lam:

Absolutely, Greg. Although man, that is a big hook you just gave us. Xenotransplantation is seriously, seriously, a hot topic. Can't wait to learn more.

Dr. Carolyn Lam:

But, for this first paper I want to talk about, well, we know that sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing, can identify carriers of pathogenic, or lightly pathogenic, variants. However, to what extent do these variants associate with clinically meaningful phenotypes, and what do we know about variants of uncertain significance?

Dr. Carolyn Lam:

So to answer this question, Dr. Dan Roden, from Vanderbilt University, and his colleagues, looked at 10 arrhythmia susceptibility genes, that were sequenced in more are than 20,000 participants without an indication for arrhythmia genetic testing in the eMERGE III study, which is a multi-center prospective cohort. Variants, previously designated pathogenic, or likely pathogenic, were identified in 120 individuals, or 0.6% population. And electronic health records revealed an over-representation of arrhythmia phenotypes. Some variants of uncertain significance were also found in individuals with arrhythmias and patch clamping, confirmed reclassification, to likely pathogenic.

Dr. Greg Hundley:

Really interesting results from this eMERGE III study, Carolyn. So what's the take home message?

Dr. Carolyn Lam:

As genetic testing becomes more common, the combination of electronic health records and in vitro testing, will help classify variant pathogenicity. Population screening has the potential to identify patients with undiagnosed Mendelian rhythm disorders. However, we need to consider the pros and cons of such an approach. And this is discussed in an accompanying editorial by doctors, Walsh, and Bezzina, and Wilde, from Amsterdam University Medical Center.

Dr. Greg Hundley:

Very nice, Carolyn. Well, my first paper comes to us from Professor Karl Heusler from the University of Wurzburg. Carolyn, this study was a pre-specified analysis of the anticoagulation using the direct factor Xa inhibitor, apixaban, during atrial fibrillation catheter ablation comparison to vitamin K antagonist therapy, or the AXAFA–AFNET 5 trial. And it randomized 674 patients with atrial fibrillation, in a one-to-one fashion, to uninterrupted apixaban, or vitamin K antagonist therapy, prior to first time ablation, with a goal to assess the prevalence of magnetic resonance imaging detected ischemic brain lesions, and their association with cognitive function, three months after first time ablation, using the continuous oral anticoagulation in patients with paroxysmal atrial fibrillation.

Dr. Carolyn Lam:

Huh. Nice. So what did they find, Greg?

Dr. Greg Hundley:

Right, Carolyn. They found that brain MRI detected chronic white matter damage, as well as, acute ischemic lesions, were frequently found after first time ablation for paroxysmal atrial fibrillation, using uninterrupted oral anticoagulation. Including, 27.2% of those receiving apixaban, and 24.8% of those receiving the vitamin K antagonists. So Carolyn, no difference there. MRI detected acute ischemic brain lesions were not associated with cognitive function at three months after ablation. And then, Carolyn, the lower Montreal Cognitive Assessment scores, both before and after ablation, were associated with older age only, highlighting the safety of atrial fibrillation ablation on uninterrupted oral anticoagulation.

Dr. Carolyn Lam:

Oh, thank you, Greg. Well, my next paper talks about basilar artery occlusion, which we know is a devastating condition without definitive evidence to guide treatment. Now, while we do know that faster treatment times with endovascular therapy is associated with better outcomes in the anterior circulation of the brain. What about this relationship for basilar artery occlusion? See? So that's the question that this paper sought to answer, and it's led by Dr. Smith from University of Calgary in Alberta, Canada, and colleagues. They used individual level patient data from the Get With The Guidelines-Stroke nationwide US registry, prospectively collected from January 2015 to December 2019, and identified 3015 patients with basilar artery occlusion treated with endovascular therapy.

Dr. Greg Hundley:

Ah, Carolyn. And so what did they find here?

Dr. Carolyn Lam:

So, here are the results. Treatment of basilar artery occlusion with endovascular therapy, within six hours of last known well, is associated with better outcomes, compared to treatment after six hours. Including, lower odds of mortality and higher odds of reperfusion, independence, and discharge home.

Dr. Carolyn Lam:

There was a non-linear association between, faster treatment with endovascular therapy for basilar artery occlusion, and better outcomes, with the greatest per hour improvement in outcomes seen within six hours of the last known well. In summary, results indicate that, faster treatment with endovascular therapy may improve outcomes in basilar artery occlusion. Efforts should therefore be made, to optimize workflow, including pre-hospital, inner-hospital, intra-hospital processes, to achieve rapid treatment with endovascular therapy in acute stroke with basilar artery occlusion.

Dr. Greg Hundley:

Very nice, Carolyn. Well, my next paper comes to us from the world of pre-clinical science. And Carolyn, as we know, pulmonary hypertension can be caused by chronic hypoxia, leading to hyperproliferation of pulmonary arterial smooth muscle cells, and apoptosis-resistant pulmonary microvascular endothelial cells. And then, upon re-exposure to normoxia chronic hypoxia induced pulmonary hypertension in mice, is reversible. So in this study, the authors led by Dr. Christine Veith, from Justus Liebig University in Giessen, aimed to identify novel candidate genes involved in pulmonary vascular remodeling, specifically, in the pulmonary vasculature.

Dr. Carolyn Lam:

Ah, a very interesting and important topic. So what, or how, did they do this, Greg?

Dr. Greg Hundley:

Right, Carolyn. So following a microarray analysis, the investigative team assessed the role of secreted protein, acidic, and rich in cysteine, or SPARC, using lung tissue from idiopathic pulmonary arterial hypertension patients, as well as from chronic hypoxic mice. In this experiment, the mice were exposed to normoxia, chronic hypoxia, or chronic hypoxia with subsequent re-exposure to normoxia, at different time points

Dr. Carolyn Lam:

Okay, so what were the results?

Dr. Greg Hundley:

Okay, Carolyn, the big drum roll. So the microarray analysis of the pulmonary vascular compartment, after laser micro dissection, identified SPARC as one of the genes down-regulated at all reoxygenation time points that were investigated. Intriguingly, SPARC was vice versa, up-regulated in lungs, during development of hypoxia induced pulmonary hypertension in mice, as well as in idiopathic pulmonary hypertension. Although, SPARC plasma levels were not elevated in pulmonary hypertension.

Dr. Greg Hundley:

Transforming growth factor, or TGF-beta 1, or hypoxia induced factor to a signaling pathways, induced SPARC expression in human pulmonary arterial smooth muscle cells. In loss of function studies, SPARC silencing enhanced apoptosis, and reduced proliferation. And so Carolyn, in conclusion, these authors provide evidence for the involvement of SPARC in the pathogenesis of human pulmonary hypertension, and chronic hypoxia induced pulmonary hypertension in mice, most probably, by affecting vascular cell function.

Dr. Carolyn Lam:

Wow. Thanks for that, Greg. Well, let me give a tour of what else there is in today's issue. There's a letter from Dr. Ng on could cardiologists support, improve, the cardiovascular risk of GnRH agonists. There's a Case Series, by Dr. Blumer, on [entitled] Hemophagocytic Lymphohistiocytosis Associated with Endocarditis: A Case Years in the Making.” There's a Perspective piece by Dr. Hillis on [entitled], Is Asymptomatic Severe Aortic Stenosis Still a Waiting Game?”

Dr. Greg Hundley:

And Carolyn, from the mailbag, we have a Research Letter, from Professor McFadyen entitled, Inherited Thrombophilias are Associated with a Higher Risk of COVID-19 Associated Venous Thromboembolism, a Prospective Population Based Cohort Study.

Dr. Greg Hundley:

Well, now onto that perspective and discussion from two viewpoints on xenotransplantation.

Dr. Carolyn Lam:

Xenotransplantation. Cool. Let's go.

Dr. Greg Hundley:

Well welcome everyone, to this feature discussion. And today, we're taking a little bit of a, different tact, and we are going to discuss a perspective piece. As you know, usually we will discuss an original article, but we have a perspective. And we have with us, the two authors that created this perspective. Dr. Jane Farr from UT Southwestern, in Dallas, Texas, and Dr. Josef Stehlik, from University of Utah. Welcome to you both.

Dr. Greg Hundley:

And listeners, our discussion today is on cardiac xenotransplantation, taking a heart from another species and implanting it in a human subject. So Josef, we'll start with you. Could you tell us a little bit about the history of cardiac xenotransplantation, and what are some of the obstacles that have to be overcome, if we're considering performing this procedure in a patient?

Dr. Josef Stehlik:

Greg, thank you for that question. The concept of xenotransplantation has been around for a long time, with the biggest attraction being, a large and ideally safe source of organs for our patients. As far as cardiac xenotransplantation, the first human art xenotransplant was done in 1964, in a man with terminal heart failure, who received a chimpanzee heart at the University of Mississippi.

Dr. Josef Stehlik:

The patient didn't survive the surgery, and the way it was done back then, brought up a number of ethical issues, and other issues as well. And so, the next xenotransplant was not done until 1984, in a neonate with hypoplastic left heart syndrome, at Loma Linda University. You might have heard the term, Baby Fae, before. And this infant survived about 20 days, and so we couldn't consider it, long term success. However, these two first xenotransplant brought up some important issues that would be studied for years to come. And I think, that the biggest lesson was that, the intra-species immune barriers were a formidable obstacle, and that really, new technologies, and then new medications, would probably have to come into the clinical arena, before we could do it again.

Dr. Greg Hundley:

Very nice. Well listeners, now we're going to turn to our second author on this particular paper. And Jane, can you describe some of the circumstances pertaining to this most recent cardiac xenotransplantation? What transpired, and what's been the outcome with that individual?

Dr. Maryjane Farr:

Thanks, Greg. And thanks for having us here on this program today. So the circumstance around this particular groundbreaking transplant was such that, there was a critically ill patient. This man who was in cardiogenic shock. Both sides of his heart were not working. He was on life saving temporary mechanical support with VA ECMO. And he unfortunately, despite his cardiogenic shock, he was not eligible for standard allotransplantation.

Dr. Maryjane Farr:

Part of that story was really about, not meeting standard criteria for organ transplantation, probably just about anywhere, in terms of a long history of, maybe not taking his meds, or taking care of himself. And there's, certain criteria that he didn't fit into. And he actually had been assessed, as I understand it, by a number of programs, before the University of Maryland approached him with this possibility.

Dr. Maryjane Farr:

One other option that could have been taken, was a mechanical circulatory assist device. But as I say, both sides of his heart were not working, and so really, total cardiac replacement was really his only option.

Dr. Greg Hundley:

And so Jane, do we know anything about what happened? How did the surgical procedure go? Do we know anything about the outcomes?

Dr. Maryjane Farr:

This is of course, patient privacy. So what we know is really, what's in the public arena. And it's actually, there's been a lot of transparency, which has been terrific, by the patient, and the family, and the doctors, because this is such groundbreaking information. But this patient was truly critically ill. There was some paperwork done to try to get FDA approval for emergency experimental surgery, with xenotransplantation. And of course, all the research at University of Maryland, and in many other centers, nationally, and internationally, have been done over the years. And so finally, there was an approval to do this, and it was basically a scheduled surgery.

Dr. Maryjane Farr:

And as I understand it, it went just like any other transplant surgery. There was obviously, a procurement team for the genetically modified pig. There was cold storage of the device. Transport, at least as far as to the next operating room, or however it went. And then, standard implantation, and release of cross clamp, and perfusion. And at least by what you can read about, the heart started to work almost immediately. And then of course, I think that's the easy part. It was really all the intense and multi blockade immunosuppressive therapy, which is really, the challenge of this type of therapy.

Dr. Greg Hundley:

Very nice. Well, Josef, Jane's alluded to this a little bit, but who would be a candidate for this therapeutic, this form of therapy?

Dr. Josef Stehlik:

Greg, so that's an excellent question. And I would like to address it. Before I do that, maybe we should also mention, very briefly, a little bit of the science behind the genetically engineered pig, that Jane mentioned.

Dr. Josef Stehlik:

There were three main things that have been done, and what enabled that is gene editing. And here, I would like to actually mention Dr. Mario Capecchi, who received a Nobel Prize in 2007, for his groundbreaking work at the University of Utah, by describing mouse gene knockout. That has been part of what has been used for engineering, of course, in newer approaches, like CRISPR.

Dr. Josef Stehlik:

Some of the things that have been done is that, the highly antigenic carbohydrates that pigs have on their cell surface, have been edited out. There have been genes that have been edited out and in, connected to coagulation and compliment, to prevent clotting and bleeding in the organ and the recipient after transplant.

Dr. Josef Stehlik:

And of course, one thing that it's very relevant also to our COVID pandemic, there has always, with xenotransplantation, been a question. Could there be trans-species infection? And pigs do have endogenous retroviruses that are parts of their genome, and those have been edited out as well. And so in this way, some of the previous obstacles have been removed.

Dr. Josef Stehlik:

So to your question, who might be a candidate? And I absolutely agree with Jane, that in the first step, it should really be patients who are not candidates for other clinically approved approaches, like allotransplantation from human donors, or mechanical assist, that can be durable, and those are the characteristics that the patient met. And I think, the next patients that will come now, hopefully, will probably be in the same category.

Dr. Josef Stehlik:

Now, I believe, and again, this is a little bit of a speculation, that the next step will be patients who are not eligible for transplant, but who may be eligible for durable ventricular assist devices. And our goal will be to show, that survival and quality of life after xenotransplantation can approach survival and quality of life, on LVADs. And of course, LVADs are evolving, as well.

Dr. Josef Stehlik:

And then, to some degree, it might be the choice of the recommendation of the team, of the multidisciplinary team. What is the best match for the patient? And to some degree, I think patient preference, to really share decision making in patient preference.

Dr. Josef Stehlik:

And in the next step, I believe, that's what we are hoping for, that at some point, we will achieve is that, xenotransplant will rival the outcomes of human allotransplantation. And so, that will be probably, the next group of patients. How long this will take is to be seen. But I think, that it addresses your question, who could be the candidates for xenotransplant in the future?

Dr. Greg Hundley:

Very good. And Jane, Josef was touching on a topic here. How do the anti-rejection treatments differ in xenotransplantation, as compared to allograft transplantation?

Dr. Maryjane Farr:

And so, that's been the thing for all these decades. And so, the first thing is, genetically engineered xenotransplant organs, that can mitigate some of the anticipated xenoantigenic responses.

Dr. Maryjane Farr:

So first, these carbohydrates that we do not see, so they are foreign to us, so there can be acute fulminant rejection. So that's, one step, and the gene knockout can take care of that mostly, but not completely. And then there's humeral rejection, and then, cellular rejection.

Dr. Maryjane Farr:

The cocktail that gets put together for a xenotransplant includes, some of the things that we standardly use, like steroids, ATGAM, or antithymocyte globulin, which is a generalized T and B-cell depleting therapy. What's nuanced, and there's also some role for anti-CD20 B-cell therapy, but what it is nuanced in xenotransplant is anti-CD40 monoclonal antibody therapy. And that was specifically developed, and then studied in heterotopics, or non-human primate pig transplant. Because what turns out is that, the robust T-cell responses, by what's called the indirect pathway, really requires significant costimulatory blockade, where anti-CD40 therapy has been critically important, and well studied by these scientists and others at the University of Maryland, and elsewhere.

Dr. Maryjane Farr:

And as I understand it, anti-CD40 was really, is the basis, the backbone, of this therapy. And then there's one last thing. And that is, temsirolimus, which is a pro drug of proliferation signal inhibitor therapy, that we standardly use in transplant. That's utilized to arrest the further growth of the xenotransplant. So that sounds like it's the cocktail, and there's some published reports, on these scientists using just such cocktail in their non-human primate transplant models.

Dr. Greg Hundley:

Well, listeners, we've heard a really interesting story here. But now, let's ask these experts, first, Josef, and then, Jane. Josef, moving forward, what are the concerns that you really see in this aspect of research?

Dr. Josef Stehlik:

Greg, I think, one of the issues that will have to be addressed, are ethical considerations. And we've seen, that after the news of xenotransplant was made public, there has been a lot of discussion among public about ethics of xenotransplant. I think it will be important to really proactively address that.

Dr. Josef Stehlik:

One aspect from the past is, we knew that primate xenotransplant have not been embraced by the public, just because of the closeness of primates to humans. I think, some of that will be mitigated, now that we are using pigs. But of course, there are many who feel strongly about humane treatment of animals. And so I think, regulation will need to be established that will address that, and that will make both the professionals and the wary public, comfortable with this approach.

Dr. Josef Stehlik:

And another thing that will need to be addressed, and Jane talked about it a little bit is, what parts of care for xenotransplant will be different from human allotransplant. Right? So how do the assessment of the biopsies differ? Right? We'll probably have a new grading scheme looking at xenotransplant. Should the antimicrobial prophylaxis be different? So we do prevent the possibility of trans-species infections we haven't seen before, et cetera. So there would be a lot of work for the transplant teams to do, as well.

Dr. Greg Hundley:

And, Jane.

Dr. Maryjane Farr:

Yes. One thing that's hard, this is amazing science, and this is a huge opportunity to transplant more patients, many of whom die on the wait list every year. But what really needs to be understood also, as we move into this area, and this is where us, as clinicians, get involved in some of these conversations in particular, is that this patient actually wasn't eligible for transplant. And these are very, very difficult decisions that centers are tasked to make.

Dr. Maryjane Farr:

It can get really tricky, and there's lots of patients who say, "Okay, I'm not a transplant candidate.", because of this or that, or the other reason. And there's, some reasons that are more important than others. They'll say, "Transplant me anyway. Give me a heart that you might turn down. Just give me a chance." And we don't do that. And insurance companies don't pay for that. And we have to actually find a way to be rational in our approach.

Dr. Maryjane Farr:

But truly, acknowledging that, if we had more resources, we could probably expand transplant even with the organs that we do have, because we turn down about, probably about 40% of organs, and maybe even more, every year, because we want to match the best organs. So it's really important that xenotransplant, in centers that can do this, demonstrate that this therapy works, and it provides a good quality and quantity of life, for at least, to be reasonable. And once you get there, then you can start to talk about, whether you need to think about allocation, and all that. So you can see how the conversation's going to go on for the next 10 years, about how this fits in.

Dr. Greg Hundley:

You both alluded to the fact, we need more research. And so, incrementally, for maybe each of you in 30 seconds. What do you see as the next research study that needs to be performed in this space? First, Josef, and then again, Jane.

Dr. Josef Stehlik:

That's a tough question, but I'll try to address it. I think, it will be a little bit in parallel to the first human allotransplant. Now that we've figured out the procedure and the organ that we can use, I think, it will be research focused on the care of the transplant recipient. And the task, number one, will be to identify immunosuppression that will be safe and effective, to protect this heart from dysfunction for many years after transplant.

Dr. Greg Hundley:

And Jane?

Dr. Maryjane Farr:

Yeah. You need to do a case series. The handful of centers in this country, and maybe the world, but I only know about this country, that have been studying and working towards this day, should take the lead. University of Maryland has taken the lead, and there are other centers who have been thinking hard about this, and preparing for this time for a long time, and they should lead the way, and try to do this with all the expertise that they've already built. And then as time passes, we can see what their outcomes are, and then we can start to think about, should there be a randomized controlled clinical trial? What should we compare it against? Who should be offered the opportunity? But at first, we need to find that there's safety and efficacy in the patients that are selected, and also, they themselves select, to go through this operation and therapy.

Dr. Greg Hundley:

Well listeners, we want to thank Dr. Jane Farr and Dr. Josef Stehlik, for providing their perspective on a recent procedure, involving the xenotransplantation of a genetically engineered porcine heart, into a human subject with advanced biventricular heart failure, that was not well suited for human heart allograft transplantation.

Dr. Greg Hundley:

Well, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week On the Run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily, those of the editors, or of the American Heart Association. For more, please visit ahajournals.org.

This week, join author Tristram Bahnson and Associate Editor Changsheng Ma as they discuss the article "Association Between Age and Outcomes of Catheter Ablation Versus Medical Therapy for Atrial Fibrillation: Results from the CABANA Trial."

Dr. Carolyn Lam:

Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Guess what, Greg? For today's feature paper, we are going to be looking at a very interesting analysis from the CABANA trial, this time, looking at the association between age and outcomes of catheter ablation versus medical therapy for atrial fibrillation. Cool, huh? Okay, but first, let's go through some other important papers in today's issue. Why don't I let you go first?

Dr. Greg Hundley:

Well, Carolyn, my first paper pertains to the cost effectiveness of coronary artery bypass surgery, and it comes to us from the STICH trial.

Dr. Carolyn Lam:

Ah, very important question, but please remind us what the STICH trial is again.

Dr. Greg Hundley:

Right, Carolyn. So the Surgical Treatment for Ischemic Heart Failure trial, or STICH demonstrated that coronary artery bypass grafting reduced all-cause mortality rates out to 10 years compared with medical therapy alone in patients with ischemic cardiomyopathy and reduced left ventricular function, defined as an ejection fraction of less than or equal to 35%. Now in this study, the authors led by Dr. Derek Chew at University of Calgary examined the economic implications of these results using a decision-analytic patient-level simulation model to estimate the lifetime costs and benefits of CABG versus medical therapy alone, using patient-level resource use and clinical data collected from the STICH trial.

Dr. Carolyn Lam:

Again, really important study. And what did they find?

Dr. Greg Hundley:

Right, Carolyn. So first, using their patient-level simulation model incorporating resource use and clinical data collected from the STICH trial, they found that coronary artery bypass grafting was estimated to cost $63,989 per quality-adjusted life year gain compared to medical therapy alone. Second, in STICH eligible patients with left ventricular ejection fraction of less than 35% in coronary artery disease amenable to CABG, routine use of CABG increased the quality-adjusted life expectancy compared to medical therapy alone for an increased cost within current benchmarks for good value in healthcare within the United States. Then finally, Carolyn, together with the improved clinical outcomes seen in the 10 year extended follow-up of STICH, the findings in this study provide additional economic support for the use of coronary artery bypass grafting in patients with ischemic cardiomyopathy eligible for STICH.

Dr. Carolyn Lam:

Wow, thanks Greg. Well, this next study contributes to the understanding of the effect of lifestyle and genetic risk on the lifetime risk of coronary heart disease. Interesting? Well, listen up. This is from Dr. deVries from UT Health Science Center at Houston and colleagues who aimed to quantify remaining lifetime risk and years free of coronary heart disease according to polygenic risk and the AHA's Life's Simple 7 guidelines in the population base cohort of ARIC. As a reminder, the Life's Simple 7 by the AHA consists of smoking status, body weight, total cholesterol, blood glucose, blood pressure, physical activity, and diet.

Dr. Greg Hundley:

Ah, Carolyn. So genes versus lifestyle. So what did they find?

Dr. Carolyn Lam:

Participants with high polygenic risk may offset their lifetime risk of coronary heart disease by up to 50% through managing their health according to the Life's Simple 7's recommendations, depending on ancestry. Individuals with high polygenic risk scores and ideal Life's Simple 7 scores had 4.5 to 20 more coronary heart disease free years than individuals with high polygenic risk scores, but low Life's Simple 7 scores and again, depending on ancestry. Appropriate management of lifestyle and clinical risk factors of coronary heart disease play larger roles in the overall lifetime risk of coronary heart disease than presently available genetic information. Thus, communicating the effects of Life's Simple 7 measures and polygenic risk on coronary heart disease in terms of absolute risk may have important implications for education, policy, and environmental changes, which can benefit not only high risk individuals, but the whole population.

Dr. Greg Hundley:

Wow, Carolyn, really informative study and so nicely summarized. So Carolyn, my next paper comes to us from the world of preclinical science and it's from Professor Yan from Shanghai, Ruijin University School of Medicine. So Carolyn, previous studies have suggested that mitochondrial dysfunction plays critical roles in the progression of heart failure. However, the underlying mechanisms often remain unclear. Now since kinases have been reported to modulate mitochondrial function team investigated the effects of dual specificity tyrosine regulate kinase one B on mitochondrial, bio energetics, cardiac hypertrophy, and heart failure.

Dr. Carolyn Lam:

Wow. Okay. So what did they find Greg?

Dr. Greg Hundley:

Right, Carolyn. So this team found that Dual Specificity Tyrosine-Regulated Kinase 1B, our DYRK1B expression was clearly up regulated in failing human myocardium as well as in hypertrophic mirroring hearts and cardiac specific DYRK1B over expression resulted in cardiac dysfunction, accompanied by a decline in the left ventricular ejection fraction, as well as the fraction shortening. And it increased left ventricular myocardial fibrosis. Carolyn in striking contrast to DYRK1B over expression, the deletion of DYRK1B mitigated tack-induced cardiac hypertrophy and heart failure. In addition, the authors found that DYRK1B was positively associated with impaired mitochondrial bio-energetics by directly binding with stat three to increase its phosphorylation and nuclear accumulation. Thereby ultimately contributing toward the down regulation of PG C one alpha. Now, furthermore, the inhibition of DYRK1B or stat three activity using specific inhibitors was able to restore cardiac performance by rejuvenating mitochondrial bio-energetics.

Dr. Carolyn Lam:

Cool, Greg. So could you give us a take home?

Dr. Greg Hundley:

Right. So in summary then, Carolyn, taken together, the findings of this study provide new insights into the previously unrecognized role of DYRK1 beta in mitochondrial bio-energetics and the progression of cardiac hypertrophy in heart failure.

Dr. Carolyn Lam:

Fantastic. Thanks, Greg. Well, other papers in today's issue include an exchange of letters between Doctors Nie and Wollert on the article myeloid derived growth factor protects against pressure overload induced heart failure by preserving sarcoplasmic reticulum calcium, ATPase expression in cardiomyocytes. There's an AHA update [AHA Advocacy Page] paper by Dr. Churchwell on improving heart health through value-based payment. An ECG Challenge by Dr. Murphy on a “Curious ECG Morphology of a Cardiac Device.” An On My Mind paper by Dr. Figtree on “Sublingual Nitrates for Patients as a Default in the Post ACS Discharge Pack. Is the Time for a Rethink?”

Dr. Greg Hundley:

Right? Carolyn. Boy, this issue is really packed with great articles. There's a Perspective piece from Professor Stewart entitled “Myocardial Edema Provides A Link Between Pulmonary Arterial Hypertension and Pericardial Effusion.” There's a wonderful Frontiers in medicine piece from Professor Kandzari entitled “A Clinical Trial Design Principles and Outcomes Definitions for Device-Based Therapies for Hypertension: A Consensus Document from the Hypertension Academic Research Consortium.” And then finally, Carolyn, there's a Research Letter from Professor Wold entitled “E-Cigarette Aerosol Reduces Left Ventricular Function in Adolescent Mice. Well, Carolyn, how about we get onto those results from the CABANA trial?”

Dr. Carolyn Lam:

Let's go, Greg.

Dr. Greg Hundley:

Well, listeners, we are now here for our feature discussion and we have with us today, Dr. Tristram Bahnson from Duke University and one of our own Associate Editors, Dr. Changsheng Ma from Beijing. Welcome gentlemen. Tristram, we will start with you first. Could you describe for us some of the background pertaining to this particular research study and what was the hypothesis that you wanted to address?

Dr. Tristram Bahnson:

Sure. Being an active electrophysiologist, a challenge we've had over the years is to try to figure out for whom catheter ablation would be a preferred therapy. I've had the privilege of being part of the CABANA study team over the last several years. As listeners might recall, the CABANA trial was a very large trial looking specifically at hard endpoints, including mortality, to try to determine whether or not catheter ablation provides significant benefits to patient. Apart from what we already knew over the years, which is the catheter ablation was more effective than drug therapy to reduce AFib recurrences. That study, the CABANA proper study was published in 2019.

Dr. Tristram Bahnson:

In the course of that study, pre-specified subgroup analyses were done initially reporting unadjusted outcomes for important clinically relevant subgroups. We found in that initial study that patients with heart failure, minorities, and patients of young age in particular appeared to do better with catheter ablation than with drug therapy. So with that as background, the CABANA study team embarked to focus on each of those subgroups and the heart failure paper was published in 2021, the minorities paper also in 2021 and the subject of our discussion now, the relationship between age and outcome in the CABANA study cohort is a subject of study today.

Dr. Greg Hundley:

Describe just quickly Tristram the hypothesis you wanted to test here and then in order to test that hypothesis, what was the study population that you included and what was your study design?

Dr. Tristram Bahnson:

So the focus was on the relationship between age and outcome in CABANA, and this was pre-specified substudy of the CABANA population. So it's probably worthwhile going over who got into the CABANA trial and to remind folks the CABANA trial enrolled 2,204 patients across 126 sites at 10 countries and randomized them one to one to a treatment strategy of either catheter ablation or drug therapy for simple traumatic atrial fibrillation that in the judgment of the treating physicians warranted therapy, patients had to have had at least two episodes of PAF or one episode of persistent AFib documented by ECG or ambulatory recordings within the six months prior to enrollment and they hadn't have failed more than one anuric drug. In other words, they would have to have been reasonable candidates for drug therapy, should they be so randomized.

Dr. Tristram Bahnson:

In addition, patients that were less than 65 years of age, had to have some additional factors that would increase the likelihood that outcome events would occur. They had to have a CHADSVASC score greater than one. That was not required of the older subjects follow up was 48 and a half months for the population at large, with the interportal range of follow up between 30 and 62 months. The patients had regular follow up every three months for the first year and then six months thereafter. In addition, 1,240 patients received a recording device that allowed them to provide either prescribed episodic recordings or recordings for when they were symptomatic and they also provided 96 hour holters every six months throughout the duration of the trial.

Dr. Tristram Bahnson:

So that's the population that we were working with. The study design, as I said, focused on trying to tease out the relationship between age and outcomes and the primary outcomes of the CABANA trial included the primary outcome, which was a composite. It included all cause mortality, disabling, stroke, serious bleeding or cardiac arrest, and the key secondary endpoints that were looked at included mortality and cardiovascular hospitalization and AF recurrence.

Dr. Greg Hundley:

Very nice. Describe for us your results.

Dr. Tristram Bahnson:

So we actually took a deeper dive into the subgroup of age, and we did a couple things that we thought would be valuable. One was to consider age as a continuous variable because after all, it's pretty arbitrary to bin people into age groups. I think the initial analysis did so with the CABANA proper publication in 2019 to correspond with the break points that we use for CHADSVASC scoring, but we elected to consider age as a continuous variable and we also elected to do adjusted Cox proportional hazard models to account for the various clinical factors that of course varied with age, such as their CHADSVASC score, the occurrence of structural heart disease, like valvular heart disease or coronary disease, the proportion of women, which typically increases with age and did so in this population. The key endpoints that we examined were the CABANA endpoints, including the primary composite endpoint of total mortality, mortality, or CB hospitalization and AF recurrence.

Dr. Tristram Bahnson:

So at the end of the day, we had 766 patients who were less than 65, 1,130 that were between 65 and 74 and 308 that were greater than 75. Mind you, CABANA admitted patients with any kind of AFib. As a matter of fact, more than half of the study population had persistent or longstanding persistent atrial fibrillation, which is not typical of many studies that have been published, looking at the relative benefits of catheter ablation. We had an unexpected finding that was hinted at, at the initial CABANA study and that was the benefit of catheter ablation was greatest in the younger patients and the benefits of catheter ablation relative to drug therapy seemed to decrease with advancing age at enrollment, which was the age criterion that we based the analysis this on and that this effect was primarily driven by changes in mortality.

Dr. Tristram Bahnson:

For the composite endpoint in CABANA, which was total mortality, serious stroke, serious bleeding and cardiac arrest, we saw that the adjusted hazard ratio increased average of 27% for every decade in advancing age, where the age was defined as that at enrollment, and for the total mortality endpoint, the adjusted hazard ratio increased an average of 46% for every 10 year increment in age at enrollment. For all age groups, catheter ablation was superior to drug therapy, a relative to a reduction in AFib consistent with many other studies. The benefit was a reduction in the adjusted hazard ratio of about 50%. So catheter ablation was agnostic to age in terms of the benefit of reducing AFib, but was not agnostic to age with result to these mortality inclusive endpoints. We did notice that there was a trend towards a relative benefit of drug therapy for the oldest age group, but we interpreted that result with caution for a variety of reasons. The oldest age group was least well represented and comprised less than 10% of the CABANA population and less than half of the next best well represented age group, which was the less than 65's.

Dr. Tristram Bahnson:

In looking carefully at the data, we could find no plausible explanation for why the older age group might do better with drug therapy. Again, it was not significant by an intention to treat analysis, but there was a trend towards drug therapy getting better with the oldest age group. We noticed that there was no excess mortality in the old age group within six months of treatment, so it didn't seem like it was related to some adverse procedural effect. We saw no evidence of more advanced forms of AFib in the oldest age group, because they had as good AFib suppression as others, and had the same distribution of paroxysmal versus persistent forms of AFib as the other age groups. There was no difference in crossover after all, if more patients in the old age group crossed over from drug to ablation therapy, who might expect that to be a confounder.

Dr. Tristram Bahnson:

We did see something that was very unusual and unexpected, which is that the mortality of the oldest age group treated with drugs was actually less than their mortality in catheter ablation, which is the issue at hand, but also less than the other age groups, which was unexpected and even less than all but the youngest age group treated with catheter ablation. So we can't explain this finding. It was not statistically significant. At the end of the day, we don't believe that elderly patients who have drug refractory AFib that is symptomatic should be denied ablation.

Dr. Greg Hundley:

Well, thank you so much, Tristram, for these very intriguing results. Changsheng, you have many papers that come across your desk. What drew you to this particular paper?

Dr. Changsheng Ma:

Yes. Dr. Bunch and colleagues should be commanded for the understand and taking important subgroup analysis of CABANA study. There has also been interest in whether the risk and the benefit of ablation may be modulated by patient age. The current analysis suggests that the related benefit of ablation was characterized for those less than 65 years of age are a tiny bit by the increasing age. It is important to emphasize that the current analysis result should not be interpreted to suggest that the cancer ablation has less value in idly patients. As a casual ablation must treated before recurrence across all age groups.

Dr. Changsheng Ma:

The current analysis is assuming we should know age related increase in safety constant in patients and taking ablation therapy. So we must be cautious not to over incorporate the result of the sub-group analysis, especially in the context of CABANA trial, treating in the permanent effect of ITT analysis. So I think it can be a possible that reach age related gradings in the relatively treatment benefits of the ablation is finding a challenge. Secondly, the CABANA trial was not a oral subgroup analysis. So the variation of treatment effect across the different age group were in the further resource. That's my opinion.

Dr. Greg Hundley:

Thank you very much. Well, gentlemen, what do you see is the next study that needs to be performed in this sphere of research and Tristram, we'll start with you.

Dr. Tristram Bahnson:

Well, clearly the clinical task at hand, for those of us who treat patients is to advise patients about relative benefits of therapy when there are choices at hand. And in the case of atrial fibrillation, the fundamental choice obviously is whether or not to pursue catheter ablation or to pursue medical therapy, either for rhythm or rate control. An important part of that decision making is to understand which patients would derive the most benefit from one versus the other therapy. And that need is perhaps the genesis of why we embarked on these subgroup analysis, which admittedly need to be interpreted with caution are not powered to give definitive results, but can certainly help guide future research. So we have noted in the CABANA trial that heart failure patients might do better and that's consistent with other studies looking specifically at heart failure with reduced ejection fraction. So we're contemplating additional studies to help tease that population out since in CABANA, in particular, our heart failure population was mostly those with a preserved ejection fraction and clinical heart failure.

Dr. Tristram Bahnson:

With regard to age, I think it'll be important to do studies to try to understand what factors resulted in the young patients apparently doing better with ablation. Again, this is hypothesis generating in terms of our result with this paper. So it'd be very interesting to find out whether there are some subsets of patients with younger ages or patients who have the relevant characteristics of the young age patients who would derive particular benefit from catheter ablation. This would obviously require a variety of approaches, including prospective randomized studies and carefully done population studies. So this issue about which patients really derive a significant mortality benefit it from catheter ablation is an important one that has not yet been teased out completely.

Dr. Greg Hundley:

Thank you. And Changsheng, do you have anything to add?

Dr. Changsheng Ma:

Yes. I think two streams say it's a very important topic for, you know, who have more and more, the older patients. So we need to answer the question, how about the real influence of age on the outcomes of the atrial fibrillation patients with ablation. So in future, we should consider randomized trial, but I think it's very difficult. So maybe we have to wait more and more, you know, other study to have a trend, how about the outcome for all the patients. It becomes too difficult for a new randomizedtrial.

Dr. Greg Hundley:

Very nice. Well listeners, we want to thank Dr. Tristram Bahnson from Duke University and Dr. Changsheng Ma from Beijing for bringing us the results from this substudy of the CABANA trial indicating that the mortality related benefits of catheter ablation for atrial fibrillation appeared to decrease for every 10 year increment in age, above the age of 65 years. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.

Dr. Greg Hundley:

This program is copyright of the American heart association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association for please visit ahajournals.org.

This week, please join author Siddharth Patel and Guest Editor Ileana Piña as they discuss the article "Sodium-Glucose Cotransporter 2 Inhibitors and Major Adverse Cardiovascular Outcomes: A SMART-C Collaborative Meta-Analysis."

For the episode transcript, visit: 

https://www.ahajournals.org/do/10.1161/podcast.20240531.705195

This week, join author Marco Valgimigli and Associate Editor Mark Link as they discuss the original research article "Amulet or Watchman Device for Percutaneous Left Atrial Appendage Closure: Primary Results of the SWISS-APERO Randomized Clinical Trial."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage fast as a journal and editors. We're your co-host, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

I'm Dr. Greg Hundley, Associate Editor, Director of Poly Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, I've got a personal interest in this feature paper that's coming up. I've always been very intrigued with the left atrial appendant closure. Well guess what? This is the results of the Swiss-Apero Randomized Clinical Trial, comparing the Amulet with the Watchman device for percutaneous left atrial appendage closure, really interesting stuff coming right up, but let's hold everyone in suspense. As we go through some of the other favorite papers in today's issue. Would you like to go first?

Dr. Greg Hundley:

You bet Carolyn, this first paper really pertains to driving restrictions and earlier arrhythmia is in patients receiving a secondary prevention, implantable cardioverter defibrillator, and it comes to us from Dr. Christian Steinberg. So Carolyn, regulatory authorities of most industrialized countries recommend six months of private driving restriction after implantation of a secondary prevention ICD and these driving restrictions result in significant inconvenience in social implications. And so Carolyn, the purpose of this study was to assess the instance rate of appropriate device therapies in contemporary recipients of a secondary prevention ICD using a retrospective across three Canadian tertiary care centers enrolling 721 consecutive patients with new secondary prevention ICD implants between the years of 2016 and 2020. And they were followed for a median of 760 days.

Dr. Carolyn Lam:

Nice. An important question. So what did they find Greg?

Dr. Greg Hundley:

Right Carolyn. So they found that the cumulative incidents of arrhythmic syncope resulting in sudden cardiac incapacitation was 1.8% within the first 90 days, and subsequently dropped to 0.4% between 91 and 180 days after ICD insertion. So Carolyn the incidence rate of appropriate therapies resulting in sudden cardiac incapacitation in contemporary recipients of a secondary prevention ICD is much lower than previously reported and significantly declines after the first three months, lowering driving restrictions to months after the index cardiac event seems safe and revision of the existing guidelines should be considered in countries still adhering to a six month period.

Dr. Carolyn Lam:

Oh, love it Greg. Elegant study with clinically impactful results as with the next paper, I'm going to talk about a post talk analysis of the Danish trial in which authors led by Dr. Boas from Denmark and Dr. Bower from Austria and their colleagues. And what they did is they tested whether periodic repolarization dynamics or P R D, which is a marker of repolarization instability associated with increased sympathetic activity. Could indeed identify patients with non-ischemic cardiomyopathy that may benefit from prophylactic ICD implantation. So, 748 patients were included in this P R D sub-study. And they were included if they had a 24 hour whole term monitor recording at baseline with technically acceptable ECG signals during the night hours. P R D as a reminder of periodic repolarization dynamics was assessed using wavelet analysis according to previously validated models.

Dr. Greg Hundley:

Very interesting, Carolyn. So what did they find?

Dr. Carolyn Lam:

Periodic repolarization dynamics was independently associated with mortality. More over P R D was significantly associated with mortality in the control group, but not in the ICD group in this Danish trial. There was a significant interaction between P R D and effect of ICD implantation on mortality, such that patients with higher P R D had greater benefit in terms of mortality reduction with the ICD. Based on P R D the investigators could identify a new group of patients where prophylactic ICD implantation was associated with a significant absolute mortality reduction of 17.5% after eight years corresponding to a number needed to treat of only six. So this is the first sub-study of Danish to identify a marker on top of age, that can predict the treatment effect of prophylactic ICD implantation in patients with nonischemic cardiomyopathy.

Dr. Greg Hundley:

Very nice Carolyn. Well, my next paper comes to us from Dr. Kory Levine from the Washington University School of Medicine. And Carolyn recent studies have established that cc chemokine receptor type two are CCR2 marks the pro inflammatory subsets of monocytes, macrophages and dendritic cells that contribute to adverse left ventricular remodeling and heart failure progression. Now elucidation of the effector mechanisms that mediate adverse effects of CCR2 plus monocytes, macrophages and dendritic cells could yield important insights into therapeutic strategies to suppress myocardial inflammation.

Dr. Carolyn Lam:

Hmm, indeed. And so what did these author determine regarding the suppression of myocardial inflammation?

Dr. Greg Hundley:

So Carolyn this team utilized mouse models of re perfused myocardial infarction, and angiotensin two and phenylephrine infusion, and diphtheria toxin cardiomyocyte ablation to investigate cc chemokine ligand 17. They found that cc chemokine ligand 17 serves as a pro-inflammatory mediator of CCR2 macrophages and dendritic cells, and their results suggest that inhibition of cc chemokine ligand 17 may serve as an effective strategy to promote T-cell regulation recruitment, and thereby suppress myocardial inflammation.

Dr. Carolyn Lam:

Wow, thanks, Greg. That was beautifully summarized great stuff. Well, there are other exciting articles in today's issue. There's an exchange of letters between Doctors Nagareddy and Spear on “Interleukin One Alpha as a Central Regulator of Leukocyte Endothelial Adhesion in Myocardial Infarction and Chronic Kidney Disease. There's an ECG challenge by Dr. Yang entitled, “A Fatal Case of Y QRS tachycardia following Sintilimab treatment for lung cancer. It can happen.” There's an On My Mind paper by Dr. Faed on “CYP2C19 Genotyping in Anticoagulated Patients Post PCI: Should it be Routine?”

Dr. Greg Hundley:

Great, Carolyn and I've got a Research Letter from Professor Poo entitled “Efficient in Vivo Hemology- Directed Repair within Cardiomyocytes.” Well, how about we get onto that feature, discuss and learn more about Watchman devices and left atrial appendage closure.

Dr. Carolyn Lam:

Ooh, let's go.

Dr. Greg Hundley:

Well, listeners. Now we are onto the feature discussion today, and we're so privileged to have with us, Dr. Marco Valgimigli from Bern, Switzerland and our own Associate Editor, Dr. Mark Link from UT Southwestern. Welcome gentlemen. Well, Marco, we will start with you. Can you describe for us a little bit of the background material as to why you wanted to perform this study and what was the hypothesis that you wanted to address?

Dr. Marco Valgimigli:

But thank you so much for having me left atrial appendage closure is a therapeutic option for a patient who have formal indication to oral anti-population because of atrial fibrillation yet have some relative or absolutely contraindication to the treatment because mainly of high bleeding risk features, mainly because of previous bleeding complications. The two most frequently use device to accomplish that procedure are from one side Watchman, which is FDA approved. And on the other hand, the Amulet, which has been historically the device, which has been most frequently used in Europe, these two devices have been formally compared in one head to head study, which is Amulet IDE and also reported in the journal some month ago. However, it was important also to compare the new Watchman iteration, which the Watchman Flex, which was not part of the original Amulet IED, which only compared Amulet with Watchman 2.5.

Dr. Marco Valgimigli:

Before we set up this multicenter study, which recruited patients across eight centers and four European countries, we roughly screened 450 patients. And we ended up randomizing 222 to either of these two device being Amulet or Watchman. We set up this study to answer a superiority hypothesis, actually, of Amulet versus Watchman and we assume that Amulet would be superior compared to Watchman with the respect to the need for crossover to a known randomly allocated device or LA Patency at 45 day SCCTA.

Dr. Greg Hundley:

Very nice Marco. And so now describe for us your study design. And then what was your study population?

Dr. Marco Valgimigli:

That was an investigate initiated and conducted multicenter study, which took place across eight centers in four European countries. We screened roughly 450 patients to be able to randomize. Finally, 222 were evenly allocated to either of these two device. We selected patients with either fibrillation and form lead for oral anti-regulation to with relatively high chat box score on average four and very high has bled at least three or greater. In fact, 95% of our patient had prior bleeding before being considered for the study.

Dr. Greg Hundley:

Very good. And describe for us your results.

Dr. Marco Valgimigli:

So the superiority that we assumed was actually not met. The primary point, which was again, crossover to a known allocated device or patency rate at 45 day SCCTA was pretty much similar with rates being 68% in the Watchman group and 70% in the Amulet group. So basically no real difference. We did see though some interesting differences with respect to some key secondary endpoints.

Dr. Greg Hundley:

And describe those.

Dr. Marco Valgimigli:

So for example, the type of leaks that was recorded was actually different with respect to the two devices with intra device leaks, being much more frequent with Amulet and peri device leak, being much more frequent with Watchman. Also the rate of any or major procedure complications were slightly yet significantly higher in the Amulet group. And interestingly as well, we had some minor differences with respect to the device related thrombosis, which was numerically slightly higher in Watchman as compared to Amulet also, we performed at 45 day TEE, Transesophageal Echo and with that respect, we did see a slightly, yet numerically and significantly higher rate of peri device leak, detected at Transesophageal Echo with Watchman as compared to Amulet, which is in a way reflecting our SCCTA findings.

Dr. Greg Hundley:

Very nice. And so lots of results comparing these two devices for a left atrial appendage closure. So Mark, you see many papers come across your desk. What attracted you to this particular paper?

Dr. Mark Link:

Yeah, this is a very important clinical paper. The left atrial occlusion devices are going to continue to be used and with increasing frequency and there can be very beneficial. The Amulet is not approved in the United States. And so comparison between Watchmen and the Amulet are very important, both for the US and for Europe and the rest of the world. And that's why we were attracted to this paper, it's a nice randomized paper comparing the two most commonly use devices.

Dr. Greg Hundley:

Help us put the results of this study into the context in really how we might manage patients and how we're considering these devices, both from the European perspective and then also here in the US.

Dr. Mark Link:

I think what this study shows is that they're more or less equivalent and there may be theoretical reasons why one may be better than the other, but in this trial it didn't really come out. So I think the Amulet used more in Europe. The Watchman is used exclusively here, but I think this opens a window for the Amulet to come to America also and be approved by the FDA.

Dr. Greg Hundley:

Very good, well, coming back to you, Marco, where do you see is the next study that needs to be performed in this arena of research?

Dr. Marco Valgimigli:

I think now we have relatively effective device in accomplishing what we would like to accomplish. Namely sitting the LAA for preventing subsequent thromboembolic events. However, the procedure despite operators have been growing in terms of interest and experience is still associated with some degree of complications. Some of them are minor, but some of them are not. I think the next future, we should try to minimize those complication to the lowest possible event so that this procedure can potentially be also offered to a broader patient population, perhaps not just as a replacement of oral anticoagulation, but perhaps in association with oral anticoagulation to further minimize the stroke and other thrombotic events.

Dr. Greg Hundley:

And Mark, do you have anything to add here?

Dr. Mark Link:

Yes. I think what we need more information on is two things. One is procedural complications, procedural complications were higher with the Amulet device. And is that because it was a newer device and people are just learning how to use it, or is there something there that's really important? So that's one and then the really important one is long term clinical outcomes. This was a relatively short term trial when you're talking about strokes and anticoagulation. And so what I'd like to see is longer term follow up with both devices in the future.

Dr. Greg Hundley:

Well, thank you Mark. So now Marco, do you have any additional studies that you're performing really on this same dataset?

Dr. Marco Valgimigli:

Well, I actually fully agree with Mark, very long term follow up is absolutely mandatory in this patient population. And I'm very glad to announce that this Swiss Apero study that we have been discussing will actually continue. Continuing patients follow up five years so that we will have much more clinical information, at least comparative effectiveness, clinical information between two devices. And also we'll be performing at 13 months, a second SCCTA to better understand the dynamic nature of these peri device or inter device list, whether they actually do see over time and which of them may or not play a clinical role.

Dr. Greg Hundley:

Very nice well listeners, we want to thank Dr. Marco Valgimigli from Bern, Switzerland and our own associate editor, Dr. Mark Link from UT Southwestern for really bringing us this very important paper that compared the results of the Watchman, which is for primarily used in the US versus the Amulet, primarily used in Europe, a left atrial appendage closure device. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.

Speaker 5:

This program is copied right of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, join author Makoto Hibino and editorialist Christoph Nienaber as they discuss the article "Blood Pressure, Hypertension, and the Risk of Aortic Dissection Incidence and Mortality: Results From the J-SCH Study, the UK Biobank Study, and a Meta-Analysis of Cohort Studies" and accompanying editorial "Taming Hypertension to Prevent Aortic Dissection: Universal Recognition of a "New Normal" Blood Pressure?"

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Poly Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn this week's feature discussion. Oh, very interesting. We are going to delve into results from the Japan specific health checkup study, as well as the UK Bio bank study and also a meta-analysis of several cohorts and investigate the relationship between hypertension and the future risk of aortic dissection. Well, Carolyn, but first, how about we grab a cup of coffee and delve into some of the other articles in this issue, and I'll go first?

Dr. Carolyn Lam:

Please do.

Dr. Greg Hundley:

I'm going to discuss with you the AVATAR trial.

Dr. Carolyn Lam:

Hold on, Greg, remind us, the AVATAR trial?

Dr. Greg Hundley:

Right, Carolyn. So the aortic valve replacement versus conservative treatment in asymptomatic, severe aortic stenosis or the AVATAR trial is an investigator initiated international prospective randomized control trial that evaluated the safety and efficacy of early SAVR or surgical aortic valve replacement in the treatment of asymptomatic patients with severe aortic stenosis, according to common criteria.

Dr. Greg Hundley:

So for example, the valve area is less than one centimeter squared with an aortic jet velocity of greater than four meters per second, or a mean trans aortic gradient of greater than 40 millimeters of mercury. They also, all of the patients had normal LV function and negative exercise testing was mandatory for inclusion.

Dr. Greg Hundley:

And so these authors, led by professor Marco Banovic from the University Clinical Center of Serbia, tested the primary hypothesis that early SAVR would reduce the primary composite endpoint of all cause death, acute myocardial infarction, stroke, or unplanned hospitalization for heart failure as compared to a conservative strategy, according to guidelines. And the trial was designed as event driven to reach a minimum of 35 pre-specified events. The study was performed across nine centers in seven European countries.

Dr. Carolyn Lam:

Wow. A big important study. What did they find?

Dr. Greg Hundley:

Right, Carolyn? So they had 157 patients and they age average, 67 years and 57% were men and they were randomly allocated to early surgery, so 78 were in that group, or conservative treatment, and 79 were in that group. The follow-up was completed in May of 2021 and the overall medium follow was 32 months, 28 months in the early surgery group and 35 months in the conservative treatment group.

Dr. Greg Hundley:

There was a total of 39 events, 13 in early surgery and 26 in the conservative treatment arm. So Carolyn, in asymptomatic patients with severe aortic stenosis, early surgery reduced the primary composite all cause death, acute myocardial infarction, stroke, or unplanned hospitalization for heart failure compared to the conservative treatment. And so, Carolyn, this randomized trial provides preliminary support for early SAVR once aortic stenosis becomes severe, regardless of symptoms.

Dr. Carolyn Lam:

Wow. Interesting. Well, this next paper that I'm looking at describes a novel therapeutic target that, listen up, can lower plasma cholesterol and prevent thrombosis simultaneously.

Dr. Greg Hundley:

What? Are you sure about this? All right, Carolyn. All right. Describe this for us.

Dr. Carolyn Lam:

Well, I'll tell you what that target is. It is the coagulation factor prekallikrein, which I'm going to call PK, prekallikrein. Okay. Now, as a reminder, coagulation cascades are activated by tissue factor initiated extrinsic pathway and the contact system initiated intrinsic pathway. Both of which converge into the common pathway. Plasma kallikrein is a serine protease playing a crucial regulatory role in the intrinsic pathway and is generated from the liver expressed prekallikrein, a pro enzyme encoded by the KLKB one gene.

Dr. Carolyn Lam:

Now that was the background. In the current study, Drs. Song and Luo from Wuhan University in China and their colleagues identified that the plasma coagulation factor prekallikrein or PK interacts with the LDL receptor and induces its degradation in the lysosomes. In young Chinese Han adults serum PK concentrations positively correlate with LDL cholesterol levels. In hamsters genetic ablation of the KLKB one decreases plasma lipid levels through up-regulating LDL receptor in a manner additively to the PCSK nine inhibitor cyclocumarol.

Dr. Carolyn Lam:

Injections of the anti PK neutralizing antibody in mice and knock down of the KLKB one gene in rats also increased hepatic LDL receptor levels and reduced plasma cholesterol levels. Furthermore, in mice with ample E deficient background PK absence arrested the progression of atherosclerotic lesions. So in totality, these results suggest that PK, remember that's prekallikrein, regulates both LDL and thrombosis, and that PK inhibition can be an attractive therapeutic strategy to lower plasma cholesterol and prevent thrombosis simultaneously.

Dr. Greg Hundley:

Very nice, Carolyn. Well, before we get to our feature discussion on aortic dissection, I've got a paper that pertains to preclinical science and involves the study of aortic dissection. And it comes to us from Professor Aijun Sun from the Shanghai Institute of Cardiovascular Diseases at the Song Hang Hospital in Futon University, the Institute of Biomedical Science in Futon University.

Dr. Greg Hundley:

So Carolyn, the development of thoracic aortic dissection is closely related to the extracellular matrix degradation and the vascular smooth muscle cell transformation from contractile to synthetic type and legumin degrades the extracellular matrix components directly, or by activating downstream signals. However, the role of legumin in the vascular smooth muscle cell differentiation and the occurrence of thoracic aortic dissection, that remains elusive or unsolved.

Dr. Carolyn Lam:

Oh, so what did this study show?

Dr. Greg Hundley:

Right, Carolyn. So these authors found that the elevation of legumin is observed in thoracic aortic dissection tissues of both human subjects and in mice and deletion or pharmacologic inhibition of legumin rescues BAPN induced thoracic aortic dissection development in mice by alleviating extracellular matrix degradation and the vascular smooth muscle cell transformation. Carolyn, legumin depletion may represent a novel therapeutic strategy for thoracic aortic dissection and further studies are required to explore the diagnostic value of serum legumin as a novel biomarker for thoracic aortic dissection.

Dr. Carolyn Lam:

Wow. That's cool. Thanks, Greg. Well, there are other really cool papers in today's issue. There's a Cardiovascular Case Series by Dr. Bockus on a “Heart of Gold: A Scintillating Leading Pericardial Effusion. And I'll give you a hint, it's a case of cholesterol pericarditis. There are letters by Drs. Lucas and Taegtmeyer regarding the article “One Year Committed Exercise Training Reverses Abnormal Left Ventricular Myocardial Stiffness in Patients with Stage B HFpEF” with a response by Dr. Levine. There are highlights from the Circulation Family of Journals by Sara O'Brien.

Dr. Greg Hundley:

Well, Carolyn, I have some other papers to discuss in this issue as well. First, there's an On My Mind piece from Professor Lawler entitled, “What Are Adaptive Platform Clinical Trials, and What Role May They Have in Cardiovascular Medicine?” Next, there's an In Depth piece from Professor Damman entitled Evidence Based Medical Therapy in Heart Failure Patients With Reduced Dejection Fraction and Chronic Kidney Disease. And then finally, Professor Yoshida has a Research Letter entitled The Efficacy and Safety of Edoxoban 15 Milligrams According to Renal Function in Very Elderly Patients With Atrial Fibrillation, a Sub-Analysis of the Elder Care AF Trial. Wow, Carolyn, how about now we get onto that feature discussion.

Dr. Carolyn Lam:

Oh, let's go Greg.

Dr. Carolyn Lam:

For our feature discussion today, we are talking about aortic dissection and the association with hypertension or elevated blood pressure. Now at first sight, you may think, well, we all know that hypertension and elevated blood pressure is an important risk factor for aortic dissection, but I'd like you to question, do we really know?

Dr. Carolyn Lam:

Surprisingly few prospective studies have been published. We know that aortic dissection is an extremely important and serious complication, but it's low incidence means we need huge numbers to be able to answer questions such as, what blood pressure does the start taking off at? For example, is it systolic or diastolic blood pressure and so on? Well, guess what? We finally, I think, have some of the best evidence on this topic published in today's issue of Circulation.

Dr. Carolyn Lam:

And I'm so proud to have the first and corresponding author with us, Dr. Makoto Hibino from the University of Toronto to discuss his fantastic paper. As well as an editorialist, Dr. Christoph Nienaber from Imperial College, London, who will discuss the significance of this paper. Well, let's start with you, Dr. Habino or Makoto, if you don't mind, could you please tell us what you did and what you found?

Dr. Makoto Hibino:

Thank you, Carolyn. So it's my honor to be here to present my case in this podcast. So first, some of the recent data shows that the number of aortic dissection operation and this increasing trend, depending on countries and given the critical nature of aortic dissection preventive strategy against aortic dissection is expected. On the other hand, hypertension is still global issue and is responsible for constant number of deaths from cardiovascular diseases, including aortic dissection, but due to the relatively rare instance of dissection and acute critical nature of the disease, the available epidemiological evidence has been limited. So this time we wanted to investigate how the relationship of hypertension and blood pressure with the instance of the aortic dissection is, in terms of strengths association and the shape of the association.

Dr. Makoto Hibino:

We also hypothesized that association may not be leading a relationship. And what we did is our study is consist of three parts. The first two parts are original cohort studies using a Japanese specific health checkup study and UK Bio bank study in both of which we prospectively followed about half a million general population and analyzed the hazard risk of other aortic dissection instance for hypertension and systolic and diastolic blood pressure using Cox proportional analysis. And the last part is meta-analysis including eight cohort studies and examine the robustness and shape of the association between hypertension and systolic and diastolic blood pressure and the risk of aortic dissection.

Dr. Carolyn Lam:

Wow. So a huge study across diverse cohorts. What did you find?

Dr. Makoto Hibino:

Yes. So in both of our cohort studies, there was significant risk of aortic dissection for hypertension and systolic and diastolic blood pressure as a continuous variable. Also, there was increasing trend in hazard ratios for categorical systolic and diastolic blood pressure with two to five, for higher risk in the highest systolic blood pressure category and four to 12 for higher risk in the highest diastolic blood pressure category in the meta-analysis. The summary relative risk shows that those with hypertension has threefold risk of aortic dissection and the robustness of the result confirmed with the sensitivity and subgroup analysis. Lastly, in the non-linear dose response, meta-analysis, there was very strong dose response relationship between systolic blood pressure and aortic dissection with evidence of non-linearity. And similar, but still, those response relationship was found between diastolic blood pressure and aortic dissection. This analysis showed that the risk of aortic dissection was significant at systolic blood pressure more than 132 millimeter mercury, and diastolic blood pressure more than 75 millimeter mercury suggesting a risk of aortic dissection, even in non-hypertensive population.

Dr. Carolyn Lam:

Wow. That last part really grabbed me. And I think I should repeat that the risk was significant at the systolic blood pressure of only 132 and a diastolic blood pressure of 75. That's really striking. Chris toff, would you agree with me when I said, I think this is like the best data that we have now, sort of correlating blood pressure and hypertension with aortic dissection. I loved your editorial by the way.

Dr. Christoph Nienaber:

Thank you very much. I'm pleased to have the chance to write this editorial. Because, when I reviewed the article, I was thrilled of the data and the fact that somebody some consortium had managed to pool data from two different, let's say population studies in two different gene pools in Japan and in the UK together. And finding in a very granular way, that even within the normal spectrum of blood pressures, up to let's say 140 systolic, we find an increasing risk of dissection with a high normal blood pressure as compared to a low normal blood pressure. This has been very convincingly shown by Makoto's analysis. The entire group has to be congratulated for that fantastic idea. Collaboration from two different ends of the world, and then coming up with a similar conclusion in both populations, tells us that this is a general principle at work, that works in both gene pools in both Asian, as well as European populations, and tells us how important it is to keep an eye on blood pressure and even manage blood pressure within the normal range to a low normal in the future.

Dr. Carolyn Lam:

And I love the way you articulated that in that beautiful editorial, but could I now ask your thoughts, both of you, what are the clinical implications of this? I love Chris toff, that you discussed in your editorial, well, do we now lower the thresholds for treatment? Because aortic dissection is not the most common of incidences, right? So does lowering the blood pressure even more or targets come at a price? Or what should we be thinking of now, clinically?

Dr. Christoph Nienaber:

We are not treating dissection. We are trying to prevent dissection by gauging or gouging to a low normal blood pressure with various drugs and combinations of drugs in patients that are considered to be at risk with a slightly elevated blood pressure. So in the future, it's not enough to accept 140 systolic or 90 diastolic we should really pay attention to strictly lowering blood pressure in the idea of preventing vascular events.

Dr. Christoph Nienaber:

And that was considered to come at a price, but we have of course, reassuring data from Hope, from Sprint recently published that showed that even the low normal doesn't hurt. I mean, you have a lower risk of cardiovascular events, generally speaking, shown in Sprint with a low normal blood pressure. It comes a little bit at the expense of watching renal function, but that doesn't contribute to kind of prognostic sequelae. You just have to pay attention to it. You would not run any additional risk by lowering the blood pressure to a normal low blood pressure. And that's, I think, the convincing message, and even with a low incidence of the most important vascular accidents, such as dissection, you could prove that, or the group could prove that in almost 3000 patients that suffered from dissection, that whole pool of analyzed data. So again, I have to congratulate to this fantastic and convincing results.

Dr. Carolyn Lam:

Thank you. And Makoto, what do you think are the most important clinical take home messages from your study?

Dr. Makoto Hibino:

Yes. So let me, a little bit, step back to the summary of our findings. So our findings is so that this is a study is a fast summary of the evidence from the prospective stakeholder studies on the association of blood pressure and hypertension with the risk of aortic dissection. And this study improves the evidence base from being based on the case studies or single study to actual estimate of the relative risk. So also, with further study are needed, the current results suggests that the reducing blood pressure either through a healthier lifestyle or medication may reduce the instance of aortic dissection and furthermore the optimal target blood pressure may even lower than the current cut for hypertension. So from my perspective given the little rare instance of aortic dissection, intensive blood pressure management may be more effective or efficient in high risk population, such as those with bicuspid aortic valve or those with very ill medical follow for aortic aneurysm and those with genetic background. So further study in a specific subgroup, is warranted.

Dr. Carolyn Lam:

Thank you. And Chris toff, that's very interesting because I buy your argument too, that on the other hand, going lower, even in non-high risk, doesn't really come at a price as far as we can see. So what do you think Chris toff, what do you think are the further studies that are needed?

Dr. Christoph Nienaber:

Well, I was intrigued to see in their analysis that even the subgroups of patients, including patients with hereditary connective tissue disorders, survivors of previous dissection, patients with other conditions, including diabetes, et cetera, they're all across the board, benefited from low blood pressure adjust or adjustment to a low blood pressure. That gives me confidence to recommend to my colleagues, not only here, but in my further environment to follow those patients that are identified either as risk groups or with a slightly elevated blood pressure to definitely lower the blood pressure to lowest, lower to blood pressure with those side effects.

Dr. Carolyn Lam:

Nice. These are association studies just to take a step back rather than sort of treatment target studies, although we've discussed some of the treatment target studies, but I have to really agree that it's some of the strongest association data that I can frankly think of for blood pressure and aortic dissection. We're just so grateful that it has been published in Circulation. And thank you so much, Chris toff, for your elegant editorial, that really puts things in perspective with a very important final key take home message.

Dr. Carolyn Lam:

And with that, well listeners, you heard it right here on Circulation on the Run from Greg and I thank you for joining us this week. And, don't forget to tune in again next week.

Speaker 5:

This program is copyright of the American heart association in 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association for more, please visit ahajournals.org.

This week, our very own Carolyn Lam is in the author role along with author Vlado Perkovic, Associate Editor Naveed Sattar, and Guest Editor John McMurray as they discuss the articles "Efpeglenatide and Clinical Outcomes With and Without Concomitant Sodium-Glucose Cotransporter-2 Inhibition Use in Type 2 Diabetes: Exploratory Analysis of the AMPLITUDE-O Trial" and "Effect of the Glucagon-Like Peptide-1 Receptor Agonists Semaglutide and Liraglutide on Kidney Outcomes in Patients With Type 2 Diabetes: A Pooled Analysis of SUSTAIN 6 and LEADER Trials."

Dr. Carolyn Lam:            

Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:          

I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:            

I have a confession. I am nervous because right after this, Dr. Greg Hundley is going to interview me and, thank goodness, not just me, but really, really interesting other authors and editors with feature papers, all about GLP-1 receptor agonists and the SGLT-2 inhibitors. Very, very, very hot topic. Do listen up! But for now, Greg, you're going to be nice, right? How would you start?

Dr. Greg Hundley:          

Well, thank you, Carolyn. I am really looking forward to that. Maybe we'll have a few quiz questions in there. Before we get started, how about we grab a cup of coffee? I am going to bring to our listeners a paper from the world of preclinical science. It's from Professor Vincent Christoffels from Amsterdam. Carolyn, there's a pathogenic variant in the fifth exon of TBX-5 entitled PG125R. It's found in a Dutch atypical Holt-Oram syndrome family with early onset atrial fibrillation. These investigators modeled this in a mouse. Carolyn, this is the first human pathogenic variant based on a patient family in this key cardiac transcription factor that's been explored in an in-vivo animal model.

Dr. Carolyn Lam:            

Wow, that's interesting. So, what did they find, Greg?

Dr. Greg Hundley:          

Right, Carolyn. The investigative team identified widespread electrophysiological transcriptional and epigenetic changes including coding and non-coding RNA, chromatin accessibility, and H3K27ac associations in the atria of TBX5-PG125R heterozygous mice distinct from the changes in the atria of TBX5 insufficient animals.

Dr. Carolyn Lam:            

Okay. Could you give us the clinical take home message, Greg?

Dr. Greg Hundley:          

Right, Carolyn. What these authors really have found is that the characterization of the TBX5-BG125R mouse model... it indicates that a patient-specific pathogenic variant in TBX5 induces changes in regulatory element activity, an altered balance in the regulatory network of atrial cardiomyocytes, and clinically relevant changes in cardiomyocyte function. So therefore, Carolyn, this work may provide insight into the epigenetic changes and transcriptional underpinning of arrhythmias in the general population caused by small increases in TBX5 expression also caused by common variants predisposing ones to atrial fibrillation.

Dr. Carolyn Lam:            

Wow. Thanks Greg. Well, guess what? I've got an interesting mouse model to share about as well. This next paper comes from co-corresponding authors, Drs. Chen, Fu, and Wu from UCSD. What they do is provide insights into possible underlying factors in a molecular mechanism responsible for left ventricular noncompaction cardiomyopathy. Now, we know this condition, but... It was discovered half a century ago, yet owing in part to the lack of a suitable mouse model that faithfully mirrors that selective left ventricular vulnerability in patients, the actual mechanisms underlying susceptibility of the left ventricle to dilatation dysfunction in this condition actually remain unknown. Well, until now.

Dr. Greg Hundley:          

Wow, Carolyn. So, what actually did this investigative team do, and what did they find?

Dr. Carolyn Lam:            

At the basis of their study is a transcription factor. This is PRDM16. This transcription factor has previously been implicated in this condition through characterization of defects associated with the 1P36 syndrome. What the authors did this time, though, is they generated two new conditional knockout mouse models of PRDM16. Their subsequent characterization of the phenotype is a tour de force of gene expression analysis that uses a myriad of functional genomic approaches, including RNA-seq, ChIP-seq, single cell RNA-seq spatial transcriptomics.

What they found is cardiomyocyte specific ablation of PRDM16 in mice indeed caused left ventricle specific dilation and dysfunction, as well as biventricular non-compaction. In other words, fully recapitulating the left ventricular noncompaction syndrome in patients. Mechanistically, PRDM16 functions as a compact myocardium enriched transcription factor which activated compact myocardial genes while repressing trabecular myocardial genes in the left ventricular compact myocardium. Consequently, PRDM16 knockout cardiomyocytes shifted from their normal transcriptomic identity to a transcriptional signature resembling trabecular myocardial cardiomyocytes and/or neurons and chamber specific transcriptional regulation by PRDM16 was in part due to its cooperation with left ventricular and rich transcription factors.

Dr. Greg Hundley:          

Carolyn, wow. Mechanistic understanding now for cardiovascular noncompaction. This is really exciting research. Clinically, how can we interpret this work from this animal model?

Dr. Carolyn Lam:            

Thought you may ask. This study provides a unique left ventricular noncompaction mouse model for developing therapeutic interventions for any person with a left ventricular dilation and dysfunction, which emerge as the most important disease features in this condition. Improper specification of compact or trabecular cardiomyocytes is likely the common mechanism in the pathogenesis. Spatial single cell gene expression profiles in normal or disease conditions can be shown in this example to facilitate future studies for identifying new targets. This paper is accompanied by an editorial by Drs. Mably, Joe Wu, and Dr. Wang.

Dr. Greg Hundley:          

Very nice Carolyn. Well, there are some other articles in this issue, and before we get to that feature forum let's go through those with our listeners. First, Carolyn, I've got a Research Letter from Professor Cornel entitled "Long Term Efficacy of Colchicine In Patients With Chronic Coronary Disease With Insights From LoDoCo2."

Dr. Carolyn Lam:            

Wow. There's an exchange of letters between Drs. Wang and Ji regarding the article "Histidine Triad Nucleotide Binding Protein-1 Attenuates Cardiac Hypertrophy Via Suppressing Homeobox A5 Expression," Global Rounds paper by Dr. Indolfi on the universal healthcare system and cardiovascular disease burden in Italy. There's a cardiovascular case series by Dr. Raber on a pacemaker red herring and a hypertrophic cardiomyopathy copycat. Finally, there's a Perspective piece by Dr. Drakos on a mechanical bridge to recovery as bridge to discovery learning from few and applying to many.

Dr. Greg Hundley:          

Well, Carolyn, I can't wait to get to this feature forum discussion, and I get a chance to interview you.

Dr. Carolyn Lam:            

Ah! All right, let's go.

Dr. Greg Hundley:          

Welcome listeners. We have on this February 22nd a forum feature discussion where we have two papers that we are going to present, and oh, what an honor it is. Guess who I get to interview first? Dr. Carolyn Lam from the National Heart Center of Singapore, along with a guest editor, Dr. John McMurray from Glasgow University in Scotland, followed by another paper from Dr. Vlado Perkovic from the Georgia Institute for Global Health in Sydney, Australia. Then lastly, Dr. Naveed Sattar, one of our associate editors who also comes to us from Glasgow, Scotland. Welcome to all of you.

Well, Carolyn, we're going to start with you today. I know you've got a paper combining the use of GLP-1 receptor agonists with SGLT-2 receptor antagonists. Can you tell us, Carolyn, a little bit about the background that went into this study? What was the hypothesis that you wanted to test?

Dr. Carolyn Lam:            

Happily, Greg. First of all, what a pleasure to be sitting on the opposite side of the mic, if I might say so, and a real privilege to be speaking on behalf of the AMPLITUDE Executive and Steering Committee about this paper. The whole idea is that we know that SGLT-2 inhibitors and GLP-1 receptor agonists are the rage being recommended for their reduction in cardiovascular events in patients with Type 2 diabetes. However, they appear to do this by complimentary mechanisms. That really raises the tantalizing question of, "Can we combine them?"

Now, What do I mean by that? Well, GLP-1 receptor agonists are known for their reduction in the risk of atherosclerotic ischemic events, particularly like stroke, that benefit being greater, whereas a relatively modest effect on kidney function, perhaps heart failure. Whereas SGLT-2 inhibitors more impressively reduce the risk of heart failure, kidney function decline, kidney outcomes, and so on with a modest effect on myocardial infarction and perhaps no effect on stroke. So, you see, very complimentary. The whole question was, "What would it be like to combine these treatments?" And, in the absence of a trial that actually does a two by two randomization perspective or anything, we decided to look back at the AMPLITUDE-O trial, which was a large multinational trial of patients with Type 2 diabetes randomized to the GLP-1 receptor agonist efpeglenatide versus placebo, but was unique in including the largest proportion thus far of concurrent SGLT-2 inhibitor use in these prospective GLP-1 receptor agonist trials to date.

Dr. Greg Hundley:          

Very nice. And so, you've told us a little bit about your study design. How about specifically your study population? And then, Carolyn, what did you find?

Dr. Carolyn Lam:            

All right. So, of the 4,076 participants in the AMPLITUDE-O trial, 618 reported SGLT-2 inhibitor use at baseline. They were fairly similar to those not receiving SGLT-2 inhibitors. They had similar age and body mass index, but were less likely to be women, they had a longer duration of diabetes, similar history of cardiovascular disease, but lower prevalence of prior heart failure and lower blood pressure, HB A1C, LDL cholesterol, and albuminuria, but similar GFR.

When we looked at the effect of efpeglenatide in the presence or absence of baseline SGLT-2 inhibitor use, we basically found no difference. The P for interaction for each of these outcomes was basically not significant, whether we were looking at MACE and expanded MACE, which included revascularization and angina on top of standard MACE, whether we were looking at a renal composite or a composite of MACE and death, or whether we were looking at heart failure hospitalization. Which, by the way, all of these were significantly reduced by efpeglenatide, and so, similarly, whether or not there was a baseline SGLT-2 inhibitor. Very importantly, side effects were also similar whether or not patients were on an SGLT-2 inhibitor concurrently. This bodes really well for the combination.

Dr. Greg Hundley:          

Very nice Carolyn. Well, John, as a guest editor to Circulation, several papers often come your way each year. What in intrigued you about this particular manuscript?

Dr. John McMurray:      

Well, exactly as Carolyn said, Greg, this asks a question and gives some of an answer to a question that all of us are asking which is, "Should we be using these two drugs together? Do they have complimentary additive benefits, or are those benefits independent of each other?" I think, as Carolyn said, her data from the AMPLITUDE-O trial, which was a fantastic trial, go some way towards addressing that.

And, Carolyn, I wondered... Maybe to give some more context to these really interesting data... I think this question was asked the other way around. I think our colleagues in the DECLARE–TIMI 58 trial looked at it in reverse. They were able to look at adding of an SGLT-2 inhibitor to the subset of patients who were in a GLP-1 receptor agonist. What... Can you remind us what they found, because I think that's an interesting alternative approach to this?

Dr. Carolyn Lam:            

Excellent point, John, thank you. Because DECLARE was so big a trial that even though the percentage of patients on a concurrent GLP-1 receptor agonist was a bit smaller if you look at percent, it was still a very large subgroup. Thankfully, those results were extremely consistent with what we are seeing, too.

In a trial of an SGLT-2 versus placebo, the SGLT-2 inhibitors benefits were regardless of concurrent GLP-1 receptor agonist, and we showed the mirror image of that. Again, I think with the totality of evidence, it's very reassuring and also very important because to truly answer this, we would need a huge prospective randomized two by two trial, or... Which, I think will not be feasibly accomplished except in a pragmatic trial.

Dr. John McMurray:      

Carolyn, maybe one very last point to make again about context, which Greg asked about. Here, we're talking about the primary, secondary prevention of cardiovascular events. You mentioned heart failure, which we're both very interested in. That's intriguing, because it looks to me like the heart failure was largely the prevention... perhaps the incident heart failure. I think there is still a question mark about the role of GLP-1 receptor agonists as a treatment for prevalent heart failure. Do you agree? Do you think that's still an unanswered question? Or, do these results in some way make you more comfortable about using GLP-1 receptor agonists in patients with established heart failure?

Dr. Carolyn Lam:            

Wow. Again, an excellent question. These data reassure me that if I had a patient with Type 2 diabetes who developed heart failure and still required glucose control I would be very comfortable continuing a GLP-1 receptor agonist, because many of these patients in this trial who got heart failure obviously didn't drop out of the trial. They continued on the GLP-1 receptor agonist and the safety profile looks okay. However, I do not agree that the GLP-1 receptor agonists have become a treatment for heart failure the same way the SGLT-2 inhibitors have. That would require, in my mind, evidence in a prospectively defined validated population of heart failure, with known ejection fraction or not. And, to be even more provocative, I suppose, even perhaps without diabetes. Now, that would really put the nail in the coffin, if I may. Basically exactly what you did, John, in DAPA HF.

Dr. John McMurray:      

All right, to finish on a provocative comment for the audience just before we leave this segment, it may of course depend on the heart failure phenotype type as well. In all of these trials, we're never really sure whether the patients have HFpEF, HFrEF, or a combination. So, lots of questions still.

Dr. Greg Hundley:          

Very nice. Well, thank you so much, Carolyn and John.

Listeners, next we want to turn to our second feature article. This one is from Dr. Vlado Perkovic. Vlado, welcome. You have a paper involving GLP-1 receptor agonists and focusing on renal disease. Can you describe for us a little bit about the background pertaining to your paper, and what was the hypothesis that you wanted to address?

Dr. Vlado Perkovic:        

Thanks so much, Craig, and thanks for having me here. It's such a joy to be part of this conversation. Our paper was a post hoc analysis of two completed clinical trials, the LEADER and SUSTAIN trials that looked at liraglutide and semaglutide, respectively, compared to placebo in people at high cardiovascular risk. We wanted to ask the question of... in more detail, the effects of these agents collectively and individually on important kidney outcomes to try and understand whether the GLP-1 receptor agonist, which, as Carolyn says, have clearly had significant benefits for MACE in particular, might also have the sorts of benefits that we've seen, for example, with SGLT-2 inhibitors on renal outcomes recognizing the massive burden of ill health, premature mortality, morbidity, economic, and social costs that go along with kidney disease as a complication of diabetes. What we've done here is we've pulled the data from the two trials and looked at them collectively and individually to try and unpack the effects of GLP-1 receptor agonists on a range of kidney outcomes.

We've looked at different thresholds of loss of kidney function. Traditionally we've used doubling of creatine, which equates to a 57% loss of kidney function. More recently, we've moved to a 40% loss of kidney function as being a good outcome in kidney trials. There's been a push for 30 and 50% outcomes to be used. Here we wanted to look really comprehensively at all of those outcomes, as well as the outcomes of change in albuminuria and change in EGFR slope, where we had more power, perhaps, to detect differences between the agents. Our hypothesis was that GLP-1 receptor agonists would have evidence of kidney protection. We thought up front that the likelihood was the kidney protection would be consistent at different levels of kidney function and might be similar between different agents. But, that wasn't what we ended up finding.

Dr. Greg Hundley:          

Very nice. So, you mentioned the SUSTAIN and the LEADER trials. Can you describe for us a little bit more, and some of the specifics, perhaps, to your study population? And then, walk us through your study results.

Dr. Vlado Perkovic:        

Yeah, so very happy to do that. Thank you. As I say, these trials were primarily cardiovascular outcome trials that were designed to assess the cardiovascular effects of the GLP-1 receptor agonists and therefore the populations reflect that intent with people who had preexisting cardiovascular disease primarily. What we found when we looked at the results was evidence of perhaps modest reduction in some of the renal outcomes based on different thresholds of loss of kidney function of the order of 10 to 20% overall when we looked at the pooled study population. Of course, that compares to a much more significant 30 to 40% reduction in the risk of these same outcomes when we look at drugs like SGLT-2 inhibitors.

Overall, they didn't appear to be quite as effective. But, we were somewhat surprised when we started to dig into the data in more detail in that we found that people who had reduced kidney function based on a lower EGFR, particularly an EGFR below 60, or those who had either micro or macro albuminuria, the benefits of treatment appeared to be greater in absolute and proportional terms. It also was much clearer, such that in people who had both had reduced EGFR and an increased level of albuminuria, there were reductions in the risk of the constant renal outcomes of approximately 40%, suggesting that these drugs may be particularly effective in people with established kidney disease, which... there's a novel finding today.

We were able to dig into that in more detail, looking at albuminuria and EGFR slope and effectively found consistent results for those outcomes as well, giving us some confidence that the findings perhaps were more likely to be real. We, in addition, looked at the different drugs and found some evidence that high dose semaglutide... in particular, one milligram weekly dose, and appeared to be more effective than the lower dose of semaglutide or liraglutide for some of those intermediate markers, if you like.

Dr. Greg Hundley:          

Very nice. Naveed, now, as the associate editor, what intrigued you about this particular study? What drew your attention to it and caused you to bring it through that review process to our readers?

Dr. Naveed Sattar:         

Yeah. Thanks Greg, and thanks Vlado. Now, I think this is a lovely study. I think we've been familiar with the effect of GLP-1 and albuminuria for a long time. I think that's fine, but not... that doesn't really float everyone's button. You know, albuminuria is not necessarily a hard endpoint. But, EGFR and EGFR slopes are becoming something that people are starting to become interested in as a marker of future diabetic kidney disease in end stage kidney disease. Vlad could probably comment on that. I think there was a suggestion if you meta-analyze all the GLP-1 trials, which we did recently on the back of efpeglenatide, both Carolyn and John were co-authors.... that there's a suggestion that GLP-1 may actually improve hard kidney outcomes. This paper, on the back of that, with a detailed look at EGFR slopes and different thresholds, does further support the fact that liraglutide and semaglutide do slow kidney outcome progression, particularly in those who've already got a degree of kidney damage.

Now, the context of that is actually really important in the sense that Vlado and colleagues and nephrologists around the world are very excited about the SGLT-2 inhibitors. But, also having another drug on top of that would might further slow kidney damage is excellent, particularly in a population which also has more atherosclerotic cardiovascular disease. These drugs could therefore have a double benefit, not only slowing kidney damage, but also preventing atherosclerotic cardiovascular disease and the population at high risk of both conditions. Of course, the future then also, as John mentioned, will be, "what about the benefit on top, and going forward in heart failure as well?" I think this study looks... well, adds to the support that GLP-1 receptor agonists actually improve hard kidney outcomes. I think that's the realization. But, going back to Vlado, I'd be interested to get his comment of, "Well, does this study and associated evidence now lead you to think when should we be using these drugs in our patients with chronic kidney disease?" That probably is the question, Vlado.

Dr. Vlado Perkovic:        

Yeah. That's an important question. I think, Naveed, for us as a community. I think one of the nice things is that we can use these drugs in people with kidney disease already. They're approved, and we don't have the same sort of EGFR restrictions as we've had with SGLT-2 inhibitors. But, what we really want to know is, "What are the benefits that we're offering to our patients, and at what price might that come? Is there an increased risk of adverse events in this very sensitive population?"

Of course, the only way to answer those questions is to test it prospectively, which we're now doing in the FLOW trial, where we're randomized three and a half thousand people on semaglutide and placebo. So, over the next couple of years we will answer that question more definitively I hope. We're particularly focused on people with kidney disease in that trial. But of course it also... These data, if they're confirmed in that trial, raise important questions, I think, about the mechanism of the renal effect that needs teasing out. If they're truly more effective in relative terms, as well as absolute terms, in people who've got established kidney disease what does that tell us about the way that they might be providing that renal benefit? And its relative interaction, not only with SGLT-2 inhibitors, but also with mineralocorticoid receptor antagonists, which have recently additionally been shown to be beneficial on the kidney in the FIDELITY and the FIGARO trials.

Dr. Greg Hundley:          

Very nice. Well, Naveed, you have led us and Vlado into our next very quick rapid fire question for our listeners, in working through each of you, both as authors and editors, what do you see is the next study to be performed in this sphere of research? Carolyn, we'll start with you, then John, then Vlado, and then Naveed.

Dr. Carolyn Lam:            

Well, I think I alluded to it a little bit earlier that what we'd, of course, really love is a prospective randomized trial looking at the combination of the treatments versus placebo and versus one of each only. That sounds like pie in the sky, though. Maybe a pragmatic trial. Maybe an... Oh, John, shut your ears, but maybe looking back at real world data to look at this a little bit better. We're going to need a little bit more, at least I think, also to reassure ourselves that the combination is really safe in these patients.

Dr. Greg Hundley:          

John?

Dr. John McMurray:      

I think we need to know about GLP-1 receptor agonists in patients who don't have Type 2 diabetes because I think it's going to be critically important going forward to know whether this is just about dysglycemia and glucose lowering, which it seems probably isn't. Because my interest is in heart failure, of course, I would like to see these drugs tested in patients with symptomatic heart failure and both the major heart failure phenotypes with and without Type 2 diabetes.

Dr. Greg Hundley:          

Vlado?

Dr. Vlado Perkovic:        

Yeah, I'd support what John says and add people with and without diabetes in kidney disease as well to that group, as we've seen with DAPA-CKD study. I think the other really big opportunity for us here that's been highlighted by work done by John and others is the possibility that we might dramatically reduce the prevalence of these terrible complications of diabetes by using combination therapy and multi-drug combination therapy. Potentially, we've got not just the GLP-1 receptor agonist and the SGLT-2 inhibitors, but we've got MRAs and other drugs, depending on which outcome we're talking about. If these drugs are truly independent, as Carolyn's important work suggests, we could have a major impact at a population level on the prevalence of these terrible disorders in our patients.

Dr. Greg Hundley:          

And finally, Naveed.

Dr. Naveed Sattar:         

Yeah, thanks. I'm glad I'm not the only one who upsets John McMurray now and again, but it's probably good for him. What I would say is I agree with all the comments thus far. I would love the fact that with the newer stronger GLP-1s giving us additional weight loss, and, perhaps, with the combined GLP-1 GIP drugs, I would love if we could test them early in diabetes, actually, to actually reverse diabetes, as it were. And, can we delay these complications for 5-10 years, and perhaps with combination SGLT-2? Of course, we can't really do that now because of the costs, but going forward... And, John and I have had lots of conversations about multi-morbidity and obesity is being a big driver to all of that. Now we've got class of drugs coming that actually could cause significant weight loss and improve multiple outcomes that we've discussed: kidney, heart failure, atherosclerotic cardiovascular disease, and also possibly improve patients quality of life, particularly if the weight loss is quite substantial. I would love if we target that, but I think that's partly linked to some of the answers that've already been heard.

Dr. Greg Hundley:          

Well, listeners, we want to thank our investigators, Dr. Carolyn Lam and Dr. Vlado Perkovic, and also our editors, Dr. John McMurray and Dr. Naveed Sattar for bringing us these two papers. The first highlighting that the efficacy and safety of GLP-1 agonists appear independent of concurrent SGLT-2 inhibitor use. And the second paper, emphasizing that GLP-1 receptor agonists offer renal protection, particularly in those with advanced renal disease.

Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week On The Run.

Speaker 7:         

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, please visit AHAjournals.org.

This week's episode is special: Circulation is proud to present the 6th annual Go Red for Women issue podcast. Please join Sana Al-Khatib and James de Lemos as they welcome authors Michelle Albert and Sadiya Khan as they discuss their articles "Shining a Light on the Superwoman Schema and Maternal Health" and "Geographic Differences in Prepregnancy Cardiometabolic Health in the United States, 2016 Through 2019." Then Sana presents an overview of the other exciting articles in this important issue.

Dr. Sana Al-Khatib:         

Hello, and welcome to this special Circulation on the Run podcast, focused on the sixth Go Red For Women issue of the journal. I am Dr. Sana Al-Khatib. I'm an electrophysiologist at Duke University Medical Center and a senior associate editor for Circulation. I have the pleasure of co-leading the sixth Go Red for Women issue with, my friend and colleague Dr. Biykem Bozkurt. Very excited to introduce Dr. James de Lemos, the executive editor for Circulation, who will co-host this part of the podcast with me. Welcome, James.

Dr. James de Lemos:     

Well, Thanks. I'm delighted to be here.

Dr. Sana Al-Khatib:         

The theme of our podcast today is social determinants of health. We will discuss a perspective article in the issue, titled The Interplay of Sex with Social Determinants of Health in Cardiovascular Diseases, led by Dr. Michelle Albert, who is a cardiologist at the University of California in San Francisco. We will also discuss a research letter on geographic disparities in pre-pregnancy cardiometabolic health in the United States from 2016 to 2019, led by Dr. Sadiya Khan, a cardiologist at Northwestern Medicine in Chicago. Welcome, Doctors Albert and Khan.

Dr. Michelle Albert:       

So pleased to be here. An honor to be part of the Go Red issue.

Dr. Sadiya Khan:             

Thank you for having us.

Dr. Sana Al-Khatib:         

Wonderful. So we'll start with the discussion and turn it over to you, Dr. de Lemos, to ask the first question.

Dr. James de Lemos:     

Well, thanks, Sana. Michelle, let's start with you. I love the title of your essay. I'd like you to sort of orient our listeners as to why this title, why the topic and what you write about in your piece.

Dr. Michelle Albert:       

Thank you, James. The title of the essay or Perspective is “Shining a Light on the Superwoman Schema and Maternal Health.” We felt, along my coauthors, Dr. Rachel Bond and Dr. Annette Ansong--Dr. Ansong is a pediatrician, actually. Dr. Bond is also a cardiologist. We felt that it was really important to put forward the psychological parts of the maternal health crisis as a major social determinant of health. Most often, the focus is only on the other risk factors that we know of, like hypertension, diabetes and obesity. And while those are also extremely important, it is actually the interplay between those risk factors and social factors, including racism, including access to care, that actually drive the maternal health crisis for women of color. Particularly for black women, who have about three to four times the mortality and pregnancy complications, compared to white women.

Dr. James de Lemos:     

Michelle, one thing that you've really defined your career by is moving to the biology of adversity. I thought the figure in your paper was striking. Can you expand a little bit on what you mean by this, and how these social determinants and the pernicious effects of things like racism and psychological stress, translate into the biology that I think Sadiya will tell us about, even in her research letter?

Dr. Michelle Albert:       

Yes, James. As you know, I've had a longstanding research history and portfolio, looking at the interplay between biology and social factors, coined the biology of adversity. The adversity part of this is something, we often think about the ACEs, adverse childhood experiences, and think about how those relate to health outcomes, including cardiometabolic and cardiovascular health outcomes. But as we think about adults, actually, it's the adult environment that actually defines adversity for children. Certainly, as it pertains to black women and other women of color, there are certain special circumstances that get embedded into the whole framework of the biology of adversity, that lead to poor overall cardiovascular outcomes, but also maternal and non-maternal health outcomes. So conceptually speaking, the framework of the biology of adversity is the incorporation of stressors into the brain. That then results in a hyper inflammatory milieu, combined with dysregulation of the hypothalamic pituitary access, as well as the flight or fright hormones or the up-regulation of the sympathetic nervous system. And actually importantly, the down-regulation of the parasympathetic nervous system, which is an area that is actively under research currently, that then results in the downstream cascade of health effects. For black women, this is characterized by, in part, the Superwoman Schema, which includes several major themes. The first major theme is the history of oppression and racism and sexism. Also, a history of disappointment, the influences of spiritual values and form other influences, interplayed. These are stressors that incorporate with other stressors. And then there's an interplay with subscales, that focus on the ability to succeed, despite limited resources. Putting others ahead of yourself. So less self-care for yourself, but putting self-care of others ahead of your self-care, the lack of showing vulnerability, as well as suppressing one's emotions. So, all of these things interact with behavior and genetics, as well as epigenetics, to flow into that cascade of the biology of adversity. For me, I gave this presentation four years ago now, at American Heart Association, where I sort of reformatted this whole biology of adversity to incorporate the Superwoman Schema, which was first defined or characterized by Cheryl Woods-Giscombé, who is a PhD scientist in the United States.

Dr. Sana Al-Khatib:         

Now, that was very helpful and insightful, Michelle. Could you tell us about, what are the main next steps that need to be done in this area, that you think are going to be important to move this line of research forward, so that we can actually change this situation and really improve healthcare for these women?

Dr. Michelle Albert:       

Well, I like to think of the answers to that question on several levels. So, I think one of the first levels is ensuring that women, especially women of color and specifically black women, are aware of the fact that hypertension, preeclampsia and eclampsia are risk factors, not only for their pregnancy, but also for cardiovascular disease later on, and for their children developing hypertension and cardiovascular disease later on. So, I think education is really important, on one level. On the next level is, actually having a continuum of care, where women are asked to get early prenatal care, even when they're contemplating pregnancy. So that they can be screened for hypertension, diabetes and their stressors, assessed and put in contact with resources. Having doulas, midwives involved in this process, as well as cardiologists who are involved in the pregnancy setting, as well as post-pregnancy for these women. Then, there's an advocacy initiative that has to take place, that focuses on getting aid. Kamala Harris has put forward a bill to actually do just that for maternal health, focusing on racism and bias in healthcare, because black women across the spectrum of socioeconomic status, experience poor maternal health outcomes. So, this is not only an access to care issue. It's not only a socioeconomic status issue. It is an issue that pertains to the women not being listened to, with racism and other stressors. I can't stress those first two things more, the whole discrimination part of it, and dumbing down the concerns of black women. Then, I think on a research perspective, certainly the American Heart Association has got now this HERN Network, which is a network that's going to focus on research around maternal health. So in that context, figuring out the best care models for women. Understanding the biology and how it interplays with poor outcomes later on, is also very important. One point around the biology that I want to point out for, let's say, African American women and actually Asian women as well, is that there's a higher prevalence of fibroids. There's very little research focusing on fibroids and its importance on maternal health outcomes and even the care for those women. Frankly, in my mind, a lot of that has to do with bias and how we value the healthcare of certain groups of women over other groups of women. So, those are some of the things, in terms of the solutions.

Dr. Sana Al-Khatib:         

Absolutely. Before we move on to the presentation by Dr. Khan, are there any final words Michelle, that you'd like to share with the group, in terms of any final wisdom, so to speak, that you want to leave the listeners with?

Dr. Michelle Albert:       

Yeah. I would just say that the maternal health crisis is preventable and it is tied into... Much of our audience are going to be healthcare providers. To the healthcare providers, I'm going to say, you really, really need to listen to these women when they tell you that they're experiencing certain symptoms. You also need to dig deeper to find out about their concerns, especially their stressors, in addition to making sure their blood pressure is controlled and that their weight is managed.

Dr. James de Lemos:     

Well, thank you, Michelle. We'll turn to Sadiya now, and her team's research letter on geographic differences in pre-pregnancy cardiometabolic health in the US. For our listeners, I think what you'll see, if you read this paper, is how remarkable the research letter format is, and how much information Dr. Kahn and her team have conveyed in this really, really powerful letter, that I think has major public health implications. Sadiya, do you mind orienting our listeners to what you studied and how you did it?

Dr. Sadiya Khan:             

Thanks, James. And again, thank you for the opportunity to join you guys in this podcast. I think Michelle very eloquently set up the preface for this research letter, which was understanding that health in pregnancy begins before conception. That was really the reason we wanted to focus on health factors, particularly cardiometabolic health factors, like body mass index, diabetes status and hypertension status in the pregnant individual, prior to pregnancy. The second piece of this that we were really interested in, is that we had observed that there are significant differences across the United States, in maternal morbidity and mortality outcomes. There are much higher rates of pregnancy-related deaths occurring in the South and Midwest, compared with other states in the US. That led us to ask this question, if we're able to better describe or define health prior to pregnancy, will we see similar patterns? We used the Centers for Disease Control Natality database, which includes all live births in the United States. So, the strength of this dataset, is that this is a surveillance system employed by the CDC, to monitor and record health outcomes of the pregnant individual and the newborn in the United States. Using this dataset, we were able to display maps for pre-pregnancy cardiometabolic health and look at changes from 2016 to 2019. Unfortunately, there's not much positive news, in that we've seen continued declines in favorable or optimal pre-pregnancy cardiometabolic health, which we defined as having a normal BMI and the absence of diabetes or hypertension. In addition, we saw that the levels of favorable pre-pregnancy cardiometabolic health were lower in the South and Midwest. It starts to set up some questions about upstream social determinants of health, that may be playing an important role as we start to address this problem at the individual level, but also at the societal and population level.

Dr. Sana Al-Khatib:         

Very interesting and important findings there, Sadiya. Are you planning to work on additional research, to build on the research that you were publishing in this issue?

Dr. Sadiya Khan:             

One of the most important questions that came from this are, what are the potential ways to start to address and support care for pregnant individuals, or as I think is Michelle really nicely put it, is for preconception care. So, thinking more about the reproductive life course before pregnancy, as well as during and after pregnancy. For that, one of the things that seems to be potentially really important, could be how Medicaid expansion has helped in states that have expanded, and differences between states that have or have not expanded Medicaid. Knowing that, that probably isn't sufficient, but it has that been helpful.

Dr. James de Lemos:     

Yeah. I was struck, Sadiya. I mean, Michelle's essay and your research project really shine a bright and distressing light on maternal health in the US, I think and the crisis that we're under, that many of us don't even maybe recognize is happening. The time trends you showed were, to me, striking, giving over such a short period of time, how much maternal cardiovascular health has declined. It seems, indirectly at least maybe, that declining at a higher rate than overall cardiovascular health. I first applaud you for writing on this topic because I think it brings this issue to light, in terms of a public health crisis, frankly. But I wonder if you have any thoughts on why specifically, things are declining at such a higher rate for pregnant women or pre-pregnant women, maybe relative to national trends? Maybe they're not. Maybe this is what's happening across all age and gender demographics.

Dr. Sadiya Khan:             

It's a really important observation. I agree with you. It seems like it's much more striking in this concentrated and focused group of individuals, that are pregnant and giving birth. It's possible because of the age range that we focus on, the 20 to 44 year old age range, that there are potentially more significant declines happening during this time period. We know cardiovascular health in general, appears to have some age-dependent dips, generally around adolescence. That early adulthood, college age period seems to be where a lot of cardiovascular health decline happens. So, I think that's what we're observing, as we're seeing these more striking trends in this age group. But it would be interesting to know, compared to non-pregnant individuals and across the life course, if that is in fact, the case.

Dr. Sana Al-Khatib:         

Then I'll ask you what I asked Michelle, Sadiya. Any final words of wisdom that you'd like to share with our listeners?

Dr. Sadiya Khan:             

I don't know if I'll be able to speak as eloquently as Michelle did. I think her responses really capture both of these papers and thinking about ways forward, about how we can dress the maternal health crisis. But I think that the word that she used, that really sticks with me and is one of the reasons that I'm so passionate about this work, is that this is preventable. That there are so many different things that could be in place, whether it's at the individual clinician and patient level, at the individual health system level, at the state level, as we looked at here, but really at the national level as well. I think we have a lot of work to do, but there's a lot of things that we know can help.

Dr. Sana Al-Khatib:         

Great. Wonderful. James, any final words from you before we wrap up this part of the podcast?

Dr. James de Lemos:     

First, Sana and the rest of the Circulation team, I congratulate you on another spectacular Go Red issue, that really is such an important endeavor. You and Biykem have done an incredible job leading this. I thank Michelle and Sadiya for coming on today, but also for their work. I think raises the stakes here, that we've got a public health crisis affecting women, and disproportionately affecting black women in the United States. It's underappreciated. I think you both point out that it's preventable. So, I think it's a call to action. It's a really well stated and an important topic.

Dr. Sana Al-Khatib:         

Wonderful. Well, thank you so much, James and Sadiya and Michelle. Thank you so much for submitting your excellent work to us. Thank you for being with us today. This concludes this part of the podcast. Thank you. Next, I'm excited to provide you with a brief overview of the issue. We have two original articles. One is on genes that escape X-chromosome inactivation, modulate sex differences in valve myofibroblasts.   This one was submitted to us by Dr. Kristi Anseth and her team. The study elucidated sex dependencies in myofibroblasts activation pathways and transcriptome analyses and small molecule interventions, implicating genes that escape X-chromosome inactivation, in regulating sex differences in the progression of aortic valve stenosis. The authors highlight the importance of considering sex as a biological variable, to understand molecular mechanisms underlying aortic valve stenosis and help guide sex-based precision therapies. The second original article is by Dr. Elena Aikawa and her team. It is on Prothymosin Alpha, a novel contributor to estradiol receptor alpha-mediated CD8+ T-cell activation and recognition of collagen cross-reactive epitopes in rheumatic heart valve disease. This paper provides novel findings that will likely have clinical impact down the road. As the authors pointed out, understanding the Prothymosin Alpha and estrogen sensitivity mechanisms to control the CD8 T-cell function may indeed provide insights into treatment for rheumatic heart valve disease. In this issue, we have three research letters. One letter was on the geographic disparities in pre-pregnancy cardiometabolic health in the US. You just heard about this paper in the first part of the podcast. Another letter, by Dr. Pradeep Natarajan and his team, offers information on the microvascular outcomes in women with a history of hypertension in pregnancy. It highlights that hypertensive disorders of pregnancy, especially preeclampsia, are independently associated with reduced microvascular indices. The investigators called for further research, to translate these findings into cardiovascular risk reduction strategies for women with these conditions. The third research letter, by Dr. Androulakis and his team, provides insights from cardiac magnetic resonance and angiography screening on spontaneous coronary artery dissection, also known SCAD. Theirs was the largest cohort of SCAD patients screened for peripheral vascular pathology by magnetic resonance and geography, to date and one of the largest to assess the SCAD-related impact size and relevant associations. They concluded that cardiac magnetic resonance has valuable contribution to the investigation of SCAD patients. In this issue, we have six perspective papers. In addition to the Perspective paper that you heard about from Dr. Michelle Albert, there are five perspective articles that span topics of great clinical and research relevance and importance. One perspective article, led by Dr. Carolyn Lam, tackles incorporating sex and gender into the design of cardiovascular clinical trials, a very important topic. Dr. Lam highlights the importance of sex and gender to the optimal interpretation, validation and generalizability of cardiovascular clinical trial results. Another perspective by Dr. Kathryn Lindley presents a call for action to address increasing maternal cardiovascular mortality in the US. This actually ties in with the initial part of the podcast. Dr. Lindley offers insightful suggestions, regarding strategies that could improve maternal cardiovascular care. Another perspective by Dr. Anne Curtis, addresses sex differences in response to rhythm management devices. Dr. Curtis reminds us that the conclusion that should be drawn from the many studies that have been conducted on cardiac rhythm management devices, is that these devices are indeed effective in both men and women, but they're still significantly underutilized in women eligible for those therapies. Dr. Curtis calls on us to be ever vigilant, to provide sex-neutral medical care to all patients, when clinical trials don't provide a strong rationale to do otherwise. I'm quoting her here. Another perspective paper by Doctors Mauricio and Khera, addresses statin use in pregnancy. They raise the of whether it is indeed time for a paradigm shift. This article was prompted by the FDA's request to remove the pregnancy Category X label for statins that was issued in July of 2021. The authors encouraged clinicians to use shared decision making. They add that those with atherosclerotic cardiovascular disease events, especially recent ones, should be encouraged to continue statins during pregnancy or resume them as soon as possible, if they're withheld. For those with heterozygous familial hypercholesterolemia, previously reasonable LDL control and no manifest vascular disease, there may be more tolerance for statin deferral during pregnancy, but they definitely highlight the need for dedicated research in this area. The last perspective, led by Doctors Okwuosa and Zaha tells clinicians what they should know about sex differences in cardio-oncology. They highlight sex differences in cancer and cancer treatment, cardiovascular diseases and the intersection of these conditions, that are likely to be quite helpful for clinicians taking care of such patients. Don't forget to check out the Pathways to Discovery section, where you will find a very interesting and motivating dialogue between Dr. Maryjane Farr and Dr. Biykem Bozkurt in which Dr. Bozkurt describes her career journey. I personally enjoyed reading that interview and found it quite inspiring. In closing, I want to express my deepest gratitude to my co-editor Dr. Bozkurt, the Editor-in-Chief for Circulation, Dr. Joseph Hill, the Executive Editor for Circulation, who was with us at the beginning of the podcast, Dr. James de Lemos and all the authors who submitted the research for this issue. I also want wholeheartedly thank and acknowledge the Circulation Associate Editors and Staff, who work tirelessly to enable us to produce an excellent Go Red for Women issue. I am very excited about this issue and hope that you will like it as much as I do. This concludes our Go Red for Women issue, Circulation on the Run podcast. Thank you for listening.

Dr. Greg Hundley:          

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Please join author David Webb and Editorialist Steven Smith as they discuss the original research article “Regular Acetaminophen Use and Blood Pressure in People With Hypertension: The PATH-BP Trial" and the editorial "Acetaminophen-Induced Hypertension: Where Have All the "Safe" Analgesics Gone?"

Dr. Carolyn Lam:

Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm your host today, Dr. Carolyn Lam, associate editor from The National Heart Center in Duke National University of Singapore. And I'm so missing my co-host Dr. Greg Hundley, who can't make it today, but will be back next week. Now, I have the privilege of telling you all about the exciting papers in today's issue, but before I even get there, I need to let you know that coming right up is a discussion you are not going to want to miss. It deals with an issue that we encounter very commonly and perhaps should have questioned many times, but haven't yet. What is it? Well, regular acetaminophen use and its blood pressure effect. Acetaminophen, what we commonly call paracetamol or Tylenol depending where you're coming from, but have we ever stopped to really ask, does this impact blood pressure? We're going to find out more in the path BP trial coming right up, but first here are your summaries.

Dr. Carolyn Lam:

The first original paper I'd like to tell you about is a study representing additional four years a follow up from the Danish trial. Now recall that Danish was a trial that found that primary prevention ICD implantation was not associated with an overall survival benefit in patients with non-ischemic systolic heart failure, doing a median follow-up of 5.6 years. Although, there was a beneficial effect on all-cause mortality in patients aged 70 years or younger. Now, the current study led by Dr. Lars Køber from Copenhagen University Hospital and colleagues showed that during a median follow up of now 9.5 years, ICD implantation did not provide an overall survival benefit in patients with non-ischemic systolic heart failure. In patients age 70 years or younger, however, ICD implantation was associated with a lower incidence of all-cause mortality, cardiovascular death, and sudden cardiovascular death.

Dr. Carolyn Lam:

The next original paper reports on pre-specified analyses from the FIGARO-DKD trial assessing the impact of finerenone known on clinically important heart failure outcomes. Now recall that FIDELIO-DKD and FIGARO-DKD, in those trials finerenone, which is a selective nonsteroidal mineralocorticoid receptor antagonist, improved cardiovascular outcomes in patients with albuminuric chronic kidney disease and type two diabetes. In the current study, Dr. Filippatos from Attikon University Hospital in Athens, Greece and colleagues presented the pre-specified analyses of FIGARO-DKD describing novel heart failure related outcomes, which were not previously published in finerenone studies, and these included new onset heart failure. Different outcomes containing first or total hospitalization for heart failure events in the overall population. The results indicated that in patients with chronic kidney disease and type two diabetes on a maximum tolerated dose of renin-angiotensin system inhibitor therapy, fenerenone reduced new onset heart failure and improved heart failure related outcomes irrespective of history of heart failure. This is the first indication that a nonsteroidal mineralocorticoid receptor antagonist may provide benefit in a population with chronic kidney disease and type two diabetes, in which patients with heart failure with reduced dejection fraction or symptomatic NYHA 2-4 were excluded, thus indicating that patients with type two diabetes and chronic kidney disease at risk of heart failure or with early stage heart failure may indeed benefit from fenerenone treatment.

Dr. Carolyn Lam:

The next original paper shows for the first time, a role of the nuclear receptor Rev-Erb, a key component of the circadian clock in obesity. So, co-corresponding authors, Dr. Song from Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, China, as well as Doctors Zheng Sun, both from Baylor College of Medicine, and their colleagues used mice with cardiomyocyte specific Rev-Erb deletion that manifested contractile dysfunction, cardiac dilatation, and heart failure. And using these models, authors showed that there was a temporal coordination between clock mediated anticipation and nutrient induced response in myocardial metabolism at multiomic levels. Obesity, together with insulin resistance via a high fat diet, paradoxically improved dysfunction and fatty acid availability from edibles lipolysis in the disrupted circadian mouse model that Rev-Erb knockout. These elegant studies reveal a punitive link between circadian regulation and nutrient induced responses in the heart, potentially helping to explain the obesity paradox. Cardiac molecular chronotropes may, therefore, be involved in human dilated cardiomyopathy. And the implication is that myocardial bioenergetics downstream of Rev-Erb may be a chronotherapy target in treating patients with heart failure. Now, all of this is discussed in an editorial by Dr. Inna Rabinovich-Nikitin and Dr. Lorrie Kirshenbaum from Manitoba, Canada.

Dr. Carolyn Lam:

The final original paper in today's issue is an important translational paper, in which ZEB2, which is a master regulator of epithelial to mesenchymal transition and is associated with many cancers, has for the first time been identified as a new coronary artery disease associated gene. This was first identified by human Genome-wide Association studies, following which the authors Dr. Quertermous from Cardiovascular Institute Stanford and colleagues used smooth muscle cell specific deletion of ZEB2 in mice, coupled with single cell transcriptomic and epigenetic profiling of smooth muscle cells specific [inaudible 00:07:31] cells, and showed that ZEB2 dramatically alters cell state trajectories of the smooth muscle cells through epigenetic regulation of TGF-β and notch signaling. Lower ZEB2 in smooth muscle cells resulted in atherosclerotic plaques with high risk features. So what are the clinical implications? Well, therapies that specifically regulate smooth muscle behavior can potentially alter the risk of plaque rupture, and may be used to further reduce the risk of myocardial infarction. Existing chemotherapies and additional drugs in development that modulate the epigenetic silencing, such as HDAC inhibitors or hypomethylating agents, may, on the other hand, increase the risk of myocardial infarction.

Dr. Carolyn Lam:

So very interesting paper. Wraps it up for our original papers, and now onto what else there is in today's issue. There's an On My Mind paper by Dr. Messerli on [entitled] “Why Are We Still Prescribing ACE Inhibitors?” and a Research Letter by Dr. Simon on one-year major cardiovascular events after restrictive versus liberal blood transfusion strategy in patients with AMI and anemia from the reality randomized trial. Well, that's it for the summaries. Thanks for joining. And please hang on tight for this next exciting feature discussion.

Dr. Carolyn Lam:

For today's feature paper, we are talking about a very familiar medication. Believe it or not, it's just paracetamol, or acetaminophen in its generic term. What we also call Tylenol in the US. And I'm sure this is something that everybody recognizes as one of the first line therapies that we take for chronic pain. It's even over the counter. It's perceived as extremely safe, and in particular, is as having little or no effect on blood pressure. But is that correct? Ah, this paper, I have to tell you audience, really sent chills up my spine. I learned so much from it and I am so, so pleased to have with us the corresponding author, Dr. David Webb from Queens Medical Research Institute in Edinburgh, as well as our editorialists Dr. Steven Smith from University of Florida in United States to discuss this very, very important paper. David, if you don't mind if I start with you, what made you look at this question? It's strikingly important, but seemingly strikingly ignored until your study, so please tell us about that.

Dr. David Webb:

So paracetamol, or acetaminophen, has a really long history going back to the 1800s, and it replaced a drug that was removed called phenacetin that caused significant toxicity. It didn't really grow in use until about the 1980s, but from then on, it really took off and now it's the most widely used and prescribed analgesic in the world. There have been observational studies, large ones, and small clinical trials that suggested an increase in blood pressure. We undertook a systematic review in 2013 that suggested this really needed to be a topic for a further study, and so we undertook a randomized control trial to answer the question of whether, in hypertensive subjects, paracetamol would increase blood pressure.

Dr. Carolyn Lam:

Well, thank you for that background. I have to admit, I didn't even know about the origins and that very first paper you talked about, and this is really beautifully summarized as well in, Steve, your beautiful editorial. But before we go there, David, could you tell us about this path BP trial, what you did and what you found?

Dr. David Webb:

So we were funded by the British Heart Foundation, and we under took a randomized placebo controlled blinded study of one gram of paracetamol given four times a day versus match placebo. And we looked primarily at the gold standard ambulatory blood pressure in patients with hypertension, a third off treatment, and two thirds on treatment, and about a hundred, more than a hundred patients took part in this study. It was a crossover study with washout, and we saw that ambulatory blood pressure compared to placebo treatment increased by five millimeters of mercury, which is substantial. It's very similar to what we see with the nonsteroidal anti-inflammatory drugs, the NSAIDs, which also have effects mediated through prostaglandin metabolism, and that increase of five millimeters of mercury would amount to an increased cardiovascular risk, if sustained, of around 20%. Our study was only for two weeks for practical reasons, but we have no reason to think the effect would not last longer.

Dr. Carolyn Lam:

And David, just before we carry on, could you clarify a few things? So, these patients did not have pain to enter, and did they have hypertension, and were they on other medications for hypertension?

Dr. David Webb:

Yeah, so they were patients with hypertension. They had to have an entry average ambulatory blood pressure daytime of more than 135 over 85, but less than 150 over 95, so this is mild to moderate hypertension. A third of them were not treated at the time of the study, but went on to treatment, and two thirds were already on treatment and stayed on their existing treatment. So this is a study in both treated and untreated hypertension, and we saw, although it wasn't powered to look at differences, we saw similar effects in those who were treated and untreated.

Dr. Carolyn Lam:

So an incredibly important question and Dr. Smith, Steve if I may, you wrote very nicely how the fact that this is individuals with hypertension, but not having an indication of pain and so on. It's really something we needed to look at this question because pain can confound, I suppose, the measurement of blood pressure and so on. So could you tell us a little bit more of why this study is so important and what do you think its impact of the findings will be?

Dr. Steven Smith:

Sure. Thank you, Carolyn. And first of all, I just say, I appreciate you having me on and getting to discuss this really interesting study by Dr. Webb and his team. I think it's a really interesting study. As you may know now, acetaminophen has been associated with blood pressure increases going back almost half a century now and there have been a number of studies, not all have been particularly strong studies and there's a number of limitations to that literature, and I think I was really fascinated by Dr. Webb's study because they really just asked a simple question and did a well designed, robust study to try to address that question and I think it provided some pretty definitive results.

Dr. Steven Smith:

As I mentioned in the editorial, despite the fact that acetaminophen has been associated with blood pressure increases in the past, if you go look at Google or whatever, your favorite search engine of choices, you'll find a number of articles right at the top that seem to imply or directly state that acetaminophen is perfectly safe for patients with high blood pressure. And I think that's a concerning thing that the medical information out there is implying or directly stating that acetaminophen is perfectly fine for these patients and so, I'm appreciative with the work that Dr. Webb is doing to try to bring to light some of the risks of acetaminophen

Dr. Carolyn Lam:

Indeed. And I think it raises a lot of questions that you also so nicely put in your editorial, and maybe this is the chance to ask David directly. For example, what do you think are the implications, in terms of generalizability, in chronic uses of acetaminophen in lower or higher doses in people without hypertension? I mean, this is a big and important issue. What do you think, David?

Dr. David Webb:

Sorry, Carolyn. Maybe I could start by just sticking to the subjects of the study itself. I think what this tells us, and it's important to recognize that there is very little evidence that paracetamol provides benefit in chronic pain. It's not of any value in low back pain. There seems to be no evidence that it's particularly useful in cancer pain and in a wide range of other forms of pain. The evidence for benefit is very limited, so harms really matter where the benefit is small, and probably most patients with chronic pain are not benefiting from the paracetamol in terms of its analgesic effect. So cautiously trying to withdraw treatment in these patients may well be a benefit in terms of reducing cardiovascular risk. So that's for what patients with hypertension. So beyond hypertension, that's a bit more difficult because we didn't study that, but we looked at a range of blood pressures.

Dr. David Webb:

And whilst we weren't powered to address this specifically, it looks as though the effects are there for lower blood pressures and for higher blood pressures. So, it would be nice to do the direct study, but it looks as though this might be slightly more general I support. We didn't look at people with chronic pain for practical reasons, but as I say, there's very little evidence that paracetamol is providing a benefit. I always thought that paracetamol was a safe drug. I use it in my hypertension clinic. And I think in my head, this is safer than using a nonsteroidal, but they're less effective and they may be no safer. So I think one needs to inform clinicians and their patients about the relative safety of paracetamol when considering treatment for chronic pain. You asked one other question. In the UK four grams a day as a common dose. It is in many parts of the world as a maximum dose. In the US, FDA has advised reducing to three grams a day as the maximum dose. You can still give four grams a day, but I think that's a helpful recommendation because this is very likely to be a dose dependent effect. So the lower maximum dose will to some extent protect subjects.

Dr. Carolyn Lam:

And Steve, would you agree with that? What would your take-home message to the audience be, or what do you think are the most important unanswered questions?

Dr. Steven Smith:

Yeah, it's a great question. If I could piggyback on David's answer, I think one of the really interesting findings from this study is that we see these blood pressure changes even after only two weeks of therapy, so this is not something that requires some chronic, very high dose of acetaminophen to start experiencing these blood pressure changes. Obviously a lot of people are on acetaminophen, as David mentioned all over the world. Many of those patients, of course, are on it for chronic therapy, for example, for osteoarthritis, but a lot take it much more sporadically or for short term use. And I think it's telling that we see these blood pressure changes pretty rapidly after starting therapy.

Dr. Steven Smith:

As far as unanswered questions go, I think Dr. Webb summarized some of those already, but I guess what I would add is we still lack some clarity on what the ultimate outcomes of these blood pressure changes are. Obviously we know that blood pressure is highly correlated with adverse cardiovascular outcomes, as well as other outcomes, but the data showing an increased cardiovascular risk with acetaminophen is a little bit more murky. And so I do think there's still some question as to how this translates to increased cardiovascular risk, and I totally agree with David that the evidence supporting efficacy of acetaminophen is so weak at this point for most things, it may be a moot point. We may want to just move on from acetaminophen to the extent that we can, because it seems to have some risks, or at least some concern for risks, without a lot of evidence.

Dr. Carolyn Lam:

Wow. Thank you so much, gentlemen, for this. It's just amazing discussion, but even more so for publishing such an important study and such an elegant editorial in our journal. I think this is one that not only may change practice, but changes my personal perception and things that I'm going to do immediately.

Dr. Carolyn Lam:

Thank you very much audience. I'm sure you agree. This was incredible. Do tune in again next week for another episode of Circulation On The Run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Please join senior author Louise Olde Nordkamp, Editorialist Sana Al-Khatib, and Associate Editor Mark Link as they discuss the original research article Efficacy and Safety of Appropriate Shocks and Antitachycardia Pacing in "Transvenous and Subcutaneous Implantable Defibrillators: An Analysis of All Appropriate Therapy in the PRAETORIAN trial" and the editorial "Just When We Thought the Debate About the Value of Anti-Tachycardia Pacing Was Over Perplexing Results from the PRAETORIAN Trial Emerged."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, your host and Associate Editor from the National Heart Center and Duke National University of Singapore. And as you can tell, I am sorely missing my co-host, Dr. Greg Hundley, who cannot make it today, but yet I am so excited to tell you about the wonderful papers in today's issue. Now, right after these summaries, we will be discussing appropriate shocks and anti-tachycardia pacing in transvenous and subcutaneous implantable defibrillators. A really interesting analysis from the PRAETORIAN trials. The results may surprise you as they did for me. I really highly recommend you listen to the discussion, important clinical take home messages there. Now, though, let me tell you about some original papers in today's issue. We know that symptomatic children with catecholaminergic polymorphic ventricular tachycardia and that's a mouthful.

Dr. Carolyn Lam:

So, I'll abbreviate it as CPVT. They are at risk for recurrent arrhythmic events, beta blockers decreases risk, but are some types of beta blockers better than others in this regard? That's what coauthors and corresponding authors, Dr. Peltonberg and van de Werf from University Medical Center, Amsterdam and colleagues looked at. Studying 329 patients with RYR2 variant carrying symptomatic children from two international registries of patients with CPVT, these authors found that beta-1 selective beta blockers were associated with a higher risk for arrhythmic events, defined as syncope, appropriate ICD shock, sudden cardiac arrest, or sudden cardiac death. And this was compared with non-selective beta blockers. The difference in non-selective versus beta-1 selective beta blockers was driven by a significantly lower risk for arrhythmic events in patients treated with nadolol compared with metoprolol, bisoprolol, and atenolol. So, what are the clinical implications? Well, symptomatic children with catecholaminergic polymorphic ventricular tachycardia should preferably be treated with nadolol or another non-selective beta blocker such as propranolol should nadolol be unavailable.

Dr. Carolyn Lam:

The next paper deals with the super hot topic of myocarditis-related COVID-19 vaccination in adolescents and young adults. Now, suspected myocarditis temporarily related to COVID-19 vaccination has been reported in adolescents above 12 years old and young adults since the emergency use authorization of the Pfizer COVID-19 vaccine. And this is particularly in male adolescents and young adults. Understanding the clinical course and short-term outcomes of suspected myocarditis following COVID-19 vaccine, of course, has important public health implications in the decision to vaccinate youth. So, these authors led by corresponding author, Dr. Truong from University of Utah and Primary Children's Hospital from Salt Lake City in Utah, retrospectively collected data on patients younger than 21 years old presenting before July 2021 with suspected myocarditis within 30 days of COVID-19 vaccination. And they found that in 139 adolescents and young adults with 140 episodes of suspected myocarditis, 49 of which were confirmed and 91 were probable.

Dr. Carolyn Lam:

And these were at 26 centers. Most patients were male and white with a median age of 15.8 years. Suspected myocarditis occurred in 98% following mRNA vaccine with 94% following the Pfizer vaccine, 91% occurring after the second dose. Symptoms started a median of two days after vaccination. The most common symptom was chest pain. 26 patients or 19% were in the ICU. Two were treated with inotropic vasoactive support and none required ECMO or died. The median hospital stay was two days. So, while the majority of patients with suspected vaccine associate myocarditis had normal ventricular systolic function on echocardiogram, many had abnormal findings suggestive of myocarditis on cardiac MRI in the setting of elevated troponin and electrocardiographic changes. The take home message is that despite lab and cardiac MRI evidence of cardiac injury, the majority of adolescents and young adults with suspected myocarditis following COVID-19 vaccination have rapid recovery of symptoms and a mild clinical course. Further studies are needed to better understand the timing of resolution of myocardial injury, mechanisms of myocardial injury, and the long term outcomes.

Dr. Carolyn Lam:

The next paper is the first study to look at examining the genetic architecture of the plasma protein using whole-genome sequencing in persons of African ancestry and really provides a chance to look at rare ancestry specific variation. Authors led by corresponding author, Dr. Gerszten from Beth Israel Deaconess Medical Center in Boston, Massachusetts performed proteomic profiling of 1,301 proteins in 1,852 black adults from the Jackson Heart Study using aptamer-based proteomics or the SOMAscan. Whole-genome sequencing association analysis was ascertained for all variants with minor allele count of five or greater. Results were validated using an alternative antibody-based proteomic platform, the Olink platform as well as replicated in the multiethnic study of atherosclerosis or MESA, and the HERITAGE family study. A huge amount of work. So, this large study added 114 novel genomic [inaudible 00:07:00] associated with protein levels and an additional 217 novel sentinel variant protein relationships. Novel cardiovascular findings included genetic variant associated with amyloidosis in persons with African ancestry shown to be associated with retinol binding protein four levels, even in those without cardiomyopathy implicating it as a potential biomarker.

Dr. Carolyn Lam:

Taken together, these results provide evidence of the functional importance of variants in non-European populations and suggest new biological mechanisms for ancestry specific determinants of lipids, coagulation, and myocardial function. And this is discussed in an excellent editorial by Professor Dr. Schunkert from German Heart Center, Munich. And the final original paper deals with high-salt intake, which we know to be the leading dietary risk factor for cardiovascular disease. We also know that clinical evidence suggests that high-salt intake is associated with non-alcoholic fatty liver disease. Now, could the two be linked, in other words, could hepatic steatosis induced by high-salt diet mediate cardiovascular damage and how? This is exactly what these authors did. Corresponding author, Dr. Zhu from Army Medical University in Chongqing, Institute of Hypertension in China and their colleagues in an elegant series of mouse experiments demonstrated that reduced SERT three expression in the liver is an important mediator of salt-induced hepatic inflammation and steatosis.

Dr. Carolyn Lam:

High-salt diet inhibits the transcription of SERT three through epigenetic modification mechanisms resulting in the persistence of hepatic inflammation in the liver. Notably, the over expression of SERT three in the liver using an adeno-associated virus eight vector or activation of SERT three by metformin effectively relieved the progression of persistent hepatic damage in mice and thus counteracted salt-induced cardiovascular damage. Taken together, these findings suggest that the MK SERT three pathway may be a promising interventional target for treatment of persistent cardiovascular damage in populations exposed to high-salt diet, and finally rounding up the other papers in today's issue, there's an AHA Update by Dr. Lloyd-Jones on the power of patient stories to inspire us to prevent cardiovascular disease and death, personal reflections on AHAs scientific sessions 2021. There is an On My Mind paper by Dr. Dashwood on 30 years of no-touch saphenous vein harvesting, a timely jubilee gift.

Dr. Carolyn Lam:

There's a Frontiers paper by Dr. Rivard on a tremendous contribution on atrial fibrillation and dementia, a report from the AF Screen Interventional Collaboration. And finally a research letter from Dr. Joe on genetic proliferation tracing revealing a rapid cell cycle withdrawal in pre-adolescents cardiomyocytes. Well, that wraps it up for the summaries. Now, let's go on to our feature discussion.

Dr. Greg Hundley:

Welcome listeners to our feature discussion today on this February one. And we're very excited because we have three individuals that will be discussing this paper, Dr. Louise Olde Nordkamp from Amsterdam, Netherlands, the primary author. Dr. Sana Al-Khatib, who is our editorialist for this paper. And finally, Dr. Mark Link, who is our associate editor. Welcome to you all. Louise, we're going to start with you. Can you describe for us some of the background pertaining to why you formulated this study and then what was the hypothesis that you wanted to address?

Dr. Louise Olde Nordkamp:

Yes. Thank you very much for joining this podcast on our study. Our study was designed because in ICD therapy, antitachycardia pacing, ATP has been developed as a painless method to terminate ventricular arrhythmias, and it might decrease the number of appropriate shocks. But on the other hand, ATP might also be given unnecessarily for VTs that would've been ended spontaneously and might even accelerate VTs. The reported efficacy ranges from 52 to 81%, and some studies have observed even higher mortality in patients treated with ATP. The subcutaneous ICD has been developed 10 years ago approximately, and it's completely extra thoracic. And due to this extra thoracic design, it is incapable of providing pacing therapy including ATP. And this was a pre-specified analysis from the PRAETORIAN trial, which was a randomized trial comparing the transvenous and the subcutaneous ICD. And in this pre-specified secondary analysis, we're aimed to determine the efficacy of ATP, the safety of ATP and shocks by comparing appropriate therapies in both arms. So, both the SICD and transvenous ICD, and specifically, we investigated whether ATP reduced the number of appropriate ICD shocks.

Dr. Greg Hundley:

Very nice. And so describe for us a little bit more the study population and the design particularly of the PRAETORIAN trial.

Dr. Louise Olde Nordkamp:

Yeah. So, we published at PRAETORIAN trial in August 2020, in The New England Journal of Medicine and it was the first randomized trial to compare the subcutaneous ICD with the transvenous ICD in patients with a regular ICD indication, but without a pacing requirement. And in 39 census throughout Europe and US of 849 patients were randomized to either the subcutaneous and transvenous ICD in a one-to-one ratio. And during a median follow up of 49 months, the rate of the primary endpoint composite of device related complications and inappropriate shocks were similar between the subcutaneous ICD and the transvenous ICD arm. But here we looked at the appropriate therapy in the study. So, it was defined as both ATP or shock therapy and appropriate therapy was also defined as therapy for ventricular arrhythmias. The PRAETORIAN trial population in overall was, as I said before, regular ICD population with a median age of 63 years, 20% were female. Two-third of patients had an ischemic cardiomyopathy and 20% of patients had a secondary prevention indication.

Dr. Greg Hundley:

Very nice. And so tell us your study results.

Dr. Louise Olde Nordkamp:

Our findings were that in this trial, there was no significant difference in number of patients with appropriate therapy, so shocks and ATP. There were 86 patients in the SICD group and 78 patients in the transvenous ICD group. But patients in the subcutaneous ICD group were one and a half times more likely to be treated with at least one shock. So, if we look at shocks only, and that has a hazard ratio of 1.52 and that was statistically different of significance between the groups. The first shock efficacy was similar in the SICD and in the transvenous ICD. And the first ATP attempt successfully terminated 46% of all monomorphic VTs, but it accelerated through arrhythmia in 9.4%. And although, ATP successfully terminated 46% of all monomorphic VTs, the total of number of shocks, as I said before, was not statistically different between the two groups.

Dr. Louise Olde Nordkamp:

So, we looked at discrete episodes where ATP does reduce the number of appropriate shocks. But when we looked at storm episodes, which was defined as more than three shocks within 24 hours, we saw that there was a higher number of shocks in the transvenous ICD arm, despite a randomized design of the trial and the distribution of shocks between the discrete and the storm episode was there for opposites in the SICD, in the transvenous ICD. So, there was a high number of shocks in storm episodes in the transvenous ICD group, which can partly explain by the number of patients and electrical storms in this group, because there was 10 patients with an SICD who had an electrical storm and there were 18 patients with a transvenous ICD who had an electrical storm. So, patients with appropriate therapy had therefore almost twofold increased risk of an electrical storm in the transvenous ICD arm.

Dr. Greg Hundley:

Very nice. Listeners, next, we're going to turn to the associate editor for this paper, Dr. Mark Link, and Mark, you have many papers come across your desk. What attracted you to this particular manuscript?

Dr. Mark Link:

Thanks, Greg. And thanks, Louise for contributing this papers. We were really very happy to have it. And the reason that we were happy to have it is that this is a very important question in our clinical practice. That is, should we give a patient a subcu ICD or a transvenous ICD? Then, there are risk and benefits of both. It's a discussion that I have multiple times a week with patients. And so getting data on the efficacy of shocks and the efficacy of ATP is very, very important for us as we will discuss this with our patients. So that's why we really like this paper, because we thought it was very clinically relevant to our readership and to the practicing EP community.

Dr. Greg Hundley:

Very nice. Next listeners, we're going to turn to our editorialist, Dr. Sana Al-Khatib from Duke University and Sana, help us put the results of this study in perspective with other research in the field of both subcutaneous and transvenous pacing.

Dr. Sana Al-Khatib:

Yeah, no, absolutely. I'd like to start by congratulating the authors on this paper, I really enjoyed reading it and thank you for sending it to circulation. I also enjoyed writing the editorial. So, certainly this paper provided results that have challenged some of the findings of prior studies, in the sense that several prior studies had shown that antitachycardia pacing reduces the risk of shocks, improves patients outcomes. And that's not at the expense of them having syncope or having adverse events. And this was the case in those trials even for faster ventricular tachycardia. So in this particular study, they excluded patients with slower ventricular tachycardia, but I would also say that several of the prior studies had looked at antitachycardia pacing for faster VT and showed better outcomes.

Dr. Sana Al-Khatib:

And so, this study certainly makes us question some of those findings, but really I feel like it will be a great impetus for different researchers to look at this question in relation to the newer generation of transvenous ICDs as well as even potentially looking at the combination of the subcutaneous ICD with perhaps leadless pacemakers that could deliver antitachycardia pacing, which is an area of research that we're going to hear more about.

Dr. Greg Hundley:

Very nice. And Sana, that really leads us into our next round of questions with our panelists. We'll start with you first, Louise, what do you see is the next focus of research that'll be performed in this space?

Dr. Louise Olde Nordkamp:

So, I think the efficacy and also the potential harm of ATP should be studied more thoroughly. So, I think a randomized trial with ATP as a main focus, because this was a secondary analysis, is the first step to do. And moreover as Dr. Al-Khatib already mentioned is that new innovations are ongoing with a leadless pacemaker in addition to a subcutaneous ICD and these clinical results will be gathered in the coming months and years. And that is really interesting to look at as well.

Dr. Greg Hundley:

And Mark, can you share your thoughts?

Dr. Mark Link:

Yeah. This study brings up many questions, tying in the leadless pacemaker with the subcu ICD is certainly one that's being explored by a number of manufacturers right now, ways to make shocks less painful also would be very critical. I mean, I think that the storms often are because of the catecholamine surges that occur with shocks, if you could make shocks less painful, that would be very keen. And that's been a focus of some researchers for quite some time without good results at the time. And then, increasing the efficacy of ATP because there was a signal here that ATP could, what did generate faster VPs and VFs. And so, the prevention of that I think is very crucial.

Dr. Greg Hundley:

Very nice. And Sana, do you have anything to add?

Dr. Sana Al-Khatib:

Yeah, no, absolutely. I completely agree with what was said. I truly feel that this is an area where we're going to see a lot of research being done. We have new algorithms of antitachycardia pacing, Greg, that are being developed and incorporated into devices that use machine learning, which is really exciting. So, trying to look at hard outcomes related to those and comparing them with, as I mentioned, the subcu ICD combination with a leadless pacemaker would be really interesting. And then, this whole question about the electrical storm, I commend the authors for looking at that, but as they pointed out this was a secondary analysis and the numbers that they had were pretty small. So, trying to look at those findings in a larger population of patients really designed to look at that question would be important.

Dr. Greg Hundley:

Very nice. Listeners, we want to thank our electrophysiology panelists today, Dr. Louise Olde Nordkamp, Dr. Sana Al-Khatib, and Dr. Mark Link for bringing us the results from this trial indicating that really there was no difference in observed shock efficacy of the subcutaneous compared with the transvenous ICDs. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2022. The opinion expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Please join authors Christopher Granger and Anthony Carnicelli, as well as Associate Editor & Editorialist Shinya Goto as they discuss the article "Direct Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation: Patient-Level Network Meta-Analyses of Randomized Clinical Trials With Interaction Testing by Age and Sex" and accompanying Editorial "Patient Level Meta-Analysis: End of the Era for DOAC Developmental Trial in AF Patients?"

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Nam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, I'm so excited about our feature discussion today. It is about DOACs versus warfarin in patients with atrial fibrillation, a really important patient-level network meta-analysis of randomized control trials with interaction testing by agent six. So you can already tell something very, very clinically relevant and important discussed by not only the authors, but our dear associate editor and editorialist.

Dr. Carolyn Lam:

Okay. You just got to tune in, but first I'm going to start us off with some coffee, as well as a description of this first paper in today's issue. The 2018 AHA ACC multi-society cholesterol guidelines states that statin therapy may be withheld or delayed among intermediate risk individuals in the absence of coronary artery calcium.

Dr. Carolyn Lam:

However, two traditional cardiovascular risk factors associate with incident atherosclerotic cardiovascular disease events among individuals with zero coronary artery calcium over the long term? Well, this is the question that investigators decided to answer in today's paper and they're led by Dr. Virani from Baylor College of Medicine in Houston, Texas.

Dr. Carolyn Lam:

They studied 3,416 individuals with coronary artery calcium score of zero at baseline from the MESA study, which is a prospective cohort study of individuals free of clinical atherosclerotic cardiovascular disease at baseline. Among these individuals with zero coronary artery calcium, cigarette smoking, diabetes and hypertension were found to be independently associated with incident atherosclerotic cardiovascular disease events over long-term follow up.

Dr. Greg Hundley:

Ah, very interesting. Another piece of information relating to how we might use coronary artery calcium scores in, it sounds like, a high-risk patient population. So, Carolyn, what's the take-home message here?

Dr. Carolyn Lam:

Well, even if individuals have a coronary artery calcium of zero, if they are current smokers, if they have diabetes melitis or hypertension, initiation and long-term use of statin therapy, along with a heart healthy lifestyle and risk factor modification may still be warranted as part of the patient/clinician risk discussion.

Dr. Greg Hundley:

Very interesting Carolyn. Well, I've got a clinical study to tell you about. And, Carolyn, as you know, obesity and diabetes are associated with a higher risk of heart failure and the inner relationships between different measures of adiposity, including overall obesity, central obesity, fat mass, and diabetes status for heart failure risk, are not well established.

Dr. Greg Hundley:

And so this investigative group, led by Dr. Ambarish Pandey, from UT Southwestern Medical Center, looked at the ARIC, the visit five in ARIC and CHS, the visit one, and cohorts together, and they were obtained from the NHLBI BioLINCC. They were harmonized and pooled for the present analysis, excluding individuals with prevalent heart failure.

Dr. Greg Hundley:

So using multi-variable adjusted fine-grade model models were created to evaluate the associations of body mass index, waist circumference, and fat mass with risk of heart failure in the overall cohort, as well as among those with, versus without, diabetes at baseline.

Dr. Greg Hundley:

And the population attributable risk of overall obesity with BMI greater than 30 kilograms per meter squared, abdominal obesity with waist circumference greater than 88 and 102 centimeters in women and men, respectively, and high fat mass above the sex-specific median for incident heart failure, was evaluated among participants with and without diabetes.

Dr. Carolyn Lam:

Ooh, I'm so in interested in this topic. So what did they find, Greg?

Dr. Greg Hundley:

Right, Carolyn. So a large study, it included 10,387 participants, about 53% from ARIC, 25% had diabetes, and the median age was 74 years. And higher levels of each adiposity measure were significantly associated with higher heart failure risk. The population-attributable risk percentage of overall obesity, abdominal obesity, and high fat mass for incident heart failure was higher among participants with diabetes versus those without diabetes.

Dr. Greg Hundley:

And so, Carolyn, we can conclude from this research that higher BMI, higher waist circumference and higher fat mass, are strongly associated with greater risk of heart failure among older adults, particularly among those with prevalent diabetes.

Dr. Carolyn Lam:

So, so nicely done. Thank you, Greg. Well, the next paper talks about common ancestry-specific ion channel variants and how they predispose to drug-induced arrhythmias. Now, we know that multiple reports associate the cardiac sodium channel gene Scn5a variants, and these are the specific variants, S1103Y and R1193Q, with Type 3 congenital long QT syndrome and drug-induced long QT syndrome.

Dr. Carolyn Lam:

These variants are, however, two common in ancestral populations to be highly arrhythmogenic at baseline. The S1103Y allele frequency, for example, is 8.1% in Africans and the R1193Q is 6.1% prevalent in East Asians. So the investigators, led by Dr. Roden from Vanderbilt University Medical Center in Nashville, Tennessee, and colleagues, determined the effect of the S1103Y variant on QT intervals among 1,479 Africans from a large electronic health record with no confounding medications or diagnosis of heart disease.

Dr. Carolyn Lam:

Now, while both the specific variants generated increased late sodium current, baseline action potential durations in cardiomyocytes from induced pluripotent stem cells carrying these variants were unexpectedly normal. The re-polarizing potassium current, IKR, was markedly increased in these induced pluripotent stem cells with the variants, accounting for normal baseline action potential duration but, with exposure to an IKR blocker, they displayed exaggerated action potential duration prolongation and after depolarizations.

Dr. Greg Hundley:

Wow, Carolyn, interesting. So tell us, what are the clinical implications of this really exciting research?

Dr. Carolyn Lam:

Yeah. So here's the take-home message. These common ancestry-specific variants do not affect baseline re-polarization, despite generating an increased late sodium current. So the authors propose that increased re-polarizing potassium current, IKR, serves to maintain normal re-polarization, but increases the risk of manifest QT prolongation with IKR blocking in these variant carriers. So we need to be aware of that and, further, these findings highlight the need to include ancestral diversity in genomic and pharmacogenomic studies.

Dr. Greg Hundley:

Oh, wow. Beautifully described, Carolyn. I really appreciate that. Just excellent discussion. Well, Carolyn, my next paper comes to us in an investigation regarding doxorubicin or anthracycline-associated induced cardiotoxicity. So, Carolyn, multiple pharmacogenetic studies have identified the synonymous genomic variant rs7853758 and the intronic variant rs885004 and SLC28A3 as statistically associated with a lower incidence of anthracycline-induced cardiotoxicity.

Dr. Greg Hundley:

However, the true causal variant, or variance, of this cardioprotective mechanism at this locus, the role of SLC28A3 and other solute carrier transporters in anthracycline-induced cardiotoxicity and the suitability of solute carrier transporters as targets for cardioprotective drugs has not been investigated.

Dr. Carolyn Lam:

Wow. Got it. So what did these investigators do and find, Greg?

Dr. Greg Hundley:

Right. So Paul Burridge and his colleagues at Northwestern University found that the patient-specific cardiomyocytes recapitulate the cardioprotective effect of the cGAS-identified SLC28A3 locus, and the authors functionally confirmed for the first time, the role of SLC28A3 in doxorubicin-induced cardiotoxicity.

Dr. Greg Hundley:

And a novel genetic variant, the rs11140490, is the potential causal variant in the SLC28A3 cardioprotective locus. And finally, Carolyn, the solute carrier transporter inhibitor desipramine protects against doxorubicin-induced cardio toxicity through decreasing the intracellular uptake of doxorubicin into the heart.

Dr. Carolyn Lam:

Wow. That is a lot of data. Could you summarize it for us, Greg?

Dr. Greg Hundley:

Right, Carolyn. So these investigators provide two potential therapeutic options to attenuate doxorubicin-induced cardiomyopathy, either repurposing FDA-approved desipramine, or therapy with long non-coding RNA SLC28A3-AS1. Also, Carolyn, they propose that a simple clinical test to detect the presence of rs11140490 can be used to predict that a patient will be less likely to experience doxorubicin-induced cardiomyopathy, and that, perhaps with future clinical trials, it may be possible for these patients to be treated with a longer duration, that is a higher accumulative dose of doxorubicin, to enhance the efficacy of their chemotherapy.

Dr. Carolyn Lam:

I love the way you took that home for us. Thank you, Greg. Well, also in today's issue is a Research Letter by Dr. Chen on multifaceted spacial and functional zonation of cardiac cells in an adult human heart.

Dr. Greg Hundley:

Right, Carolyn. And Professor Constantine has a Letter to the Editor entitled Pravastatin Versus Placebo in Pregnancies at High Risk of Term Preeclampsia. Well, Carolyn, how about we get onto that feature article and learn about DOACs versus warfarin in this very large network meta-analysis?

Dr. Carolyn Lam:

Yes, yes, yes. Let's go, Greg. Thanks.

Dr. Greg Hundley:

Welcome, listeners, to our feature discussion today. And we're very fortunate. We're going to review the utility of DOACs in patients with atrial fibrillation. And we have with us two of the authors of this original research, Dr. Anthony Carnicelli from Duke University, and Dr. Chris Granger from Duke University.

Dr. Greg Hundley:

Additionally, we have with us our associate editor, Dr. Shinya Goto, from Japan. Welcome, gentlemen. Anthony, we'll start with you. Describe for us a little of the background information pertaining to your study and what was the hypothesis that you wanted to address?

Dr. Anthony Carnicelli:

Yeah, thanks so much, Greg, for having us here to discuss this. I started working in the DOAC space when I was a resident at Brigham and Women's Hospital with mentorship from Dr. Bob Guigliano there, and was really fortunate to connect with Dr. Granger when I came to Duke for a fellowship, and we had this unique opportunity to take data out of the four largest trials of anticoagulants in the atrial fibrillation, and take individual patient data from these international centers and combine them to form the combined AF database from which we did this analysis.

Dr. Anthony Carnicelli:

So a very unique opportunity here to have individual patient-level data from over 70,000 patients, and perform this analysis. And, really, what we aimed to do was to do the kind of highest quality meta-analysis using network meta-analysis methods to investigate the relative safety and efficacy of DOACs versus warfarin and a broad and diverse, but randomized, population of patients with atrial fibrillation.

Dr. Greg Hundley:

Very good. So you started to describe for us your study population and your study aligns. So tell us a little bit more, who were these patients, and then maybe specifically give us a little bit of the outline of your meta-analysis.

Dr. Anthony Carnicelli:

Yeah, so these were, again, a very broad patient group, but from kind of 10,000 feet, this was a population of patients with atrial fibrillation who were at risk of stroke, from CHADS score perspective. So there are some nuances from each of the included studies, of course, regarding the individual risk of stroke from one study to the next. But largely, as I mentioned, in patients with non-valvular atrial fibrillation randomized to either DOAC or warfarin.

Dr. Anthony Carnicelli:

And, from a method standpoint, we are fortunate at Duke and at DCRI, to have an expert in the network, meta-analysis methodology, whom we've worked with, Dr. Bonnie Huang, who helped to put together the analysis here and to proceed with this kind of network methodology.

Dr. Anthony Carnicelli:

And so, again, our goal was to evaluate the overall safety and efficacy of DOACs versus warfarin, but then also to dive into some specific subgroups, both from a categorical covariant perspective, and then also to evaluate some continuous covariants, specifically age, and to assess gender across the entire spectrum of continuous age in our population, which, of course is a unique opportunity in the individual patient-level data.

Dr. Greg Hundley:

And, Anthony, you had, gosh, it looks like over 70,000 patients in this particular analysis. Tell us a little bit about the results.

Dr. Anthony Carnicelli:

Yeah, so interesting, actually, and I agree that the biggest strength of our meta-analysis is the individual patient-level data and also the profound number of randomized patients included. So I think, from a high level, the most important results to highlight are the fact that there is a 19% relative risk reduction in stroke or systemic embolism among patients who are randomized to DOACs compared to warfarin, with an 8% reduction in all-cause death and a 55% reduction in intracranial hemorrhage.

Dr. Anthony Carnicelli:

So a massive reduction in the most feared complications of both atrial fibrillation and then also those associated with systemic oral anticoagulation. We also found a trend towards less bleeding in patients randomized to the standard-dose DOAC group, as well.

Dr. Greg Hundley:

Very good. Well, Chris, we're going to turn to you. What an exciting discovery here, and beautiful methodology. I wonder, in addition to what Anthony has shared with us, were there particular outcomes that were pertinent to men versus women or perhaps related to age?

Dr. Christopher Granger:

Yeah, Greg. So, again, we're proud of this as being really the state-of-the-art ability to evaluate safety and efficacy in this incredibly important population of patients with Afib and at risk for stroke, and to be able to dive into the subgroups and to the individual outcomes, even the less common outcomes. And one of the most striking things, and this really reinforces prior data, but with the greatest confidence of any study ever done, there was this 55% at reduction in intracranial hemorrhage and 19% reduction in total stroke and systemic embolism, really highlighting that these drugs are clearly better than warfarin, from reinforcing the guidelines.

Dr. Christopher Granger:

And the message with the subgroups is there was really a remarkable amount of consistency. And specifically in the older population where people are really concerned about anticoagulation, there was a clear and consistent major advantage of DOACs over warfarin. Men versus women, clear, clear, compelling benefit of DOACs over warfarin across each of these outcomes, including mortality, by the way, 8%. But highly statistically significant reduction in total mortality.

Dr. Christopher Granger:

A couple of the interesting ones, there was some effect modification. In other words, some evidence of an even greater benefit in patients who were not previously on a vitamin K antagonist or who had lower creatinine clearance, really important group, right? The renal impairment group.

Dr. Christopher Granger:

And then there was a greater benefit of lower risk of bleeding for patients with low body weight. And, in fact, the younger population, if anything, had a greater benefit with respect to less bleeding. And the bleeding is so important, Greg and Shinya, right? Because that's the major reason that people are not using anticoagulation, warfarin or DOACs, for this large population of patients who are untreated. And I hope this meta-analysis will be viewed as evidence that have really safe and effective treatments that are underused for this population that we're concerned about bleeding.

Dr. Greg Hundley:

Excellent. Thanks so much, Chris. Well, Shinya, you see a lot of papers come across your desk. What attracted you to this particular paper? And then can you help us put these results in the context with others that have evaluated the utility of DOACs in patients with atrial fibrillation?

Dr. Shinya Goto:

Thank you, Greg. Let me congratulate for Anthony and Chris and also group for conducting this great work. I mean, combine AF with amazing success for sharing the clinical trial database. So that all the four with a DOAC available is approved by each country based upon individual trial. Individual trial itself, large enough, right? Include more than 10,000 patient, but this time the [OSA 00:19:49] accumulated all four DOAC trial database together so that it is easy to say clinical trial data sharing provided robust evidence.

Dr. Shinya Goto:

But it is difficult, actually, to conduct it. I really commended OSA to conduct this success. So the data is predicted, I would say. Individual clinical trial itself shows lower risk of bleeding in DOAC as compared to warfarin. But this paper really provides the first time standard dose of DOAC reduce the risk of stroke and systemic embolism and death as compared to warfarin.

Dr. Shinya Goto:

So I really commented OSA. So this paper have a strong impact on the medical care. DOAC rapidly change the standard of care already. But superior efficacy was shown only in a few dose of DOAC, like 150 milligram BID of dabigatran, 60 milligram QD edoxaban, and five milligram apixaban. But this combined AF provides a stronger and a trustable robust evidence DOAC is better than warfarin.

Dr. Greg Hundley:

Very nice. Well, gentlemen, I want to turn back to you. I'll start with Anthony and then Chris, and then Shinya. Anthony, what do you think is the next study to be performed, really, in this space?

Dr. Anthony Carnicelli:

Well, it may be a bit of a pitch, but I mean, we have many opportunities in the combined AF data set to perform additional analyses, but I think that one of the most important next steps in this space that I'm most excited about is with respect to the newer oral anticoagulants that are coming down the pike.

Dr. Anthony Carnicelli:

For example, the Factor 11 inhibitor space. I mean, I think that there is another opportunity in the near future to potentially revolutionize the systemic anticoagulation space. And I think that data from combined AF could potentially be used to help continue moving the ball forward, again in the development of newer agents. So I think that's probably the thing that I'm most excited about in this space.

Dr. Greg Hundley:

Very good. And, Chris?

Dr. Christopher Granger:

Greg, I think there's so many unanswered questions and I think, as Tony points out, this highlights the fact that we know a lot, but there's a lot of unanswered questions. And those, some of the ones that I'm most interested in are low burden AFib, this AFib that we're detecting now with smart watches and devices, and what we do with that. And patients with renal impairment, including all the way down to renal failure, where those are relatively underrepresented, including in the combined AF data set.

Dr. Greg Hundley:

Very good. And, Shinya?

Dr. Shinya Goto:

Yeah. Yeah, Anthony and Chris talked about a little bit the plans to space, but I insist there is a lot of space that also could do with the combined AF database. We can expect a lot of sub-analysis, like you conducted as a continuous variable in this paper, but you can do that with eGFR as continuous variable, PMI as continuous variable. So we can expect a lot of sub-analysis. Probably, this is the end of publication from the individual DOAC development trial. You change the game with the combined AF data set.

Dr. Greg Hundley:

Very good. Well, listeners, we want to thank Dr. Anthony Carnicelli, Dr. Christopher Granger and our own associate editor, Dr. Shinya Goto, for bringing us this very interesting result from the meta-analysis that, compared to warfarin, DOACs have a more favorable efficacy and safety profile among patients with atrial fibrillation. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Please join author Mohamed Abdel-Wahab and Associate Editor Stefan James as they discuss the article "Comparison of a Pure Plug-Based Versus a Primary Suture-Based Vascular Closure Device Strategy for Transfemoral Transcatheter Aortic Valve Replacement: The CHOICE-CLOSURE Randomized Clinical Trial."

Dr. Carolyn Lam:

Welcome to Circulation on the Run. Your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, a very interesting topic, looking at closure devices at the sites of access for patients that are undergoing TAVR procedures. But before we get to that, how about if we grab a cup of coffee and start with some of the other articles in the issue. Would you like to go first?

Dr. Carolyn Lam:

I would love to and I would like to describe not just one, but two articles from recent SGLT2 inhibitor trials. So, the first paper is an analysis of the DAPA-HF trial. Now we know that circulating high sensitivity, cardiac troponin T predominantly reflects myocardial injury. And higher levels are associated with a higher risk of worsening heart failure and death in patients with heart failure with reduced ejection fraction or HFrEF. But what about the prognostic significance of changes in high sensitivity troponin T over time and the effects of Dapagliflozin and on clinical outcomes in relation to baseline levels, as well as the effect of dapagliflozin on the high sensitivity troponin T levels? Well, this is what this study answers. It's a biomarker substudy of the DAPA-HF trial from Dr. Berg of the TIMI study group at Brigham women's hospital and colleagues.

Dr. Greg Hundley:

Wow. Carolyn, very interesting. So remind us about the DAPA heart failure trial. What was it about?

Dr. Carolyn Lam:

Ah, well, DAPA-HF was a randomized double blind placebo control trial of dapagliflozin in patients with symptomatic HFrEF defined by injection fraction 40% or less wherein dapagliflozin significantly reduced the primary endpoint of cardiovascular death or worsening heart failure events. And in today's biomarker substudy increases in high sensitivity, cardiac troponin T over a one year interval of time were highly predictive of subsequent risk of worsening heart failure and cardiovascular death. The effect of dapagliflozin on the primary endpoint was consistent irrespective of baseline troponin T concentration with no evidence of attenuated treatment benefit in those with very high troponin T concentrations.

Dr. Greg Hundley:

Very interesting Carolyn. Now you've got another study. Is this one on EMPA?

Dr. Carolyn Lam:

You are right. Thank you. The next paper is and analysis of the Emperor-Preserved trial. As a reminder, Emperor-preserved study the SGLT2 inhibitor empagliflozin in patients with HFpEF this time, which is a left ventricular ejection fraction above 40, and showed a significant reduction in the risk of cardiovascular death or heart failure hospitalization. The current paper evaluated the efficacy of empagliflozin on health related quality of life in patients with HFpEF and whether the clinical benefit observed with empagliflozin varied according to baseline health status.

Dr. Greg Hundley:

Very nice, super review Carolyn. So what were the results of this study?

Dr. Carolyn Lam:

In Emperor-Preserved, baseline health status and quality of life did not influence the magnitude of effect of empagliflozin on the risk of cardiovascular death or hospitalization for heart failure. Empagliflozin improved health status and quality of life as assessed by the Kansas city cardiomyopathy questionnaire across all domains and at all measured time points. Thus an effect that appeared early and was sustained for at least one year.

Dr. Greg Hundley:

Very nice. So two really informative papers on SGLT2 inhibitors. Well Carolyn, I'm going to turn the conversation to the world of preclinical science and talk about Titin. So Carolyn, titin truncation variants are the most common inheritable risk factor for dilated cardiomyopathy and their pathogenicity has been associated with structural localization. The A-band variants with overlapping myosin heavy chain binding domains appear more pathogenic than the I-band variants and the mechanisms for this are not well understood. So these investigators led by Dr. Hinson at the Jackson Laboratory for genomic medicine, performed a study demonstrating why A-Band variants are highly pathogenic for dilated cardiomyopathy and how they could reveal new insights into dilated cardiomyopathy pathogenesis. Titin functions and therapeutic targets were assessed.

Dr. Carolyn Lam:

Wow, interesting. So what did they enroll in? How did they do this? what did they find?

Dr. Greg Hundley:

Great Carolyn, so human Cardiomyocytes and cardiac micro tissue functional assays revealed that highly pathogenic A-Band Titin truncation mutations generate four shortened titin poisoned peptides and diminish full length, titin protein levels. While less pathogenic I-band titin mutations only diminish titin protein levels. And so Carolyn, the authors developed a one and done, genome editing therapeutic approach using CRISPR technology to repair the reading frame of Titin truncation mutations in cardiomyocytes. And therefore these genome editing therapeutics could correct the underlying genetic lesion responsible for dilated cardiomyopathy due to these Titin mutations.

Dr. Carolyn Lam:

Wow. Interesting. One and done genome editing. You learn something new every day with circulation. You've got another paper?

Dr. Greg Hundley:

Yes, Carolyn. Thank you. And so this paper comes to us from Dr. Beiyan Zhou From the Yukon health, school of medicine and again, from the world of preclinical science. So Carolyn, while several interventions can effectively lower lipid levels and people at risk for atherosclerotic cardiovascular disease, cardiovascular event risks remain, suggesting an unmet medical need to identify factors contributing to this cardiovascular event risk. Now monocytes and macrophages play central roles in atherosclerosis, but previous work has yet to provide a detailed view of macrophage populations involved in increased atherosclerotic cardiovascular disease risk.

Dr. Carolyn Lam:

Huh? Okay. Well, I'm super excited to hear what these investigators did Greg.

Dr. Greg Hundley:

Right, Carolyn. Well these authors developed a novel computational program. They call AtheroSpectrum, which identified a specific gene expression profile associated with inflammatory macrophage foam cells. And additionally, a subset of 30 genes expressed in circulating monocytes jointly contributed to the prediction of symptomatic atherosclerotic vascular disease. So therefore Carolyn, in the future, perhaps incorporating this new pathogenic foaming gene set with known risk factors may significantly strengthen the power to predict atherosclerotic cardiovascular disease risk.

Dr. Carolyn Lam:

Wow. Super interesting and well summarized. Thank you, Greg. Well also in today's issue, there's a Perspective by Dr. Kirtane on “The Long-Awaited Revascularization Guidelines are Out. What's In Them?” A Research Letter by Dr. Laffin on rise in blood pressure observed among us adults during the COVID 19 pandemic.

Dr. Greg Hundley:

Very Nice Carolyn. Well in our Cardiovascular News Segment, there's a piece on metabolic risk factors and how they drive the burden of Ischemic heart disease. Well, what a great issue here and now, how about we get onto that feature discussion?

Dr. Carolyn Lam:

Very Cool. Closure devices after TAVR. Here we go.

Dr. Greg Hundley:

Well, listeners welcome today to our feature discussion and we have with us Dr. Mohamed Abdel Wahab from Leipzig Germany. And we are going to discuss some issues pertaining to transcatheter aortic valve replacement, in terms of access to the arteries in the lower extremity. Welcome Mohamed. And can you start with, what was some of the background that led you to perform your study and what was the hypothesis that you wanted to address?

Dr. Mohamed Abdel-Wahab:

Thank you, Greg. And thank you for having me here. So as you mentioned, there are several cardiovascular procedures that currently require large-bore arterial access. The most common of these procedures is transcatheter aortic valve replacement. But there are other procedures as well, like endovascular aortic repair, mechanical circulatory devices. All of these require large-bore arterial access and of course, closure afterwards. And what we were interested in looking at was whether different types of vascular access site closure devices or strategies behave differently in the setting. Particularly in the setting of transcatheter aortic valve replacement. The reason behind this is that for many years, we only had one technique, to percutaneously close arterial access sites after these procedures. And these were mainly based on suture based devices or suture based techniques. Very recently, alternative techniques based on collagen plugs have been introduced.

Dr. Mohamed Abdel-Wahab:

And we know these types of devices or closure techniques from usual coronary intervention procedures for smaller access sites or for smaller sheath size. But they have been developed a step further for these large-bore procedures. These newer devices, particularly what we call the MANTA device, which is based on the collagen plug has been shown in initial visibility studies and also in registry based analysis to be very safe and effective. It leads to a very rapid hemostasis. And data from observational studies have suggested that it may be even superior to the suture based techniques, largely based on what we call the ProGlide device or the [inaudible 00:10:56]. And this is actually what we were aiming to look at. To compare these two different strategies based on two different devices. The suture based, the classical suture based technique using two ProGlides compared to the newer plug based technique using the MANTA in a population treated with TAVR.

Dr. Greg Hundley:

Very nice. And describe for us, your study design. And then also maybe explain a little bit more about the study population. Who did you include in this study?

Dr. Mohamed Abdel-Wahab:

So the design was more or less, very inclusive. So we designed the trial to more or less represent real word population. More or less [inaudible 00:11:40] population receiving transcatheter aortic valve replacement. So we included patients, of course where the procedure is being thought to be indicated and feasible by a multidisciplinary heart team. And also where the heart team thought that the transfemoral access route, which is the main route for the majority of patients, is obtainable and use of a percutaneous closure device is also possible.

Dr. Mohamed Abdel-Wahab:

Of course we had some exclusions. For example, patients where the use of a surgical access technique was necessary. They couldn't be naturally included in the trial. Patient that already had complications related, for example, to previous coronary angiogram PCI at the access site, they couldn't be included. But we were more or less, very inclusive in this trial. The trial population reflects the patients that are currently being treated with TAVR, so more or less an elderly population. More or less equally split-by males and females, which is very particular, again to the TAVR population. So this is a little bit different than the population that receives PCI, where we usually have a predominantly male population. This is not the case here. So these are the broad lines. Also reflecting current practice, the population that has been included in the trial is more or less overall, an intermediate risk population, when you look at the surgical scores.

Dr. Greg Hundley:

Very nice. So this was multicenter and then also patients were randomized to each of the two therapies, I believe. And was that a one to one randomization?

Dr. Mohamed Abdel-Wahab:

Exactly. So it was a multicenter trial. Patients were randomized between these two techniques. We mentioned the ProGlide based and the MANTA based in 1:1 fashion. And steering committee of course was more or less dominated by interventional cardiologists. Of course, in the context of this particular trial setting, the trial was only performed in Germany and it was an investigative initiated trial, not sponsored by the industry.

Dr. Greg Hundley:

Very nice. And can you describe for us, Mohamed, your results?

Dr. Mohamed Abdel-Wahab:

Yes. We actually hypothesized based on the observational data we have, that we will have less vascular complications with the MANTA based technique or the collagen based technique. At the end of the day, what we observed is completely the opposite. So the primary endpoint of the trial, which was what we call major and minor vascular complications defined according to the standardized criteria provided by the valve academic research consortium. These events occurred significantly more common in patients that were randomized to the MANTA based technique, as opposed to the ProGlide based technique, which was statistically significant.

Dr. Greg Hundley:

And did you observe those results across both the men and the women? And also, were there any differences in the results related to participants' age?

Dr. Mohamed Abdel-Wahab:

Yeah. So there were no interactions with various subgroups, both the predefined ones, including age and sex, as you mentioned. But also we looked at some post hoc subgroups, including for example, whether this is being affected by the size of the access vessels or by the presence and location of calcification, for example. But there were no interactions in all subgroups we looked at, with one exception which was chronic renal insufficiency. But all other subgroups showed actually no significant interaction, favoring the suture based, ProGlide based technique in all subgroups.

Dr. Greg Hundley:

Very good. And so can you describe in terms of, for individuals performing TAVR procedures and obtaining access, how do we use the results of your study to inform how we might move forward with closure of the artery in the future?

Dr. Mohamed Abdel-Wahab:

I mean, the first thing I would like to stress is the importance of doing randomized trials in general. Because I think this is not the first time we see opposite results when we are comparing randomized evidence with the evidence from observation studies, with the known limitations of observational comparative analysis. The second thing I think is really reassuring that the suture based technique that we know and that we have been using for many years now is safe and appears to be even more effective than the newly developed plug based technique. So this is one important information I think from this trial. The third piece of information is that the recently developed plug based technique, although being inferior in the study, it still may have some advantages in selected patients. And this is what we probably need to look at in a little bit more details in the future.

Dr. Mohamed Abdel-Wahab:

For example, what we realized from the study is that it could be a good option as a bailout device. So in some cases where the suture based technique has failed in the study, the crossover to the MANTA device was successful in the majority of cases. And may lead or help avoid complex endovascular interventions and implanting for example, stents or covered stents or even doing surgery. So this is something that is a nice observation from the dataset we have, but of course needs validation in larger studies.

Dr. Greg Hundley:

Very nice. And so really you've answered, kind of one of our key questions is, your thoughts on the next study that you see needs to be performed really in this area of research?

Dr. Mohamed Abdel-Wahab:

Yeah, so I think there are several things. One thing is, again, to look at potential patient subgroups that may benefit from the plug based device from the beginning. So probably it's not something that we should be using as a default strategy based on the results of this trial. But there could be certain subgroups we need maybe to dig a little bit more into the details or subgroups, if you wish to say so. Look a little bit more granularly at some patient groups that could benefit. But as mentioned, I think that the bailout indication is a very interesting one and needs to be looked at.

Dr. Mohamed Abdel-Wahab:

Not only in the TAVR setting, but also in the setting of other procedures. Such as for example, the use of mechanical circulatory assist device or ECMOs, where it may be difficult to apply these sutures post hoc. So the sutures that we apply during a TAVR procedure and what we use in this trial, this is the so-called preclosure technique. So you apply the sutures after gaining access. Then you insert your large-bore sheaths through the procedure. And then the sutures are already there and you can close the access site, usually without problems. Which is difficult, if you obtain access, for example, with an ECMO or an Impella. And then after a couple of days, you need to close it. So the sutures are not yet in place. In this particular scenario, it may be beneficial to use a plug afterwards. Or as a bailout device as previously Mentioned.

Dr. Greg Hundley:

Very nice well listeners. We want to thank Dr. Mohamed Abdel Wahab from Leipzig Germany for bringing us this study indicating that among patients treated with transfemoral TAVR, this pure plug based vascular closure technique using the MANTA VCD was associated with a higher rate of access site or access related vascular complications. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.

Dr. Greg Hundley:

This program is copyright of the American heart association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American heart association. For more, please visit AHA journals dot org.

This week's Feature is a Panel Discussion. Circulation invited the Young Investigator Finalists who had a Simultaneous Publication for AHA's 2021 Sessions. Please join authors Amgad Mentias, Matthew Burrage, Shaan Khurshid, Sevedeh Maram Zekavat, and Neel Butala as they discuss their articles.

Dr. Greg Hundley:

Welcome listeners to this very special January 11th issue of Circulation on the Run. And I'm going to tell you why it's special. I'm Dr. Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia and also associate editor at Circulation. Why is this issue special? Because we have the opportunity to speak with finalists for several of the awards that were presented or that these investigators presented for at the American Heart Association sessions. And so we have with us today, five early stage investigators and we are going to hear about each of their research projects and the manuscripts that are coming out and are published in this issue. Want to welcome all five of you and we'll introduce one at a time as we work through their research projects. And the first is Dr. Amgad Mentias from Cleveland Clinic and he was in the session competing for the Elizabeth Barrett-Connor Research Award for early career investigators in training. Welcome Amgad. And we'll start with you. Can you tell us a little bit about the background for your study and what was the hypothesis that you wanted to address?

Dr. Amgad Mentias:

Hi, Dr. Hundley. How are you? Thank you so much for inviting me today. A little background, we know that community economic distress affects outcomes in patients with heart failure. It actually affects both short term and long-term outcomes. What was not studied on a nation level before is how is that impact different or if it's actually different between different races. In White patients and Black patients and Hispanic patients, what would be the differentiated effect of community economic distress on their short and long-term outcomes with heart failure after a heart failure admission?

Dr. Greg Hundley:

Absolutely. And so that hypothesis that you were going to address, what were you hypothesizing here?

Dr. Amgad Mentias:

We were hypothesizing that each race has probably some shared risk factors but also some specific risk factors. We were hypothesizing that the community level economic distress effect on heart failure outcomes is not homogeneous or not exactly the same between all races.

Dr. Greg Hundley:

Very nice. And so what was your study design? And describe a little bit for us the study population.

Dr. Amgad Mentias:

We included the Medicare population. We included patients who were admitted with a primary diagnosis of heart failure from the years 2014 till 2019. We included patients from Black and White and Hispanic races or ethnicities. And we only included the first admission for a patient if the patient was admitted more than once during these years. That was the study population. And we had about 1.6 million White patients and about 205,000 Black patients and around 89,000 Hispanic patients.

Dr. Greg Hundley:

Great. And so was this a cohort design?

Dr. Amgad Mentias:

Yes, it was a cohort design. The study start date was when they were admitted to the hospital for our mortality outcome and when they were discharged from the hospital for readmission outcomes. And then we followed them in time up to one year.

Dr. Greg Hundley:

Very nice. And so tell us, what did you find?

Dr. Amgad Mentias:

Our primary exposure of interest, like we said, was economic distress and race and our primary outcome was three things, mortality, the second thing is readmission burden, which is number of admissions over time the patient is alive and third thing is home time how many days the patient spends at home, out of the hospital and out of skilled nursing facilities and LTACs. And we looked at these outcomes at three different points, at 30 days, at six months and at one year follow up. Initially we did an interaction and that is to see whether our hypothesis, that the effect is different or not between a race and term and the economic distress term. And the interaction was significant, in all three outcomes. Then we went deeper and we started to study each race separately and see how economic distress affects their outcomes. We defined economic distress by distress score called the distressed community index, which is a composite measure of seven things, including education of the people in the zip code, unemployment, poverty rate and income in the zip code compared to the state level and that stuff.

Dr. Amgad Mentias:

We actually found that in White patients, economic distress was actually associated with adverse outcomes in the short and long term. In Black patients, it was affecting the outcomes more robust and more evident in the long term, not in the short term. We also found the geographic location and their approximate location, whether it's urban or rural, residential zip code also affected outcomes. We found that in all races being in a rural distressed community had the highest posterity and the highest admission burden and the worst home time compared to other communities. In fact, people in distressed urban communities had comparable outcomes. People in rural, non-distressed communities had comparable outcomes to urban distressed. We found that the rural location and approximate location near resources affected outcomes in all races but specifically also in Black patients.

Dr. Greg Hundley:

Very nice. And how do you put your results in context with others that are doing research in this area?

Dr. Amgad Mentias:

We show that the interplay between economic distress and societal factors and different things for heart failure is very complex and there is a complex interplay between different factors. I think it's very important for health policies that targeting improvements in community with economic distress and access to care, they are key to improving outcomes and reducing racial disparities among patients with heart failure.

Dr. Greg Hundley:

Beautiful. Well, Amgad, we want to congratulate you on this just excellent work in identifying associations between community level economic distress and risk of adverse outcomes across different race ethnic groups. Congratulations to you.

Dr. Greg Hundley:

Well listeners, next we're going to turn to Matthew Burrage from University of Oxford. And Matt was a finalist for the Melvin Judkins Early Career Clinical Investigator Award. Matt, just like with Amgad, could you tell us a little bit about the background that went into your research project? And what was the hypothesis that you wanted to address?

Dr. Matthew Burrage:

Yeah, certainly. And thank you very much for the invitation to take part in this discussion. Really it's a pleasure to be here. The inspiration for this study was really driven by the difficulties that we've been having in trying phenotype heart failure with preserved ejection fraction or HFpEF, given that until very recently, there were really no therapeutic agents that have significantly improved outcomes for this population. This is despite the fact that around half of all heart failure is classified as HFpEF. And so the thought is that this is a very heterogeneous population but when you dig down into the physiology, there seems to be a central mechanism which involves impairment of myocardial relaxation and in a subsequent rise in intracardiac filling pressures. And this is something that's often unasked by exercise and typically this then results in pulmonary congestion and symptoms of breathlessness. And so some recent translational studies suggests that abnormal cardiac mitochondrial function and energetics may be a unifying feature in the pathogenesis of HFpEF.

Dr. Matthew Burrage:

And given that we know myocardial contraction is dependent on cardiac energy metabolism and that diastolic relaxation is even more energy dependent, we hypothesized that impairment of myocardial energetics may underpin a lot of the physiological changes in the heart that occur during exercise and thus could potentially present a metabolic basis that underlies symptoms in patients with HFpEF, with the hope that this could then lead to new translational drug targets for HFpEF in the future. But then alongside this as well, there's been some really pivotal work on pulmonary congestion during exercise in HFpEF that's been led by Barry Borlaug's group at the Mayo Clinic as the main determinant of patients' symptoms. This has been very well validated against invasive hemodynamics. The second component of our study was to see if we could noninvasively assess pulmonary congestion during exercise and HFpEF. And so to do this, we developed and implemented a new MRI sequence that could quantitatively assess changes in lung water.

Dr Greg Hundley:

Very nice. How did you address the hypothesis in terms of your study design and your methodology?

Dr. Matthew Burrage:

This was a prospective study that followed essentially a basket trial design, where we recruited four distinct groups of participants that were felt to really encompass the spectrum of worsening diastolic dysfunction in HFpEF, which was based on clinical scoring systems, blood biomarkers and echocardiography. We recruited 43 participants split across this group and so we had a cohort of age matched, healthy controls. We had patients with cardiometabolic risk factors for HFpEF like diabetes and obesity who were included essentially if you think of it like a pre-HFpEF group, patients with carefully clinically phenotyped HFpEF and then a cohort of patients with cardiac amyloidosis. And the amyloid group was recruited really as a positive control, that the proof of principle lung imaging sequences, as the presence of restrictive physiology in those patients meant they would be the group that would be far most likely to develop pulmonary congestion during exercise.

Dr. Matthew Burrage:

And so each participant underwent blood sampling, a targeted echocardiogram, they had magnetic resonance spectroscopy to assess myocardial energetics and cardiac metabolism. We do this by measuring the phosphocreatine to ATP ratio and also a cardiopulmonary exercise MRI. The exercise protocol for the study was a fixed low intensity workload of 20 Watts for six minutes with the patient supine within the MRI scanner using an ergometer. And then during exercise, we did whole heart free breathing cine stacks to assess cardiac volumes at rest and exercise, as well as performing our custom proton density weighted lung imaging sequence to look at changes in pulmonary congestion. And if you're interested, the whole rest and stress protocol together can be done within about 15 minutes.

Dr. Greg Hundley:

Wow. Boy, very exciting. Exercise during an MRI scan. Matt, we're very anxious to hear, what did you find?

Dr. Matthew Burrage:

The key findings from this study is that there really is a clear gradient myocardial energetic impairment that exists across the spectrum of diastolic dysfunction and HFpEF phenotypes of increasing clinical severity and worsening diastolic function. And this gradient of impaired myocardial energetics was associated with progressively abnormal exercise responses compared to normal physiology in the age matched controls. And so a greater degree of energetic deficit was linked to impaired left ventricular systolic and diastolic functional reserve. It was also linked to altered right ventricular reserve and abnormal RV-PA coupling and also to exercise induced pulmonary congestion.

Dr. Matthew Burrage:

And we also showed that the pulmonary congestion or changes in lung water could be quantitatively assessed using our new proton density lung imaging sequence and that there is a subgroup of patients with HFpEF who do demonstrate transient pulmonary congestion during exercise that we can assess noninvasively. Overall, the findings suggest a pathway where impaired energetics are linked to patient symptoms and they do this by limiting cardiac reserve during exercise and promoting pulmonary congestion. There seems to be a really important role of resting cardiac energetics in signaling the abnormal ability of the heart to perform high energy consuming processes like active diastolic relaxation and augmentation of contractility and then this leads of course to the downstream effects that we see.

Dr. Greg Hundley:

Very nice. And you were able to even also observe the lung water. It sounds like, help us put this in context for our listeners of how do your results really advance some of the understanding of the pathophysiology of heart failure with preserved ejection fraction?

Dr. Matthew Burrage:

I think one of the key impacts of this study is the fact that the heterogeneity of clinical HFpEF syndromes has been such a major challenge to efforts to develop new therapies to improve symptoms and prognosis in these patients. Pathophysiological phenotyping may represent an important step towards targeting the right therapies to the right patients and specifically targeting myocardial energy metabolism may be a promising therapeutic strategy to improve cardiac reserve and potentially reduce pulmonary congestion in patients with HFpEF. And this really builds on all the translational studies that exist today and have gone before it.

Dr. Matthew Burrage:

Hopefully the mechanistic insights that we get from this could lead to some new translational drug targets, which can be tested against myocardial energetics in patients to see if this metabolic substrate is modifiable. And if this then leads to improvements in symptoms and outcomes. The second aspect very quickly, relates to the evaluation of patients with breathlessness, particularly because invasive hemodynamic assessments may not be possible in all patients who have breathlessness on exertion. The lung water imaging represents a potentially new diagnostic tool that can help to differentiate HFpEF from other causes of dyspnea and I think this is some something that may have a lot of direct clinical applications for patient diagnostics for a wide range of conditions in future.

Dr. Greg Hundley:

Very nice. Well, thanks so much for what outstanding work, identifying this myocardial energetic deficit and then linking that to both cardiac performance, as well as the development of pulmonary congestion.

Dr. Greg Hundley:

Well listeners, we are going to switch to our third author today, Dr. Shaan Khurshid from Mass General and Shaan was a finalist for the Samuel A. Levine Early Career Investigator Award. And so, Shaan, can you give us a little bit of the background information pertaining to your study? And what was the hypothesis that you wanted to address?

Dr. Shaan Khurshid:

Thanks for having me, it's a pleasure to be here. A little bit of background that predicting the risk of atrial fibrillation or AF, may increase the efficiency of AF screening and effectively prioritize individuals for preventive interventions that are designed to reduce the risk of incident AF in the first place. And to that end, risk of AF can be estimated with reasonable accuracy using clinical factors. We already know that. And for example, the CHARGE-AF score is a well validated score that been used in multiple settings. More recently, work suggests that artificial intelligence or AI enabled analysis of the 12 lead electrocardiogram can extract latent information that may be relevant for predicting AF risk. Past models however, have had some limitations. They've utilized very short time intervals. They have not incorporated survival time and censoring with is important for prognostic models. They are kind of a black box and therefore difficult to interpret and they haven't undergone a broad external validation.

Dr. Shaan Khurshid:

Therefore, in this current study, we sought to develop a deep learning model, utilizing the 12-lead ECG to predict risk of incident AF at five years. We call this model ECG-AI quote unquote and compared the performance of ECG-AI directly to the CHARGE-AF clinical risk score that I was mentioning. We also sought to assess a model that combines both ECG-AI and CHARGE-AF to each score alone. We hypothesized that the ECG-AI model utilizing 12-lead ECG could improve the ability to predict five year AF risk as compared to clinical risk factors alone. And we felt that such a model may have practical applications, particularly since wearable devices like smart watches are increasingly able to provide single lead ECGs.

Dr. Greg Hundley:

Really nice. Sounds like a very interesting application of artificial intelligence with electrocardiograms in assessing patients with atrial fibrillation. Can you describe for us your study population and your study design?

Dr. Shaan Khurshid:

Of course. We trained our models utilizing a retrospective cohort. The training population was 45,000 individuals receiving regular primary care at Massachusetts General Hospital or MGH. We then validated our models in three completely independent samples, an MGH internal test set, so individuals from MGH but were not included in training, a separate set of primary care patients at Brigham and Women's Hospital and the UK Biobank Prospective Cohort Study in the UK. The total population in which the models were validated was over 83,000. ECG-AI itself was trained as a convolutional neural network, which was inputted with 10 seconds of the 12-lead ECG and utilized a specialized loss in encoding function that incorporated survival time and censoring in order to produce a five year risk estimate for each individual. We trained models utilizing all ECGs available for each person but evaluated the models utilizing a single ECG alone. We compared each model, ie. ECG-AI, CH-AI and CHARGE-AF by incorporating risk estimates into analogous Cox proportional hazards model so we could compare them apples to apples and calculated traditional epidemiologic metrics of prognostic model performance, including discrimination, calibration and reclassification.

Dr. Greg Hundley:

Very nice. And so what did you find, John?

Dr. Shaan Khurshid:

From our study, we had two major findings. First, the ECG-AI model consistently discriminated five year AF risk comparably to the CHARGE-AF 11 component clinical risk score with C statistics ranging from 0.7 to 0.8. Second, the CH-AI model, which was the combination of ECG-AI and CHARGE-AF, consistently offered greater discrimination than either model alone. Both AI models were very well calibrated across the three test sets with calibration error consistently less than 1%. The ECG-AI and CHARGE-AF scores were moderately correlated, suggesting that the AI model is able to leverage clinical risk factor information extracted from the ECG, yet also adds something further.

Dr. Shaan Khurshid:

Saliency analyses, which are a method of determining which areas of the ECG are most relevant for the model's prediction, highlighted the P-wave and surrounding regions, which provides important evidence of biologic plausibility in our models. Importantly, in sub-analyses assessing the AI models, including only one lead of the 12-lead ECG, we found that model performance was similar, suggesting that AI models utilizing only single lead ECGs may also be effective. We also found that the models performed reasonably well in individuals with prevalent heart failure and stroke, which are populations in whom AF risk destination is particularly relevant.

Dr. Greg Hundley:

Very nice. And so clinically, moving forward, how do we put your results in the context of really where you see this field moving and how we might use it to identify patients at risk of atrial fibrillation?

Dr. Shaan Khurshid:

We're excited. Our work we think provides an important demonstration that ECG-AI based models can utilize a 12-lead ECG to estimate future risk of AF up to five years. And importantly, the AI models were generalizable, providing good discrimination across three large and independent datasets spanning two continents. We're most excited about this finding that models perform well when utilizing single lead ECG data alone, which has important ramifications for wearable devices. In particular, one could imagine a future application of AI in which a wearable device is able to not only be used to screen for atrial fibrillation or AF, but also stratify an individual's risk for AF utilizing ECG based analysis and therefore potentially prioritizing that individual for preventive interventions and also potentially determining how intensely to screen that individual all in a single closed group.

Dr. Greg Hundley:

Excellent. Wow, Shaan, just beautiful presentation, listeners. Really discussing how the artificial intelligence assessment of these EKGs may enable efficient quantification of the future risk of developing atrial fibrillation.

Dr. Greg Hundley:

Well listeners, we're going to turn now to our fourth presenter, Maryam Zekavat from the Bird Institute, Yale University. And Maryam was a finalist for the Genomic and Precision Medicine Council's Early Career Investigator Award. Welcome Maryam. And can you describe for us some of the background pertaining to your study? And what was the hypothesis you wanted to address?

Dr. (Sevedeh)Maryam Zekavat:

Absolutely. And thank you for the invite to be part of this podcast. The title of the work that we presented and that was published in Circulation is Deep Learning of the Retina Enables Phenome and Genome-wide Analyses of the Microvasculature. And so as a little bit of a background, we know that the microvasculature has key roles in maintenance of organ health and that microvascular disease is implicated in conditions across all organ systems. Here, to study the human microvasculature noninvasively, we used data across about a 100,000 retinal fundus photographs. And the purpose of our work was really to address two main things.

Dr. (Sevedeh)Maryam Zekavat:

First, an unbiased assessment of the phenotypes associated with the retinal microvasculature had yet to be performed and that motivated us to ask our first question, namely, what information can the retinal vasculature provide on future ocular and systemic disease risk? And then secondly, therapies such as anti-VEGF, which pharmacologically influence vascular density, are the mainstay of treatment for multiple ocular conditions, including wet AMD, proliferative diabetic retinopathy, as well as many cancers. However, an unbiased screen of genetic targets for other treatments that may influence the microvascular has yet to be performed. And so that motivated us to ask for our second question, namely, what genes influence the retinal vasculature? And so from there, I'll go to our hypothesis, which was that analyses of retinal fundus photos may enable an understanding of the connection between microvascular geometric indices, diseases and genetics.

Dr. Greg Hundley:

Very nice. And so boy, I heard you had almost a 100,000 participants involved in this study. Tell us a little bit about your study design and clarify for us, where did you get all these patients from? What was your study population?

Dr. (Sevedeh)Maryam Zekavat:

Yeah, of course. The study list we utilized the UK Biobank, which is a cohort of half a million individuals, including over a 100,000 fundus photographs from about 50,000 individuals. We first implemented deep learning to remove poor quality images and then to segment out the vasculature fundus photos. And then from there, we went on to quantify two vascular features, branching complexity as measured using fractal dimension and also vascular density. And lastly, we performed phenome and genome-wide association studies to understand how these vascular geometric indices influenced disease risk and what genetic factors influence the vasculature.

Dr. Greg Hundley:

Excellent. And tell us, what did you find?

Dr. (Sevedeh)Maryam Zekavat:

Yeah. First using deep learning, we were able to successfully perform image quality control and vessel segmentation to extract two geometric features of the retinal vasculature. Next through phenome-wide analyses, we identified that lower retinal vascular fractal dimension and density were significantly associated with higher risk for incident mortality, as well as cardiometabolic conditions, including hypertension and type 2 diabetes, heart failure and renal failure among others. And also multiple incident ocular conditions, including future risk of retinal detachment. Thirdly, genome-wide association of these two geometric indices identified seven and 13 novel loci associated with vascular fractal dimension and vascular density respectively. And these were enriched in pathways linked to angiogenesis, such as VEGF, angiopoietin and WNT signaling pathways, as well as inflammation via interleukin and cytokine signaling. And then fourth, through Mendelian randomization for genetic causal inference analysis, we identified that a genetic risk for hypertension and type 2 diabetes is associated with lower microvascular density and that a genetic risk for lower microvascular density is associated with increased risk of retinal detachment.

Dr. Greg Hundley:

Wow. Really interesting. The intersection of this beautiful phenotype characterization of the retina with this genetic information. Where do you see this research moving forward in the future?

Dr. (Sevedeh)Maryam Zekavat:

Yeah, so clinically these findings may support the use of retinal microvascular indices for risk prediction and disease monitoring of systemic and ocular conditions. And of course, further assessment of the identified biological pathways influencing the microvasculature can potentially lead to therapies for not only retinopathies but also other conditions linked to microvascular disease, including oncologic, renal and cardiovascular conditions. And more broadly, our results illustrate the potential for using deep learning on retinal imaging to understand the microvasculature with wide applications across diseases. And of course, more research is needed to evaluate the added benefit, in addition to existing clinical predictors and the feasibility for incorporation into clinical workflows.

Dr. Greg Hundley:

Just beautiful. And thank you so much Maryam and for highlighting for us, the results of your study, indicating that the retinal vasculature may serve as a biomarker for future cardiometabolic and ocular disease and provide insights on genes and biological pathways that influence microvascular indices.

Dr. Greg Hundley:

Well listeners, now we are going to turn to our last speaker today and it's Dr. Neel Butala from Mass General, Beth Israel. And he also was a finalist for the Samuel A. Levine Early Career Investigator Award. Welcome, Neel. And could you describe for us the background pertaining to your study and what hypothesis did you want to address?

Dr. Neel Butala:

I appreciate the opportunity to be here and chat with you. And so there's conflicting evidence on the optimal duration of dual anti-platelet therapy, which is DAPT, after drug eluting stent implantation. Older studies, such as the DAPT study show fewer ischemic events with more bleeding, with longer DAPT duration and our site and the guidelines for DAPT duration after PCI but newer studies show similar ischemic events and actually less bleeding with shorter DAPT, even among those with high ischemic risk at baseline. We wondered whether the DAPT study, which is the only study powered to detect ischemic endpoints and still influences a major cardiovascular guidelines still applies to contemporary practice.

Dr. Neel Butala:

And so we asked two key questions. Now, number one is a US contemporary real world population of patients receiving PCI, different from the DAPT trial population. And again, the DAPT trial enrolled between 2009 and 2011. And here we hypothesized that the populations are probably a little different. And number two, we asked how would trial treatment effects change if a real world population had been enrolled instead? And here we hypothesized that perhaps the ischemic benefit of longer DAPT would actually go away, would be similar to the newer trials that have been done.

Dr. Greg Hundley:

Very nice. And describe for us your study design and your study population.

Dr. Neel Butala:

Yeah. We compared characteristics between DAPT study patients, with those of a more contemporary real world cohort of NCDR cath PCI registry patients. And to do this, we used novel transportability methods to really create a propensity score model to predict an individual's likelihood of trial participation based on patient characteristics. And this type of propensity score model actually gives us inverse probability weights, which we used to reweight the DAPT study patients based on the distribution of characteristics in the real world patients. The intuition here is really to up weight the trial patients with characteristics more common in the real world and down weight trial patients with characteristics less common in the real world. We then compared treatment effects in the DAPT study patients with those of the reweighted DAPT study patients to understand whether DAPT study results would change if a real world population had been enrolled instead.

Dr. Greg Hundley:

Very nice. And what were the results associated with these comparisons?

Dr. Neel Butala:

First, we found that trial and real world populations were different. We found that the contemporary real world population was older, less likely to be White, more likely to have comorbidities and then more likely to present with ACS. Additionally, nearly a 100% of real world patients received a second generation drug eluting stent versus only 58% of trial patients. And then these differences led to differences in the estimated average treatment effects of DAPT, to the results of the DAPT study. And the real world treatment effect in reducing ischemic endpoints is actually no longer present but the increase in bleeding persisted. And so we found that the average top line treatment effect in the DAPT study may not be applicable to contemporary practice. We did find however, the DAPT score in the subgroup did still identify subsets of patients who may benefit from prolonged DAPT beyond one year after PCI in the contemporary population.

Dr. Greg Hundley:

Very nice. And so clinically as we're managing patients, how would we interpret your results and help us with clinical management today?

Dr. Neel Butala:

Yeah, great question. These results really harmonize the DAPT trial with results of newer clinical trials of DAPT duration, which all demonstrate the safety of shorter duration DAPT to reduce bleeding risk and these results more broadly illustrate the importance, the nuance interpretation of clinical trials to guide clinical decision making and really highlight the risk of simply applying the top line trial results to all patients in contemporary practice, even beyond the study. These results emphasize the importance of accounting for patient specific factors and leveraging risk scores when available in deciding how clinical trials results actually apply to a particular patient. And finally, the results actually illustrate the importance of continually evaluating the generalizability of cardiovascular trials to ensure that the guidelines reflect treatment effects in contemporary clinical practice. And the methods that we use in the study can actually be used to do this in RCTs more broadly.

Dr. Greg Hundley:

Very nice, Neel. And thank you for really bringing us this study highlighting the differences between patients and devices used in contemporary clinical practice compared with those in the DAPT study. And how they were associated with attenuation of benefits and greater harms attributable to prolonged DAPT duration.

Dr. Greg Hundley:

Well listeners, what an exciting day. Getting to see these papers in print and also have these early stage investigators from the 2021 sessions that were finalists in many of these competitions, we're so grateful to Amgad Mentias, Matt Burrage, Shaan Khurshid, Maryam Zekavat and Neel Butala for their time today.

Dr. Greg Hundley:

On behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Please join author George Dangas and Associate Editor Brendan Everett as they discuss the article “Colchicine in Cardiovascular Disease.”

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley: Welcome, everyone, to 2022. I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Carolyn, oh, we're starting off the year with a twist on the feature article. It's a review article on colchicine and cardiovascular disease.

But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue?

Dr. Carolyn Lam: Absolutely. The new year is starting off with a bonanza issue. This first topic is so important. We know that various non-invasive, intermittent rhythm monitoring strategies have been used to assess arrhythmia recurrences in atrial fibrillation ablation trials. But the question is, what is the frequency and duration of non-invasive rhythm monitoring that accurately detects arrhythmia recurrences and approximates the atrial fibrillation burden derived from continuous monitoring using the gold standard, implantable cardiac monitor?

Now to answer this question, investigators Jason Andrade and colleagues from the Montreal Heart Institute, who looked at the rhythm history in 346 patients enrolled in the CIRCA-DOSE trial. They reconstructed the rhythm history using computer simulations and evaluated event-free survivals, sensitivity, negative predictive value, and AF burden in a range of non-invasive monitoring strategies including those used in contemporary AF ablation trials.

Dr. Greg Hundley: Ah, very interesting, Carolyn. So what did they find?

Dr. Carolyn Lam: Detection of arrhythmia recurrence following ablation was highly sensitive to the monitoring strategy employed between trial discrepancies and outcomes, in fact, may reflect these different monitoring protocols. Binary efficacy outcomes, such as time to AF recurrence, appeared to underestimate the true impact of catheter ablation on the burden of atrial arrhythmia.

The most commonly performed intermittent rhythm monitoring techniques, like short duration 24- or 48-hour ambulatory Holter, they do miss a substantial proportion of arrhythmia recurrences and significantly overestimate the true AF burden in patients with recurrences. So based on measures of agreement, serial long-term, that is four seven-day or two 14-day intermittent monitors accumulating at least 28 days of annual monitoring provide estimates of AF burden that are comparable with the implantable cardiac monitor.

However, implantable cardiac monitors outperform intermittent monitoring for arrhythmias and should be considered the gold standard for clinical trials.

Dr. Greg Hundley: Very nice, Carolyn. It sounds like a lot of clarification on monitoring of AF burden. Well, my first paper comes to us from Dr. Prabhakara Nagareddy from The Ohio State University, The Wexner Medical Center.

Carolyn, acute myocardial infarction results in an overzealous production and infiltration of neutrophils in the ischemic heart, and this is mediated in part by granulopoiesis induced by the S100A8/A9 NLRP3, IL-1 beta signaling axis in injury-exposed neutrophils.

In this study, Carolyn, the investigators evaluated a hypothesis as to whether IL-1 beta is released locally within the bone marrow by inflammasome prime and reverse migrating neutrophils.

Dr. Carolyn Lam: Ah, okay. So what did they find, Greg?

Dr. Greg Hundley: Okay, Carolyn. In response to myocardial infarction, the NLRP3 inflammasome prime neutrophils upregulated CXCR4 and reverse migrated to the bone marrow, where they adhered to adhesion molecules like P-selectin on the bone marrow endothelial cells.

Second, Carolyn, in the bone marrow, the inflammasome prime neutrophils released IL-1 beta through gasdermin-dependent conduit pores without undergoing the mandatory pyroptosis.

Third, genetic and/or pharmacological strategies aimed at limiting reverse migration of inflammasome prime neutrophils to the bone marrow or release of IL-1 beta, both suppressed granulopoiesis and improved cardiac function in mouse models of myocardial infarction.

So Carolyn, therefore, strategies aimed at targeting specific signaling pathways within the neutrophils or reducing retention of the inflammasome prime neutrophils in the bone marrow may provide novel avenues to regulate inflammation and improve cardiac outcomes.

Dr. Carolyn Lam: Wow, neat, Greg. Thanks for explaining that so nicely. Well, the next paper deals with my favorite topic, heart failure with preserved ejection fraction of HFpEF, and this time looks at mechanisms of sinoatrial node dysfunction.

The investigators, led by Dr. Cingolani from Smidt Heart Institute at Cedars-Sinai Medical Center, sought to investigate the role of the intrinsic pacemaker on chronotropic incompetence in HFpEF. They performed extensive sinoatrial node phenotyping, both at baseline and after stress in the well-characterized Dahl salt-sensitive rat model of HFpEF.

These rats exhibited limited chronotropic response associated with intrinsic sinoatrial node dysfunction, including impaired beta-adrenergic responsiveness and an alternating leading pacemaker within the sinoatrial node. Prolonged sinoatrial node recovery time and reduced sinoatrial node sensitivity to isoproterenol were confirmed in the two hit mouse model. Adenosine challenge unmasked conduction blocks within the sinoatrial node, which were associated with structural remodeling.

Finally, single-cell studies and transcriptomic profiling revealed HFpEF-related alterations in both the membrane clock or iron channels and the calcium clock of the spontaneous calcium release events.

Dr. Greg Hundley: Wow, Carolyn, lot of really interesting data here. So what were the clinical implications?

Dr. Carolyn Lam: Yeah, it's a really great study. Two models of HFpEF-consistent result in an important topic. Basically, here at the take-home messages. Provocative testing can be valuable to elicit functional abnormalities to facilitate HFpEF diagnosis and considering the exceptionally high clinical and epidemiologic convergence between AFib and HFpEF, sinoatrial node dysfunction may underlie the development of abnormal atrial rhythms in HFpEF.

Dr. Greg Hundley: Very nice, Carolyn. More information on HFpEF, again, one of your favorite subjects. Next, we're going to turn to a paper from Dr. Jian Li from the Peking Union Medical College Hospital. Carolyn, doxycycline has previously been demonstrated in a retrospective study to be associated with greater survival in patients with light chain AL amyloidosis.

Therefore, Carolyn, this group prospectively compared the efficacy of bortezomib, cyclophosphamide, dexamethasone, or cyclophosphamide B or D, and cyclophosphamide B or D combined with doxycycline for cardiac amyloidosis.

Dr. Carolyn Lam: Cool. So what did they find, Greg?

Dr. Greg Hundley: Carolyn, this was a multi-center, open-label, randomized controlled trial, and 140 patients underwent randomization. The primary outcome was two-year progression-free survival. Progression-free survival was defined as the time from randomization to death, hematologic progression or organ progression, and that's the heart, the kidney, or the liver.

And so Carolyn, these investigators in this trial demonstrated that doxycycline combined with cyclophosphamide B or D failed to prolong progression-free survival or cardiac progression-free survival compared with cyclophosphamide B or D alone in patients with cardiac AL amyloidosis.

So Carolyn, a negative study that's quite informative and a very nice editorial that accompanies this article pertaining to future directions for management of AL cardiac amyloid.

Dr. Carolyn Lam: Indeed important. Thank you. And there are other important papers in today's issue. There's a Research Letter by Dr. Pfeffer on the impact of sacubitril/valsartan versus ramipril on total heart failure events in the PARADISE-MI trial.

Dr. Greg Hundley: Great, Carolyn. In the nail bag, boy, I've got a big list today. First, Dr. Churchwell has an AHA update on the need for policy change to improve maternal cardiovascular health. Next, Dr. Piazza has a Perspective piece on expanding the role of coronary CT angiography in interventional cardiology. There's an ECG challenge from Dr. Yarmohammadi entitled “Dancing Bundles with Stable Sinus Rhythm.” And next, we have our own Darren McGuire who, in this issue for all of 2021, is really recognizing our outstanding reviewers.

And we want to thank all the listeners and everyone that reviews for us in this journal. Such an important feature and aspect to the publication of the wonderful articles that we receive. And then finally, there are some highlights from the circulation family of journals. Well, Carolyn, how about we get on to that feature discussion and learn more about colchicine and its use in cardiovascular disease.

Dr. Carolyn Lam: Let's go and a Happy New Year, again, everyone.

Dr. Greg Hundley: Welcome listeners to this January 4th feature discussion. This week, we're deviating a little bit because we are going to have an author discuss one of our in-depth reviews. As you know, we select those occasionally where they're is a topic that's very relevant in cardiovascular medicine and an investigator or team of investigators or authors will put together a very nice review of a topic.

This week, we're going to talk about colchicine, and we have with us Dr. George Dangas from the Icahn School of Medicine at Mount Sinai and our associate editor, Dr. Brendan Everett, who manages this paper and he is from Brigham and Women's Hospital. Welcome, gentlemen. George, we'll start with you. George, why colchicine? Can you tell us a little bit about mechanism of action? Tolerability? Why would we want to use this particular agent in patients with cardiovascular disease?

Dr. George Dangas: Thank you very much for the opportunity to join this interesting podcast. Colchicine is indeed an interesting drug. It's been around for centuries, in all honesty. In general, I would say it's a mild anti-inflammatory and in general, it's rather well tolerated. We'll go into those perhaps a little bit later.

The precise mechanism is actually interestingly not quite defined. It may have a few ways to act by blocking perhaps the chemotaxis of the leukocytes or the adhesion of the leukocytes or the ability to release their granules, et cetera, but there isn't a specific major one that is targeting. Perhaps, it's targeting more than one mechanism in a mild way, and I think that goes into each utility, as well as the absence of the major side effect that might limit it.

Dr. Greg Hundley: Very nice. So you started to mention the word utility, so maybe let's go through some clinical indications, or clinical uses perhaps rather than indications, can you tell us a little bit about its use in individuals with pericarditis?

Dr. George Dangas: I think this is where it started to enter the cardiovascular field because we all recognize that pericarditis is an inflammatory disease and inflammation of the pericardium of different reasons perhaps. And anti-inflammatory drug is rather fitted to treat an inflammatory disease and besides, it's not like we had any other drug, in all honesty. Clearly, recurrent pericarditis might be treated with steroids for example, but steroids is not something any cardiologist would jump as a first line and give high doses and all that.

Colchicine made its way to pericarditis like acute or recurrent pericarditis, post-cardiac cardiology syndrome, restless syndrome or the specific post-cardiac surgery, major inflammation. And indeed has a daily dosage perhaps with some loading dose or double the daily dosage or something initially and then we give it for a prolonged period of time in order to suppress.

I would say this is a reasonable choice rather than jumping to the steroid. And of course, you reserve the steroid for the, I would say, more severe or more recurrent cases. I think everybody understands this type of activity. There've been quite a few clinical studies in this aspect. Again, in the absence of a competitor, I think it's a winner in this area.

Dr. Greg Hundley: Very nice. And then, how about atrial fibrillation? Are there uses of this colchicine in patients with atrial fibrillation?

Dr. George Dangas: Well, again, it's very interesting that a lot of atrial fibrillation, it may be in some ways inflammatory in origin. And quite frankly, we had an interesting [inaudible 00:14:50] clinical trial in American Heart Association in 2021. I'd like to point out here, the study that postoperative atrial fibrillation was mitigated when, during cardiac surgery, there was a slicing of the posterior pericardial. This allowing the inflammation in some ways that's related there.

To me, that was a very interesting observation, though I related to colchicine because it validates the fact that there is something inflammatory in pericardial that related with the postoperative atrial fibrillation. So along these lines, let's go back to colchicine, Afib, and postop Afib, and post-ablation I would say patients. Again, there are risks of some inflammation and that's where the theory of a mild, rather well-tolerated, anti-inflammatory might come in. And there's been few studies, not a large definitive study, but several studies that are the, I would say, component with interesting results with colchicine in these patients.

Dr. Greg Hundley: Very good. Another area of cardiovascular disease that's emerging literally with some demonstrable results using colchicine is the realm of ischemic heart disease. Can you walk us through some of the utility myocardial infarction or maybe even post-percutaneous coronary artery intervention?

Dr. George Dangas: Again, the hallmark in this type of diseases, cardiovascular disease or coronary heart disease, is the hallmark of role of inflammation in this disease. And we know very well from the studies of the C-reactive protein, importance is a marker of inflammation. Very, very important in the CAD as well as in even the treatment with the antibody canakinumab a little bit earlier in the CANTOS trial a few years earlier at the very high level inhibited inflammation had a benefit and colchicine comes in maybe a milder anti-inflammatory about this agent, but at the same time with significantly less cause and significantly better recognition among the clinicians and a lot less, I would say, tolerability problems or issues are less unknowns. And I think that's where it comes in.

The difficulty has been that whenever you go to cardiovascular, the cardiovascular, I would say coronary artery disease specifically, ACS and all that, the level evidence required for the doctors to believe in a therapy is very different than the areas we discussed before where there's little bit of a pericardial disease, for example, not that many drugs, all of a sudden, coronary artery disease, the bar is so high, and that's where the difficulty has been.

There've been several studies. They've been interesting results with some benefits, particularly due to the decrease in inflammation and the secondary prevention, one can say. That is really the hallmark of where it aims to benefit in the secondary prevention, but there hasn't been one massive study with clearly superb results. I would say adequately powered single study that is missing in some ways.

But several studies have been, again, very, very encouraging, but we learned that there's no much point if loading a lot of doses of high doses of colchicine, and it's a little bit better, again, when you aim with a daily dose towards reduced recurrences, particularly if you started early after an acute event.

Dr. Greg Hundley: Very nice. Well, listeners, we're going to now turn to our associate editor, Dr. Brendan Everett, from Brigham and Women's Hospital. Brendan, you have a lot of papers come across your desk. First and foremost, what attracted you to this particular article?

Dr. Brendan Everett: Well, thanks, Greg. And kudos to George and his team for putting together a really nice paper. It's great to have this kind of paper come into my inbox. That's specifically because colchicine, I think, has exploded as a really important novel therapy even though the therapy itself is perhaps hundreds of years old, as you heard George say a moment ago, but its role in treating cardiovascular diseases has really begun to emerge rapidly.

I think there's a tremendous amount of enthusiasm for other ways to treat our patients who have really a recalcitrant cardiovascular disease, whether that's pericarditis, atrial fibrillation or I think, importantly, ischemic heart disease, because that's such a common disease and something where we're always looking for new ways to help patients live longer with fewer recurrent events. And so this paper I thought did a really good job of capturing the existing evidence for these conditions and some others and giving us a sense of where the strengths of that evidence lay and where the weaknesses were.

I thought particular strength was in the tables where the authors laid out each of the trials and the results of the trial, their endpoints, where the benefit was potentially. And also importantly, where risks were seen because I think that's one of the really important questions that remains open with respect to colchicine therapy when we begin to talk about using it in a vast population of people with stable ischemic heart disease or post-myocardial infarction ischemic heart disease.

Dr. Greg Hundley: Brendan, tell us a little bit about those risks.

Dr. Brendan Everett: I'd be happy to do that. I want to emphasize before I dive in that I think the benefits that George has laid out are important, and I don't want to overshadow what the major trials have seen. But I think the thing that it is at least a little bit of the fly in the ointment, if you will, for colchicine in ischemic heart disease is that a couple of the large trials have shown an increased risk of non cardiovascular mortality or bad non-cardiovascular outcomes.

And that's of concern, I think, as we saw in the CANTOS trial, which was the monoclonal antibody trial for canakinumab that George mentioned earlier, there was an increase in infection-related mortality. And so whenever you use an anti-inflammatory drug, you're worried about whether or not you're blunting other compensatory mechanisms that the body has to protect against infection and other diseases.

I think it's likely that these findings are the play of chance, but we don't know for sure. For example, in the COLCOT trial, which I think is probably the largest and most interesting trial, which was designed and run in Canada, there was a slightly higher level of pneumonia in patients who got active therapy as compared to placebo.

And then, two of the trials that were published more recently including LoDoCo2, which was a trial of about 5,000 patients run in the Netherlands and Australia. There was actually a marginally increased risk of non-cardiovascular mortality. That didn't reach statistical significance, but it was awfully close, and I think it gave people some concern.

And then, there was also the COPS trial. Again, all these are really outlined in wonderful detail in the manuscript where there was a slight increase of total death and non-cardiovascular death. These events are few, but they're in a direction in two trials, and so they make people a little bit worried. I think the other thing that I noticed was the high prevalence of myalgia as a side effect.

I think, Greg, you're always interested in the clinical implications and yesterday I was in clinic and saw a young patient who had had pericarditis. He had been prescribed colchicine by his primary care physician, and he literally couldn't stand and walk up straight because of the amount of abdominal pain he had, which was unusual. To be honest, I've given colchicine to a hundred patients at least, and none of them have had that profound of a side effect, but it's at least worth considering that some patients will not tolerate the therapy because of adverse effects.

Dr. Greg Hundley: Very good. Well, in just 30 seconds or so, for each of you, first George and then Brendan. George, balancing some of the efficacy and then some of the concerns, what do you see is the next studies to be performed really in this sphere of research?

Dr. George Dangas: This is a great question. And indeed, the concerns one can say or the issues, I would say, regarding this drug, are indeed real because any drug that suppresses inflammation has this risk. There are two ways one can address those. One is with term administration. You don't prescribe it as an annuity forever, but you prescribe it in a three- to six-month or one-month or try to control the time. I think this is done in clinical practice, in all honesty.

I don't think that people are prescribing colchicine for life. Same way when we prescribe statins, for example. On the other hand or from investigational point of view, I think the two sets of information we need and, in all honesty, when you investigate issues regarding mortality or these are rare events, there's only one. You need a very large trial or a very large register. A very large trial preferably and colchicine being an often genetic drug, funding sources are rather limited, but we have NIH chipping in with some funding periodically and that might really be needed.

So I want to outline that in the last table of our very large, I would say large table of our manuscript but were very happily outlined many ongoing trials. There are, in atrial fibrillation, three coronary artery disease. One in PCI and two in stroke. Something we didn't touch up again. But again, there's the question of inflammation in stroke. I think there's a lot of work ongoing. Perhaps you can see some meta-analysis, again, in order to get a handle of those risks, but at a rather low rate. It's just a difficult thing to come around.

Dr. Greg Hundley: Very good. Brendan, anything to add?

Dr. Brendan Everett: I would just add I agree a hundred percent with George just said. I think the only missing piece there is heart failure, which I think is and many have shown that there's an inflammatory component to heart failure, whether it's heart failure with reduced ejection fraction or preserved ejection fraction.

And the timing of when that intervention might be, whether it might be before the development of symptoms or because there's a lot of trials out there that have struggled with this question and have unfortunately failed to show any benefit, I would just encourage the listeners of the podcast to look at this paper because it's a really marvelous compilation of the evidence for what is a really hot topic in cardiovascular medicine, a really important topic for a lot of the reasons that George mentioned. It's just very well done and comprehensive.

Again, kudos to the authors for making such a great effort at putting something together that has a lot of clinical relevance, I think, and also points the way forward for research as you ask, Greg.

Dr. Greg Hundley: Very nice. Well, listeners, we want to thank Dr. George Dangas from Icahn School of Medicine in Mount Sinai and our own associate editor, Dr. Brendan Everett from Brigham and Women's Hospital for bringing us this data pertaining to colchicine benefits, as we know in acute and recurrent pericarditis, but also emerging indications related to post-procedural atrial fibrillation or coronary artery disease. And really, colchicine's targeting of cardiovascular inflammation is being helpful in those alleviating those processes.

Well, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week on the run.

Dr. Greg Hundley: This program, this copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This week, please join authors Jonathan Leor and Tal Caller, as well as Associate Editor Gabriele Schiattarella as they discuss the article "Small Extracellular Vesicles From Infarcted and Failing Heart Accelerate Tumor Growth."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240524.921966

In this week’s edition of Circulation on the Run, Dr. Amit Khera introduces the new Social Media Editors to our Circulation listeners. Please welcome Dr. Vanessa Blumer, Dr. Pishoy Gouda, Dr. Xiaoming (Ming) Jia, Dr. Peder Langeland Myhre, and Dr. Sonia Shah to Circulation.

Dr. Amit Khera:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Amit Khera, Associate Editor from UT Southwestern Medical Center in Dallas, and Digital Strategies' Editor for Circulation. And today I have the privilege of sitting in for your usual host, Dr. Carolyn Lam, and Dr. Greg Hundley. Well, two times a year, we really have a special issue, there's no print issue for Circulation in the summer and here in that holiday time. So, fortunately, we get to use this for really whatever we want to do.

Dr. Amit Khera:

And today we have a very special issue. A few months ago, we transitioned over from a prior social media editor team that was Jainy Savla Dan Ambinder, and Jeffrey Hsu. We were able to recruit a fantastic group of new social media editors. You probably have seen their work behind the scenes, but you've not gotten to meet them personally. So, today I have the privilege of introducing you to our new social media editors. This group of five, that's been working for several months and we get to know them a little bit. Get to hear a little bit about their perspective on social media from fellows in training, and also what they've learned so far in their few months in working with Circulation. So, I'm going to go one by one and introduce you. And first I want to introduce you to Dr. Vanessa Blumer. Vanessa, tell us a little bit about yourself.

Dr. Vanessa Blumer:

Thank you so much, Dr. Khera, it is such an honor to be here. And I've had so much fun the months that I've been working for Circulation, it's truly just a privilege to work alongside this talented group. So I'm Vanessa Blumer. I am originally from Caracas, Venezuela, born and raised there, did all of my medical training back home. That included medical school, a year of rural service, or rural medicine. Then I actually did residency training in Venezuela as well. It wasn't really in my plans straight away to come to the US, but a little bit due to the political situation that we all know that Venezuela's going or suffering, I decided to come to the US.

Dr. Vanessa Blumer:

I did residency in the University of Miami, Jackson Memorial hospital, which I loved. Stayed there for a chief year. And then after that came to Duke University to do cardiology fellowship. I'm currently a third year cardiology fellow at Duke, doing a year of research at the DCRI, which I am enjoying a lot, and will be doing heart failure next year. I will be going to Cleveland Clinic for a year of advanced heart failure.

Dr. Amit Khera:

Well, you've had quite a journey, Vanessa, and congratulations, I think your match was relatively recently. So, we're excited to see where your career takes you from here and appreciate your contribution so far. Now I'm going to introduce you to Pishoy Gouda. Pishoy Tell us a little bit about yourself.

Dr. Pishoy Gouda:

Morning, Dr. Khera. My name is Pishoy. I have had the privilege of doing my medical trading all over the world. I was born here in Toronto and moved to Edmonton where I mostly grew up. Since then, I traveled to Galway Ireland where I spent six years to do my undergraduate medical training. Hopped over a short flight and did my Masters in Clinical Trials in the London School of Hygiene and Tropical Medicine before returning to Canada to start my residency training. Got to work with some amazing people in Calgary while I completed my internal medicine training, and then finally returned home to Edmonton where I am in the last few months of my adult cardiology training.

Dr. Pishoy Gouda:

Next year, I'm really excited to start my interventional cardiology training, which is going to be really exciting. Some of my interests, working with social media, wearable technology so working with this great group has been really awesome.

Dr. Amit Khera:

Thank you Pishoy. Obviously lots of travels from you as well, and we definitely appreciate your expertise and interest in social media and in technology. It's been very valuable. Next someone who's closer to my backyard. Ming Jia. Ming, welcome.

Dr. Xiaoming (Ming) Jia:

Hello from Houston, and thank you Dr. Khera. So, it's been a great opportunity to be involved as a social media editor for Circulation. So I'm a current cardiology fellow at Baylor College of medicine in Houston, Texas. Was originally born in China, and grew up in sunny Florida. I did my medical training in Florida as well, and then moved over to Houston, Texas for residency, and now wrapping up my last year in general fellowship. Next year, I'll be staying in Houston at Baylor for interventional fellowship. Then, hopefully after that career in interventional cardiology, but as well as preventional cardiology as well, I tended to actually interest in both interventional and preventional cardiology.

Dr. Amit Khera:

Very cool. I know you and I were talking about this right beforehand, how that nexus of the two fields and just some of your interest in a lot of the research you've done so far. So again, offering a unique and different perspective, which we appreciate so, welcome, Ming. Next, Peder Myhre. Peder, welcome.

Dr. Peder Langeland Myhre:

Thank you so much, Dr. Khera. This is Peder Myhre from Norway, all the way across the pond. And it's such a great honor to be part of this podcast, which I've been a big fan since it started a couple years ago and where Carolyn Lam has been doing with it, it's been really amazing. And I've actually been promoting it to everyone I know with any kind of interest in cardiology. My position in training right now is that I'm in the last year of cardiology training and I'm also doing a 50% post-doc at the University of Oslo with Professor Torbjørn Omland as a mentor. And as a part of my training, I was one year at Harvard University at Brigham Women's Hospital to do research with Professor Scott Solomon's group a couple of years ago.

Dr. Amit Khera:

Well, we appreciate your affinity and now you get to be on the podcast. That's pretty exciting as well. I should say, each of you is linked to an outstanding Associate Editor at your home institution. And so we're glad you have that mentorship as well there too. And speaking of someone at home institution, someone who I've known for a very long time, Dr. Sonia Shah. Sonya, introduce yourself, please.

Dr. Sonia Shah:

Thank you, Dr. Khera. No, just to echo what everyone has said already, it truly has been an honor and a privilege to work with this awesome team. And it's been a lot of fun along the way. So I'm Sonia Shah. I'm a third year cardiology fellow at UT Southwestern in Dallas, Texas. Originally from Central Florida, actually. And then did my undergrad medical school training in Chicago and then went out to the West Coast for my residency training was out at Stanford and now I'm loving being in Dallas. So it's been a lot of fun. So I particularly have an interest in women's cardiovascular health and advanced imaging. And so currently looking for jobs now.

Dr. Amit Khera:

Well, I can say you've been a star fellow and have a really incredible and unique skillset. And, so we look forward to seeing what your career brings and certainly you've brought a lot to our podcast. And we'll talk more about that in just a bit, since you are longest standing social media editor currently. Well, I want to now dig in a little bit and you all again, I want to thank you for what you've done for the last several months. I certainly have learned a lot from you. We've had some discussions as a group about, thoughts about social media and how social media works.

Dr. Amit Khera:

And so maybe we'll start with the sort of existential question about, why social media? What is the value for journals, if you think about Circulation, but really any journal. What does social media bring? And again, you all have a unique perspective as largely fellows in training and Vanessa, maybe I'll go back to you a little bit about, why social media? What's the point of relevance about all this work that you're doing?

Dr. Vanessa Blumer:

Yeah. Thank you so much, Dr. Khera. I think that's a great question. And I do think that that's a question that we ask ourselves every day as we're doing this. I think the way that the medical literature has been evolving, it's been evolving in a way of social media and people are consuming more and more social media daily. I think in my own daily life, I discover articles that I'm interested in through social media a lot more than I used to before. And I also discover that I'm interested in particular articles, the way that they are transmitted in social media or the way that they're presented in social media.

Dr. Vanessa Blumer:

So I think we're reinventing ourselves and reinventing the way that we present to the public, the articles that we have in Circulation, so that people want to read our articles or want to read the articles that authors are doing such a great job at putting together. So I think, we are coming up with creative ideas every day and it's part of what we discuss as a group of how do we present this so that people want to read the articles and discover all the hard work that authors are putting together through different social media platforms. Because we know that people consume not just one social media platform, but several. So I think there's huge potential in social media if we use it in the right way.

Dr. Amit Khera:

Yeah. I think your points well taken. I know we're going to talk a lot about Twitter today, but as you pointed out, there are other media as well. That's just in the sort of main, I guess, currency and in the medical and cardiovascular literature. And you mentioned value to authors and one thing you mentioned, which I'll transition a little is about the way things are presented, help you get interested in them. And so that gets to the art of the tweet. Something we've talked about a little bit and, there's a little bit of on the job training, if you will. And we've talked about is there a gold standard in terms of what makes a good frankly, a medical journal tweet. Well, Ming, what do you think? You've been toiling over this for a few months now and tell us what you think is helpful in a medical journal tweet in terms of achieving the goals that Vanessa mentioned. Getting an audience interested in reading these articles is really doing justice for the authors to transmit their research.

Dr. Xiaoming (Ming) Jia:

Great question, Dr. Khera, and this is something that, as a social media editor, I'm still learning. So for me, writing a concise tweet is very important. Trying to get that essence of a entire study into a very limited number of characters. Obviously having a great figure that highlights the key findings of a study is also very important as well. Now at the same time, I think the most effective posts though, are those that serve as a hook for the paper. So, while we want are tweet to stand on their own. I think the most effective tweets helped to entice the audience to want to read a little bit more and go and read the entire manuscript. So certainly there is a art and skillset in terms of writing these effective posts.

Dr. Amit Khera:

Yeah. You certainly bring up some key points, right? So being concise, one by definition and but two is, there are tweets that sometimes can go on and on and that comes into using some interesting hashtags and some shortcuts. But I think your point about innuendo, enticing, not giving away the whole story, but just enough to get people to want to read more. And I think that that is an art.

Dr. Amit Khera:

And I've certainly seen as you all have done this more and more about how your own writing and tweets have evolved. Pishoy, we've talked a little bit about, all of you are researchers, you've all done some great research, about thinking about social media, sort of a research area. Again, since there's no gold standard about what's a great tweet, just thinking about it more of a discipline as we do any other area that we want to explore scientifically. What are your thoughts about, how do we figure out more, learn more about what makes a great tweet?

Dr. Pishoy Gouda:

Yeah. Evidence based tweeting is something that I've been interested in. Everything that we do, we want to make sure that we do it well and that we do it effectively and the same goes with social media posts. So what works, what raises interactions with our content. And that's something that other disciplines and advertising have been doing all the time and we should be doing the same as well. If our goal is to increase interactions with our content, then we want to make sure that we are doing it in the most evidence based way. And we've learned a few things. We know that cardiologists and individuals in medicine in general have been using Twitter much more frequently as a way to consume in both your medical and research content.

Dr. Pishoy Gouda:

So what makes a post great and what increases its interaction and the bottom line is we don't really know. We have a few studies and a few small randomized controlled trials that have been done that give us some insight. We know that vigor, that tweets that include images might pull readers to them a little bit more. But you know what exactly works. We have a lot of observational data, but we don't have a lot of high quality data that gives us the answer to this question. So what we've learned so far is use images, use links. If you can use graphical abstracts, that seems to help as well. But, it's something that we're continuously looking at and we're really excited to put together some new evidence coming up soon in the future.

Dr. Amit Khera:

Evidence based tweeting. I like it. As you and I have discussed, my predecessor Carolyn Fox had a randomized trail called Intention-to-Tweet using Circulation and then a follow-up study to that. So we hope to do also some good high quality research about social media and what works. Well, that gets to who's your audience, right? I always like to think about when you start something, who's your audience. And there could be lots of people. I think probably our strike zone is researchers, scientists, clinicians, of course, there's lots of lay individuals too, that are paying attention on social media. One thing that's different about Circulation than some other journals is this melding of basic science and clinical science. Some journals are all basic science and all clinical science and Circulation's both.

Dr. Amit Khera:

And I mean, frankly, that's posed an interesting challenge for this group. None of you are, including myself, are card carrying basic scientists, if you will. So we've had to translate those articles. And I would consider that both a challenge, but also an opportunity because, if we're speaking to a basic science audience, of course we may have one tone we use, but we want this basic science. I think that's the purpose of Circulation is basic science applicable to the clinician and clinical researchers. So, translating that's been a real opportunity. And Peta, maybe I can ask you about that opportunity of translating basic science for clinical researchers and clinicians.

Dr. Peder Langeland Myhre:

Yes. I completely agree. And I've learned so much from this job as a social media editor to really try to get the essence out of a basic science paper and the translational outlook for clinicians. Because all of the papers that are basic science that at least I came across in Circulation also have a clinical implication and a translational side of it. And I think when we read these papers and try to sum it up in one tweet, we want to keep the most important essentials of the basic science, but also extend it to clinicians so that they understand in what setting and what this can potentially mean in the future. So for me, that's the biggest challenge when we review basic science papers, but it's also perhaps the part of this job that I learn the most.

Dr. Amit Khera:

Yeah. I agree. I think we're all learning a lot. I've certainly learned a lot by delving in deeper into the basic science papers and figuring out how to translate them appropriately. And I think this really highlights, as you mentioned, what Dr. Hill our Editor in Chief, his feeling is basic science papers in Circulation all have to have important clinical implications. That's the benchmark, if you will. So I think we've seen that shew in terms of what papers have come across for you all.

Dr. Amit Khera:

Well, I'm looking now at our longest standing social media editor, Sonya Shaw, she started a few months before as sort of a transition because we certainly wanted someone in place that could help bridge between the old and the new. And Sonya, you've had a decent amount of experience now with two editorial teams. Tell us what you've learned so far by working as a social media editor at Circulation. What are some of the observations you've had and some of the things you've learned in this space?

Dr. Sonia Shah:

Yeah, certainly. So I think a couple things. I think my ability to accurately and concisely convey the important key points from each journal has definitely improved. But I think the other unique thing, unique perspective that we gain as social media editors is getting to actually see the behind the scenes workings of how the journal works and how papers are put together and accepted. And so I think it's been interesting to see how papers are being analyzed and the teamwork that's required by the Associate Editors and the Editors and making sure to do each paper justice and properly evaluate it. So I think that's been a really cool experience. It certainly has improved my ability to write when I try to think of, what are the key points I want to include. And how to convey information in a way that will be appealing to journals.

Dr. Amit Khera:

Well, thank you for that. We take this job very seriously, as you all have in that point about doing each paper justice, because you've seen, one, from the author's perspective about how much work they put in and you've been an author before and want to make sure that we appropriately appreciate that. And then also the Associate Editors, there are hours and hours of work for each paper. So even though it comes out, maybe in a few characters in a tweet, we appreciate all that's going behind it. And I'm glad you've gotten to see that process through. Ming, maybe I can come back to you. What have you learned so far by working in Circulation for the last few months?

Dr. Xiaoming (Ming) Jia:

I do want to echo what Sonya just said in terms of really getting a glimpse of the behind the scenes work is quite amazing. The amount of work and coordination it takes to get a paper from publication to promotion. And, we don't really get that exposure as a author for a manuscript or even as a peer reviewer. So, that part has definitely been a great learning experience. On the other side, I do find it interesting that ever since taking on this role as a social media editor, my way of writing has changed as well. So, trying to be more efficient, getting key points across and really being concise and focused in my manuscript writing. So that's been very helpful from a personal level as well.

Dr. Amit Khera:

We're very thankful for that. I think we always want this to be bidirectional where you all are contributing in meaningful ways. But that the goal here with fellows in training in this role, social media editors. But for you all to be learning something as well. So I'm glad that that has occurred. And we'll talk more about that in just a few minutes.

Dr. Amit Khera:

Well, we have a couple of international social media editors and this is my intention. We want to make sure we have a diverse group of social media editors. By background, by thought, by location. And, one way that the beauty of that is again, we get different perspectives. I guess the downside is time zones. We were just joking before, as we were starting this podcast about some of us are very early in the morning and one of our social media editors unfortunately is always late at night when we have our meetings. Peta, tell us a bit about unique observations from an international perspective. You said you've been following Circ for a while, but tell us, from your perspective in Europe, the social media process and how you see it.

Dr. Peder Langeland Myhre:

Thank you so much. And it's actually been a really transformation for me from before I spent my year in Boston to after. Because I really learned the potential of using social media and especially Twitter to stay updated and get the latest papers and thoughts from experts in the field. And I remember before I went there, I was often very frustrated that it was so inconvenient to get across important papers that was within my field of interest. Because all the journals were not longer sent in paper to our hospital and the websites were confusing.

Dr. Peder Langeland Myhre:

So when Dr. Vaduganathan at the Brigham & Women's Hospital introduced me to Twitter, that really was an eye opener for me. And, ever since that, 90% of the papers that I read I first see on Twitter. Because that's the first place, the people that are within my field, publish it or tweet it. And also I'm able to, you follow a certain amount of scientists and physicians and they have the same interest as you. So it's also, most of it is relevant for what I want to read. So it's really been a revolution for me to start to use Twitter and social media for medical and scientific purposes. And not only for friends and family.

Dr. Amit Khera:

Yeah. I think it's some great points. One, is even simplistically just be able to access articles, which we don't always appreciate, from people from around the world. And then obviously what many can, is follow people that have similar interests and amazing to see sort of how different people consume the literature. And for you Twitter being your entry point, I guess, for how you do that, which is I'm sure many, many people do the same. And we have another international editor you met earlier. Pishoy, tell us your perspective. And obviously you're in Canada now and have moved many places. What's your perspective from an international perspective, looking at social media?

Dr. Pishoy Gouda:

Coming to work at Circulation, I expected a very niche editorial board, but what I'm really finding out is boy, does it take a village. And it is people from all over the world. And it really hits home that collaboration and research has become a global phenomenon. And to be able to do art well and to appropriately represent researchers from across the world. We have an editorial board and team that is global and it really does take a village to take a paper from submission all the way through the publication team, starting from the authors to the peer reviewers, editors. But then the entire post-production team, which is behind the scenes and don't get a lot of glory, but they do a lot of the heavy lifting to make sure that, the research that's submitted gets in front of readers. And that's something that I hadn't really thought of before. And it's been really interesting to see how that process unfolds. So that's definitely been eye opening for me.

Dr. Amit Khera:

Well, I appreciate what you said about, when it takes a village and I would be remiss if I don't always call out Augie Rivera, who is the engine and mastermind behind Circulation, who's helping us do this podcast today and every week. But the other part is the international workings I think many may not appreciate. We have editorial board meetings every other week at very different time zones on purpose because we have people in Europe and in Asia and in Africa. And as you know, Dr. Lam who's the main podcast editor is in Singapore.

Dr. Amit Khera:

So, this is by intention. It really gives us a wonderful international perspective. And so we're so glad to have you two as part of our international team. Well, I think that's a great transition, a little bit to just talking about fellows in training and involvement in journals for Circulation perspective, and from the AHA, I should say, getting fellows in training involved in cardiovascular research, the editorial process, this is something that's really important to us and something we continually strive to find new ways to do. So, Vanessa, I'm going to come back to you. I know, not just at Circulation, but I know at other journals you've had some responsibilities. Tell us a little bit of what you tell other fellows in training about getting involved in journal activities. How to, and what's the benefit.

Dr. Vanessa Blumer:

Thank you so much Dr. Khera. I think this is such an important question. First my recommendation is, get involved in one way or another. I think there's different ways of getting involved as simple as just start reviewing articles. And the reason I say this is as I aspire to become an academic, a well-rounded academic cardiologist, I think my involvement with journals has just made me a much better researcher, a much better academic cardiologist. It's made me, I think, Sonya said this so well, it's made her a better author. It's made me a better writer. So I think it compliments what you do just so much better. I think you're better at what you do when you see the behind the scenes and you understand what happens in scholarly publishing. So I think there's different ways of getting involved. I know that Circulation has many and then probably a good way is to reach out.

Dr. Vanessa Blumer:

I know that people can reach out to us and we can probably guide them along the way, but different journals have different ways of getting involved. But I think if you want to start, one way is start reviewing. You learn a lot through the review process in itself on how an article is structured. And there's some journal that have a little bit more of a mentorship approach towards reviewing. And, that's also a good way starting out. When we start off as residents, we get some papers get in our inbox to review and we really don't necessarily know how to approach it. So maybe a mentorship approach to it is a good way to start. But overall, I would just say, start getting involved. I think it's a great experience. Personally, I have learned so much from it and I think I'm just a better academic cardiologist because of it.

Dr. Amit Khera:

Thank you for that. And I think your point about just find ways to get involved. And I think our challenge is to continue to facilitate ways for trainees, fellows in training and others to get involved. But I think that that first step in finding maybe a mentor of your institution that could help guide you would be important. And I'm going to finish with Sonya. I'm going to come back to you. You've not only had the social media editor window for quite some time. Being at Circulation, you get to see behind the curtain perhaps more than others because, Circulation is such a big part of what we do at UT Southwestern. And, we've had this Fellow Reviewer Program where you've been able to participate in reviews and things like that. From your perspective, maybe telling the fellows in training, listening out there about getting involved in journal activities, the value that you've seen and how to do so.

Dr. Sonia Shah:

Yeah, I think that's a really important question. At the end of the day, the ability to read and interpret and take away the major conclusions and properly interpret a study is a skill. And so I think the more you do it, certainly the better you get at it. And being part of a journal being on the reviewer end, being on the end where you're creating social media posts is really an opportunity to develop and refine that skill. And so to all the fellows out there who are interested, regardless of whether you want to do academic cardiology or not, it is an important skill, even in the future, to be able to read and properly interpret studies. So I highly recommend it. I find for me, I've definitely learned a lot through the process and have certainly improved.

Dr. Amit Khera:

Well, there you have it, our five social media editors. First, I want to thank you all for your contributions to Circulation. You're an incredibly bright group as everyone learned about. I have future leaders in cardiology. And we're very fortunate to have you contributing to Circulation and to our authors and readers. So thankful to have you as part of Circulation and look forward to working with you and innovating and coming up with some creative, new ways to think about social media and ways to transmit research for journal.

Dr. Amit Khera:

Well, I think there you have it. Again, I'm Amit Khera. I'm associate editor and standing in this week for Carolyn Lam and Greg Huntley, who will join you again next week. So thank you for joining us for Circulation on the Run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more visit ahajournals.org.

Please join Guest Host and Associate Editor Mercedes Carnethon and author Christine Albert as they discuss the article "Effect of Long-Term Marine ω-3 Fatty Acids Supplementation on the Risk of Atrial Fibrillation in Randomized Controlled Trials of Cardiovascular Outcomes: A Systematic Review and Meta-Analysis."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. We are your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, today's feature paper is such an important question clinically. It's something I've asked myself and so I cannot wait to discuss it in greater detail. It refers to the effect of long-term marine omega-3 fatty acid supplementation, and the risk of atrial fibrillation in randomized controlled trials of cardiovascular outcomes. So it talks about a systematic review and meta-analysis published in this week's issue.

Dr. Carolyn Lam:

All right. Okay. You got to wait in suspense, as do I, and let's discuss other papers, very important papers in today's issue too. I'd like to start with a bit of a quiz. So Greg, for converting atrial fibrillation, is the anterior-lateral or anterior posterior electrode position better? What's your guess?

Dr. Greg Hundley:

Oh, wow, Carolyn. That's interesting. We put these pads on and we kind of just follow the directions on whatever the particular device says. Interesting question. It's a guess, Carolyn, it's a guess. Antro-lateral?

Dr. Carolyn Lam:

Smarty pants. Well, let's see. Frankly I didn't know the answer. It's just such an elegant question, isn't it? To answer in a study. And this is exactly what Professor Løfgren from Randers University Hospital and Denmark and colleagues did. They performed a multi-center investigator initiated open label trial, where they randomly assigned 468 patients with atrial fibrillation scheduled for elective cardioversion to anterior-lateral versus anterior-posterior electrode position.

Dr. Carolyn Lam:

The primary outcome was the proportion of patients in sinus rhythm after the first shock. And so drum roll. The primary outcome occurred in 54% assigned to an anterior-lateral electrode position. And in 33% assigned to an anterior-posterior electrode position, a significant risk difference of 22% in favor of the anterior-lateral electrode position.

Dr. Carolyn Lam:

Cheers, Greg. There were no significant differences between groups in any safety outcomes and the superiority of the anterior-lateral electrode position was statistically significant both after the initial low energy shock and after a final high energy shock. So this study really suggests a practice change in the standard approach to electrode positioning for cardioversion in favor of anterior-lateral electrode position.

Dr. Greg Hundley:

Very nice, Carolyn. Very nice. Well, I'm going to come at you using your heart failure expertise and ask you a quiz here in just a second. But first I want to introduce this paper from Dr. Javier Barallobre-Barreiro from King's College London. Okay, Carolyn, here's your quiz. Do you think that the extracellular matrix fibrosis contributes to LV dysfunction in heart failure patients?

Dr. Carolyn Lam:

Absolutely.

Dr. Greg Hundley:

Very nice. I think, of course, you are correct. So Carolyn, remodeling of the extracellular matrix is a hallmark of heart failure and this team's previous analysis of the secretome of mirroring cardiac fibroblast returned ADAMTS5, a disintegrin and metalloproteinase with thrombospondin motifs 5 as one of the most abundant proteases. So ADAMTS5 cleaves chondroitin sulfate proteoglycans such as Versican. The contribution of ADAMTS5 and its substrate Versican to heart failure is unknown.

Dr. Carolyn Lam:

Ah, so what did the authors find, Greg?

Dr. Greg Hundley:

Well, first Carolyn, there was a methodologic advance here. Left ventricular tissues from 86 heart failure patients and non-failing controls were analyzed by quantitative mass spectrometry, constituting the largest proteomics analysis on human heart failure today. And so what did they find? Accumulation of proteoglycan Versican was regulated by ADAMTS5, that disintegrin and metalloproteinase with thrombospondin motifs 5, and was associated with the reduction in proteins involved in intercellular communication. And Carolyn, interestingly, proteoglycan accumulation in ischemic heart failure was attenuated by beta blocker administration.

Dr. Carolyn Lam:

Oh, that's very interesting. Could you put that all together for us? What's the clinical implications, Greg?

Dr. Greg Hundley:

You bet, Carolyn. So proteoglycan secretion by cardiac fibroblast constitutes an important component of cardiac fibrosis after ischemic heart failure, just like you stated at the beginning with your quiz answer. This contributes to impaired cardiac function and besides their negative chronotropic and inotropic effects, beta blockers may modulate extracellular matrix remodeling.

Dr. Carolyn Lam:

Wow, nice, Greg, thank you for that. I've got another original paper and it deals with the very important topic of endothelial to mesenchymal transition. Now it has been reported that cardiac endothelial cells contribute to a substantial proportion of myofibroblast through this process called endothelial to mesenchymal transition. Lineage tracing studies have demonstrated that myofibroblasts are derived from expansion of resident fibroblasts rather than from transdifferentiation from endothelial cells.

Dr. Carolyn Lam:

However, it remains unknown whether endothelial cells can transdifferentiate into myofibroblast reversibly or would these endothelial to mesenchymal transition genes just transiently activated in endothelial cells during cardiac fibrosis? So these authors, corresponding authors, Dr. Sun from Shanghai Jiao Tong University School of Medicine, Dr. Lui from Price of Wales Hospital and Chinese University of Hong Kong, as well as Dr. Zhou from the University of Chinese Academy of Sciences in Shanghai and their colleagues.

Dr. Carolyn Lam:

What they did is they used the dual recombination technology to generate a genetic lineage tracing system for tracking endothelial to mesenchymal transition in cardiac endothelial cells and their genetic fate mapping results basically showed that although mesenchymal gene expression was activated in cardiac endothelial cells throughout the endothelial to mesenchymal transition in the developing heart, the endothelial cells do not transdifferentiate into myofibroblasts, nor do they transiently express some known mesenchymal genes during homeostasis or fibrosis in the adult heart. Resident fibroblasts that are converted to myofibroblast by activating mesenchymal gene expressions are in fact the major contributors to cardiac fibrosis.

Dr. Greg Hundley:

Ah, Carolyn, very interesting. So can you put this together? What are the clinical implications?

Dr. Carolyn Lam:

So what it really says is that it's the resident fibroblasts that are converted to myofibroblast by activating mesenchymal genes. These are the ones that represent a major therapeutic target and really unraveling these mechanisms, driving endothelial to mesenchymal transition in such a detailed way, provided new insights into therapeutic development to target cardiac fibrosis.

Dr. Greg Hundley:

Wow, Carolyn. You know, two really good preclinical science articles speaking to us about myocardial fibrosis.

Dr. Carolyn Lam:

Well, there are other papers in today's issue too. There's a Perspective piece by Dr. Christopher Lamb on “Liver Cirrhosis and Hepatocellular Carcinoma After the Fontan Operation: Reaching Clarity in the Face of Uncertainty. And this is paired with a Research Letter by Dr. Toshio Nakanishi on incidents and expected probability of liver cirrhosis and hepatocellular carcinoma after the Fontan operation.

Dr. Greg Hundley:

Very nice, Carolyn, and I've got an “In the News” piece from Bridget Kuehn entitled “Centering Equity in Cardiovascular Care as Michelle Albert Lays Out a Roadmap for our Profession.” Well, Carolyn, how about we learn a little more about those long term marine omega-3 fatty acid supplementations and the risk of atrial fibrillation?

Dr. Christine Albert:

Oh, I can't wait. Let's go, Greg.

Dr. Mercedes Carnethon:

Thank you so much for joining us for today's episode of Circulation on the Run. My Lame is Mercedes Carnethon, Professor and Vice Chair of Preventive Medicine at the Northwestern University Feinberg School of Medicine and Associate Editor at Circulation. And I have the great pleasure today of having a conversation with a long time friend, Dr. Christine Albert from the Department of Cardiology at the Smidt Heart Institute at Cedars-Sinai Medical Center in Los Angeles.

Dr. Mercedes Carnethon:

And today I've got the great pleasure of hearing directly from Christine about a wonderful original research piece that is being featured in Circulation about the effect of long term marine omega-3 fatty acid supplementation on the risk of atrial fibrillation in randomized controlled trials of cardiovascular outcomes. And the exciting innovation of this piece that we'll dig into is what we're learning from the systematic review and meta-analysis that Dr. Albert and her team carried out. So, thank you so much for joining us today, Christine.

Dr. Christine Albert:

Well, thank you, Mercedes. It's really great to be here.

Dr. Mercedes Carnethon:

Great. Well, I'd just like to launch with you telling us a little bit about the study, what you found, why you decided to conduct this meta-analysis and review.

Dr. Christine Albert:

Yeah. Great. So my first author, Dr. Baris Gencer and I decided to do this because we actually had participated in a randomized trial called the Vital Rhythm Trial, where we actually randomized people to omega-3 fatty acids and atrial fibrillation, and found a slightly elevated risk, but it wasn't significant. And at that time, a number of other articles came out saying that there really was an increased risk of atrial fibrillation.

Dr. Christine Albert:

So we wanted to put together the data to see what the combined data, our data, that's been published before, on this sort of long term treatment with omega-3 fatty acids and atrial fibrillation. As you may know, there have been studies that have looked at short term treatment, and specifically for atrial fibrillation, and did not find benefit. So this is why we went ahead and did this study. And what we did is we were able to find seven randomized trials that collected data on atrial fibrillation that had randomized people to omega-3 fatty acids over an average of about five years of follow up between all the different trials. And we found that when you combine all these trials together, you actually see that there is a slightly elevated risk of atrial fibrillation in the participants that were randomized to the omega-3 fatty acids.

Dr. Mercedes Carnethon:

Thank you so much for that summary, Christine. I think the findings themselves surprised me. This is not my primary area of work, but we hear so much about supplements and their benefits that I thought it was really telling to actually have these data coming from a large number of studies, and particularly large studies that suggest that there is a risk to benefit ratio that we need to consider. How would you recommend that clinicians weigh this evidence that you've generated today?

Dr. Christine Albert:

So I think that it's got to be individualized. There are benefit, as you said, of these omega-3 fatty acids. And I think it's just awareness, awareness that this potentially is a risk. If you have a patient on omega-3 fatty acids and they start to have atrial fibrillation, there could be a link. Also when you talk about it with patients, I think it's reasonable, especially with the higher doses, we can just discuss that this is a potential side effect. Does it prevent you from using it? I don't think so. I think you have to look at what is, again, as you said, the risk benefit ratio for the individual patient. And as I alluded to, we did do a dose analysis and we found that the risk was primarily seen, and it was higher, in those that were given more than a gram of omega-3 fatty acid a day.

Dr. Christine Albert:

However, I will say that the trials are very different when you take a meta-analysis, it's really hard to say, "What is the cause of the differences between trials?" You know, these trials that had the higher dose, the reduce it trial that used just a purified EPA was very different than the dose of the medication that was used in vital, different than the type of medication that was used in strength. And as you know, there's the whole debate about the placebo and reduce it versus strength. And so there are other differences, but one thing that is pretty consistent is that most of the point estimates are on the side of harm. So there is the thought that I think this is potentially very real and we should be considering it when we use these supplements.

Dr. Mercedes Carnethon:

You know, that's a really nice summary which really launches me into two subsequent questions. The first would give you the opportunity to speculate beyond the findings in your particular study, and this is one of the benefits to me of this Circ on the Run podcast, because you, of course, produced excellent science and weighed all of your findings based on what you found. But can you tell me, based on your experience, could you speculate about what you think the mechanism of elevated risk of atrial fibrillation is, particularly with those higher doses?

Dr. Christine Albert:

Yeah, no, it's interesting. You know, if you look at the epidemiology for this, Mercedes, it was totally inconsistent. When I postulated doing the vital rhythm trial, I actually have to be honest with you, I thought that there might be an increased risk, because when you look at some of the data of what these omega-3 fatty acids do, they increase vegal tone, they lower heart rate. They can actually slow conduction. So potentially those electrophysiologic actions might, might allow atrial fibrillation to emerge in people who are susceptible.

Dr. Christine Albert:

On the flip side, all of those things might be good for ventricular arrhythmias. So you see, if you look at the literature, there's benefits for…sudden death and epidemiologic studies and in some of the randomized trials, but then when you look at atrial fibrillation, at least the short terms, really didn't show a benefit. And again, that point estimate was more towards harm.

Dr. Christine Albert:

And then when you look at epidemiologic studies, looking at fish consumption, there's actually a lot of studies that suggest that people who eat more fish get more AFib. So it is really paradoxical. And we know as electrophysiologist that atrial arrhythmias and ventricular arrhythmias are not the same, we give drugs to prevent atrial arrhythmias that then cause ventricular arrhythmias. So it is interesting. And I think it's something that hopefully some of our translational scientists will help us to figure out.

Dr. Mercedes Carnethon:

All those contradictions are so challenging, but you were certainly speaking my language in describing the hypothesized mechanisms. It calls to mind, back in the day, in your early research on sudden cardiac death that I was citing as part of my dissertation work in epidemiology. So thank you for that.

Dr. Christine Albert:

Yeah.

Dr. Mercedes Carnethon:

You know, the second question that builds off of that is I thought that the figure where you display the heterogeneity by the dosage of omega-3's really underscores the argument that you were just presenting. What I was wondering is, did you happen to study heterogeneity by any other characteristics, particularly sex or age?

Dr. Christine Albert:

That would be fantastic to be able to do, unfortunately, because it's a summary level meta-analysis, we really can't do that. And that's one of the things that we'd love to do in collaboration with some of these authors if they would like to do that, is to really get that sort of paid participant level data, so we could do those kinds of analysis.

Dr. Christine Albert:

But what we did do is sort of separate out studies that had like confirmed AF, studies that had incident AF versus recurrent AF, so things where the studies were completely different, we were able to look for heterogeneity and we didn't find anything that suggested that there was heterogeneity on that basis. But there's a number of things that I would love to look at and age is definitely one of them, and also sex. And actually looking at, which would be really interesting, is to look at the omega-3 or EPA and DHA levels in these individuals. And again, I think each study has sort of tried to do it on their own and you can't because there's just not enough data. So putting all this data together would be great to have a better understanding of what's going on.

Dr. Mercedes Carnethon:

Oh, it sounds speaks to a number really thoughtful future directions for this work. One of the benefits of me being able to speak with you today in my role as a guest podcast host, but I was also the Associate Editor for the piece and was really excited when it came in. The discussions that we had amongst the editors about this were really very stimulating and raised a number of questions that led to you responding and making some modifications and explaining certain things. Could you tell our audience, why did you select trials over a certain size? You know, quite often we do meta-analyses in order to pull together smaller studies, but why did you choose larger studies?

Dr. Christine Albert:

I think it was so that, there were two criterias, one was larger and one was long term, because we felt that the smaller studies had been merged together previously and we wanted to have at least some data on atrial fibrillation. One of the problems I think that I think I want to emphasize a little bit here about research in general in cardiovascular disease is that until now, most studies hadn't really measured atrial fibrillation, and I think it's really important. And I think you can see, you can find off target effects of some of the agents that we use for cardiovascular disease on atrial fibrillation. So for instance, the Statin Trials, everybody said, "Oh, well statins might lower atrial fibrillation," but then nobody measured atrial fibrillation, so we never knew. And then people went back and tried to measure it as a side effect or something that has all kinds of biases to it.

Dr. Christine Albert:

So I think that what is exciting about this work is that both reduce it and strength and vital, pre-specified that they were going to look at atrial fibrillation. And so if we do that, we may actually find other agents that are beneficial, not just harm, but beneficial, like the SGLT2 inhibitors, there's lots of hypotheses. So the reason that we did pick the bigger trials was that we wanted to find trials that really kind of looked at atrial fibrillation, had enough power to look at atrial fibrillation and then over a long term, a follow up to gather enough events.

Dr. Mercedes Carnethon:

Again, it has been such a pleasure to hear directly from you. I really hope that our listeners today and our readers of The Journal will dig into this in the same way that we have as editors and really appreciate the thoughtfulness with which you've presented this outstanding work. So I want to thank you so much, Dr. Albert for joining us today.

Dr. Christine Albert:

Thank you for having me.

Dr. Mercedes Carnethon:

I guess I will sign off now. This is Mercedes Carnethon from the Northwestern University Feinberg School of Medicine and Associate Editor for Circulation.

Disclaimer:

This program is copyright of the American Heart association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American heart Association. For more, visit ahajournals.org.

Please join Guest Host Mercedes Carnethon, author Jason Roberts, and Associate Editor Vlad Zaha as they discuss the article "Epigenetic Age and the Risk of Incident Atrial Fibrillation."

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-host, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center in Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature we're going to learn more about the risk of incident atrial fibrillation, but as that pertains to epigenetics. But before we get to that feature, how about we grab a cup of coffee and get started on some of the other articles in the issue. Would you like to go first?

Dr. Carolyn Lam:

I would love to. And the first paper I want to highlight asks the question, are social economic variables associated with 30 day survival after out of hospital cardiac arrest. And this comes from Dr. Jonsson from Karolinska Institute in Stockholm, Sweden, and colleagues. They linked data from the Swedish Registry of Cardiopulmonary Resuscitation with individual level data on social economic factors. In other words, educational level and disposable income, all from statistics, Sweden. And what they found was that both higher disposable income and higher educational level independently associated with better 30 day survival following out of hospital cardiac arrest. The relationship between disposable income and 30 day survival was more robust for mediating factors compared to educational level.

Dr. Greg Hundley:

Oh, wow Carolyn. Really interesting in a very, what I would call hot topic these days. So what are the clinical implications of this particular study?

Dr. Carolyn Lam:

Well, the results really highlight the importance of preventive efforts aimed at patients with lower social economic status. And these preventive actions could include both early recognition and warning signs and for example, CPR and AED training. So very lovely paper there.

Dr. Greg Hundley:

Absolutely. Very nice Carolyn. Well, my first paper comes to us from Dr. Nan Wang from Columbia University Medical Center. And Carolyn this paper focuses on a common genetic variant called link RS 3184504, and it is associated with increased platelet and neutrophil counts, coronary artery disease, thrombotic stroke, and autoimmune diseases. And so this research group previously has shown that hematopoietic link deficiency synergizes with hyperlipidemia to promote platelet production and activation, neutrophilia, platelet neutrophil aggregates, atherosclerosis and arterial thrombosis, all of those things. So platelet activation and platelet neutrophil interactions have been shown to promote neutrophil extracellular traps or net formations. So nets are formed when neutrophils release their contents leading to the formation web-like structures made of DNA, myeloperoxidase, citrullinated histone and proteases that entrap and kill bacteria. Now, while nets may help to suppress infection, the formation of nets called NETosis in blood vessels can promote atherosclerosis and thrombosis. And so this study was undertaken to investigate the hypothesis that linked deficiency might promote NETosis leading to formation of unstable atherosclerotic plaques, and arterial thrombosis.

Dr. Carolyn Lam:

Wow. What a really neat hypothesis and NETosis. I learn new things all the time. So what do they find?

Dr. Greg Hundley:

Right Carolyn. First of all, hypercholesterolemic mice with hematopoietic link deficiency displayed accelerated arterial thrombosis with nets in thrombi and these changes were reversed by PAD4 deficiency or OxPL antibodies. Second, linked deficient platelet from hyperlipidemic mice expose and release increased OxPL when activated promoting NETosis, when incubated with link deficient neutrophils. Third, an AntiOxPL antibody reduced OxPL levels, NETosis and arterial thrombosis specifically in link deficient mice, and finally Carolyn targeting atherothrombotic risk using OxPL antibodies might be particularly effective in genetically defined populations with reduced link function or increased JAK-STAT signaling.

Dr. Carolyn Lam:

Wow. Okay. So they proved their hypothesis. Could you sum it up for us, Greg?

Dr. Greg Hundley:

You bet Carolyn. So this foundational work suggests that perhaps future studies targeting NETosis and OxPL in patients carrying the common link loss of function variant, could reduce atherothrombotic risk.

Dr. Carolyn Lam:

Wow. Thanks, Greg. My next paper is super interesting in its approach. Listen up. Now the assessment of the relationship between myocardial ATP production and cardiac workload. We know is important for better understand disease development and choice of nutritional or pharmacological treatment strategies. So what Dr. Berndt from Charity University and colleagues did, was they developed a comprehensive physiology based mathematical model of cardiac energy metabolism. And this model is called cardiokine one. And what it does is it recapitulates numerous experimental findings on cardiac metabolism obtained with isolated cardiomyocytes, perfused animal hearts and in vivo studies with humans. The model encompassed all pathways along, which the possible energy delivering substrates like glucose, long chain fatty acids, keto bodies, acetate, branch chain, amino acids are utilized.

Dr. Carolyn Lam:

They use the proteomic space, the abundance of metabolic enzymes and cardiac tissue to generate individualized metabolic models of cardiac energy metabolism. And so to prove their case, they further applied this approach to the left ventricles of controls in patients with mitral insufficiency and aortic stenosis, and showed that despite overall preserved systolic function, the ATP producing capacity of these left ventricles of patients with valvular dysfunction was generally diminished and correlated positively with mechanical energy demand and cardiac output.

Dr. Greg Hundley:

So Carolyn really interesting findings. Sort of linking metabolism them with ventricular dysfunction in those with valvular heart disease. So what were the clinical implications here? What's the take home?

Dr. Carolyn Lam:

Well, this methodology is just awesome, but what they also found I think is a very important physiological principle. And that is, while metabolic capacity have a significant correlation with biomechanical properties like myocardial power and cardiac output, they can also vary considerably between individual patients and therefore help us to understand in future perhaps why some patients develop heart failure over time while others with similar hemodynamic conditions do not. So just interesting. I think it just opens the space to a lot more.

Dr. Greg Hundley:

Absolutely beautiful summary there Carolyn. Well, in the rest of the mailbag for this issue, we have an exchange of letters between Professors Hu and Trifon on the previously published paper, entitled “Short Term Treatment with Aspirin plus Clopidogrel Compared to Monotherapy of Aspirin May Not Significantly Decrease the Risk of Stroke Recurrence.” Also, there's a Research Letter from Professor Catalucci entitled, “Nano miR-133A Replacement Therapy, Blunts Pressure Overloaded Induced Heart Failure.” And then finally Carolyn, there's an In-Depth article from Professor Aengevaeren entitled, “Exercise-Induced Cardiac Troponin Elevations From Underlying Mechanisms to Clinical Science.” Well Carolyn, how about we get onto that feature discussion and learn more about incident atrial fibrillation and the age of epigenetics.

Dr. Carolyn Lam:

Let's go.

Dr. Mercedes Carnethon:

Welcome to this episode of Circulation on the Run, where we're going to have a very exciting discussion about a paper on epigenetic age and the risk of incident atrial fibrillation. We're extremely excited to have the lead author here with us, Dr. Jason Roberts from the Population Health Research Institute, McMaster University and Hamilton Health Sciences in Ontario Canada. And I am really excited to host this episode alongside the handling editor. My name is Mercedes Carnethon and I'm the professor and vice chair of Preventive Medicine at the Northwestern University School of Medicine. And I'm pleased to be hosting this with Dr. Vlad Zaha from UT Southwestern Medical School, who was the associate editor who handled the piece. So I'm really excited to jump right into this because I think there's a lot that we can all learn from this. So welcome Jason, and thank you so much, Vlad.

Dr. Jason Roberts:

Thank you so much for having me, it's a delight to be here.

Dr. Mercedes Carnethon:

So Jason, tell us a little bit about the rationale for this study, what you found and what it means.

Dr. Jason Roberts:

Absolutely. So as a cardiac arrhythmia specialist, I see a lot of patients with atrial fibrillation. And in 2021, our understanding of its underlying pathophysiology still remains modest. Our treatment strategies for the condition are also somewhat modest, although catheter ablation and antiarrhythmic drugs can potentially be very effective. In the context of these limitations, they're also exacerbated to some extent by the prevalence of atrial fibrillation, increasing dramatically in developed countries. Part of this is related to the obesity epidemic. Things like hypertension increasing becoming more common, but because atrial fibrillation is age dependent and because of our aging populations in developed countries, this is felt to have a major contribution to the growing prevalence of atrial fibrillation. Unlike obesity and hypertension and other risk factors, which are potentially modifiable, chronological aging is viewed as non-modifiable. It's not something that we can tackle. That said, we know within the population and just from personal experience that people age at different rates. There are some people that are 65 who behave more like they're 50, other people that are 50 who behave more like they're 65.

Dr. Jason Roberts:

And in that context, biological aging, we wondered whether or not, does biological aging independent of chronological aging potentially impacts the risk of atrial fibrillation. If that was the case, because there are gradually accumulating to suggest that biological aging is potentially modifiable, that could potentially open up the possibility of tackling aging as a respective for atrial fibrillation. So that drove us to ask this question. In terms of what we found in the approach that we used. So we used our biological marker of aging, was something called an epigenetic clock. So it's been found that modifications to DNA, specifically methylation at CpG at dinucleotides, they correlate with aging. This has been appreciated for a few decades. It was initially felt that with aging, methylation levels gradually reduced over time. But with more careful interrogation, it's shown that there's patterns. Some methylation areas increase, other methylation areas there's decreases.

Dr. Jason Roberts:

And Steve Horvath, who is a scientist at UCLA has found that using mathematical algorithms, you're able to very accurately ascertain chronological age based on the patterns of DNA methylation, he's called these things epigenetic o'clock. That said, even though they very accurately ascertain chronological age, they aren't perfect in each individual in terms of matching up to their chronological age, but that's actually turned out to be a good thing. So when people, their epigenetic age is older than their chronological age, they're said to have positive epigenetic age acceleration. They may be biologically older than their actual chronological age. And then the reverse also holds. So using this concept of epigenetic age acceleration, we ask whether or not do people that are older biologically on the basis of their epigenetic age, do they have an increased risk of atrial fibrillation? And then we tackle that using a few different core works that I'm certainly happy to elaborate on in terms of what we found.

Dr. Jason Roberts:

So we used three population based cohorts from the United States, the well known Framingham Heart Study, the Cardiovascular Health Study and Eric as well. There were approximately just under 6,000 people from those studies that had undergone genome wide methylation analysis that in the enabled us to calculate their epigenetic ages. The follow period for these people was just under 13 years. And then we look to see whether or not these epigenetic clocks associated with instant atrial fibrillation. In these cohorts, we look at five different clocks. So there's the Horvath Clock and the Hannum clock that were designed to predict chronological aging. The more recent clocks, things like DNAm PhenoAge and DNAm GrimAge are more designed to predict aspects of clinical phenotype and also mortality. We found that in unadjusted analyses, all of these clocks were associated with atrial fibrillation. When we then adjusted for multiple different clinical variables, we found that the DNAm PhenoAge clock and the DNAm GrimAge clock continued to exhibit statistically significant associations with atrial fibrillation.

Dr. Jason Roberts:

Interestingly, the multi-variable adjustment, one concern is, do these clinical factors, are they confounders where we should be adjusting, or are they potentially mediators. If we adjust for mediators that potentially masks the effect of the clock. But regardless of how we treat them both DNAm PhenoAge and DNAm GrimAge, we're associated with increased risks of incident atrial fibrillation. Alluding to the possibility that biological aging independent of chronological aging is important in terms of determining risk for atrial fibrillation. And it may be that if we're able to modify biological aging, we could potentially reduce the risk of atrial fibrillation. So that's the study in a nutshell.

Dr. Mercedes Carnethon:

No, that is really exciting. You said something early on about chronological age being immutable. And I would have to say, both Vlad and I are not aging. And in fact, we are going in the opposite direction. If only this were not just an audio podcast, you would see that I steadily gotten younger and younger and I'm suddenly about 25 now. But no, these are really important findings. I really like the innovation of using multiple different strategies to characterize epigenetic age and genetic aging. So tell me Vlad, I want to turn to you. When this came across your desk, what excited you about this particular piece and why did you think that it would be of great interest to our readership?

Dr. Vlad Zaha:

Good morning Merci and Jason. This is a great question. And as in associate editor at Circulation for the bridging discipline section, it was fascinating to see this topic coming on my desk, thinking about all the genome wide association studies in nature of fibrillation and predisposition to atrial fibrillation, that in that case would not be changed by interventions because of different loci that would be determined. This was coming as a completely new perspective that was opening some new potentials. And it was very interesting to see some of the findings.

Dr. Mercedes Carnethon:

Certainly. So Jason, I have a question. So what surprised you about the findings of this particular study?

Jason Roberts:

Yeah, that's a great question. So we had hoped that biological aging would be associated with atrial fibrillation. I think the concept of being able to tackle biological aging is exciting. In terms of what surprised us, I guess we were hoping for these results, I guess.

Dr. Mercedes Carnethon:

Yeah.

Dr. Jason Roberts:

But we were…Yeah. So I guess we were pleasantly surprised that our hypothesis was born out. It's important to note that the epigenetic clocks don't tell the full story with chronological aging. So after we insert the clock into the model, chronological age continues to remain associated with instant atrial fibrillation. So this measure biological aging is just part of the story. So I think that's very important. I had wondered whether or not inserting the epigenetic clocks would that potentially eliminate the subsequent association of chronological aging. So that finding suggests it's part of the story.

Dr. Jason Roberts:

I think that in terms of the overall concept, the idea of this being reversible really excites me. In terms of the approach of how to reverse biological aging. Right now healthy lifestyle seems to be very important. I think it provides more evidence to suggest to patients with atrial fibrillation, living healthy from a diet perspective, from exercise, keeping your weight under control, all of these things that seem to impact epigenetic aging and biological aging can be helpful for preventing atrial fibrillation. So I think that can help reinforce this message to our patients.

Dr. Jason Roberts:

I think ultimately in terms of where we'll be at in 15 to 20 years, it's possible that new therapies in the future are developed that are able to more powerfully address biological aging. As you alluded to, will it be possible to reverse biological aging as you and Vlad are experiencing that?

Dr. Mercedes Carnethon:

Most definitely. Yes.

Dr. Jason Roberts:

I think it may be possible. This is an intense area of investigation that's being pursued and it's still in its relative infancy. But I think that could it be small molecules? Could it be potentially gene editing that can help adjust biological aging and not only increase lifespan, but also health span? I think those concepts are really exciting.

Dr. Mercedes Carnethon:

I completely agree. There's a lot of richness in this paper and I think our readership is going to really enjoy digging in. Part of the richness is the use of three different cohorts and the use of multiple measures of epigenetic age. And I think you provided a really nice description of the unique information that each of these markers of epigenetic age provide. One thing I note are differences in the strength of association across the different measures of epigenetic age, which I think makes sense, because you said they characterize different aspects of the phenomenon, but I also see what looks like some variability across the cohorts with Framingham in particular seeming to stand out. And that being the only cohort that is 100% one race. It's white. Versus both the cardiovascular health study and the Eric study, which have more diverse study populations. I'm wondering what your hypothesis is about the differential strength of association that it seems Framingham is demonstrating and what you think is possibly the source of those differences.

Dr. Jason Roberts:

Yeah. I think those are great questions for all of genetics. The question is, does it apply to all races? For example, polygenic risk scores. It seems like when a polygenic risk scores develop for one race, it may not perfectly translate over to other races. So how relevant is that for epigenetic age acceleration. In this study, I think it's difficult to make definitive conclusions about it. We needed the three cohorts to have adequate statistical power in terms of being able to determine a differential effect of race. I think it would really be primarily hypothesis generating. We weren't really powered to look at the different races. So it's difficult for me to comment.

Dr. Jason Roberts:

I think ultimately and I want to believe anyways, that epigenetic age acceleration is relevant to all races, but in terms of, was it race that drove the differential impacts that we saw to some extent in terms of the magnitude of the hazard ratios, it's difficult to know in terms of tests for interaction and were these actually truly statistically different. We weren't adequately powered to address that hypothesis. So it's difficult for me to comment in a definitive matter I'd say. And sorry to cop out on…

Dr. Mercedes Carnethon:

No, not at all. I mean, I think there are a lot of things where there is no firm answer and that was just one of my hypotheses when I saw what was going on differently across the cohorts. I think that's a perfectly reasonable answer that sets us on a course for thinking about how we set up future studies. So I wanted to turn to you Vlad for the closing frame around this. As the editor, how do you hope that our readership will use these findings?

Dr. Vlad Zaha:

That is an excellent question. I was going to follow on this excellent unpacking of the core messages of the manuscript by Jason here to get his perspective as an electrophysiologist into what these type of work may represent for the everyday life of an electrophysiologist in the connecting with the patients and how would this type of approach influence, and maybe now, maybe later when our treatment for atrial fibrillation.

Dr. Jason Roberts:

Yeah. So that's a great question. I think, as I alluded to some extent before, as far as reinforcing healthy lifestyle, I think this provides more evidence in that respect. So we know that things like excessive alcohol consumption, being excessively obese, poor diets, not engaging in enough exercise, all of those things seem to accelerate your epigenetic age. And those are all things that we think or feel that are important with atrial fibrillation in terms of driving the path of physiology and people progressing. So I think this gives more data to us to reinforce the patients that in addition to the treatments that we're offering in terms of catheter ablation and antiarrhythmic drugs, the concern is that the substrate can continue you to progress. And that's likely driven by to some extent these modifiable risk factors. So keeping all of these under best control as possible, and hence trying to slow your biological aging as much as possible.

Dr. Jason Roberts:

I think that this will provide us more motivation to push these messages to our patients. A lot of patients can sometimes be like, "Let's just get on with a catheter ablation and I want to get on with my life…" but it really I think, provides more data to suggest that modifying these very important risk factors that can lead to accelerated biological agents, is very important. And in terms of the future as mentioned, so chronological aging, as people get older, people view it as, "Well, there's nothing I can do, and I'm just going to get gradually more and more unhealthy." I think, and this is somewhat futuristic, but to what extent can we slow biological aging? Can we potentially reverse it in the future? There's certainly lots of very compelling and interesting animal work and people are starting to delve into this in a big way.

Dr. Jason Roberts:

And not only to increase lifespan, will we some day live until we're 200. Who knows? But the concept of prolonging your health span as well. So the number of healthy years that you have before your body starts to gradually give way, I guess to some extent. Hopefully in the future will have therapies that will help keep us healthy. And if we do that increased health span, I think this data suggests that atrial fibrillation will be one thing that benefits from this. So hopefully in the future, maybe in terms of curbing the AFib pandemic, being able to address biological aging will help push things in the right direction.

Dr. Mercedes Carnethon:

Well, thank you so much Jason. And thank you so much Vlad for your thoughtful questions. I really like that the final bottom line leans towards my area as an epidemiologist, which is maintaining and promoting healthy lifestyles as a way to hopefully help prevent some of the difficulties of atrial fibrillation and its long-term outcomes. Really pleased to have you on this episode of Circulation on the Run, Jason, and thank you again Vlad, and I hope everyone enjoys this episode of the journal and has an opportunity to really dig into this piece. This is Mercedes Carnethon from Northwestern University Feinberg School of Medicine, saying thanks for listening today.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American heart association for more visit ahajournals.org.