This week, join author Rohan Khera and Associate Editor Nicholas Mills as they discuss the article "Phenotypic Selectivity of Artificial Intelligence-enhanced Electrocardiography in Cardiovascular Diagnosis and Risk Prediction."

For the episode transcript, visit: 

https://www.ahajournals.org/do/10.1161/podcast.20251103.917420

This week, Marc Ruel guest-hosts in this episode of Circulation on the Run as it features the annual Surgery Issue for Circulation. First, Marc is joined by author Duk-Hyun Kang as they discuss his article "Comparison of Long-Term Outcomes of Early Surgery Versus Conventional Treatment for Asymptomatic Severe Mitral Regurgitation: A Propensity Analysis." Then Marc is joined by authors Enoch Akowuah and Janelle Wagnild as they discuss their article "Accelerometer-Measured Physical Activity After Mitral Valve Surgery: An Analysis of the UK Mini Mitral Randomized Controlled Trial."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20251027.193601

This week please join author Rebecca Lawn and Associate Editor Mercedes Carnethon as they discuss the article "Experiences of Stalking and Obtaining a Restraining Order Are Associated With Onset of Cardiovascular Events in Women: A Prospective Analysis in the Nurses' Health Study II."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250902.860161

This week, please join author Ahamed Idris as he discusses the article "Bag-Valve-Mask Ventilation and Survival From Out-of-Hospital Cardiac Arrest: A Multicenter Study."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20231204.859686

This week, please join author Jan Vincent Beltran and Associate Editor Charles Lowenstein as they discuss the article "Single-Cell Meta-Analysis of Neutrophil Activation in Kawasaki Disease and Multisystem Inflammatory Syndrome in Children Reveals Potential Shared Immunological Drivers."

For episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20231127.335747

This week, please join author Peter Henriksen and Guest Editor Ileana Piña as they discuss the article "A Multicenter, Prospective, Randomized Controlled Trial of High Sensitivity Cardiac Troponin I-Guided Combination Angiotensin Receptor Blockade and Beta-Blocker Therapy to Prevent Anthracycline Cardiotoxicity: The Cardiac CARE Trial."

For the episode transcript, visit: 

https://www.ahajournals.org/do/10.1161/podcast.20231120.338829

This week, please join author Sameed Ahmed Khatana and Associate Editor Mark Link as they discuss "Projected Change in the Burden of Excess Cardiovascular Deaths Associated with Extreme Heat by Midcentury (2036–2065) in the Contiguous United States."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20231113.953480

This week, please join author Jung-Im Shin and Senior Associate Editor Sana Al-Khatib as they discuss "Associations of Apixaban Dose With Safety and Effectiveness Outcomes in Patients With Atrial Fibrillation and Severe Chronic Kidney Disease."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20231106.465546

This week, please join author Daniel Jones and Associate Editor Dharam Kumbhani as they discuss "Computed Tomography Cardiac Angiography Before Invasive Coronary Angiography in Patients With Previous Bypass Surgery: The BYPASS-CTCA Trial."

For the episode transcript, visit: 

https://www.ahajournals.org/do/10.1161/podcast.20231030.705281

This week is a very special podcast: please join Circulation's Executive Editor James de Lemos and Associate Editor Marc Ruel as they discuss the articles in this year's Surgery Issue.

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20231023.446837

This week, please join author Sebastian Reinstadler and Senior Associate Editor Victoria Delgado as they discuss "Cardiac Magnetic Resonance Imaging Versus Computed Tomography to Guide Transcatheter Aortic Valve Replacement: A Randomized, Open-Label, Noninferiority Trial."

For the episode transcript, visit: 

https://www.ahajournals.org/do/10.1161/podcast.20231016.898440

This week, please join senior author Nathaniel Smilowitz and Associate Editor Joshua Beckman as they discuss the article "Existing Nongated CT Coronary Calcium Predicts Operative Risk in Patients Undergoing Noncardiac Surgeries (ENCORES)."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/10.1161/podcast.20231009.345628

This week, please join author Karen Joynt Maddox and Associate Editor Sandeep Das as they discuss the article "Changes in Cardiovascular Spending, Care Utilization, and Clinical Outcomes Associated With Participation in Bundled Payments for Care Improvement−Advanced."

For the episode transcript, visit: https://www.ahajournals.org/do10.1161/podcast.20231002.799650

This week please join author Sheri Hartman and Associate Editor Jarett Berry as they discuss the article "Impacts of Reducing Sitting Time or Increasing Sit-to-Stand Transitions on Blood Pressure and Glucose Regulation in Postmenopausal Women: Three-Arm Randomized Controlled Trial."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250825.890592

This week, please join author Milton Packer and Associate Editor Brendan Everett as they discuss the article "Blinded Withdrawal of Long-Term Randomized Treatment With Empagliflozin or Placebo in Patients With Heart Failure."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230925.181139

This week, please join authors Robert Yeh, Rahul Aggarwal, as well as Associate Editor Mark Link as they discuss the article "Development and Validation of the DOAC Score: A Novel Bleeding Risk Prediction Tool for Patients With Atrial Fibrillation on Direct-Acting Oral Anticoagulants."

For the episode transcript, visit: 

https://www.ahajournals.org/do/10.1161/podcast.20230918.938511

This week, please join author Mark Hofmeyer and Guest Editor Mauro Giacca as they discuss the article "Rare Variant Genetics and Dilated Cardiomyopathy Severity: The DCM Precision Medicine Study."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230911.59229

This week, please join Guest Host Pishoy Gouda, author Kiran Khush, and Associate Editor Maryjane Farr as they discuss the article "Left Ventricular Dysfunction Associated With Brain Death: Results From the Donor Heart Study."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230905.6639

This week, please join Carolyn Lam and author Frans Van de Werf as they discuss the article "STREAM-2: Half-Dose Tenecteplase or Primary Percutaneous Coronary Intervention in Older Patients With ST-Segment−Elevation Myocardial Infarction: A Randomized, Open-Label Trial."

For the episode transcript, visit: 

https://www.ahajournals.org/do/10.1161/podcast.20230828.941314

This week, please join author Jason Glotzbach and Associate Editor Wendy Post as they discuss the article "Familial Associations of Prevalence and Cause-Specific Mortality for Thoracic Aortic Disease and Bicuspid Aortic Valve in a Large-Population Database."

For the episode transcript, visit: 

https://www.ahajournals.org/do/10.1161/podcast.20230821.396745

This week, please join Guest Host Pishoy Gouda, author Xin Du, and Guest Editor Walter Paulus as they discuss the article "The Effect of Frailty on the Efficacy and Safety of Intensive Blood Pressure Control: A Post Hoc Analysis of SPRINT Trial."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230813.441244

This week, please join author Joe-Elie Salem and Guest Editor Allan Jaffe as they discuss the article "Cardiomuscular Biomarkers in the Diagnosis and Prognostication of Immune Checkpoint Inhibitor Myocarditis."

For the episode transcript, visit:

https://www.ahajournals.org/do/10.1161/podcast.20230807.753501

This week, please join author Susmita Sahoo and Associate Editor Thomas Eschenhagen as they discuss the article "Extracellular Vesicle-Encapsulated Adeno-Associated Viruses for Therapeutic Gene Delivery to the Heart."

For the episode transcript, visit: 

https://www.ahajournals.org/do/10.1161/podcast.20230731.330982

This week, please author Markus Schlaich as he discusses the Research Letter "Effect of Initial Treatment With a Single Pill Containing Quadruple Combination of Quarter Doses of Blood Pressure Medicines Versus Standard Dose Monotherapy in Patients With Hypertension on Ambulatory Blood Pressure Indices: Results From the QUARTET Study."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230724.155005

This week please join authors Eric Olson and Qianqian Ding, and Senior Guest Editor Gianluigi Condorelli as they discuss the article "Genomic Editing of a Pathogenic Sequence Variant in ACTA2 Rescues Multisystemic Smooth Muscle Dysfunction Syndrome in Mice."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250818.61174

This week, please join our very special panel discussion to accompany Circulation's 2023 Disparities Issue. Please join Guest Host Mercedes Carnethon as she leads a discussion of equity, diversity, and inclusion in scientific research with panelists Karol Watson, Rishi Wadhera, and author Ambarish Pandey.

For the episode transcript, visit: https://ahajournals.org/do/10.1161/podcast.20230709.293635

This week, please join author Douglas Johns and Associate Editor Thomas Eschenhagen as they discuss the article "An Orally Bioavailable Macrocyclic Peptide That Inhibits Binding of PCSK9 to the Low Density Lipoprotein Receptor."

For the episode transcript, visit: https://ahajournals.org/do/10.1161/podcast.20230709.411427

This week, please join author Vivek Reddy and Associate Editor Mark Link as they discuss the article "Safety and Effectiveness of Pulsed Field Ablation to Treat Atrial Fibrillation: One-Year Outcomes From the MANIFEST-PF Registry."

For the episode transcript, visit: https://ahajournals.org/do10.1161/podcast.20230630.576031

This week, Digital Strategies Editor Maryjane Farr welcomes two guests, Joshua Beckman and Esther Kim, as they discuss vascular medicine, the current state of vascular medicine research, and two recently published vascular medicine articles in Circulation.

For the episode transcript, visit: https://ahajournals.org/do/10.1161/podcast.20230626.231366

This week, please join author Aidin Rawshani and Guest Editor Todd Brown as they discuss the article "Twenty Years of Cardiovascular Complications and Risk Factors in Patients With Type 2 Diabetes: A Nationwide Swedish Cohort Study."

For the episode transcript, visit: https://ahajournals.org/do/10.1161/podcast.20230619.624297

This week, please join authors Emmy Okello and Andrea Beaton as they discuss the articles "Rheumatic Heart Disease Research Collaborative in Uganda" and "Refining Risk Stratification Among Children With Latent Rheumatic Heart Disease."

For the episode transcript, visit: 

https://ahajournals.org/do/10.1161/podcast.20230612.642952

This week, please join author Leslie Gordon and Associate Editor Torbjørn Omland as they discuss the article "Plasma Progerin in Patients With Hutchinson-Gilford Progeria Syndrome: Immunoassay Development and Clinical Evaluation."

For the episode transcript, visit: 

https://www.ahajournals.org/do/10.1161/podcast.20230601.394643

This week, please join author Ewa Jankowska and Associate Editor Justin Ezekowitz as they discuss the article "Association Between Hemoglobin Level and the Efficacy of Intravenous Ferric Carboxymaltose in Patients With Acute Heart Failure and Iron Deficiency: An AFFIRM-AHF Subgroup Analysis."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230526.118098

This week, please join author David Cohen and Associate Editor Stefan James as they discuss the article "Economic Outcomes of Transcatheter Versus Surgical Aortic Valve Replacement in Patients With Severe Aortic Stenosis and Low Surgical Risk: Results From the PARTNER 3 Trial."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230519.961111

This week, please join author Braden Manns and Associate Editor and Editorialist Sandeep Das as they discuss 2 articles: "Self-Management Support Using Advertising Principles for Older Low Income Adults at High Cardiovascular Risk: A Randomized Controlled Trial" and "Eliminating Medication Copayments for Low-Income Older Adults at High Cardiovascular Risk: A Randomized Controlled Trial."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230515.95172

This week please join author Joachim Skovbo and Associate Editor Brendan Everett as they discuss the article "Association of Statin Treatment and Dose With the Clinical Course of Small Abdominal Aortic Aneurysms in Men: A 5-Year Prospective Cohort Study From 2 Population-Based Screening Trials."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20250812.716960

This week, Carolyn, Greg, and Peder welcome podcast hosts Laxmi Mehta and Eva Rocha of The Journal of the American Heart Association's new podast "Aha! With JAHA."

Then, please join author Leopoldo Pérez de Isla and Associate Editor Stefan James as they discuss the article "Alirocumab and Coronary Atherosclerosis in Asymptomatic Patients With Familial Hypercholesterolemia: The ARCHITECT Study. 

For the episode transcript, visit:

https://www.ahajournals.org/do/10.1161/podcast.20230508.620091

This week, please join author Hyo-Soo Kim and Associate Editor Stefan James as they discuss the article "Comparison of 3- to 6-Month Versus 12-Month Dual Antiplatelet Therapy After Coronary Intervention Using the Contemporary Drug-Eluting Stents With Ultrathin Struts: The HOST-IDEA Randomized Clinical Trial."

For the episode transcript, visit: 

https://www.ahajournals.org/do/10.1161/podcast.20230428.322841

This week on Circulation: On the Run, please join author Charles Hong and Associate Editor Gabriele Schiattarella as they discuss the article "Impaired Reorganization of Centrosome Structure Underlies Human Infantile Dilated Cardiomyopathy."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230421.342161

This week, please join authors Marc Sabatine and Prakriti Gaba, as well as Associate Editor Amit Khera, as they discuss the article "Association Between Achieved Low-Density Lipoprotein Cholesterol Levels and Long-Term Cardiovascular and Safety Outcomes: An Analysis of FOURIER-OLE."

Dr Greg Hundley:

Welcome listeners, to this April 18th issue of Circulation on the Run and I am Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Peder Myhre:

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

Dr Greg Hundley:

Peder, today's feature discussion, very interesting. We're going to evaluate the association between what's achieved with LDL cholesterol lowering, and then also long-term cardiovascular and safety outcomes. 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 Peder Myhre:

Yes, Greg. I would love to. And the first paper is from the World of Preclinical Science and it comes to us from corresponding author, Jan Magnus Aronsen from University of Oslo in Norway. And perhaps, as you know, Greg, cardiomyocyte contraction and relaxation depend on the activity of the sarcoplasmic reticulum CA+2 ATPase 2, abbreviated SERCA2, and lowered levels or reduced activity of SERCA2, as seen in chronic heart failure, weakens contractile force and delays relaxation and no available therapy involves direct manipulation of the SERCA2 activity. And Greg, phosphodiesterase 3A is proposed to be present in the SERCA2 interactome limit SERCA2 activity and disruption of phosphodiesterase 3A from SERCA2 might thus be a strategy to develop SERCA2 activators. And in this study, the authors investigated and mapped SERCA2 and phosphodiesterase 3A and assessed this in experiments assessing the binding between these two in cardiomyocytes and in vesicles.

Dr Greg Hundley:

Wow Peder, sounds very interesting. So what did they find and how about the clinical implications of the findings?

Dr Peder Myhre:

So Greg phosphodiesterase 3A bounded directly to SERCA2 in the cardiomyocyte. So that's the first finding. Second, they demonstrated that SERCA2 phosphodiesterase 3A disruption increased SERCA2 activity independently of the catalytic activity of phosphodiesterase 3A in both normal and failing cardiomyocytes. And third, SERCA2 activity by the optimized SERCA2 phosphodiesterase 3A disruptor peptide OPT F reduced mortality and improved contractility after aortic binding in mice. So the clinical implication is that direct targeting of phosphodiesterase 3A binding to SERCA2 could be a novel approach to increase SERCA2 activity and thus cardiac contractility in patients with heart failure.

Dr Greg Hundley:

Very nice Peder. What a great new finding in the world of preclinical science. Well my paper is going to delve into the world of clinical science and involves patients with stroke. So Peder in this study led by corresponding author, Dr. Dileep Yavagal from University of Miami Miller School of Medicine performed a survey in 75 countries through the Mission Thrombectomy 2020+ Global Network between November of 2020 and February of 2021 to determine the availability of mechanical thrombectomy for large vessel occlusion in patients with stroke. Now Peder, the primary endpoints were the current annual mechanical thrombectomy availability, the mechanical thrombectomy operator availability and the mechanical thrombectomy center availability. All of these availabilities were defined as the proportion of estimated large vessel occlusion for patients receiving mechanical thrombectomy in a given region annually.

Dr Peder Myhre:

Okay, Greg, so this is really an access question. So in essence, what is the availability of mechanical thrombectomy worldwide? So what did they find?

Dr Greg Hundley:

Right, great Peder. So what they found, the authors received 887 responses from 67 countries and low-income countries had 88% lower mechanical thrombectomy availability compared to high-income countries. The global mechanical thrombectomy operator availability was 16.5% of optimal, and the mechanical thrombectomy center availability was only 20.8% optimal. And with these results, the authors indicate that global cooperation and targeted region-specific public health interventions, including all stakeholders involved in stroke care delivery, are really needed to rapidly increase access to this brain-saving and disability-sparing treatment with mechanical thrombectomy really worldwide.

Dr Peder Myhre:

Oh wow. What a beautiful summary, Greg. Thank you so much. And we also have some other interesting papers in the mailbag today. We have an exchange of letters between Dr. Yang and Dr. O'Donoghue regarding the article "Long Term evolocumab in Patients with Established Atherosclerotic Cardiovascular Disease."

Dr Greg Hundley:

Great Peder, and also Professor Perera has a Frontiers article entitled "Unloading the Left Ventricle in Venoarterial ECMO in Who, When and How?" and then finally there's a Research Letter from Professor Verma entitled "Prevalence of Diabetes and Cardiovascular Risk in the Middle East and Africa: The Primary results of the PACT-MEA Study." Well Peder, how about we jump to that feature discussion?

Dr Peder Myhre:

Can't wait.

Dr Greg Hundley:

Welcome listeners to this feature discussion on April 18th and we have with us today Prakriti Gaba and Marc Sabatine from Brigham and Women's Hospital and our own associate editor, Dr. Amit Khera. Welcome everyone. Well Marc, we'll start with you. Can you describe for us some of the background information that really helps constitute the preparation of your study and what was the hypothesis that you wanted to address?

Dr. Marc Sabatine:

Yeah, thanks Greg and thanks for having us. So we've seen in a variety of epidemiologic cohorts the association between LDL cholesterol and the risk of adverse cardiovascular events like in Framingham Heart Study and UK Biobank. But in those cohorts, in these industrial societies, we don't have the benefit of lots of data in individuals with very low levels of LDL cholesterol and so we had the opportunity with the FOURIER study that was the randomized comparison of evolocumab PCSK9 inhibitor versus placebo to get patients down to extremely low levels of LDL cholesterol and evolocumab. We were able to get individuals down to about 30 mg/dL. And so in addition to all the studies we've done showing the comparison of evolocumab to placebo, we also then had the chance to use FOURIER, and as you'll hear from PK, FOURIER-OLE, the open-label extension, as a cohort to then examine patients' new baseline, if you will, their new achieved LDL cholesterol and then it's association not only with cardiovascular events but safety events.

And so the hypothesis is that there would be a relationship with the lower the LDL cholesterol, the lower the risk of cardiovascular events and we wanted to explore how far down that went. And then the second one for safety would be that there wouldn't be any association between low levels of LDL cholesterol and a variety of safety outcomes that rightly or wrongly people have ascribed to low levels of LDL cholesterol.

Dr Greg Hundley:

Thanks so much, Marc. Well listeners, now we're going to turn to PK, the first author, on this very interesting paper and PK, Marc mentioned to us the FOURIER-OLE study. Maybe describe for us here your study design and then what specifically was your study population?

Dr. Prakriti Gaba (PK):

Yeah, definitely. Thanks so much for the introduction. So the study population included 27,564 patients with stable atherosclerotic cardiovascular disease and LDL cholesterol levels that were greater than or equal to 70 mg/dL or non-HDL cholesterol greater than or equal to a 100 mg/dL on statin therapy. The patients who then went on to the FOURIER-OLE or the open-label extension part of the trial consisted of about 6,635 patients. And so in this study we essentially evaluated the combination of those populations in 2 separate analyses. We then categorized patients according to 6 pre-specified bins based on their achieved LDL cholesterol levels at designated time points and those ranged from LDL levels of less than 20 mg/dL all the way up to 100 mg/dL. And then we looked at their baseline characteristics and evaluated the cardiovascular and safety outcomes that Dr. Sabatine mentioned earlier.

Dr Greg Hundley:

Very nice PK. Well we've got a great listening audience today and they're anxious to hear your study results, so can you share those with us please?

Dr. Prakriti Gaba (PK):

Definitely. So over the course of more than 77,000 patient years of follow-up, we found that there was a monotonic relationship between achieving lower LDL cholesterol levels down to very low levels of less than 20 mg/dL and a lower annualized risk of the primary efficacy endpoint, which was a composite of 5 individual endpoints. We also found that there was a similar relationship observed between lower LDL achieved, LDL cholesterol levels and a lower annualized risk of the secondary efficacy endpoint, and then when we looked at safety, there were actually no clear monotonic trends between lower achieved LDL levels and the risk of any of the 8 adverse events and these included things like serious adverse events, hemorrhagic stroke or muscle related events.

Dr Greg Hundley:

Very nice PK and I'm sure our listeners are wanting to know, did you find any discrepancy in your results based on either age or gender?

Dr. Prakriti Gaba (PK):

That's an excellent question, and we did look at age and gender throughout. I think across the board the results were pretty consistent, but additional subanalyses will further address this question.

Dr Greg Hundley:

Very good. Well listeners now we're going to turn to one of our associate editors, Dr. Amit Khera, who has helped move this article through the process of evaluation with the editorial team. Amit, you have many papers come across your desk, what attracted you to this paper and then how do we put this study's results really in the context of other studies that have sought to dramatically lower LDL cholesterol?

Dr. Amit Khera:

Well first thanks a lot Greg for allowing me to participate today. I want to congratulate Drs. Gaba and Sabatine on a fantastic paper and the minute I saw it, and you know can tell when you've done this for a while what's a great paper, and this one certainly is and we work closely with them to try to make it better and enhance the analyses and as a group, I think we achieved that. I was fortunate to write an accompanying editorial that you'll see.

So I got to take a pretty deep dive in this paper and I want to just talk about sort of what's important here, why is this important, and I think as Dr. Gaba mentioned, there's two sides to this. There's the efficacy side where you talk about LDL lowering and getting to very low levels. Now mind you, they got to, what I call, ultra low levels, even explored for a down to a median of 7 mg/dL, so really, really low. And first I think what our listeners need to know when we look at guidelines, these numbers of 70 or 55, these are completely arbitrary and they're based on what was observed in clinical trials, what was achieved in high intensity versus moderate intensity statins in IMPROVE-IT.

There's no biology behind that, and I think what this study does is reminds us there is no biology behind how low we need to go. This group previously published their shorter-term data approximately 2 years with this construct of lower is better and I think that's fine, but people worry, particularly on the safety side about extension, and we'll get to that in a minute, so where this fits is it gives us even more reassurance that lower is better, reminds us there's no biologic basis of that even down to very low levels. And so what does that mean? I think that comes back to guidelines. We have some discrepancy between European, ACC, Multisociety Guidelines that are around 55 and so from a guideline perspective, I think we'll see a little bit more enthusiasm about lower cut points or lower thresholds. And from a clinical standpoint, as a clinician it reminds me that when I see someone that's very high risk, there's no magic to achieving a number that if the risk is high, we need to be quite intensive and get their LDL down as low as possible and as safely as possible.

I do want to also acknowledge, there's not, to your point about context, the IMPROVE-IT study also showed very low levels show additional efficacy and there's also a lot of other data, genetics and ecologic data supporting this. So this is... we look at Bayesian analysis that this is consistent that we're seeing across different platforms.

I do want to talk about safety too, Greg. That's really important because honestly this is when it comes to patient level, the safety part of it. We as clinicians may have comfort with very low levels, but the safety is important. I also want to, just from a steady design, this is post-hoc, so those that achieve very low levels are different. You can see that in their table 1, but these investigators did lots of things. They did pretty extensive multi-variable analysis, they looked at time-dependent LDLs, they looked at it multiple different ways, but as mentioned, there really did not seem to be a safety signal. And this is where time matters.

Safety in two years, interesting, but safety 5 to 8 years really offers us much more reassurance. So I think that's where this really comes in about that safety piece with the extended analysis. So again, I think from a guideline perspective, from a clinical perspective, there's so many implications from this paper and I really hope people take the time to take a deep dive and also put it in context, like you said, to the other literature where this is not standalone, but it's corroborating what we're seeing.

Dr Greg Hundley:

Very nice, amit. Marc, I want to come back to you, just two quick questions thinking about the preparation of your study. One, did you sample cognition? One thing we hear about frequently in dramatic lowering of LDL cholesterol are questions around cognition, particularly in the elderly?

Dr. Marc Sabatine:

Yeah, it's a great question Greg. So first of all, in the FOURIER study itself, there was an embedded study called EBBINGHAUS that Bob Giugliano from our group led that actually did formal neurocognitive testing in individuals using basically a iPad-like test. We also collected the usual neurocognitive adverse events as part of safety collecting. So 2 ways, the general asking about any adverse events and then the specific neurocognitive testing. We had previously reported out the results of EBBINGHAUS that there wasn't any relationship between evolocumab and the low LDL cholesterol and the risk of any neurocognitive AEs. We just were able to recently do this OLE analysis over time for the major adverse cardiovascular events and for the general safety events including cognition, so all that looked good. As PK indicated, we're now digging into the EBBINGHAUS formal neurocognitive testing, which was also extended out. So stay tuned for those results.

Dr Greg Hundley:

Very nice. And then eligibility, maybe just walk us through that really quickly. Patients that are going to be randomized to this form of therapy, were they already on high-dose statins? Who exactly did we randomize in this trial?

Dr. Marc Sabatine:

Yeah, so at the get-go, as PK indicated, these are patients with atherosclerotic cardiovascular disease, so they had a prior MI, prior stroke, symptomatic PAD. They were to be on an optimized lipid-lowering regimen, optimized statin therapy, so for close to 70%, that was a high-intensity statin. We had a small percentage on ezetimibe, but that's because we hadn't yet published the results of the IMPROVE-IT trial that Amit mentioned when we were enrolling in FOURIER, but it was a well-treated population on statin therapy. So these results would apply to your typical patient with ASCVD who's on a good statin regimen.

Dr Greg Hundley:

Very nice. Well, listeners now we're going to go back to both of our authors and investigators, as well as Dr. Khera. PK we'll start with you. What do you see as the next study to really be performed in this sphere of research?

Dr. Prakriti Gaba (PK):

I think that's an excellent question. I think with the data presented here now we know that the lower the LDL, the lower the risk of adverse cardiovascular events and that having a low LDL is safe in the long term. I think moving forward, as Dr. Khera mentioned, there needs to be a shift of these recommendations into the guidelines. So I think additional studies confirming these findings is what we need, but we do have the evidence available.

Dr Greg Hundley:

Very nice. And Marc?

Dr. Marc Sabatine:

Yeah, and I agree with PK of course. I think there's a couple things that we want to look at. We had looked in the parent FOURIER trial and found some groups who were higher risk, who seemed to have a bigger benefit early on, and those by and large were people who had a lot of athero. But as Amit indicated that the parent FOURIER trial was relatively short at about in two and a quarter years median follow up, and so now we have the benefit of an additional half decade of follow up in a subset of people and so now we're starting to look through and see the subgroups where we saw some differential benefit and this was a paper we published in circulation soon after we published the primary results of FOURIER.

Now we have the ability to go through and look at those same subgroups and see what happens now with an additional 5 years. And so that'll be quite interesting, I think, to see how those groups play out now over time. I think as Amit indicated, time is critical. We know the benefit of lipid lowering really tends to grow with time. We saw that in FOURIER, we saw that in FOURIER-OLE and then as Amit indicated, I think for safety also it's now very reassuring, being able to go out to not two and a half years, but 5, 6, 7, 8 years of safety follow up.

Dr Greg Hundley:

Very nice. Well, listeners we're next going to turn to Dr. Khera. I'm going to put him on the spot a little bit. I don't know if many of you know he's a cardiologist with expertise in primary prevention. So here we've really focused today, I think, on a very unique set of results in secondary prevention. Amit, as you think about studies to be performed in the future, is there a role for really lowering LDL cholesterol as a primary prevention target?

Dr. Amit Khera:

The short answer is absolutely. I think, to be fair, you can't necessarily directly extrapolate these results 'cause it's a secondary prevention population, but I think if we step back for a second, is there any reason I think this wouldn't work in primary prevention, there's not, and I think there's tons of genetic data, tons of other long-term data that suggests that lower is better than primary prevention. I think the challenge, as you know, is just from primary prevention is it's just about the number that you need to treat and primary prevention is pretty profound in terms of to lower events. So this is where the trade-off comes.

I think even in their study, we do have to appreciate while lower is better, when you have very low levels and you're going to even lower, let's say when you go from in secondary prevention from 50 to 40, as much as that sounds valuable, that delta's pretty small and then the absolute risk reduction is still going to be pretty small for those individuals and that's only magnified in primary prevention. So the short answer is I have no reason to believe that lower is better is not applicable in primary prevention, but I do know that the cost and what entails to get there, you don't get as much return on investment.

I do want to say one last thing though. We're talking about lower is better, and I know these investigators know this well, but it's not only just how low but how long and I think that's where primary prevention about to go to clinic and I play the long game for primary prevention that we know we've magnified these benefits over the long term and even a little bit early in life can pay off long dividends. So that's how I look at it.

Dr Greg Hundley:

Very nice. Well, listeners we want to thank Dr. Prakriti Gaba, Dr. Marc Sabatine, both from Brigham and Women's Hospital and also our own associate editor, Dr. Amit Khera from University of Texas Southwestern Medical Center for bringing us this study involving patients with arteriosclerotic cardiovascular disease indicating that long-term achievement of lower LDL cholesterol levels down to values less than 20 mg/dL was associated with a lower risk of cardiovascular outcomes and not and not an increase in the risk of significant safety related events.

Well, on behalf of Peder, 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 2023. 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 Kavita Sharma and Associate Editor Svati Shah as they discuss the article "Myocardial Metabolomics of Human Heart Failure With Preserved Ejection Fraction."

Dr. Greg Hundley:

Welcome listeners, to this April 11th issue of Circulation on the Run. And I am one of your cohosts, Dr. Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

And I am Dr. Peder Myhre from Akershus University Hospital, and the University of Oslo in Norway.

Dr. Greg Hundley:

Well, Peder, wow. This week's feature discussion, very interesting. We spend a lot of time, especially with our colleague, Dr. Carolyn Lam, on heart failure preserved ejection fraction. But this week's feature discussion, it's going to focus on some of the myocardial metabolomics in this condition. 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? How about if I go first?

Dr. Peder Myhre:

Let's go, Greg.

Dr. Greg Hundley:

Okay. So Peder, some believe that cardiovascular disease may be the main reason for stagnant growth in life expectancy in the United States since 2010. And so, the American Heart Association, as you know, recently released an updated algorithm for evaluating cardiovascular health. Life's Essential 8, and it has a very nice score. So these authors, led by Dr. Lu Qi, from Tulane University, aimed to quantify the associations of the Life Essential 8 scores with life expectancy in a nationally representative sample of US adults. And the team included 23,000 non-pregnant non- institutionalized participants who were age 20 to 79 years, who participated in the National Health and Nutrition Examination survey, or NHANES, from 2005 to 2018. And whose mortality was identified through linkage to the National Death Index, from the period extending through December of 2019.

Dr. Peder Myhre:

Oh wow. So really, a validation of the Life's Essential 8. Greg, that's so interesting. What did they find?

Dr. Greg Hundley:

Right Peder, as you say, very interesting. So here are some of the data, and let's itemize them. So, during a median of 7.8 years of follow up, 1,359 total deaths occurred. Now, the estimated life expectancy at age 50 was 27.3 years, 32.9 years, and 36.2 years, in participants with low Life's Essential 8 scores, less than 50. Moderate, so Life's Essential 8 scores of greater than or equal to 50, but less than 80. And then, high scores, greater than 80. Okay? So equivalently, participants with high Life's Essential 8 scores had an average of 8.9 more years of life expectancy at age 50, compared to those with low scores.

Next, on average, 42.6% of the gained life expectancy at age 50, from adhering to sort of that cardiovascular health, those recommendations, was attributable to reduced cardiovascular death.

Next, significant associations with the Life's Essential 8 score and life expectancy were observed in both men and women.

Next, similarly significant associations of cardiovascular health, Life's Essential 8, with life expectancy were observed in non-Hispanic Whites and non-Hispanic Blacks, but not in those originating from the country of Mexico.

So Peder, finally, in summarizing all of this, adhering to the cardiovascular health lifestyle, defined by the Life's Essential 8 score, it was related to a considerably increased life expectancy. However, because of the findings from the individuals from the country of Mexico, more research is needed to be done in some of these minority groups, and particularly, those of Hispanic ethnicity, and perhaps other races.

Dr. Peder Myhre:

Oh, wow. Very interesting. And I would love to learn more about this subgroup analysis in future studies.

So Greg, the next paper is about the hospitalization for heart failure measures. Because contemporary measures of hospital performance for heart failure hospitalization, the 30-day risk standardized readmission and mortality rate, are estimated using the same risk adjusted model and overall event rate for all patients. Thus, these measures are mainly driven by the care quality and outcomes for the majority racial ethnic groups, and may not adequately represent the hospital performance for patients of Black or other races. And in this study, led by co-corresponding authors, Mentias from Cleveland Clinic and Pandey from University of Texas Southwestern Medical Center, the authors used fee for service Medicare beneficiaries from 2014 to 2019 hospitalized with heart failure, in hospital level 30 day risk standardized remission and mortality rates were estimated using traditional race agnostic models and the race specific approach, with measures derived separately for each race ethnicity group.

Dr. Greg Hundley:

Ah, very interesting, Peder. So what did they find from this study?

Dr. Peder Myhre:

So the study included more than 1.9 million patients, comprising of 75% White patients, 15% Black patients, and 10% patients of other races, with heart failure from 1,860 hospitals. And compared with the race agnostic model, composite race-specific metrics for all patients demonstrated stronger correlation with 30 days readmissions. And that is correlation coefficient 0.78 versus 0.63, and 30 day mortality rate 0.52 versus 0.29 for Black patients. In concordance in hospital performance was for all patients and patients of Black race was also higher with race specific as compared to race agnostic metrics.

So Greg, the authors conclude that among patients hospitalized with heart failure race specific 30 day risk standardized remission and mortality rates are more equitable in representing hospital performance for patients of Black and other races.

Dr. Greg Hundley:

Very nice, Peder. What a beautiful summary in a very elegant study. Peder, myocardial insulin resistance is a hallmark of diabetic cardiac injury. However, the underlining molecular mechanisms for this relationship remain unclear. Now, recent studies demonstrate, that the diabetic heart is resistant to several cardioprotective interventions, including adiponectin and pre-conditioning. The universal quote, unquote, resistance to multiple therapeutic interventions suggest, impairment of the requisite molecule, or molecules, involved in broad pro survival signaling cascades. Now caveolin is a scaffolding protein coordinating trans-membrane signaling transduction. However, the role of caveolin-3 in diabetic impairment of cardiac protective signaling and diabetic ischemic heart failure is unknown. And so these investigators, led by Dr. Xinliang Ma, from Thomas Jefferson University, studied mice fed a normal diet or high fat diet for two to 12 weeks, and subjected them to myocardial ischemia and reperfusion.

Dr. Peder Myhre:

Oh wow. What an interesting preclinical science paper, Greg. What did they find?

Dr. Greg Hundley:

Right. So the authors found that nitration of caveolin-3 at tyrosine 73 and resulted signal complex dissociation was responsible for cardiac insulin adiponectin resistance in the pre-diabetic heart. And this contributed to ischemic heart failure progression. Now, early interventions preserving caveolin-3 centered signal zone integrity was found to be an effective novel strategy against diabetic exacerbation of ischemic heart failure. And Peder, I think these very exciting results suggest that this is a new area of research and further experiments are warranted.

And there's a very nice editorial by Professor Heidenreich, entitled "Pursuing Equity in Performance Measurement.

Well Peder, there's some other articles in this issue, and we'll dip in this week to the mail bag, for a Research Letter from Professor Hibbert, entitled "Utility of a Smartphone Application in Assessing Palmar Circulation Prior to Radial Artery Harvesting for Coronary Artery Bypass Grafting."

Dr. Peder Myhre:

That is so cool. And we also have a Letter from Dr. Kim, regarding the article entitled, "Detection of Atrial Fibrillation in a Large Population Using Wearable Devices: The Fitbit Heart Study."

Dr. Greg Hundley:

Very nice. Well, how about we get along to one of Carolyn's favorite topics, heart failure with preserved ejection fraction, and learn more about myocardial metabolomics?

Dr. Peder Myhre:

Can't wait.

Dr. Carolyn Lam:

Today's feature discussion is on my favorite topic, heart failure with preserved ejection fraction, or HFpEF. But today, what we're focusing on is truly novel. We are looking at the myocardial metabolomics of human HFpEF, very, very valuable data and insights. We're so pleased to have with us the corresponding author of today's feature paper, Dr. Kavita Sharma, who's from the Johns Hopkins University School of Medicine, and our associate editor, Dr. Svati Shah, who's, of course, from Duke University School of Medicine.

So welcome Kavita and Svati. Kavita, if I could start by, please put us and bring us all to the same level of knowledge, by perhaps explaining in simple terms, what is metabolomics? And what is normal versus perhaps abnormal metabolomics, in a known condition, like systolic heart failure or heart failure with reduced ejection fraction?

Dr. Kavita Sharma:

Sure. Well thank you, Carolyn, for the opportunity to chat around this topic. And it's great to be with you and Svati this morning. Metabolomics is a broad general study of essentially, all the chemical processes involving metabolites, or small molecule substrates, their intermediates, and even the products of cellular metabolism. This can be studied in really, any organ system, in any organ. What is really unique, I think, to this particular paper in our project is that, it has yet to have been defined or described in human HFpEF from the myocardial tissue. We call this heart failure with preserved ejection fraction, and inherent to that name in this complicated syndrome is that, there is something probably wrong with the heart, yet we have not really had much insight to what that might be from direct myocardial tissue.

We are also still learning about what metabolomics looks like in, for example, the heart failure with reduced ejection fraction state. Though, there is more published in this space than in HFpEF. From the limited knowledge that we have, it does appear that heart failure with reduced ejection fraction hearts, and this is certainly seen in the plasma, which is where most of metabolomic studies have generated from, those hearts tend to utilize various forms of energy banks, if you will. Whether that's fatty acid oxidation, whether that is glucose utilization or intermediates and so on. And our primary interest was to understand, how do the preserved EF parts in patients fare in comparison?

Dr. Carolyn Lam:

Oh, thank you so much, Kavita. That was beautifully explained. And indeed, what's so special about your paper is, it's not just circulating metabolites but myocardial metabolites. And you have the control groups that are so important to study at the same time. So patients with HFpEF, but also those with HFrEF and versus controls. And thank you for establishing too, that if I'm not wrong, fatty acid metabolism accounts for the majority of ATP generation in the normal heart. Whereas, this declines a little in the HFrEF heart. And now, I think we're about to find out what happens in the HFpEF heart. So if you could explain what you did and what you find.

Dr. Kavita Sharma:

Yes, absolutely. So we examined, again, tissue and plasma metabolomics from 38 subjects with HFpEF. These are patients referred to the Hopkins HFpEF Clinic. And so they have been essentially, clinically evaluated, and have what we define as HFpEF, based on hemodynamic testing. So a right heart catheterization, often with exercise, that meets criteria for diagnosis of the syndrome.

As you stated, we compared our HFpEF patient tissue and plasma samples to samples coming from patients with HFrEF, dilated cardiomyopathy, and non-failing controls. And the latter two sources were a tissue bank from the University of Pennsylvania, that is long-standing, where patients with endstage dilated cardiomyopathy are able to have tissue banked at the University of Pennsylvania at the time of explant prior to transplant. So albeit, we are comparing to fairly advanced end stage dilated cardiomyopathy, and control tissue comes from unused donor hearts, essentially. So presumably, normal heart function patients, likely in a brain death state, who for whatever reason, the hearts were not utilized for transplantation. Again, not an entirely perfect controlled state, but again, given the nature of the work, the fact that it's myocardial tissue, the closest that we have found we've been able to come to for a control comparison.

We started out performing what we call quantitative targeted metabolomics. We measured organic acids, amino acids, and acylcarnitines in the myocardium. And that was totaling around 72 metabolites. And we did the same in plasma, so close to 69 metabolites. And our metabolomics work was actually completed at the University of Pennsylvania. And so, I wish to credit Dr. Zoltan Arany and Dr. Dan Kelly for their great collaboration in this study.

Dr. Carolyn Lam:

That's wonderful. Kavita, if you could tell us a little bit more about the patients with HFpEF. We understand it was end stage dilated cardiomyopathy, HFrEF, and donor hearts as the controls, but the patients with HFpEF, in relation to obesity, diabetes, and how that may impact the interpretation of the results.

Dr. Kavita Sharma:

Sure. So these are HFpEF patients that are in an ambulatory state outpatient setting. They have many of the comorbidities we know are intrinsic today to HFpEF. Out of our HFpEF population, the majority were women. So 71%, that's 27 out of the 38 we serve. And we're very fortunate to serve a African-American enriched population in Baltimore that's intrinsic to our center. And so, over half of our patients were Black. The remaining Caucasian, one non-Caucasian. Over half had been hospitalized, for example, in the prior one year. So these are certainly symptomatic patients. And all had NYHA II or greater symptoms.

We do have a rather obese cohort at Hopkins. And so, our median BMI, for example, was 39, our mean is very similar. And the majority have, as we see often in HFpEF, the majority with hypertension, over half with diabetes. In fact, it was actually 70% or so. Rather few with coronary disease, and this is a trend we're seeing in general in HFpEF in the present day kind of common phenotypes, and about a third with atrial fibrillation. So really, representative, I think, of this kind of cardiometabolic as we call it, phenotype of HFpEF, that is the predominant phenotype we're seeing, at least in North America.

Dr. Carolyn Lam:

Oh, that's perfect. And then, maybe just a few words about the results before I bring Svati in for her thoughts. Thanks.

Dr. Kavita Sharma:

Sure, absolutely. So we conducted this study in a couple different stages. We first started with performing a principal component analysis and hierarchical clustering analysis, to see whether the myocardial metabolites and the plasma metabolites, respectively, would they distinguish these three patient groups? So HFpEF from HFrEF and controls. And interestingly, in the myocardial tissue, our PCA analysis and our hierarchical clustering analysis show that actually, in fact, as few as 70 metabolites in the myocardium really distinctly differentiate these three subgroups. The top contributors that separated HF from controls, for example, and HFrEF, were mostly related to amino acids, including branched chain amino acids and their catabolites, as well as medium and long chain acylcarnitines, which are byproducts of fatty acid oxidation.

When it came to the plasma metabolome, on the other hand, there was far less distinguishing between the groups, and significant overlap, both in PCA and hierarchal clustering. And really, the take home there is that, the myocardial tissue and the plasma were really quite distinct for the overall metabolite analysis. But then, even as we broke it down by fatty acid oxidation, by glucose metabolism, and even branched chain amino acids, we saw this trend continue, that the plasma was quite distinct from the myocardial tissue.

Now, which of the two is more representative of the disease state? Which is the one that we should be paying more attention to? I think that remains to be fully understood further. And of course, it would be really nice to replicate these findings in another cohort. But that is something that, I think, is a first, that certainly, that we have seen and important for the community.

Dr. Carolyn Lam:

Indeed. Oh, Kavita, we could go on talking forever, but I'd really love Svati's thoughts. Why was this paper so special? What does it tell us clinically with any implications?

Dr. Svati Shah:

Yeah. I just want to commend Dr. Hahn, Dr. Sharma, on this incredible work. If you can just imagine how much painstaking work this took for Dr. Sharma and Dr. Hahn. It's a very careful phenotyping of HFpEF. These are true HFpEF patients. The ability to get tissue, and to pair the tissue to the plasma, so that we can really understand. When we measure things in the circulation, and we think they're telling us about the heart, are they actually telling us about the heart? So I really want to commend this incredible work.

And Carolyn, I love talking about cardiac metabolism, because the heart is an incredible organ, right? The heart is a metabolic omnivore. It'll eat many different kinds of fuels, and a lot of different things determine which fuels it uses. And as you nicely outlined, Carolyn, earlier, in the normal heart, the heart prefers to use fatty acids.

But what we are not completely certain of is, what happens in HFpEF? So in HFrEF, we know that the heart switches to glucose, which is not a great fuel, actually. It's actually, a metabolically inefficient fuel. And so we know in HFrEF, that the heart has this metabolic inflexibility. All of a sudden, it's not an omnivore, and it's kind of stuck with certain fuels, which are not very healthy for it.

But what Dr. Sharma and Dr. Hahn have shown, for the first time really, is what happens in HFpEF? And so, I think it's really cool that, actually, it just highlights how complex HFpEF is as a disease. So they were able to show that in some ways, HFpEF is similar to HFrEF, including that there's impairments in use of these fatty acids, which is what the normal heart does.

But, they also show that HFpEF may be different than HFrEF in many ways, including, because of these branched chain amino acids. And that may be because of some of the clinical differences that we know exist in patients with HFpEF, including the obesity and diabetes, that Dr. Sharma nicely outlined. Although, I want to point out, they were very careful about trying to take these clinical factors into account when they looked at differences in the metabolites.

So really incredible work, highlighting that the HFpEF heart also has this metabolic inflexibility. It also is not a metabolic omnivore like the normal heart is, but highlighting important differences, potentially, between HFpEF and HFrEF.

Dr. Carolyn Lam:

Oh, Svati, thank you for putting that so clearly.

Dr. Kavita Sharma:

No, I think that was a really elegant summary of the findings, Svati. And thank you for your kind words and support in allowing us to share our work through Circulation. I really couldn't say it better, but that's exactly what we seem to find is that, when we look at various sort of stores or banks of energy resource, what we really found is that these HFpEF hearts are energy inflexible, as Svati said, that begins with fatty acid metabolism. And so, when we look at, for example, medium and launching acylcarnitines, what we find is that these are markedly reduced in HFpEF myocardial tissue, quite similar to HFrEF. Again, both of them reduced compared to controls. And again, these are byproducts of fatty acid oxidation, and that is really responsible for almost 80% of generally what we think of energy metabolism in the normal state.

In the plasma, however, again, back to that theme where we don't see that reproduced in the plasma, we find that HFpEF is actually not too dissimilar from controls for certain medium and long chain acylcarnitines, and then closer to HFrEF in some cases. And interestingly, we compared our metabolomics study to our prior report of our RNA sequencing paper, that was also published in Circulation now two years ago. And what we found is that, there is reduced gene expression of many of the proteins involved with fatty acid uptake and oxidation, when we compare them to control states. So the story is sort of, fits with what we have seen previously, and when we focus in on this group of genes.

Our analysis of glucose metabolism though, did not include glycolysis or glucose oxidation intermediates. We still found that, majority of the TCA cycle intermediate, so succinate, for example, fumarate, malate, were all reduced in HFpEF versus control. It was really only pyruvate in isolation that was increased in HFpEF myocardium, compared to controls. And again, a number of genes implicated in glucose metabolism in general, we found to be lower in HFpEF versus control, including gluten 1, or SLC2A1, which is involved in glucose uptake.

So again, this theme of, we have patients with significant obesity, many in the diabetic state, we would think that these hearts would utilize these energy stores, but they don't seem to be. And finally, we see distinct differences in the tissue and branched chain amino acid pathways as well. There appears to be some sort of a block between the branched chain amino acids, and then sort of byproducts, as you continue down through ketoacids and further. And we don't fully understand where those blocks are, but that was certainly notable.

And then lastly, I'll say, one interest that we've had, and really, what led to much of this work in the tissue, is to pursue what we call deep phenotyping. Can these molecular signatures, whether it's gene expression, or metabolomics, or what we're working on now, which is proteomics, can these really help us identify unique subgroups within HFpEF? And so, we've tried to do that with the metabolomics, and we found that, using various sort of clustering analytical methods, in fact, there is significant overlap, as it turns out, within HFpEF, when it comes to the metabolomic signatures. And we only found, really, two subgroups within HFpEF. And even these two really did not have much that distinguished them, beyond branched chain amino acids.

And so, this is the first time, at least that our group has seen, at a tissue level, that there is actually a fair bit of homogeneity now in the metabolomic signatures, compared to our RNA sequencing work. And that may be reflective of now, this increasingly cardiometabolic phenotype of HFpEF. And now, we may be seeing signs of that at the clinical and at the treatment level, where we have therapies like SGLT2 inhibitors, that are showing benefit to what seems to be a much broader spectrum of HFpEF, compared to prior therapies. So a lot of questions that have been generated from the work, and we're looking forward to exploring much of this in more detail.

Dr. Carolyn Lam:

And Svati, may I give you the last word? Where do you think this field is headed next?

Dr. Svati Shah:

I think there's so much to do, and I think Dr. Sharma and Dr. Hahn have highlighted how much work there is to do in this space. We're brushing the surface and understanding cardiac metabolism with this really important paper. But Carolyn, as you pointed out, we really need to understand what happens to these patients over time? What happens to, not just cardiac metabolism, but molecular biology more broadly, in patients with HFpEF with these various treatments? Including now, thank goodness, we have SGLT2 inhibitors as a therapeutic intervention for patients with HFpEF. And in fact, we published in Circulation a few months ago, a paper led by a very talented junior faculty, Senthil Selvaraj, where we actually showed that these acetylcarnitine levels that reflect fatty acid oxidation actually are changed by SGLT2 inhibitors, and are associated with changes in clinical outcomes in HFpEF. So we really need larger sample sizes, being able to look at these patients in a longitudinal fashion. But really, doing what Dr. Sharma and Dr Hahn have done, which is careful, careful phenotyping and multidisciplinary teams, so that we can understand the molecular biology, as well as the clinical implications.

Dr. Carolyn Lam:

Oh, wow. Thank you so much, Kavita and Svati, for this incredible interview. I learned so much, and enjoyed it so thoroughly, as I'm sure our listeners did as well.

Well, listeners, 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 2023. 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 Tatsuhiko Naito and Kosuke Inoue as well as Associate Editor Wendy Post as they discuss the article "Genetic Risk of Primary Aldosteronism and Its Contribution to Hypertension: A Cross-Ancestry Meta-Analysis of Genome-Wide Association Study."

Dr. Greg Hundley:

Welcome listeners, to this April 4th discussion of Circulation on the Run. I am one of your co-hosts, Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

And I'm Dr. Peder Myhre from Akershus University Hospital and the University of Oslo in Norway. So Greg, today we have the feature paper, discussing the genetic risk of primary aldosteronism and its contribution to hypertension. So this is such an interesting topic and av very important cost on hypertension. And in this paper, they use cross-ancestry meta-analysis from GWAS studies to assess this very interesting discussion.

But first, Greg, I have a paper that comes to us from the DELIVER trial, and it is about dapagliflozin to patients with HFpEF, and assessing the association with the duration of the heart failure.

So Greg, it is important to understand how the effects of new treatments vary by the duration of heart failure. Because on one hand, physicians may think that a patient who has longer standing heart failure represents a stable survivor where new treatment is unnecessary. On the other hand, the view has been expressed that patients with long-standing heart failure may have more advanced disease, and there may come a point where they no longer respond to or tolerate the addition of new therapies, particularly because of hypotension, kidney dysfunctional and electrolyte abnormality. So the investigators from the DELIVER trial, led by corresponding all author John McMurray from University of Glasgow, therefore, aimed to assess the efficacy and safety of the SGLT2 inhibitor dapagliflozin, according to the duration of heart failure with EF above 40%. So that is mildly reduced or preserved.

Dr. Greg Hundley:

Wow, Peder, very timely, very timely article. So what did they find?

Dr. Peder Myhre:

So Greg, the authors categorized patients by duration of heart failure, one category less than six months, and then six to 12 months, and then one to two years, two to five years, and finally, more than five years. And longer duration heart failure patients were older, and more comorbid with worse symptoms, and the rate of the primary outcome increased with heart failure duration. And so, the benefit of dapagliflozin was consistent across heart failure duration categories with hazard ratios 0.67, 0.78, 0.81, 0.97, and 0.78. And that gives a P4 interaction of 0.41. So the absolute benefit was therefore since there was no P4 interaction, greatest among those with highest risk, and that it was the longest duration heart failure. So there was a number needed to create for heart failure above five years of 24, versus 32 for those with the shortest duration of heart failure. And the authors therefore conclude, that even in patients with long-standing heart failure and generally mild symptoms cannot be considered stable, and it is not too late for such patients to benefit from an SGLT2 inhibitor.

Dr. Greg Hundley:

Ah, very practical information, Peder, beautiful description. Well Peder, this next paper comes to us evaluating low density lipoprotein cholesterol. And as you know, low density lipoprotein cholesterol is an important causal risk factor for atherosclerotic cardiovascular disease. However, a sizable proportion of middle-aged individuals have not developed coronary atherosclerosis as assessed by the presence of coronary artery calcification. Now whether the presence of coronary artery calcification modifies the association of LDL cholesterol with atherosclerotic cardiovascular disease risk, well, that's unknown. So these authors, led by the corresponding author of Martin Mortensen from Aarhus University Hospital, evaluated the association of LDL cholesterol with future atherosclerotic cardiovascular disease events, in patients with and without coronary artery calcium, from 23,132 consecutive symptomatic patients evaluated for coronary artery disease, using coronary commuted tomography angiography, or CTA, that were included in the Western Denmark Heart Registry, which is a semi-national multi-center based registry with longitudinal registration of both patient and procedural data.

Dr. Peder Myhre:

Oh, that is so important, Greg. So we're looking at LDL cholesterol and the association with ASCVD in patients with and without coronary artery calcification. So what did they find?

Dr. Greg Hundley:

Right, Peder. So during a median follow up of 4.3 years, 552 patients experienced a first cardiovascular disease event. In the overall population, LDL cholesterol per 38.7 milligrams per deciliter increase, was associated with cardiovascular disease events during the follow-up period. Now, when stratified by the presence or absence of a baseline coronary artery calcium score, LDL cholesterol was only associated with a cardiovascular disease event in the 47% of patients with a coronary CAC score greater than zero. While no association was observed in the 53% of individuals with a coronary artery calcium score equal to zero.

Now similarly, very high LDL cholesterol, so greater than 193 milligrams per deciliter, versus an LDL cholesterol of less than 116 milligrams per deciliter, was associated with a cardiovascular disease event in patients with a CAC score greater than zero, but not in those without coronary artery calcium. Next, Peder, in patients with coronary artery calcium equal to zero, diabetes, current smoking, and low HDL cholesterol levels, were associated with future cardiovascular disease events. This principle finding was replicated in the multiethnic study of atherosclerosis.

And so, Peder, LDL cholesterol appears almost exclusively associated with a cardiovascular disease event over the ensuing five years of follow-up in middle-aged patients with versus without evidence of coronary atherosclerosis, as identified by coronary artery calcium scores. This information is quite valuable for individualized risk assessment among middle-aged patients.

Dr. Peder Myhre:

Oh, that is so important, Greg. So really, LDL seems to be more predictive of atherosclerotic cardiovascular disease than those with calcium in their coronaries, while there was no association in those with no calcium in their coronaries. Very interesting.

Dr. Greg Hundley:

Absolutely. And there's a very nice editorial by Professor Sniderman entitled, "Cholesterol Coronary Calcification and Cardiovascular Prevention: Lessons We Can Learn from the Western Denmark Heart Registry."

Dr. Peder Myhre:

Thank you, Greg, that was a beautiful summary. And we are going to stay in clinical science, but we're going to move to aortic disease and look at gut microbiota. Now, Greg, large scale human and mechanistic mouse studies indicate a strong relationship between the microbiome dependent metabolyte, Trimethylamine-N-oxide, abbreviated TMAO, and several cardiometabolic diseases. And in this study, which comes to us from corresponding author Philip Owens from University of Cincinnati, the investigators aim to assess TMAO's role in the pathogenesis of AAA and targeting its parent microbes as a potential pharmacologic intervention.

Dr. Greg Hundley:

Ah, very interesting, Peder. So what methodology did they use?

Dr. Peder Myhre:

So Greg, this is one of those fantastic studies combining clinical and preclinical science. And the investigator measured TMAO in two independent patient cohorts, with a total of 2,129. And in addition, they used the murine AAA model, and fed the mice a high choline diet, which is a diet that markedly augment plasma levels of TMAO. And these mice were then treated with broad spectrum antibiotics, targeted inhibition of a gut microbial enzyme with fluorometer chloroquine, called FMC, or utilizing mice genetically deficient of Fmo3.

Dr. Greg Hundley:

Very nice. So what did they find, Peder?

Dr. Peder Myhre:

So the authors found that elevated TMAO was associated with increased AAA incidence and growth in both patient cohort studies. And dietary colon supplementations augmented plasma TMAO and aortic diameter in both mouse models of AAA, which was suppressed with poorly absorbed oral broad spectrum antibiotics. In treatment with FMC ablated TMAO production attenuated colon augmented aneurysm in the initiation, and halted progression of an established aneurysm model. And additionally, the Fmo3 knockout mice had reduced plasma TMAO, aortic diameters, and were protected from AAA rupture compared to wild type mice.

So Greg, in conclusion, this study defined a role for gut microbiota generated TMAO in AAA formation, and additionally, increased microbiome derived TMAO may serve as a novel therapeutic approach for AAA treatment where non currently exists.

Dr. Greg Hundley:

Beautifully described, Peder. And another one of their articles in Circulation that, as you indicated, very nicely complying the world of preclinical and clinical science.

Well, we've got some other articles in the issue, and how about we jump into some of those? So first, there's a very nice Letter to the Editor from Professor Wong entitled, "Frailty and Age Correlation in Clinical Trials." And there is another reply to a prior Letter to the Editor from Professor McMurray entitled, "Efficacy and Safety of Dapagliflozin According to Frailty in Patients with Heart Failure, a Pre-specified Analysis of the DELIVER Trial." And then next, Peder, Michelle A. Albert has a very nice synopsis of the American Heart Association Presidential Address, entitled, "Economic Adversity and Healthcare."

Dr. Peder Myhre:

Nice. And finally, there's a Research Letter from Dr. Baggish entitled, "Association Between Concussion Burden During Professional American-style Football and Post-career Hypertension."

Dr. Greg Hundley:

Very good, Peder. Well, what a packed issue we have this week, and how about we jump next to that feature discussion with our colleague Carolyn? Ah.

Dr. Peder Myhre:

Let's go.

Dr. Carolyn Lam:

Primary aldosteronism, or, we're going to say PA for this discussion, is one of the most common causes of secondary hypertension, and it is also a particularly morbid form of secondary hypertension. So identifying this subgroup of hypertensive patients with primary aldosteronism, again PA, would allow us to perhaps, direct more aggressive management to their cardiometabolic risk. Now, is a genetic approach the way to do it? Well, we're about to find out in today's very special paper.

We're very honored to have the first author, Dr. Tatsuhiko Naito, from Osaka University Graduate School of Medicine, and his second and co-author Dr. Kosuke Inoue, from the Graduate School of Medicine in Kyoto University, as well as our associate editor, Dr. Wendy Post, from Johns Hopkins University School of Medicine, here to discuss this very important paper. Perhaps I could start with you, Dr. Tatsuhiko. Could you please, perhaps, tell us a little bit about what made you do this study, what you did, and what you found?

Dr. Tatsuhiko Naito:

I would like to thank you for inviting us to present the information from our paper. In terms of genetic, germline genetic factors behind the development of PA has not been isolated. And in addition, the PA is the cause of hypertension, but the genetic relationship between hypertension and PA has not been discussed previously. That is why we conducted a genome-wide association study, GWAS, of PA here. Our GWAS consisted of three defined cohorts of our Japanese cohort, UK Biobank, and FinnGen. In our Japanese cohort, we collected samples in Hiroshima University, and we used controls from Biobank Japan, which is the largest Japanese biobank. And we also used two publicly available biobanks, UK Biobank and FinnGen. So they can be used upon registration. By utilizing these resources, we conducted a cross-ancestry, meta-analysis of GWAS.

Dr. Carolyn Lam:

Thank you. And the results, please?

Dr. Tatsuhiko Naito:

In the meta-analysis, we identified five genetic loci that were significantly associated with the risk of PA satisfied in the genome world significant threshold. The strongest association was observed at WNT2B, which is located in chromosome 1. And in addition, we identified one near the genome-wide association locus CYP11B1 and B2, which is located on chromosome 8. So CYP11B2 is the key enzyme that acts in producing aldosterone in the adrenal gland, thus, we consider that resource. This locus would be also our PA risk associated locus with a high probability.

Of interest, these loci were reported to be associated with hypertension, but we thought this results is resemble, because PA occupies around five to 10% of causes of hypertension. Does the PA associated loci could be reported as hypertension associated loci in previous GWAS with large sample size?

So to support our assumption, we compared the risk effect of these genetic loci between PA and hypertension. So if there are risk effects who are coming from PA, these loci should present higher effect on PA than on hypertension. And expectedly, these loci presented significantly higher effect on PA here.

And lastly, inspired by these results, we hypothesized that some of other loci, that had been reported to be associated with hypertension, might come from the primary effects on PA. To investigate this, we picked up blood pressure rated genetic loci from previous GWAS of blood pressure, and compared their risk effects between PA and hypertension. The result was that, 66.7% presented a higher risk effect for PA than for hypertension. And two strictly demonstrates the result. We also performed the adjustment of blood pressure values, and even in this adjustment, 61.9% showed a higher effect on PA than on hypertension. So considering the prevalence of PA among hypertensive individuals, this result is little bit surprising, we think. So PA may explain an unexpectedly large amount of genetic background of hypertension, we think.

Dr. Carolyn Lam:

Wow, thank you so much, Tatsuhiko. So first, genome-wide evidence for genetic predisposition to PA susceptibility, and then, revealing that two thirds of previously established BP associated variants were in fact a higher risk effect for PA than for hypertension. Wow. So Wendy, could you help us put these findings into perspective, please?

Dr. Wendy Post:

Thank you, Carolyn. Congratulations to the authors. This was a really interesting paper that we enjoyed discussing in our meetings. We were especially interested in the clinical potential, clinical implications of your study. We all see patients with hypertension, whether we're cardiologists, or endocrinologists, or primary care physicians. And so, trying to understand more about what is potentially the underlying causes for hypertension, from a biological standpoint, that might help us to identify and treat our patients appropriately, is really so important. And so, I was wondering, Kosuke, if you could tell us, from your perspective as an endocrinologist and a researcher, how you interpret these studies in a way that our readers might be able to use these results to think about the next patient we're seeing in our clinic with hypertension?

Dr. Kosuke Inoue:

Yeah. Thank you very much for asking this important point, Wendy. We're, first of all, I'm very pleased that our research is published in Circulation, and thank you very much for your consideration. And I think there are two major implications of our findings, treatment and a diagnosis.

First of all, for treatment, well, our findings advance our current state of knowledge about PA pathogenesis. Like Wendy said, what is the causes? And what is the genetic causes of primary aldosteronism ? And particularly, it'll be helpful for better precision medicine in the future. And therapy involving genetic information, this may not be the clinical practice tomorrow, but this would advance our clinical practice in the future.

And the second point is diagnosis. Well, primary aldosteronism is really important to diagnose, because treating only blood pressure, or hypertension, is not enough for patients with primary aldosteronism. Like Tatsu said, aldosteronism itself has a direct effect on organ damage beyond blood pressure, elevated blood pressure. So diagnosis of primary aldosteronism is critical, and our findings showed 10%, the current percentage of 10% primary aldosteronism, may not be fully diagnosed patients, given that 67% of PA associated variants presented higher alteration for the PA. So I think, we needed to be more careful about diagnosing primary aldosteronism. So for those who have a resistant hypertension, or who are suspected to have primary aldosteronism, we needed to screen more for such patients.

Dr. Wendy Post:

Thank you, that was really helpful. Can I ask you a little bit more about what you recommend in clinical practice? I've been asking around, we actually just had our American College of Cardiology meeting in New Orleans, and I knew this paper had just been published online, and the editorial is about to come out. And so, I noticed that there's a lot of variability in practice, as to whether we screen for PA, or just treat with aldosterone blocking medications, such as spironalactone. So can you tell me a little bit more about what you recommend? And maybe your practice is different as an endocrinologist, but should we just presume people have primary aldo, and aldosteronism, and treat them for that? Or should we be searching for aldosterone producing adenomas, and surgically removing them? If you could, tell us a little bit more about what you recommend.

Dr. Kosuke Inoue:

Thank you very much for asking this, Wendy. So to be honest, I don't think we can conclude something only from our result, of course. But what I can recommend is, from our findings, it is better to always thinking about primary aldosteronism when treating patients with hypertension. So those may have and those may not have that. I think thinking about primary aldosteronism is important, and if there's a possibility they have, or if their clinicians have trouble treating hypertension, then I would recommend screening for such patients about primary aldosteronism.

Dr. Wendy Post:

In order to find an adenoma, is that the purpose of the screening?

Dr. Kosuke Inoue:

I think, whether they have an adenoma or, there are two types of primary aldosteronism, aldosteronism producing adenoma, and BAH bilateral adrenal hypocardia. And rather does not have adenoma itself, but they have a hyper aldosteronism in their blood. So we cannot tell whether they have a PA or BAH. But anyway, we needed to think about whether they have excess level of aldosterone, and if they have, we needed to think about the proper treatment, such as medication therapy or surgical treatment.

Dr. Wendy Post:

Thank you. So if they have bilateral adrenal hyperplasia, then medical therapy.

Dr. Kosuke Inoue:

Yes.

Dr. Wendy Post:

If they had an adenoma, you might consider surgical excision.

Dr. Kosuke Inoue:

Generally, yes.

Dr. Wendy Post:

Thank you.

Dr. Carolyn Lam:

Wendy, I love that clinical focus, because much as PA is a highly morbid cause of secondary hypertension, it's also sometimes seen as potentially curable, or at least targetable with specific medical therapy. And thank you for inviting that beautiful editorial, I'd love to quote from it. Because the final sentence of it really does say that this paper really reminds everyone treating hypertension, to maintain a high clinical suspicion for PA, and hopefully, such a high clinical suspicion will lower the threshold for biochemical testing. Will motivate the pursuit of localization studies, to determine if a surgical cure is possible. And at minimum, allow for early initiation of mineralocorticoid-receptor blockade. How beautifully put, huh?

So thank you for inviting that editorial. And if I may, are there any final take home messages from anyone? May I start with Dr. Tatsuhiko? Any take home messages or next steps you'd like to mention?

Dr. Tatsuhiko Naito:

Okay. Yeah. I think the future advances in this study first, as Kosuke said, of PA is mainly classified into aldosterone producing adenoma and bilateral adrenal hyperplasia. However, we couldn't identify subtype specific risk associated loci, due to the lack of statistical power. And specifically, we know that histopathological features of aldosterone producing adenoma are reported, vary depending on the causative somatic mutations. So further insights may be obtained by investigating the genetic risk of aldosterone producing adenoma, according to the causative somatic mutations. But anyways, we are happy to present the genome-wide association genetic loci that associated with PA in the cross-ancestry cohort for the first time. Thank you.

Dr. Carolyn Lam:

Thank you. Kosuke?

Kosuke Inoue:

Sure. So I totally agree with what Tatshu said, and also, aldosterone is a nasty hormone. So as a clinician, I would recommend, for all clinicians who treat patients with hypertension, please always consider aldosterone, and whether their aldosterone should be treated or not. And thank you.

Dr. Carolyn Lam:

Wendy?

Dr. Wendy Post:

I also wanted to get back to your statements, Kosuke, about precision medicine. And this was a genetic study, and you did mention how this could potentially lead to precision medicine, practical approaches to identifying patients who might be treated with specific therapies, based on their genetics. And of course, we're not there yet, but thanks for helping us to get closer to that vision in the future.

Dr. Carolyn Lam:

Indeed, thank you so much for publishing this very important paper in Circulation, and for coming online to discuss it today.

You've been listening to Circulation on the Run. Thank you listeners 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 2023. 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 Vincent Aengevaeren and Associate Editor Jarett Berry as they discuss the article "Exercise Volume Versus Intensity and the Progression of Coronary Atherosclerosis in Middle-Aged and Older Athletes: Findings From the MARC-2 Study."

Dr. Gregory Hundley:

Welcome listeners to this March 28th issue, and I am one of your co-hosts, Dr. Gregory Hundley, Associate Editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

And I'm Dr. Peder Myhre, Social Media Editor from Akershus University Hospital and University of Oslo in Norway. And today, Greg, we have such an interesting feature paper. It comes to us from Professor Aengevaeren and it discusses the progression of coronary atherosclerosis in middle-aged and older athletes. They're looking at exercise volume versus intensity in the MARC-2 study. So Greg, this is really something us master athletes are interested in, and I'm really excited to hear this discussion.

Dr. Gregory Hundley:

Very nice. Well, how about we jump into some of the other articles first, Peder? And I could go first. So Peder, my first article involves pregnancy related complications. And as you know, these pregnancy complications are associated with increased risk of developing cardiometabolic diseases and an earlier mortality. However, much of the prior research has been limited to individuals of White race. So these investigators led by Professor Cuilin Zhang from the National Institutes of Health aimed to investigate pregnancy complications in association with total and cause specific mortality in a racially diverse cohort, and then evaluate whether associations differ between Black and White individuals. And they performed their work using the Collaborative Perinatal Project, which was a prospective cohort study of 48,197 pregnant women across 12 US clinical centers from the period of time of 1959 through 1966.

Dr. Peder Myhre:

Oh wow, Greg. Almost 50,000 pregnant women. Very huge initiative. So what did they find?

Dr. Gregory Hundley:

Right, Peder. So overall, 15% of participants had preterm delivery, 5% had hypertensive disorders of pregnancy, and 1% had gestational diabetes or impaired fasting glucose. Now, the preterm delivery was higher in individuals of Black race at 20% relative to those of White race, which were 10%. Now, in relation to all-cause mortality, the following were associated with increase adjusted hazard ratios. One, spontaneous labor; two, induced labor; three, pre-labor cesarean delivery. And all of those, those adjusted hazard ratios in comparison with a full term delivery.

Next, in the world of blood pressure, preeclampsia and eclampsia as well as superimposed preeclampsia and eclampsia were all associated with adjusted hazard ratios that were elevated compared to individuals with normal blood pressure. And then finally, in those individuals with gestational diabetes or impaired fasting glucose, their adjusted hazard ratio, again for all-cause mortality, was elevated relative to those with normal glycemia. Now interestingly, in comparing the two racial groups, preterm induced labor was associated with greater mortality risk among those of Black race relative to those of White race. However, or while, preterm pre-labor cesarean delivery interestingly and conversely was associated with a higher adjusted hazard ratio for those of White race as compared to individuals of Black race.

So Peder, in summary, within this large diverse US cohort, pregnancy complications were associated with higher mortality almost 50 years later. And the higher incidents of some complications occurred in individuals of Black race. And differential associations with mortality risk indicate that because of these racial differences, there could really be disparities in pregnancy related health. And finally, that these disparities and their relationship with overall health really could have long life implications for earlier mortality in these patients.

Dr. Peder Myhre:

Well, that is really interesting, Greg. Are you ready for the next paper?

Dr. Gregory Hundley:

Absolutely.

Dr. Peder Myhre:

So this paper is about the glucagon-like peptide-1 receptor agonist and large CV outcome trials clearly show that several GLP-1 agonists reduce CV outcomes in patients with Type 2 diabetes. Whether their cardioprotective effects are related to drug dose or potency remains uncertain however, but important due to recent introduction of high dose and high potency agents for diabetes and for weight loss indications. And therefore, Greg, in this paper, the investigators from the AMPLITUDE-O trial led by corresponding author Hertzel Gerstein from McMaster University Hamilton Health Sciences analyzed the effect of the different doses of the GLP-1 agonist efpeglenatide that is four milligram, six milligram compared to placebo. And the effect was assessed on major adverse cardiovascular events.

Dr. Gregory Hundley:

Interesting, Peder. So what did they find?

Dr. Peder Myhre:

So Greg, during a median follow-up of 1.8 years, MACE occurred in 9.2 participants assigned to placebo, 7.7 in participants assigned to efpeglenatide four milligrams, and 6.2% in participants assigned to efpeglenatide six milligrams. And participants receiving high dose of this GLP-1 agonist also experienced fewer secondary outcomes, including the composite of MACE coronary revascularizations or hospitalizations for unstable angina, a kidney composite outcome comprising sustained new microalbuminuria, decline in eGFR more than 40%, or renal failure. And there was also a clear dose response relationship noted for all primary and secondary outcomes with a P4 trend that was significant. So Greg, the authors conclude that the graded relationship between efpeglenatide dose and CV outcomes suggests that titrating this drug and potentially other GLP-1 agonists to high doses may maximize their cardiovascular and kidney benefits.

Dr. Gregory Hundley:

Very nice, Peder. Well, my next paper comes to us and involves the world of bleeding associated with Factor Xa inhibitors. So Peder, andexanet alfa is a modified recombinant inactive Factor Xa designed to reverse Factor Xa inhibitors. ANNEXA-4 is a multicenter prospective phase 3B single group cohort study that evaluated andexanet alfa in patients with acute major bleeding. And the study is led by Dr. Truman Milling of Seton Dell Medical School Stroke Institute and colleagues, and they present the results of their final analyses.

Dr. Peder Myhre:

Oh, this is really interesting, Greg. So what did they find?

Dr. Gregory Hundley:

Right, Peder. So first, 479 patients were enrolled. And their average age was 78 years. 54% were men, 86% were White. 81% of the individuals enrolled were anticoagulated for atrial fibrillation. And they had received this drug 11 hours median time since the last dose. 51% of the individuals were on a apixaban, 37% were on rivaroxaban, and 8% were on edoxaban, and then finally 5% were on enoxaparin. Now bleeding, Peder, was predominantly intracranial in 69%, it was GI in 23%. In evaluable apixaban patients, median anti Factor Xa activity decreased from 146.9 to 10 nanograms per milliliter. That's a 93% reduction. In rivaroxaban patients, it decreased from 214 to 10.8 nanograms per milliliter. That's a 94% reduction. In edoxaban patients, it decreased from 121 to 24 nanograms per milliliter; a 71% reduction. And in enoxaparin, it decreased from 0.48 to 0.11 international units per milliliter or a 75% reduction.

So Peder, excellent or good hemostasis occurred in 274 of the 342 evaluable patients. So in 80%. In the safety population, thrombotic events occurred in about 10% of patients. And in 16 patients, this occurred during treatment with prophylactic anticoagulation that began after the bleeding event. So no thrombotic episodes occurred after oral anticoagulation restart. So Peder, in conclusion, in patients with major bleeding associated with the use of Factor Xa inhibitors, treatment with enoxaparin and andexanet alfa reduced anti Factor Xa activity and was associated with good or excellent hemostatic efficacy in 80% of patients.

Dr. Peder Myhre:

Oh wow. That was really impressive.

Dr. Gregory Hundley:

Yeah, what a very practical study. Well, Peder, we have some other articles in the issue. How about I go first? So first, there's a Research Letter from Professor Eleanor entitled "A Mouse Model of Atrial Fibrillation in Sepsis." And then from Tracy Hampton we have some Cardiology News. First from Professor Shane et al, a paper on the impact of coffee subtypes on incident cardiovascular disease, arrhythmias, and mortality, long-term outcomes from the UK Biobank study, which is published in the European Journal of Preventive Cardiology. Next from Professor Morashige, there is a paper entitled "Extra Cardiac BCAA Metabolism Lowers Blood Pressure and Protects From Heart Failure." And that's published in Cell Metabolism. And then finally from Professor Kessler and associates, the paper is entitled "Common and Rare Variant Associations with Colonial Haematopoiesis Phenotypes." And that particular paper is published in Nature.

Dr. Peder Myhre:

That's great, Greg. And we also have an exchange of letters by Dr. Ding and Dr. Kirshenbaum regarding the article "Proteasomal Degradation of TRAF2 Mediates Mitochondrial Dysfunction in Doxorubicin-Cardiomyopathy." And finally we have On My Mind by Bertram Pitt entitled "Early Implementation of aldosterone Targeted Therapy in Patients with Hypertension." Now Greg, let's go to the feature paper to discuss the progression of coronary atherosclerosis in middle-aged and older athletes.

Dr. Gregory Hundley:

Very good. Let's go.

Welcome listeners to this feature discussion on March 28th. And we have with us today Dr. Vincent Aengevaeren from Radboud University Medical Center in Nijmegen in the Netherlands. And also with us one of our associated editors, Dr. Jarett Berry from University of Texas Southwestern Medical Center in Dallas, Texas. Welcome gentlemen. Well, Vince, we'll 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. Vincent Aengevaeren:

So this specific study is actually a follow-up study of a previous study that we did on the relationship between exercise and coronary atherosclerosis. The original study was published also in circulation in 2017 and it really looked at the association of relationship between exercise volume, lifelong exercise volume and coronary atherosclerosis. And at that time we found that there was actually a sort of paradoxical association between lifelong exercise volume and coronary atherosclerosis that with higher lifelong exercise volumes, there was a dose upon dependent association with the prevalence of coronary atherosclerosis.

And there was actually in the same issue, there was another paper in 2017 from a London group shown similar findings. And actually, yesterday on the ACC, there was another paper also showing increased coronary atherosclerosis in athletes. And this study of course there was also some critic like is this caused by confounding, these were observational perceptional studies, could there be other factors playing, but also none of the studies looked at the differentiation between exercise volume and exercise intensity. So the composition of the exercise. So that was the main question actually for this study. We want to do a follow-up study after at least five years do another CT scan, again, get everyone back the questionnaire, exercise habits, and then also specifically look at exercise volume versus exercise and density.

Dr. Gregory Hundley:

Very nice. So it sounds like in this study you have a cohort that you're following over time. So maybe describe for us a little bit more the specific study design and who is included. Who is your study population here?

Dr. Vincent Aengevaeren:

The study population is called the MARC study, Measuring Athletes Risk of Cardiac events. And the study was originally designed mainly based on the fact that healthy athletes, mainly male athletes, sometimes suddenly die of coronary atherosclerosis, which is not really recognized beforehand. So the main study idea was to look at healthy male athletes who didn't experience any symptoms and who underwent the screening, including an exercise test with EKG with normal findings and who then subsequently underwent a coronary CT scan. So blank CT scan for corona calcification score, but also contrast enhanced CT scan to look at the degree of coronary atherosclerosis to those of [inaudible 00:15:18] characteristics.

So that's how the original study was designed and it included 318 male individuals over the age of 45 with a very heterogeneous exercise exposure. So they all had to do some type of sports, but there was no minimal dose. So it really depended. So we have some very high level athletes, but also some more of the regular people who exercise a lot less. So very heterogeneous exposure. And for this study, so in the follow-up study, we actually included 291 of those 318 individuals after six years, which I was pretty happy with. And for this specific analysis we excluded two individuals due to their PCI in between. So that's pretty much the cohort that we're looking at. And during this follow-up period of six years, they did the equivalent of about 40 MET hours per week, which equates to about five hours of the exercise.

Dr. Gregory Hundley:

Very nice. And Vince, you said you had a very diverse group. I mean, a lot of times I'll think about the extremes here. Folks that do a lot of aerobic exercise, those that I think about the power weightlifter. What kind of distribution of athlete, maybe just some practical identifiers for our listeners here.

Dr. Vincent Aengevaeren:

So it's a very important point. So the main type of athletes in this group who are endurance athletes, so mainly runners and cyclists. Of course also some other type athletes and some athletes do multiple type of sports, but mainly runners and cyclists and definitely large proportion of [inaudible 00:16:53] athletes.

Dr. Gregory Hundley:

Very nice. So Vince, describe for us your study results.

Dr. Vincent Aengevaeren:

During this follow-up period, and it's important to state that for this follow-up study we used the exercise characteristics during the follow-up period, we found that exercise volume during follow-up was not associated with progression of coronary atherosclerosis, but exercise intensity was. So we defined exercise intensity based on the MET score, the metabolic equipment of task score, which is derived from previous studies. And there's a compendium explaining MET scores for all the different sports and we used that to categorize the different sports. And we've found that vigorous intensity exercise, for example cycling, was associated with less progression of coronary calcification, but very vigorous intensity exercise, for example running was associated with more progression or coronary calcification. And if you then also look at plaque types, we also saw that those who did the most very vigorous exercise also had a bit more calcified plaque progression. So that was the main findings.

Dr. Gregory Hundley:

And Vince, describe for our listeners, many whom are cardiologists or others fellows, et cetera. Can you give me a specific example of vigorous exercise versus very vigorous exercise? Like, if I'm doing something during the week, describe for me those two categories, examples.

Dr. Vincent Aengevaeren:

So typically, and of course this is a very typical vigorous exercise was cycling and very vigorous exercise was running. But of course as you do cycling at a higher intensity, for example spinning on a spinning bike, it's traditionally at a higher exercise intensity. So that was counted as a very vigorous intensity exercise. And I have to say this was based on questionnaire data, so I did not have six-year or lifelong heart rate data. So it is based on questionnaire data, the categorization of exercise intensity. That's a good example. Other things of [inaudible 00:19:03] intensives, for example, soccer, hockey, I don't know how popular those sports are in America, but those are pretty popular in Netherlands as well.

Dr. Gregory Hundley:

When you mean very vigorous for some of our runners out there, I mean for the casual runner that might run two or three miles a day, is that very vigorous or are you talking about someone that's training periodically for marathons and running three or four marathons a year?

Dr. Vincent Aengevaeren:

That is really more, I guess, about volume. So if people do a lot of marathons, that can actually be at a lower intensity. Like, with intensity, we really, really mean the heart rate intensity and not the intensity of the volume. So I have to specify that. It's really exercise intensity such as for oxygen consumption or heart rate and not the volume in the hours per week. So typically the runners that we had were mostly very vigorous runners. So couple hours per week traditionally they did like trainings of one and a half hour, which is usually at a higher intensity.

Dr. Gregory Hundley:

Very nice. Well listeners, now we're going to turn to one of our associate editors, Dr. Jarett Berry, who really has some expertise in this area. And Jarett, you see many papers in circulation. What do you find is unique about this particular study and then how do you put its results really in the context of other studies that have focused on exercise both in duration as well as intensity?

Dr. Jarett Berry:

Yeah, thanks Greg. And Vince, a fantastic paper, such a privilege to be able to visit with both of you today about this important paper. I think if you take a step back here, challenges I think we all have as physicians is dealing with these uncertain questions that arise clinically where you encounter patients who are exercising at these extreme levels. And although it's not super common, we do encounter these scenarios clinically. And what we need in context like this is we need some data and understanding of what's happening clinically to be able to provide guidance. And so we're really in a context like this in a scenario where we have the common clinical problem of incomplete information. And I think it's studies like this that really help us move the needle to help us understand how to think about those patients of ours that exercise at very high levels.

I do think it's important to put it into context, about 10% of the participants in this study exercised below 1,000 minutes per week. And so for those of you taking notes at home, that's the guidelines in 500 and 1,000 minutes per week would be, I mean you'd be hitting the guidelines. And two-thirds of these individuals were exercising at 2,000 minutes per week. So I think it's important to put it into context when we think about applying and understanding the question about toxicity of exercise, putting that into context that most of the patients that we encounter are not exercising at these high levels. However, as I mentioned, we do encounter this and we have to know what to do with it.

The key here I think is... The other context is with a point that's been raised already in some of the questions and discussion is the heterogeneity that we see in individuals who exercise at these high levels. When you're trying to think about dose of exercise, we have to think about not just intensity but volume. And I think what the study's done here has done a really nice job of trying to parse that out because we can achieve the dose of exercise that's recommended or the dose of exercise that we want to achieve for personal reasons, but we can get there through different ways. We can get there through more hours or we can get there through a higher intensity. And then of course, obviously combinations of the two.

And I think this study here does two things for us. Number one, it gives us a delta question. We've seen this before with just looking cross-sectionally and we have all the challenges that come with that with regard to recall of exercise. Here we have a prospective cohort that we're following or that events followed. And secondly, the ability to parse out both volume and intensity over time. And I think that for me, the finding that really sticks out is that in addition to all the complexities that are right here, we see that the story with regard the components of the dose may not be uniform. That intensity or exercising at very high intensity may be a different part of the equation beyond just volume.

And I think that as we think about counseling our patients as they are engaging in this type of high level of exercise, I think it's one additional component of our way of interpreting this and providing counsel to these patients about how to think about volume and intensity. And maybe these data suggests the hypothesis that the volume part of the dose equation may be safer or maybe something that's more palatable for the heart perhaps over time than the intensity. I think the big elephant in the room, of course, is the fundamental question is that we're dealing with an intermediate phenotype and we know lots of observational data showing that more atheros bad. We all recognize that, but you can get to athero through different mechanisms here.

And I think that these data and others suggest that exercise is one mechanism perhaps that though you can get athero, the question is what is the true clinical significance from a [inaudible 00:24:32] standpoint down the road as we try to extrapolate the intermediate phenotype into the future. And I think there's controversy, I think agreement about what the intermediate phenotype means in these high volume exercisers. And I think that question remains unknown, I think.

But in the interim, as I said in the beginning, that as we think about putting all this into context, we don't have perfect information and we do have to take the information that we do have to provide the counsel that we need to provide if these patients. And I think I take away from this that when providing counsel, maybe I lean more towards volume and less towards this really high volume, sorry, this really high intensity for those individuals whose coronary calcium or their athero burden is particularly high. But a fantastic study. Another step in the road and it's really trying to understand an incredibly complex story and one that will continue to unfold.

Dr. Gregory Hundley:

Very nice, Jarett. And listeners, we're going to turn back to both Vince and Jarett here each in 30 seconds. Vince, what do you see as the next study that your group or others might want to be considering in this sphere of research?

Dr. Vincent Aengevaeren:

For me personally, the next big thing that we should do is really cardiovascular risk. So what's the clinical relevance of this finding? So coronary calcification is strongly associated with cardiovascular risk, but how that is in these athletes in which we see increased coronary calcification, that's still pretty much the question. I mean, any plaque is worse than no plaque, but how is this for the very vigorous exercisers who may show some more calcification and whether that risk is different. I mean, that's the question that all the athletes that email me after this type of publication have the question. And also the mechanisms. Like, what are the underlying mechanisms? That's also a next lead study for me.

Dr. Gregory Hundley:

Very nice. And Jarett?

Dr. Jarett Berry:

Yeah, I think the ultimate question is, I completely agree, is what is the clinical significance. I think that's going to be... That's a challenging question to answer just because of the on average these individuals are more rare. And so following these individuals over time to really tease out the clinical significance of this type of athero in these athletes, I think, is a challenge. I think for me the next step would be more studies like this where we can get more granular with regard to measured exercise intensity. I think wearable devices, things that Vince alluded to with regard to heart rate, really trying to get more quantitative to try to parse out the contribution of more objectively measured exercise intensities, I think would probably, for me, represents kind of probably the next step, is digging a little deeper into the phenotype and being a little bit more precise perhaps with studies like this to help us begin to understand the significance of these findings.

Dr. Gregory Hundley:

Very nice. Well, listeners, we want to thank Dr. Vincent Aengevaeren from Radboud University Medical Center in Nijmegen in the Netherlands, and our own associated editor, Dr. Jarett Berry from University of Texas Southwestern Medical Center in Dallas, Texas for bringing us this study highlighting that exercise intensity but not volume was associated with progression of coronary atherosclerosis during a six-year follow-up of this cohort of really trained athletes and intriguingly the very vigorous. So we want to distinguish that. The very vigorous intensity exercise was associated with greater coronary artery calcium calcified plaque progression, whereas simply just vigorous intensity exercise, casual riding of the bike, casual running, et cetera, was associated with less coronary artery calcium progression.

Well, on behalf of Peder and 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 2023. 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 Mikael Dellborg and Associate Editor Gerald Greil as they discuss the article "Adults With Congenital Heart Disease: Trends in Event-Free Survival Past Middle Age."

Dr. Greg Hundley:

Welcome listeners to this March 21st issue. And I am one of your co-hosts, Dr. Greg Hundley, Associate Editor Director of the Pauley Heart Center at VSU Health in Richmond, Virginia.

Dr. Peder Myhre:

And I am the other co-host, Dr. Peder Myhre, from Akershus University Hospital and University of Oslo in Norway.

Dr. Greg Hundley:

Well, Peder, we have a very interesting feature discussion this week. It focuses on adults with congenital heart disease. And as you are aware, over the last 25 to 30 years the survival rate of individuals with congenital heart disease has really improved. And this group, led by Professor Dellborg, will discuss with us more on results from a Swedish registry examining patients after the age of 18 with adult congenital heart 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? Would you like to go first?

Dr. Peder Myhre:

I would love it to, Greg, thank you. So Greg, the first paper is about aortic stenosis and the genome-wide association study looking at aortic stenosis in patients from the Million Veteran Program. And as you know, Greg, calcific aortic stenosis is the most common valve of heart disease in older adults and has no effective preventive therapies. Genome-wide Association studies, GWAS, can identify genes influencing disease and may help prioritize therapeutic targets for aortic stenosis. And in this study, which comes to us from co-corresponding authors, O'Donnell from VA Boston Health System and Dr. Natarajan from Massachusetts General Hospital, both in Boston Massachusetts, performed genetic analysis in 14,451 cases with aortic stenosis and almost 400,000 controls in the Multiancestry Million Veteran Program. And replication for these results was performed in five other cohorts.

Dr. Greg Hundley:

Wow, Peder, so a very large gene-wide association study. So what did they find?

Dr. Peder Myhre:

So Greg, the authors found 23 lead variants representing 17 unique genomic regions. And of the 23 lead variants, 14 were significant in replication, representing 11 unique genomic regions. And five replicated genomic regions were previously known risk loci for aortic stenosis, while six were novel. And of the 14 replicated lead variants, only two of these were also significant in atherosclerotic cardiovascular disease GWAS. And in Mendelian randomization, lipoprotein a and LDL cholesterol were both associated with aortic stenosis, but the association between LDL cholesterol and aortic stenosis was attenuated when adjusting for LP a. So Greg, in conclusion this study identified six novel genomic regions for aortic stenosis, and secondary analysis highlighted roles of lipid metabolism, inflammation, cellular senescence and adiposity in the pathobiology of or stenosis, and also clarified the shared and differential genetic architectures of aortic stenosis with atherosclerotic cardiovascular disease.

Dr. Greg Hundley:

Wow, Peder, what a beautiful description. Very comprehensive study. Well, my study comes to us from the world of preclinical science and, Peder, it involves embryonic heart development. So Peder, placental and embryonic heart development occur in parallel, and these organs have been proposed to exert reciprocal regulation during gestation. Poor presentation has been associated with congenital heart disease, an important cause of infant mortality. However, the mechanisms by which altered placental development can lead to congenital heart disease remain really unresolved. So in this study, led by Dr. Suchita Nadkarni from Queen Mary University of London and colleagues, the team used an in vivo neutrophil-driven placental inflammation model via antibody depletion of maternal circulating neutrophils at key stages during time-mated murine pregnancy, embryonic day 4.5, 7.5, and then the animals were culled at embryonic day 14.5 to assess placental and embryonic heart development.

Dr. Peder Myhre:

Oh, wow. Very interesting design. And, Greg, I'm curious to know what did they find?

Dr. Greg Hundley:

Right, Peder. So they found that neutrophil-driven placental inflammation leads to inadequate placental development and loss of barrier function. And consequently, placental inflammatory monocytes of maternal origin become capable of then migrating to the embryonic heart and alter the normal composition of resonant cardiac macrophages and cardiac tissue structure. This cardiac impairment continues into postnatal life, hindering normal tissue architecture and function. Also, they found that tempering placental inflammation can prevent this fetal cardiac defect and is sufficient to promote normal cardiac function in postnatal life.

So in conclusion, Peder, these observations provide a mechanistic paradigm whereby neutrophil-driven inflammation in pregnancy can preclude normal embryonic heart development as a direct consequence of poor placental development. And this in turn certainly has major implications on cardiac function into the adult life of these animals. And this really warrants further study in larger animal models and perhaps human subjects.

Dr. Peder Myhre:

Very interesting, Greg. Thank you for summarizing that. And we also have some other articles in the mail bag today. Do you mind going first?

Dr. Greg Hundley:

Sure, Peder. So what I've got is a very nice exchange of letters from Doctors Deng, Schmidt, and Tabák regarding a prior paper entitled, "Risk of Macrovascular and Microvascular Disease in Diabetes Diagnosed Using Oral Glucose Tolerance Test With and Without Confirmation by Hemoglobin A1c: The Whitehall II Cohort Study."

Dr. Peder Myhre:

And Greg, we also have a Research Letter from Dr. Niklas Bergh entitled, "Risk of Heart Failure in Congenital Heart Disease: A Nationwide Register-based Cohort Study." And then there is an article summarizing Highlights from the Circulation Family written by Molly Robbins [and Dr. Parag Joshi] where she summarizes, first the characteristics of pleomorphic ventricular tachycardia described in Circulation: A and E, then racial inequities in assessing advanced heart failure therapies reported in Circulation: Heart Failure. Outpatient clinic-based vascular procedure outcomes are compared with those done in a hospital setting in Circulation: Cardiovascular Quality and Outcomes. Then there's a paper about immune cell imaging using nuclear methods from Circulation: Cardiovascular Imaging. And finally, temporal trends in left main PCI from the UK described in Circulation: Cardiovascular Interventions.

And then Greg, we have one final very interesting paper, which is a joint opinion from the European Society of Cardiology, American Heart Association, and American College of Cardiology, in addition to the World Heart Federation and it's entitled, "Randomized Trials Fit for the 21st Century."

And I'm going to read you a quote from the beginning of this article, Greg. It is, "Randomized controlled trials are the cornerstones for reliably validating therapeutic strategies. However, during the past 25 years, the rules and regulations governing randomized trials and their interpretation have become increasingly burdensome, and the cost and complexity of trials has become prohibitive. The present model is unsustainable, and the development of potentially effective treatments is often stopped prematurely on financial grounds, while existing drug treatments or non-drug interventions, such as screening strategies or management tools, may not be assessed reliably." What do you think about that?

Dr. Greg Hundley:

Oh, wow, Peder. Very provocative. So it'd be interesting for our listeners to take a gander at that particular paper. Well, what a great issue and how about we get on to that feature discussion?

Dr. Peder Myhre:

Let's go.

Dr. Mercedes Carnethon:

Thank you for joining us on this episode of Circulation on the Run Podcast. My name is Mercedes Carnethon. I'm an Associate Editor at the journal Circulation and Professor and Vice Chair of Preventive Medicine at the Northwestern University, Feinberg School of Medicine. I'm thrilled today to be able to host this podcast alongside my colleague at Circulation, Gerald Greil, and with our special guest today, Dr. Mikael Dellborg from the Sahlgrenska Academy at the University of Gothenburg and Sahlgrenska University Hospital. Welcome this morning, Mikael, to our podcast. We're really excited that you shared this important work to us about adults with congenital heart disease, particularly given the burden of the condition and how many more individuals are living to adulthood with congenital heart disease. So I'd love to really just open with asking you to tell us a little bit about your study and what you found.

Professor Mikael Dellborg:

Well, first thank you for inviting me to talk about these issues. I very much appreciate the opportunity and I appreciate having the paper published by Circulation, which of course is a great honor.

Our study included 37,278 patients with congenital heart disease born between 1950 and 1999, and alive at 18 years of age. Follow-up was started in 1968 and at 18 years of age, and went on until the end of 2017 or death. So the mean follow-up was 19.2 years. And for every patient with CHD, we had 10 randomly chosen controls from the general population registry, matched for year of birth and sex and, of course, without CHD, so 37,000 patients and 412,000 controls. During the follow-up, 1,937 patients with CHD died or 5.2%, as compared to 1.6% of controls, a mortality three to four times higher among patients with CHD.

Still, at 50 years of follow-up, i.e. at age 68, more than 75% of all patients with CHD were still alive, and I think that is the positive news of this paper. Mortality wise, this could be expected highest among those with the most severe defects, the conotruncal defects, i.e., the transposition of the great arteries, the tetrology patients, double out ventricles and so on. And there the hazard ratio for death was 10.1 times that of controls. But also, for non-com complex conditions such as that we consider very malignant such as atrial septal defect, the ASD, there was a slight but significant increase in risk with the hazard ratio 1.4 times that of controls. We also looked at how the increased risk of mortality changed over time. And when comparing birth year by birth year, we could see that things started to really change in the mid 1970s, where the hazard ratio began to decline.

So if you were born around 1950, '60 or '70, once you reached 18 years of age, your risk of dying had not really changed over the years. But once you were born '75, '80, '85 and on, your risk past 18 years of age declined and was lower as compared to those born before that, although still higher than the risk for controls. This decline was dramatic and significant for all patients with complex CHD. For patients with less complex conditions, it was smaller and not statistically significant. Although it trended in the same direction. The excess risk also declined with age. Typically, it declined from 20 to 100 times the risk of controls in the first years after turning 18, to seven to eight times after 30 years of follow-up. In other words, when you were in your fifties the difference between CHD and controls was much smaller, although still existed.

Dr. Mercedes Carnethon:

Oh, wow. So that really seems to shift over time and that gap got a little smaller with aging. What about these findings surprised you?

Professor Mikael Dellborg:

What surprised us was to see that there is a... For the CHD population as a group, we can see that the changes in operative techniques, the possibility to operate on much earlier time that became used in the '70s, mid-late '70s, early '80s, that has really changed life for so many patients. When we started the Adult Congenital Heart Unit at our hospital in 1996, there was a belief that either you were cured or you are a sad person to follow. You will only have trouble and you will die in your thirties or you'll get a transplant. That was the three conditions that we could see coming, but that's not true. I mean, again, once you turn 18, once you come to the adult cardiologist, you will most likely be 68, 70 years, 75 years of age.

Dr. Mercedes Carnethon:

Now, that is fantastic. I want to turn to you, Gerald, because you were obviously the handling editor of this piece and saw a lot of strengths. Can you tell us a little bit about why you wanted this piece for Circulation?

Dr. Gerald Greil:

Mikael, thank you so much for submitting to Circulation. The numbers of the patients you had for this study, including the controls, is impressive and we all think that it's one of the largest patients areas we looked at. Mikael, obviously this is all exceptional, but can you line out to us what are the strengths and limitations of your study? And how you think the results of your investigations are going to impact patient care in the future?

Professor Mikael Dellborg:

Thank you, Gerald. I think that the strengths are obviously, like you pointed out, there's 37,000 patients. There is 50 years of patients, there's 20 years of follow-up on average and that's clearly a strength. Also, that we have virtually no patients lost to follow-up. We have many controls and the registers we used are public, mandatory and have been fully operational for CHD care and CHD hospitals and including the death registry since 1968, which is when we really started the follow-up. So it's a broad and complete spectrum of patients with congenital heart disease, excluding none, and I think it's fair to say that our data reflect what you can expect from a population of eight to 10 million people, which is the Swedish population during these years.

The weaknesses are clearly, as with any data of this sort, i.e. Large public registers, you will always lack the granularity. The clinical data, the blood pressure, weight, ECG, the echocardiogram, the cath data, et cetera. And also the lifestyle information, smoking, exercise, diet.

It's also important to realize that Sweden was, particularly at this time before 2000, it was a fairly homogenous society in terms of ethnicity. One feature, which I'm not sure if it's a strength or a limitation, is that we group patients with CHD into one or sometimes two complex non-complex or at the most six groups. And since CHD consists of about 400 different diagnosis and entities, we paint a broader general picture. But if you want to know more about specific conditions such as say, hypoplastic left heart syndrome, you need to look for other and more specific papers.

We're currently working on several more analysis based on this material for more narrow patient groups where we can take into consideration also things such as type of surgery or intervention, timing of intervention, medication and so on. We have a lot of data on this, but it was simply not possible to put everything into one paper.

Dr. Gerald Greil:

Yeah, I mean speaking about getting more specific, we were fortunate enough having one of your colleagues publishing about patients with congenital heart disease. They looked at the time period from 1930 to 2017 using the same database. And they focused specifically on heart failure in this group of patient describing it in a research letter, actually in the same volume your paper's published. How does this study relate to your work? And how do you think are their results impacting the care of these patients?

Professor Mikael Dellborg:

I think they relate to our paper in a nice way, because one of the things we also could show was that the morbidities of patients with adult congenital heart disease are significant. The risk of heart failure, atrial fibrillation, stroke, nonfatal MI, diabetes, and so on, is much larger in that group. And the cumulative risk of having any such adverse event is about 75% at age 68 after 50 years of follow-up. The letter by Bergh et al. focuses on, as you say, heart failure. And during a follow-up or 25 years, there was an overall, like you said, 8.7 times higher risk for patients with CHD to develop heart failure. The most, I think, important factor from this is not only that the risk is increased, it has been described before and it's obvious and quite intuitive, but there was a dramatic difference in the age of onset of heart failure, which was about 40 years in patients with CHD compared to 66 years of age for the controls who developed heart failure.

And again, it was obvious that it was highest among the most complex CHD. The risk was 20 to 40 times higher. But also among non-complex CHD, the atrial receptor defects, the ventricular receptor defects, the risk was significantly higher, five to 10 times. One thing we saw there was that... That could be seen there was that the risk was particularly high in the youngest age group, the youngest patients, as compared to controls. And not so much, although still significant, it increased also in the higher age groups. We could also see that the risk of heart failure seemed to increase. It was higher among those born after 1970 as compared to those before 1930 to '69.

And I have two explanations for that. One is that a lot of patients born in 1930 and so on were not captured by our registers, because they have died before that. But it also reflects that the most complex patients, the most likely to develop heart failure, they survive these days. They did not survive in their thirties, forties, fifties, sixties and early seventies and so on, so that's why. So things haven't been worse, but we do have a much sicker group of patients with congenital heart disease that are alive today.

Dr. Mercedes Carnethon:

That's very hopeful. When I hear that and I think about the impact that treatment and therapy has had on these improvements in survival, it's really exciting to hear. We were really enthusiastic because our colleagues, Dr. Rosenthal and Qureshi from London, submitted an editorial to discuss your piece as well as Dr. Bergh's piece. And they're discussing in it some of the complexity in providing this care and what it has taken to get us to this point where survival is better. Can you tell us a little bit based on the findings from your study and what you know of the field, how do you envision the future care of adults with congenital heart disease?

Professor Mikael Dellborg:

Yes, Mercedes, thank you. I think this is a very nice editorial. It summarizes very well where we are today, and I think they see the future very much along the same lines as I do and as we do. But the large number of patients with CHD living into their sixties, seventies, and eighties, they will not only live longer, they will also have more comorbidities. And I think that's what our data shown and what the editorial is discussing. This will require some changes to be made to the care of adults with congenital heart disease. We will clearly, as pointed out, need large, highly specialized, very competent ACHD centers located close to, or at least in close corporation with pediatric centers. There's no doubt about that building such centers need to continue and you need roughly one large complete such center with outpatient clinic, surgical interventions, structured transfer, specialized physicians, physiotherapists, nurses, education research, et cetera.

You need about one such center per 5 million people. But over time the need of ACHD patients will also change and this will have impact also on the large specialized centers. For instance, if you have an adult patient with say, tetrology of Fallot, fairly common disease in this setting, well operated on a early childhood, well-functioning, modest right ventricular dysfunction, modest pulmonary valve insufficiency, and it's followed by a large centralized ACHD unit. You will keep track of the right ventricle size waiting for the proper time to intervene and replace the right ventricular outflow tract by surgery or catheter. This waiting is probably 10, 15, maybe 20 years before anything needs to be done. But during that time the patient develops hypertension, type 2 diabetes, AFib, and the chances of this happening at some time are fairly substantial. So either the ACHD unit needs to take care of also these comorbidities and that's not always the case today.

And I think it's unrealistic to expect primary care GPs to do this. I mean, would you as primary... As a GP start the SGLT2 treatment? Is that okay for a patient with Fallot? Or the indications for anticoagulation the same as... And that's not easy patients to handle. So on the other hand, if the ACHD unit will take care also of all these comorbidities, they will, I think, have too much to do and I think they will find it difficult to completely cope with this. So as in increasing role for cardiologists who are knowledgeable on ACHD care, but who perhaps spend most of the time caring for the usual patients with heart failure and AFib, post-MI, type 2 diabetes and who are confident in using novel anti-diabetic medications, but at the same time they know about Fallot. They know enough to understand the do's and don'ts, and they can interact on a regular basis with the local ACHD units. So patients will see their general cardiologist twice a year perhaps, and the ACHD center every two years, something like that. I think there's a great need for that.

Dr. Mercedes Carnethon:

I really appreciate having your insights on that. Do you have anything, Gerald, that you'd like to follow up with? I think the feedback that you've shared with us, Mikael, about where you see the treatment field going for adults has been very comprehensive and it's fantastic to be able to have these conversations with you, because obviously these discussions go beyond what you can share in the original research article, which is why we really enjoy this opportunity with the podcast. So Gerald, I'd really like to turn it to you for a final wrap up, given your expertise in this area.

Dr. Gerald Greil:

Yeah, I mean, Mikael, thank you so much to you and your colleagues just giving us this great overview, and even more importantly giving us the perspective how this field is going. I think we are getting more and more aware that there are more patients with and adults with congenital heart disease we need to take care of. We need to find new strategies, as you correctly pointed out, to cope with the enormous burden of disease and providing these patients good quality of life and excellent outcome after sometimes a very difficult start in their lives. And we need to be aware of the pediatricians and adult cardiologists and other subspecialties are forming a team and working together and not working as separate entities. So thank you so much for giving us this perspective. And I would hand over to Mercedes to wrap up the whole discussion please.

Dr. Mercedes Carnethon:

Well, yes, I just really want to thank our listeners for tuning in with us today. It was such a delight to have you here with us, Dr. Dellborg, and thank you as well for sharing your insights.

Thank you for joining us again for this episode of Circulation on the Run Podcast. It's meant to whet your appetite and turn you towards the journal so that you can read more. So thank you very much.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2023. 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 Milind Desai and Associate Editor Mark Link as they discuss the article "Dose-Blinded Myosin Inhibition in Patients With Obstructive Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy: Outcomes Through 32 Weeks."

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:

Oh, Greg. Today's feature paper is just so, so important. It's the long-term follow up or the longer term follow up of the VALOR-HCM trial. And this, if I can remind you, examined the effect of mavacampten on the need for septal reduction therapy in patients with intractable symptoms from obstructive hypertrophic cardiomyopathy. So we're going to hear the results through 32 weeks, but not until we discuss the other papers in today's issue. And I'd like to go first.

I'd like to tell you about a paper that really provides the foundation for deciphering chamber selective gene transcription. So in this study from Dr. William Pu of Boston Children's Hospital and colleagues, authors mapped the chromatin features of atrial and ventricular cardiomyocytes and nominated candidate chamber selective enhancers based on differential features. The candidate enhancers were tested in vivo using adeno associated virus delivered massively parallel reporter assay leading to identification of 229 chamber selective enhancers. They then characterized chromatin features of these chamber selective enhancers and used dense mutagenesis to identify their essential features. Altogether the study suggested that estrogen-related receptor promoted ventricular chamber selective enhancer activity. They validated this prediction by showing that estrogen-related receptor inactivation led to loss of ventricular cardiomyocyte identity. So in aggregate, the studies yielded a rich resource of chamber selective chromatin features and chamber selective enhancers, and began to unravel the molecular basis for chamber selective transcriptional programs.

Dr. Greg Hundley:

Wow. So Carolyn, estrogen-related receptor promotion and then inactivation and finding really very interested preclinical results. So tell us now what are the clinical implications of this very nice study.

 Dr. Carolyn Lam:

Wow. I mean, there are just so many implications. It can facilitate functional interpretation of genetic associations between variants and cardiac disease. Of course, it opens the doors to potential gene therapies and regenerative medicine and finally, identification of transcription regulators of the chamber identity really yield important mechanistic insights into the pathogenesis of important diseases like atrial fibrillation and cardiomyopathy.

Dr. Greg Hundley:

Wow, Carolyn, beautifully summarized. Well, my next paper pertains to COVID vaccines. So Carolyn, as we have seen SARS-CoV-2 targeted mRNA vaccines are a life-saving medical advancement developed to combat, of course, the COVID-19 pandemic. But in rare cases, some individuals can develop myocarditis following these mRNA vaccinations. Cases of adolescents and young adults developing post vaccine myocarditis have been reported globally, although the underlying immuno profiles of these individuals, they really haven't been described in detail. So these authors led by Dr. Lael Yonker from Massachusetts General Hospital, performed extensive system serology SARS-CoV-2 specific T-cell analysis and cytokine and SARS-CoV-2 antigen profiling on blood samples collected from adolescents and young adults either developed myocarditis or were asymptomatic following SARS-CoV-2 targeted mRNA vaccination.

 Dr. Carolyn Lam:

Wow. Wow. Important question. Everyone's interested in the results. So what did they find?

Dr. Greg Hundley:

Right, Carolyn. So 16 cases with post vaccine myocarditis and 45 asymptomatic vaccinated controls were enrolled with extensive antibodies profiling, including assessment for autoantibodies or antibodies against the human relevant virome. And Carolyn, they found that T-cell responses were essentially indistinguishable from controls despite a modest increase in cytokine production. Notably, markedly elevated levels of full length spike protein unbound by antibodies were detected in the plasma of individuals with post vaccine myocarditis, a finding that was absent. It was absent in the asymptomatic vaccinated controls. So Carolyn, in conclusion, immunoprofiling of vaccinated adolescents and young adults revealed that the mRNA vaccine-induced immune responses did not differ between individuals that developed myocarditis versus individuals that did not. However, free spike antigen was detected in the blood of adolescents and young adults who developed post mRNA vaccine myocarditis. Now while this finding does not alter the risk benefit ratio favoring vaccination against COVID-19 to prevent severe clinical outcomes, it may provide some insight into the potential underlying etiology associated with post mRNA vaccine-induced myocarditis.

Carolyn, this is accompanied by a wonderful editorial by Dr. Biykem Bozkurt indicating that these results raise a question as to why the circulating spike protein levels remain elevated despite adequate levels and functionality of the anti-spike antibodies. Well, Carolyn, we do have some other articles in the issue and from the mailbag we have a research letter from Professor Cho entitled PERM1 Protects the Heart From Pressure Overload Induced Dysfunction by Promoting Oxidative Metabolism. Also, there's a new drugs and devices piece from Professor Kabatano entitled Pharmacology and Clinical Development of Factor XI inhibitors. And then Tracy Hansen has a wonderful cardiology news summary regarding articles entitled The Study Reveals Rapid Intestinal Adaptations after Switching to High Fat Diet From Cell Research. Another article entitled New Insights into Immunotherapy Related Myocarditis from Nature. And finally, an article entitled Scientist Identified Genetic Variants Linked to Longevity published in the Journal of Science.

 Dr. Carolyn Lam:

Wow. Interesting. There's also an exchange of letters between Drs. Monzo and Shah regarding the article, "Metabolomic Profiling of Effects of Dapagliflozin in Heart Failure with Reduced Ejection Fraction." That is a Perspective piece by Dr. Davenport on contrast induced acute kidney injury and cardiovascular imaging, danger or distraction? Wow. What a beautiful issue. Thank you so much, Greg. Let's go to our feature discussion, shall we?

Dr. Greg Hundley:

Absolutely.

Welcome, listeners, to this feature discussion on March 14th. And we have with us today Dr. Milind Desai from Cleveland Clinic in Cleveland, Ohio, and our own associate editor, Dr. Mark Link from University of Texas Southwestern Medical Center in Dallas, Texas. Welcome, gentlemen, Milind, we'll begin with you and bringing to us this study of mavacampten. Can you describe for us some of the background information that went into the preparation of this study, and what was the hypothesis that you wanted to address?

Dr. Milind Desai:

Thank you to the editorial staff, Dr. Hundley and the editorial staff at Circulation. So yes, mavacampten, as we know, is a novel first in class cardiac myocin inhibitor that was developed in the context of managing patients with hypertrophic obstructive cardiomyopathy. So the preliminary early stage studies have shown that it helped significantly in reducing outflow tract gradients as well as improved symptoms. But we wanted to take the conversation a bit further. In highly symptomatic patients, the current standard of care treatment is septal reduction therapy, which requires an experienced center and an experienced set of providers.

So what we wanted to see was in such patients that are referred for septal reduction therapy, what does mavacampten do versus placebo? So does it reduce the need for septal reduction therapy? We divided the study into three parts. The first part was the placebo controlled 16 week study. The second part was we wanted to see what happens when the placebo arm crossed over to mavacampten and the mavacampten arm continued long-term. And that was the genesis of the study that we are discussing today.

Dr. Greg Hundley:

Very nice. So we've got a planned study, patients with hypertrophic cardiomyopathy, they ordinarily, because of guideline related therapeutic recommendations would undergo septal reduction therapy, but before that you're going to randomize patients to mavacampten versus a placebo. So we've sort of described a little bit the study design, and let's clarify specifically perhaps the study population and how many patients did you enroll?

Dr. Milind Desai:

Yes. In the original study, we enrolled 112 patients, 56 to mavacampten and 56 to placebo. After week 16, four patients, two of which underwent SRT and two withdrew consent. So essentially for the 32 week analysis, we had 108 patients, 56 in the mavacampten group and 52 in the placebo group that crossed over to mavacampten. So 108 patients.

Dr. Greg Hundley:

Very nice. So Milind, what were your study results?

Dr. Milind Desai:

Yes. What we found was at week 16, we have previously demonstrated that the group that got randomized mavacampten had a significant reduction in outflow tract radius, both resting and Valsalva, as well as biomarkers. And at week 16, what we found was 82% patients from the original group did not meet criteria for septal reduction therapy. So a hundred percent to begin with, 82%, that was at week 16. What we wanted to see, is the effect continued longer lasting and what happens to the placebo group that crossed over? So essentially what we found was at week 32, 89% of the total population no longer met criteria for septal reduction therapy. In addition to that, the mavacampten group continued to have reduced outflow tract gradients, continued improvement in Kansas City Score as well as biomarkers.

But more importantly, the similar findings were demonstrated in the placebo arm that cross over to the mavacampten where, again, a significant proportion continued to show improvement in outflow tract gradient, Kansas City Score, as well as biomarker. The important point here in this study was at week 32, 95% patients chose to remain on medical therapy as opposed to going for SRT. Remember, a hundred percent patients were referred at the outset to undergo SRT.

Dr. Greg Hundley:

And Milind, did you notice any differences in your study results based on the age of the patients or based on their sex?

Dr. Milind Desai:

No, actually, we did not. This had a beneficial effect across gender, age, all the other variables. In fact, this is one of the strengths of the study because almost 50% patients that were randomized were women. So this was well represented across different genders.

Dr. Greg Hundley:

And then you mentioned a marked reduction in the gradient across the left ventricular outflow tract. What about the patient's symptomatology? Did you notice differences there?

Dr. Milind Desai:

There were significant improvement in patient symptomatology. More than 70% patients had a improvement in one NYHA class, 30% or thereabouts had a significant improvement in two NYHA class compared to placebo. So yes, there was a significant improvement in their functional capacity.

Dr. Greg Hundley:

And then last question, hypertrophic cardiomyopathy. Were most of these patients, was this concentric? Was this asymmetric septal hypertrophy? What was the breakdown, if you will, of the morphology of the left ventricles?

Dr. Milind Desai:

The vast majority of the patients had asymmetric septal hypertrophy, the characteristic with dynamic outflow tract gradient. There were some patients, but the vast majority of them were asymmetric septal hypertrophy.

Dr. Greg Hundley:

Very nice. Well, listeners, we're going to turn to our associate editor, Dr. Mark Link. Mark, this really sounds striking, randomized clinical trial, patients needing septal reduction therapy. They're randomized. The group randomized to mavacampten has marked reductions in left ventricular outflow tract gradient, symptomatology, and so much so that they no longer met the criteria for septal reduction therapy. I know you have a lot of papers come across your desk. Can you help us put what seemingly are exciting results into the context of other studies pertaining to mavacampten as well as treatment for patients with symptomatic hypertrophic cardiomyopathy?

Dr. Mark Link:

Yeah. There are very few randomized studies in patients with hypertrophic cardiomyopathy, probably only two that I know of. And mavacampten is a very exciting new drug that's a novel drug, a novel mechanism and has the potential to really improve life for our patients with hypertrophic cardiomyopathy. So this is a longer term study of mavacampten that's ever been published. So yeah, it was very exciting for us to look at this data to see how the patients did and we were very, very pleased to publish this paper.

Dr. Greg Hundley:

Very nice. So maybe, Milind, turn this back to you. What do you think are some of the next studies that'll be performed really in this arena of research?

Dr. Milind Desai:

Yes. Obviously, as Mark pointed out, this was one of the longest term studies, but we need to do a lot longer. So long term extension studies are ongoing. We should be evaluating one year outcomes in this specific population as well as longer, number one. Number two, I think in the grand scheme of things, this is a brand new class. So overall it is obviously now FDA approved and post-marketing survey and analysis should help us see a signal in terms of outcomes, mortality, et cetera. In your sister journal Circulation Imaging, we have simultaneously also published that mavacampten is causing a significant improvement in the structural changes like diastolic dysfunction, like LV mass, LA volume index. So we need to see how that plays out.

Another important piece is about 30% patients have non-obstructive hypertrophic cardiomyopathy and there's no real treatment for this group and there's no outflow tract obstruction to cure in this. So we have just recently launched and started to randomize ODYSSEY HCM trial, which is checking the role of mavacampten versus placebo in non-obstructive HCM group. And I am fortunate. So it's a multi-centered trial that is being led out of Cleveland Clinic. So more data in that exciting field. But overall, this entire field of hypertrophic cardiomyopathies is exploding with multiple randomized controlled trials. There's another drug that is being tested in phase three trials, cardiac myocin inhibition. So that story also remains to see how that plays out. So a lot of stuff that is happening in this space. And then now there's gene therapy emerging.

Dr. Greg Hundley:

Right. And Milind, since you have quite extensive experience here, for our listeners, what side effect profiles have you observed in some of these patients? And if someone is considering working with placing a patient on this therapy, what are some of the considerations that they should be thinking about?

Dr. Milind Desai:

So that's a very important question. So the drug, as you are aware, was approved by the FDA under the REMS or Risk Evaluation Mitigation Strategy program. So the fundamental thing is both the patient and the physician have to sign up for the REMS program. The biggest issue that FDA wants us to be careful about is this is a cardiac myosin inhibitor. So it means we have to be very careful about over inhibition of the cardiac myosin and a drop in ejection fraction and its downstream ramifications including heart failure. The other aspect is drug-drug interaction because of its pathway of metabolism. So these are the two key things we have to be on the careful about.

Now you asked my clinical experience. So we have been prescribing this for almost six, seven months, and we have dozens of patients on this using the REMS strategy, careful echocardiographic monitoring and clinical decision making. So far, we have been very successfully able to navigate these patients without any major adverse events. And the vast majority of the patients, true to form as we have shown in the clinical trial, are doing very, very well in terms of their symptoms, their need for SRT, as well as their markers, including outflow tract gradient.

Dr. Greg Hundley:

Very nice. And Mark, turning to you from the perspective of an electrophysiologist, what potential future studies do you see forming in this space?

Dr. Mark Link:

Yeah, very similar to Milind. And I think the long term efficacy and safety really has to be looked at. There's a signal for potential harm in that the EF can drop, and Milind mentioned that too, that we have to learn how to deal with that. The way to prescribe it now, you have to be in a special program. You have to be trained, you have to agree to get echoes every three months, I believe it is, essentially for the rest of their life. So we need to see what happens long term with these drugs and we need to know how to dose them and how to do it safely.

Dr. Greg Hundley:

Very nice. So for our listeners, really a class of drugs that is emerging and at this time only under really strictly supervise protocols. Well, from the perspective of our listeners, we want to thank Dr. Milind Desai and our own associate editor, Dr. Mark Link, for bringing us this informative new early randomized trial study results indicating that in severely symptomatic patients with obstructive hypertrophic cardiomyopathy, 32 weeks of mavacampten treatment showed sustained reduction in the proportion proceeding to septal reduction therapy.

Well, on behalf of Petter, 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, 2023. 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 Xuerong Wen, Associate Editor Sandeep Das, and Guest Host Mercedes Carnethon as they discuss the article "Comparative Effectiveness and Safety of Direct Oral Anticoagulants and Warfarin in Patients With Atrial Fibrillation and Chronic Liver Disease: A Nationwide Cohort Study."

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 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:

Greg, I'm so excited about today's feature paper. It deals with the important condition where atrial fibrillation exists in patients with chronic liver disease and what do we do for anticoagulation in these patients. It's a comparative effectiveness and safety study of direct oral anticoagulants compared with warfarin in these patients. A huge, wonderful, important study that we're going to discuss. But before we get there, I'd like to tell you about some papers in this issue and I'd like you to tell me about some too. You got your coffee?

Dr. Greg Hundley:

Absolutely.

Dr. Carolyn Lam:

All right. I'll go first In this paper that describes a quantitative prognostic tool for the mitral valve prolapse spectrum and it's derived from the new mitral regurgitation international database quantitative or MIDA-Q registry, which enrolled more than 8,000 consecutive patients from North America, Europe, Middle East. And these were patients all diagnosed with isolated mitral valve prolapse or MVP in routine clinical practice of academic centers, all of which also did prospective degenerative mitral regurgitation quantification. The MIDA-Q score was calculated based on characteristics collected in routine practice combining the established MIDA score, which integrated guideline based markers of outcomes like age, New York Heart Association status, atrial fibrillation, LA size, pulmonary artery pressure left ventricular and systolic, I mentioned, and ejection fraction. Integrating that with scoring points based on the degenerative mitral regurgitation quantitation that is measuring effective regurgitant orifice and volume.

Dr. Greg Hundley:

Very interesting Carolyn. So a scoring system that combines clinical information with what we might assess with echocardiography like regurgitant volume or regurgitant orifice area. So how well did this mortality risk score perform?

Dr. Carolyn Lam:

So the new score was associated with an extreme range of predicted survival under medical management and that ranged from 97% to 5% at five years for the extreme score ranges. And it was strongly, independently and incrementally associated with long-term survival over all the markers of outcomes. So the authors concluded, and these by the way were authors led by Dr. Maurice Serrano from Mayo Clinic, Rochester, Minnesota. These authors concluded that the score should allow integrated risk assessment of patients with mitral valve prolapse to refine clinical decision making in routine practice and ultimately reduce degenerative mitral regurgitation under treatment.

Dr. Greg Hundley:

Wonderful description Carolyn. Well I'm going to switch to the world of electrophysiology, Carolyn. And so as you know, the Brugada syndrome is an inherited arrhythmia syndrome caused by loss of function variants in the cardiac sodium channel gene SCN5A and that occurs in about 20% of subjects. And these authors led by Dr. Dan Roden at Vanderbilt University School of Medicine identified a family with four individuals diagnosed with Brugada syndrome, harboring a rare missense variant in the cardiac transcription factor, TBX5, but no SCN5A variant. And upon identifying these individuals, their objective was to establish TBX5 as a causative gene in Brugada syndrome and to define the underlying mechanisms by which it would be operative.

Dr. Carolyn Lam:

Oh wow. So a new gene variant. So what was the relationship?

Dr. Greg Hundley:

Right Carolyn? So using induced pluripotent stem cell derived cardiomyocytes from members of the affected family, multiple electrophysiologic abnormalities were detected in these cardiomyocytes including decreased peak and enhanced late cardiac sodium current. In these cells these abnormalities were entirely corrected by CRISPR/Cas9 mediated editing of that TBX5 variant and transcriptional profiling and functional assays in unedited and edited pluripotent stem cell derived cardiomyocytes showed direct SCN5A down regulation caused decreased peak sodium current and that reduced PDGF receptor expression and blunted signal transduction to phosphoinositide-3-kinase. And interestingly, PDGF receptor blockade markedly prolonged normal induced pluripotent stem cell derived cardiomyocyte action potentials.

And also Carolyn interestingly in this study they did a separate analysis. It reviewed plasma levels of PDGF in the Framingham Heart Study and they found that they were inversely correlated with the QT corrected interval. And so Carolyn, these results established decrease SCN5A transcription by the TBX5 variant as a cause of Brugada syndrome and also reveal a new general transcriptional mechanism of arrhythmogenesis of enhanced late sodium current caused by reduced PDGF receptor mediated phosphoinositide-3-kinase signaling.

Dr. Carolyn Lam:

Wow. Wow, that's significant. Thanks Greg. So this next paper is also really important and could change the practice in the field of cardiac resynchronization therapy or CRT. You see, it suggests that the practice of what we do now, which is combining right bundle branch block with intraventricular conduction delay patients into a single non-left bundle branch block category when we select patients for CRT, that this may not be the way to go.

So let's go back a bit and remember that benefit from CRT varies with QRS characteristics and individual trials are actually underpowered to assess the benefit for relatively small subgroups. So the current authors led by Dr. Friedman from Duke University Hospital and colleagues, therefore performed a patient level meta-analysis of randomized trials of CRT to assess the relationship between QRS duration and morphology with outcomes.

Dr. Greg Hundley:

Very interesting Carolyn. So another wonderful paper from the world of electrophysiology in trying to understand optimal mechanisms to resynchronize the ventricle in patients with differing bundle branch blocks or intraventricular conduction delays. So what did they find?

Dr. Carolyn Lam:

They found that patients with intraventricular conduction delays and a QRS duration of 150 milliseconds or more, CRT was associated with lower rates of heart failure hospitalizations and all cause mortality. The magnitude of CRT benefit among these patients with the interventricular conduction delay of 150 milliseconds or more and those with the left bundle branch block of 150 milliseconds or more were similar.

In contrast, there was no clear CRT benefit for patients with a right bundle branch block of any QRS duration, although the authors could not rule out the potential for benefit at a markedly prolonged QRS duration.

So they concluded that the practice of combining right bundle branch block with intraventricular conduction delay patients into a single non-left bundle branch block category when we make patient selections for CRT is not supported by the current data. And in fact, patients with an intraventricular conduction delay of 150 milliseconds or more should be offered CRT as is done for patients with a left bundle branch block of 150 milliseconds or more.

Dr. Greg Hundley:

Wow, Carolyn, so really interesting point. No clear CRT benefit for patients with right bundle branch block regardless of the QRS duration. Well we've got some other articles in the issue. I'll describe a couple from the mail bag. There's a Research Letter from Professor Lassen entitled "Risk of Incident Thromboembolic and Ischemic Events Following COVID-19 Vaccination Compared with SARS-COV2 Infection." Also Bridget Kuhn has a wonderful Cardiology News piece entitled "Collaborative Care Model Helps Heart Failure Patients Meet End-of-Life Goals."

Dr. Carolyn Lam:

There's an exchange of letters between Doctors Donzelli and Hippisley-Cox regarding that risk of myocarditis after sequential doses of COVID-19 vaccine, there's an AHA Update by Dr. Churchwell on continuous Medicaid eligibility, the lessons from the pandemic. There's an On My Mind paper by Dr. Parkhomenko on Russia's war in Ukraine and cardiovascular healthcare.

Wow, what an issue. Thanks so much, Greg. Shall we go on to the feature discussion?

Dr. Greg Hundley:

You bet.

Dr. Mercedes Carnethon:

Well welcome to this episode of Circulation on the Run podcast. I'm Mercedes Carnethon, associate editor of the journal Circulation and Professor and Vice Chair of Preventive Medicine at the Northwestern University Feinberg School of Medicine.

I'm very excited to be here today with Xuerong Wen and Sandeep Das, my fellow associate editor here at Circulation to talk about a wonderful piece by Dr. Wen and colleagues from the University of Rhode Island. So welcome this morning Xuerong and thank you so much for sharing your important work with us.

Dr. Xuerong Wen:

Thank you Dr. Carnethon. It was great meeting you all and I'm the Associate Professor of Pharmacoepidemiology and Health Outcomes at the University of Rhode Island. I'm happy to introduce my study to everyone.

Dr. Mercedes Carnethon:

Well thank you so much and thank you as well Sandeep for identifying this fantastic article and bringing it forth.

Dr. Sandeep Das:

Thanks Mercedes. It's great to be with you.

Dr. Mercedes Carnethon:

Great. Well let's go ahead and get into it. There's so much here to talk about. So Dr. Wen and colleagues studied the comparative effectiveness and safety of direct oral anticoagulants or DOACs and warfarin in patients with atrial fibrillation and chronic liver disease. So this is such an important topic. Can you tell us a little bit about what your study found?

Dr. Xuerong Wen:

So our study is a comparative effectiveness and the safety analysis using a national health administrative data from private health plans. So we compared the risk of hospitalized ischemic stroke, systemic embolism and major bleeding between DOACs and warfarin in patients with atrial fibrillation and chronic liver disease. So we also had to had compare to these primary outcomes between apixaban and rivaroxaban in the study population.

So our studies show that among patients with atrial fibrillation and chronic liver disease, DOACs as a class was associated with lower risk of hospitalization of ischemic stroke and systemic embolism and major bleeding, compared with warfarin. And when compared risk outcomes between individuals apixaban has lower risks as compared to rivaroxaban. So that's our study results.

Dr. Mercedes Carnethon:

Well thank you so much. This seems like such an important question. We hear a lot about DOACs and some of their risks as well as their considerable benefits. I think what leaves me the most curious is why did you choose to pursue this question and in particular in patients with both atrial fibrillation and liver disease. So why was the intersection of these two particular conditions of interest to your study team?

Dr. Xuerong Wen:

That's a great question. So the liver actually plays a central role in both the synthesis of coagulation factors and the metabolism of anticoagulant drugs. And the clearance of the anticoagulants in liver ranges from 20% to 100% for DOACs and warfarin. So in clinical practice anticoagulation abnormalities and elevated risk of spontaneous or unprovoked venous thrombotic complications have been reported in patients with liver disease. While these patients with cirrhosis were excluded from the clinical trials of DOACs and also population based, the real world experience is very limited. So that is why we initiated this retrospective cohort study and based on the real world data in this specific population.

Dr. Mercedes Carnethon:

Oh, thank you so much for explaining that. I definitely learned a lot and really enjoyed reading the piece. I think it was very well organized and well written and I know that our readership will appreciate it. It obviously stood out to you as well, Sandeep. Can you tell me a little bit about why you thought that this would be an excellent piece for circulation?

Dr. Sandeep Das:

Yeah, absolutely. Thanks for the question.

So in the broad field of what we call observational comparative effectiveness research, so basically that's using large observational data sets to try to answer important clinical questions and it's a really challenging thing to do. I mean we're all very familiar with the idea of using randomized trials to assess important clinical questions because of the structure of that design allows you to mitigate some of the effects of confounding. Here, it has to be done analytically. So what's the important factor that really drives you towards a great observational comparative effectiveness piece? So first the clinical importance. I feel a little guilty because I'm old enough to remember when warfarin was the only option available, but really as a clinician, or every patient, I really prefer DOACs over warfarin just for ease of use and lifestyle. So there's a huge sort of importance to the question.

Second, the patients with chronic liver disease were excluded from the larger RCTs and the DOAC trials. So really we don't have the answer to the question already. It's an important question. Obviously the bleeding risk is tied up with the liver, warfarin directly antagonizes vitamin K, so there's real questions about safety and so this is the perfect storm and then on top of it was a really well done and well executed study. So when this came across my desk, the very first thing I thought was not, "Is this something that we're interested?" But rather, "How do we make it better? How do we make it more useful to the reader?" This had me from hello.

Dr. Mercedes Carnethon:

Well thanks so much. We rarely have the opportunity when we read an article to be able to ask the authors questions. So Sandeep, I know that you had mentioned that you had some follow up questions as well.

Dr. Sandeep Das:

Yeah. So the real thought that I have then is would you argue based on this that we know enough that we should change our practice? And that do you feel comfortable advocating that people now prescribe DOACs to these patients?

Dr. Xuerong Wen:

I would say yes. Okay.

Although this is not a clinical trial, but our study is actually systematically compare the effectiveness and safety between DOAC users and also the warfarin users. And if you look at our table one, we compare with so many variables between these two users and we use the propensity score adjustment and we after propensity score weighting and the two control group almost balanced.

And I know right now FDA actually suggested that emulate the trial using the large real world data to do the emulated trial. So our study actually conducted is based on the large population using large data and we use the propensity score weighting to control all this potential compounding factors. Although there are still some limitations in this study. I think we mentioned that in the discussion section and we discussed all potential compounding factors that still may exist.

And also there are some misclassifications and out of all this limitations and we still found the two drugs performed differently in this specific population. So we feel that comfortable to say that a DOAC drug performs better than warfarin. And also I think based on other studies that based on the clinical trial in the general population, DOAC drug is performs much better than warfarin and considering that the clearance in liver for DOAC is less than warfarin. So plus all this information together, I think DOAC may be safer than wafarin in the patients with AF and chronic liver disease.

Dr. Sandeep Das:

Yeah, I would say that I agree that these data, even if you're skeptical about observational CT generally, which I admit that I tend to be, these are really reassuring data that at least the DOACs are... There's absolutely nothing that suggests that they're any worse than warfarin and all of the sort of soft indications for ease of use and patient happiness really would seem to favor DOACs. So I think this is the sort of rare observational CT paper that may actually change my practice.

Dr. Mercedes Carnethon:

I have a follow-up question, Xuerong, related to the design and as well your strategy to address differences between the groups. So inverse probability weighting is certainly a standard in the field to be able to manage differences between groups when you have a situation where can't, where it's not a randomized trial. Do you as well, and educate me, I admit I'm an epidemiologist whose methodological skills are sometimes challenged. Do you have the opportunity using this design and with inverse probability weighting to evaluate subgroup effects? So my specific question is were you able to determine whether or not these associations were similar based on age and gender in particular?

Dr. Xuerong Wen:

That's a great question. We did conducted a lot of subgroup study but not by age or gender. We conducted I think this study in a lot of subgroups using the propensity score weighting, but the subgroup that I think we did a subgroup like a patient with a different chronic liver disease. So that's what we did. And we also tested different methods inverse probability score weighting. So we did trimming and we used a different percentage of trimming and to see how that affect the study results. So we have done a lot of subgroup studies. We did not check the age and the gender, but that's a very good point. Maybe later, well I'll ask my student to do that.

Dr. Mercedes Carnethon:

Well, you're a good mentor. So I think that is a really certainly an appropriate approach. Sandeep, did you have additional questions?

Dr. Sandeep Das:

No, I wish I had thought of yours before you did. I think exactly the older age, women, racial ethnic groups that are underrepresented historically in trials. I think that that's really, again, the sweet spot of this observational research. We definitely, and NH definitely working on trying to increase enrollment of all these groups in our CTs. However, while we wait for that, I think that's exactly what we should be doing.

Dr. Mercedes Carnethon:

Well that's great. And Xuerong, you really alluded to really, I think what is one of my final questions related to what do you think based on what you have observed in this study, what do you see as the next steps in the research field for your team, your students, or other people who are carrying out this type of work?

Dr. Xuerong Wen:

Well, that's a great question. We currently have a couple of more manuscripts ongoing in this field, and we will continue conducting the comparative effectiveness and analysis to compare drugs head to head as well as developing and implementing new methodologies to this field. And we hope our study provides real world evidence for clinical decision making, prescribing anticoagulants to patients with atrial fibrillation and chronic liver disease. We also expect the physicians and researchers more and more value the real world data studies, especially when clinical trials are not feasible or ethical.

Dr. Mercedes Carnethon:

Well, thank you so much. That was such an excellent vision that you provided us with and we're just very grateful that you submitted this fantastic work to the journal Circulation. I know that our readers will enjoy really digging in. The podcast is meant as a teaser to bring you to the journal so that you can read about this wonderful work by Dr. Wen and colleagues. So again, thank you. I'm Mercedes Carnethon, joined with my associate editor partner here, Dr. Sandeep Das. And thank you very much for spending your time with us today, Dr. Wen.

Dr. Xuerong Wen:

Thanks for this great opportunity to disseminate my study with us, thank you.

Dr. Sandeep Das:

Thanks Mercedes.

Dr. Mercedes Carnethon:

Thank you for joining us for this episode of Circulation on the Run.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2023. 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 Christian Ruff and Associate Editor Andrea Russo as they discuss the article "Abelacimab Versus Rivaroxaban in Patients With Atrial Fibrillation on Antiplatelet Therapy: A Prespecified Analysis of the AZALEA-TIMI 71 Trial."

For the episode transcript, visit: 

https://www.ahajournals.org/do/10.1161/podcast.20250804.510827

This week, please join author Jennifer Conway as she discusses the article "The Prevalence and Association of Exercise Test Abnormalities With Sudden Cardiac Death and Transplant-Free Survival in Childhood Hypertrophic Cardiomyopathy."

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 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 VSU Health in Richmond, Virginia. Carolyn, wow. We're closing out the month of February, this is February 28th. And the feature discussion today, very interesting. So in patients with hypertrophic cardiomyopathy, we often see them as adults, and guidelines are very clear on how to manage them. What about patients' children that present with hypertrophic cardiomyopathy? How do we manage them? Should we do exercise testing? Well, to get the answers to some of those questions, you'll have to wait listeners to our feature discussion today. But first we're going to grab a cup of coffee and jump into some of the other articles in the issue. Carolyn, would you like to start?

Dr. Carolyn Lam:

I would love to. With this first paper, which is a preclinical study revealing a novel signaling axis in cardiorenal interaction.

Dr. Greg Hundley:

Wow. Pray tell.

Dr. Carolyn Lam:

I will. So this paper is from Dr. Molkentin and colleagues from University of Cincinnati. And using mouse models of ischemia reperfusion acute kidney injury and unilateral ureteral obstruction, these authors found that interleukin 33 release from the kidney endothelium during acute kidney injury communicates with the heart through the suppression of tumorigenicity 2 or ST2L receptor on cardiomyocytes. And that's where it causes hypertrophy, fibrosis, and loss of cardiac function. Mice lacking interleukin 33 or mice lacking the gene encoding this ST2L receptor on cardiomyocytes, but not endothelial cells or fibroblasts, were protected from acute kidney injury induced hypertrophy and cardiomyopathy. Indeed, inhibition of acute interleukin 33 release from the kidney after acute kidney injury with a monoclonal antibody prevented cardiomyopathy. So the interleukin 33 ST2L signaling axis is a novel potential therapeutic target to protect the heart during kidney injury.

Dr. Greg Hundley:

Wow, Carolyn, really interesting preclinical science relating acute kidney industry and cardiomyopathy. Well, I have another paper from the World of Preclinical Science. And, Carolyn, this pertains to the metalloprotease ADAMTS7, and it is a novel locus associated with human coronary atherosclerosis. ADAMTS7 deletion protects against atherosclerosis and vascular restenosis in rodents. Carolyn, these authors led by Professor Wei Kong from Peking University designed three potential vaccines consisting of distinct B-cell epitopic peptides derived from ADAMTS7 and conjugated with the carrier protein KLH as well as aluminum hydroxide as an adjuvant. And they tested the efficacy of the vaccines to evaluate coronary intimal hyperplasia in mirroring wire models and after stent implantation in porcine models.

Dr. Carolyn Lam:

Oh, wow. So a vaccine against atherosclerosis? Cool.

Dr. Greg Hundley:

Yeah, it is really a vaccine concept against restenosis. Carolyn, this peptide vaccine against metalloproteinase ADAMTS7 efficiently mitigated atherosclerosis in vaccinated hyperlipidemic mice without lowering lipid levels and impeded intimal hyperplasia in both the murine wired injured arteries and the swine stented coronary arteries without any significant immune related organ injuries. Carolyn, the clinical implications are that the vaccine against the metalloproteinase ADAMTS7 is a novel atherosclerosis vaccine, mainly targeting vascular remodeling, thereby also alleviating instent restenosis. And perhaps in the future the application of this vaccine would be a complimentary therapeutic avenue to current lipid loading strategies for atherosclerotic disease. And this is nicely followed by an editorial from Professors Heribert Schunkert and Thorsten Kessler.

Dr. Carolyn Lam:

Cool, thanks, Greg. Well, this next paper asks the question that if coronary artery calcium can be identified on non-gated chest CTs, can this finding be effectively incorporated into care with the help of AI? So the Notify One was a randomized quality improvement project in the Stanford healthcare system. Patients without known atherosclerotic cardiovascular disease or a prior statin prescription were screened for coronary arterial calcium on a prior nongated chest CT from 2014 to 2019 using a validated deep learning algorithm with radiologist confirmation. Patients with incidental coronary artery calcium were randomized to notification of the primary care clinician and patient versus usual care. Notification included a patient specific image of coronary artery calcium and guideline recommendations regarding statin use. And the primary outcome was statin prescription within six months.

Dr. Greg Hundley:

Really interesting, Carolyn. So coronary artery calcium observed when a patient might happen to come in for another chest CT scan or actually randomizing a patient population to being notified and maybe doctors act on it versus not. So what did they find?

Dr. Carolyn Lam:

Yep, beautifully summarized. And this is from Dr. Sandhu and colleagues from Stanford University. And what they found was among more than 2000 patients who met initial and clinical inclusion criteria, coronary artery calcium was identified by the algorithm in 424 patients and confirmed by a radiologist in 89% who were randomized to notification or usual care. At six months, the statin prescription rate was 51% in the notification arm versus 7% with usual care. Thus, opportunistic coronary artery calcium screening of prior nongated chest CTs followed by clinician and patient notification led to a significant increase in statin prescriptions. Further research is of course needed to determine whether this approach can actually reduce atherosclerotic cardiovascular disease events. This is discussed in an editorial by Doctors Joshi, Nasser, and Navar.

Dr. Greg Hundley:

Wow, Carolyn, you know, this all fits with behavioral science. When we see something, then often we change our behavior much more readily. And so, gosh, boy, just a perfect example of that in this last paper. Well, there's some other articles in the issue, and I see again, just as it was last week, you've got a whole list here to describe.

Dr. Carolyn Lam:

Oh, you bet Greg. First, there's an exchange of letters between Doctors Du and Lee on physical activity has no significant association with stroke. There's a primer by Dr. Leyva on "Declining Risk of Sudden Cardiac Death in Heart Failures, Is that a Fact or a Myth?" There's a Research Letter by Dr. Soehnlein on "Time Restricted Feeding Enhances Early Atherosclerosis in Hypercholesterolemic Mice." There's also Highlights from the Circulation Family of Journals by Molly Robbins. The characteristics of patients with recurrent sudden cardiac death are described in circulation arrhythmia and electrophysiology. A proof of principle gene therapy for correction of long QT two and short QT one syndromes is presented in circulation, genomic and precision medicine.

The impact of food insecurity on heart failure mortality is reported in circulation heart failure. The associations of hypertension and hypertension treatment with differences in sexual identities are presented in circulation, cardiovascular quality and outcomes. A multi-modality imaging and biomarker strategy to detect early decompensation with chronic aortic regurgitation is reported in circulation cardiovascular imaging, and an analysis of revascularization at the time of TAVR on cardiovascular outcomes is reported in circulation cardiovascular interventions. Finally, that's a Perspective piece by Dr. Turer on cardiac myosin inhibitors unlocking potential to improve treatment in hypertrophic cardiomyopathy.

Dr. Greg Hundley:

Wow, Carolyn, just another issue that's so rich with both preclinical and clinical science. Well, how about we get off to that feature discussion and learn more about management of children and young adults with hypertrophic cardiomyopathy?

Dr. Carolyn Lam:

So important. Let's go.

Dr. Greg Hundley:

Welcome listeners to this February 28th feature discussion where we're going to work into the world of hypertrophic cardiomyopathy in children. And we have with us today Dr. Jennifer Conway from Stollery Children's Hospital in Edmonton, Alberta. Welcome Jennifer. And maybe Jennifer, let's start off, could 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. Jennifer Conway:

Sure. And I would just like to start by thank you for inviting us to really present the information from our paper. We think it's a very exciting paper and are excited to share our results. When you think about hypertrophic cardiomyopathy in children, a lot of the information in the past has really been extrapolated from adults. And we know from the recent 2020 guidelines that exercise testing is really no longer part of risk stratification for adults. It's mostly used to look at functional outcomes and really when assessing patients more for heart failure related symptoms. So we wanted to see whether or not exercise testing in children had a different role because we know the recent risk stratifying calculators such as the primacy calculator that's come from this cohort of patients or HCM risk kids, has different risk factors that have been identified for sudden events, for instance, than in the adult population. And that's really kind of sparked us to see, well, maybe exercise has a different role in children than it does in adults.

Dr. Greg Hundley:

And so we wanted to investigate the role of exercise testing in children with hypertrophic cardiomyopathy. So how did you arrange your study design, and what was your study population?

Dr. Jennifer Conway:

This is an international cohort of 20 centers from the US, Canada, and Australia. And it's an observational cohort, and there is over 724 patients' information that has been collected within this cohort of patients. And for this particular study, 630 of them had an exercise test and therefore were included in the study to look at.

Dr. Greg Hundley:

And in the study population, I know it's a pediatric population, what was the age range?

Dr. Jennifer Conway:

The average range was about 13 years old with probably the youngest being around eight because that's really where you can do an exercise test with and that's up to 18 years of age. So that's kind of the general age range of patients.

Dr. Greg Hundley:

And of these pediatric populations, what percentage were, I guess, boys versus girls?

Dr. Jennifer Conway:

Yeah, so just over 75% were males within this study population.

Dr. Greg Hundley:

Okay. And then now Jennifer, can you describe for us your study results?

Dr. Jennifer Conway:

Sure. I think the first main result is that we can really think about what we defined as an abnormal exercise test so maybe we'll start with that and kind of explain our findings there. So abnormal exercise test in this study was really a threefold one if you had an abnormal blood pressure response. The other one is if you had ventricular ectopy or if you had ST-T wave changes, which we described as ischemia. And so taking those three together, about 28% of our pediatric patients had an abnormal finding on their exercise test. So that's kind of the first main finding. So then we took those abnormal exercise patients and compared those with a normal exercise test to try to look for outcomes. And the two outcomes that we mainly focused on all cause mortality and transplantation is one outcome and the other one was sudden cardiac death events.

So when we looked at the five-year freedom for all cause mortality and transplant, we found that those who had an abnormal exercise test had a lower five-year freedom from all cause mortality and transplantation. And when we sub-analyzed the different abnormalities in the exercise test, we found that ischemia and an abnormal blood pressure response were both associated with kind of a higher risk of mortality and transplantation. And then when we went on to look at sudden cardiac death events, there was really no difference seen between those with an abnormal or normal exercise test in terms of sudden cardiac death events. But when we looked at the individual factors once again exercise induced ischemia was associated with a lower freedom from a sudden cardiac death event.

Dr. Greg Hundley:

Jennifer, frequently in adults we're often examining with exercise how the intracavitary or left ventricular outflow tract gradient may change with exercise. What did you find in children in regards to that parameter?

Dr. Jennifer Conway:

Yeah, so we couldn't actually study that because this was a compilation of different types of exercise tests. So not everybody at each institution did the same form of exercise tests. So some patients had an exercise echo, some had a CPET test, and some had an exercise stress test. And so we took the common parameters from all of those to study, so we weren't specifically able to look at LV outflow tract gradients for instance.

Dr. Greg Hundley:

Jennifer, as a pediatrician managing a patient with hypertrophic cardiomyopathy, how do we use the results of your study to influence how we might manage patients moving forward?

Dr. Jennifer Conway:

I think this is an excellent question, and there's probably really two things that we can think about. The first is, what is the role of exercise testing in pediatrics? And just as we're starting to discover what our risk factors are for sudden cardiac death events, I think we have to do a little bit more to discover what our role is truly going to be with exercise test. So one of the things that we're doing as part of the primacy group is trying to decide is if we add exercise testing abnormalities to the already developed primacy calculator, does it change its power at all? That's one of the things kind of for the future to see with the current kind of sudden death risk factor calculators, can exercise, add to them? The second thing is I think that there is probably a role in exercise testing in general with patients that you see in your clinic to look at these predictive outcomes, and that is not standard across centers.

We know that because not everybody in this cohort had an exercise test. I think there are some higher risk patients that likely are not suitable for exercise tests, but I think a majority of the patients that we see likely can undergo exercise testing. And although it's not published in this paper, of the 630 patients, there's only one patient who had a kind of aborted arrest during the exercise test. And that patient was a higher risk patient who had a previous reported aborted arrest. And this actually corresponds with two other papers in the literature, one from CHOP in Boston where it's a very low event rate when exercise testing is done in a controlled environment with professionals around and have a lab set up to specifically do that. The other aspect of this I think is that as we're starting to understand hypertrophic cardiomyopathy in general better, I think using exercise tests to try to help design exercise interventions is going to be important.

Another study that I'm doing that's not part of this is looking at the cardiovascular health of children with hypertrophic cardiomyopathy across Canada. And we are finding that there's a high level of obesity, sedentary lifestyle, high lipid profiles for instance, all of which put people at risk for cardiovascular disease as adults. And so I think as we're getting more comfortable potentially with looking at exercise prescriptions for hypertrophic cardiomyopathy patients and understanding risks a bit better, then exercise testings going to be a key in trying to design maybe some of that programming for patients.

Dr. Greg Hundley:

Wow, Jennifer, just a beautiful explanation of where we need to move with your research results in the future. One thing that kind of caught my attention as you were speaking, really safety. So for all our listeners, in terms of exercising children with this condition or young adults, would you recommend a specialized center or what would you describe in that, at least in terms of safety precautions?

Dr. Jennifer Conway:

Well, if you look at all the... There's not a lot of studies that have been published, but the ones that have, they're in a lab that commonly exercises children. They have protocols of who they will exercise and who they won't and when you would stop an exercise test. For instance, the paper from CHOP nicely describes how they approach the exercise in hypertrophic cardiomyopathy, and they have clear guidelines of when they stop testing. So in their 140 patients, for instance, they stop testing in two patients, one who had, I think ST segment changes and the other one who developed some ventricular ectopy. I think it needs to be in a controlled environment where you have safety measures in place and you have guidelines to direct you in terms of if this happens, this is the response to that. I think that's all very important when you're kind of thinking about exercising what has been deemed as higher risk patients.

Dr. Greg Hundley:

Very nice. Well, listeners, we want to thank Dr. Jennifer Conway from Stollery Children's Hospital in Edmonton, Alberta for sharing with us these really interesting results, highlighting that exercise abnormalities are common in childhood hypertrophic cardiomyopathy, and an abnormal exercise test was independently associated with lower transplant free survival especially in those with ischemic or abnormal blood pressure responses during that exercise testing.

Well, on behalf of Peter, 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 2023. 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 Amil Shah and Associate Editor Ntobeko Ntusi as they discuss the article "Stages of Valvular Heart Disease Among Older Adults in the Community: The Atherosclerosis Risk in Communities 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 at the Pauley Heart Center at VCU Health in Richmond, Virginia.

Carolyn, this week's feature, very interesting. Many times in older individuals we understand how to manage severe valvular heart disease, for example, severe aortic stenosis. But do we really know how to manage individuals with mild valvular heart disease, for example, mild mitral regurgitation or aortic valve sclerosis?

Well, our feature today will address that issue. And so, listeners, grab a cup of coffee. We're going to go through some of the other articles in the issue first, and then we'll get to that really interesting, very practical feature discussion.

Well Carolyn, now that I've got my cup of coffee, this paper's from your group. And I'm going to ask you, Carolyn, as if it was a feature discussion, what was the background information that went into this and what was the hypothesis that you wanted to address?

Dr. Carolyn Lam:

Oh, it's great because it's at least not a Carolyn quiz, so I'm very happy to talk to you about it. Sex differences, as you know, it's a passion of mine.

And in response to heart failure pharmacotherapies, in particular, we know that there are sex differences, wherein women appear to benefit from newer hormonal modulators across a wider heart failure ejection fraction range compared to men. And this was particularly evident in the Paragon heart failure trial of Arne versus Valsartan.

However, whether these considerations also apply to the sodium-glucose Cotransporter 2 inhibitors or SGLT 2 inhibitors, remains unclear. So along with the groups from the DAPA-HF and DELIVER trial, we therefore examine and assess the impact of sex on the efficacy and safety of dapagliflozin in a pre-specified pooled analysis of these trials.

Dr. Greg Hundley:

Very interesting, Carolyn. So, differences between men and women and evaluation of efficacy of SGLT 2 inhibitors. So what did you find?

Dr. Carolyn Lam:

In essence, women and men derived similar benefits from dapagliflozin for both the primary outcome of worsening heart failure or cardiovascular death. And for secondary outcomes, including improvement in health status across the full spectrum of ejection fraction in heart failure.

Dapagliflozin was also safe and well tolerated in both sexes. So these findings are consistent with other SGLT 2 inhibitors and suggest a class effect. And in fact, this is very, very nicely discussed in an accompanying editorial by Dr. Ileana Piña.

Dr. Greg Hundley:

Ah, very nice, Carolyn. Well, my first study here comes from the world of preclinical science. And Carolyn, this study assesses the role of epsins in modulating endothelial to mesenchymal transition in atherosclerosis.

So Carolyn, you may ask what are epsins? Well, epsins are ubiquitously expressed adapter proteins involved in the regulation of endocytosis. And then Carolyn, there's a second process addressed in this study. And Carolyn, it is known that chronic vascular inflammation, a hallmark of atherosclerosis, induces a process called endothelial to mesenchymal transition.

And during endothelial to mesenchymal transition, the transition of non-smooth muscle cell-derived cells that are capable of maintaining indices of atherosclerotic lesion stability are lost. And this allows atherosclerosis to progress to a more advanced stage.

So Carolyn, in this study led by Dr. Hong Chen, from Boston Children's Hospital, these authors wanted to know if impacting epsins could reduce endocytosis and thereby modify endothelial to mesenchymal transition and attenuate atherosclerosis progression.

Dr. Carolyn Lam:

Sounds like an important concept to address in the progression of atherosclerosis. So what did they find, Greg?

Dr. Greg Hundley:

Right, Carolyn. So the authors found that epsins are required for endothelial to mesenchymal transition, and that the loss of these proteins in the endothelium reduces endothelial to mesenchymal transition by permitting sustained fibroblast growth factor receptor-1 protein, FGRF1, signaling by inhibiting the degradation of this receptor complex.

They also demonstrate the efficacy of blocking epsin FGRF1 interactions specifically in atheromas using systemic administration of a targeted epsin UIM containing peptide to inhibit endothelial to mesenchymal transition and atherosclerosis progression in APO deficient and PCSK9 mutant viral induced atherosclerotic models.

So Carolyn, in summary, these authors show that blocking these epsin FGRF1 interactions could provide a new approach to combat atherosclerosis progression.

Dr. Carolyn Lam:

Wow, Greg, thanks. Well, this next paper is an important preclinical paper showing that agents that induce senescence in cells of pulmonary vasculature can unexpectedly worsen rather than ameliorate pulmonary hypertension.

So this paper is from Professor Serge Adnot and colleagues from Hospital Henri-Mondor in France. And they began by showing that in human lung tissues from pulmonary hypertension patients, about 30% of lung endothelial and smooth muscle cells have elevated P16, an observation recently also reported by others, as further evidence of senescence.

Many of the cells with elevated P16 also had an increase in unrepaired DNA damage. They then used multiple senolytic strategies in several animal models to remove senescent cells and then found unexpectedly that eliminating senescent cells aggravated rather than suppressed pulmonary hypertension development.

As models of pulmonary hypertension, the authors examined a number of animal models of pulmonary hypertension. That included rats exposed to chronic hypoxia, rats injected with the toxin monocrotaline, and rats injected with a VEGF receptor blocker prior to exposure to chronic hypoxia. As well as mice over-expressing the serotonin transporter in smooth muscle cells. And mice with P16 over-expression that develop pulmonary hypertension with age.

So lots of animal models were tested and these animals also received the senolytic ABT 263 or FOX04-DRI, that would be expected to remove senolytic cells with equivalent results.

Dr. Greg Hundley:

Wow, Carolyn, so multiple animal models highlighting that senescent cells in the pulmonary vasculature can worsen rather than attenuate pulmonary hypertension. So what are the clinical implications of these models?

Dr. Carolyn Lam:

Well, this is discussed in a beautiful editorial by Dr. Rabinovitch that accompanies this paper. And quoting from that editorial, "The study is therefore extremely important in pointing out the potential overkill of senolytics in promoting rather than reversing pulmonary hypertension.

The study also has particularly important translational implications as it indicates that the potential efficacy of an emerging therapy relies on the underlying disease mechanism and animal model use, the cell specificity dose, and root of administration."

So lots of translational implications of this paper.

Dr. Greg Hundley:

Wow, Carolyn, so we've got some other articles in this issue and it looks like you've got a great review of those to describe.

Dr. Carolyn Lam:

Sure, I'd love to tell you about them. First there's a letter from Dr. Liao regarding the article, "Association Between Device Measured Physical Activity and Incident Heart Failure: A Prospective Cohort Study of the UK Biobank Participants."

There's also a Cardiovascular Case Series by Dr. Ostrominski on "Pulling Out All The Stops: A Case of Progressive Dyspnea."

In Cardiology News by Tracy Hampton, there's a story of scientists creating spatial map of cardiac remodeling after myocardial infarction, published in Nature.

Loss of Y chromosome in myeloid cells promoting cardiac fibrosis, published in Science. And details behind the DNMT3A and TET2 mutations linking atherosclerosis. And that's published in Immunity.

There's also a Perspective piece by Dr. Somers on "Whom to Screen and How to Screen for Obstructive Sleep Apnea in The Cardiology Clinic?" And a Research Letter by Dr. Felker on the clinical implications of negatively adjudicated heart failure events, data from the Victoria study.

Dr. Greg Hundley:

Wow, Carolyn, this issue, it's just packed with information. Well, how about we get on to that feature discussion?

Dr. Carolyn Lam:

Let's go. Thanks.

Dr. Greg Hundley:

Welcome listeners, to this feature discussion on this February 21, where we're going to delve into the world of valvular heart disease. And we have with us today Dr. Amil Shah from Brigham and Women's Hospital in Boston, Massachusetts, and our own associate editor, Dr. Ntobeko Ntusi from Cape Town in South Africa. Welcome gentlemen.

Well Amil, we'll start with you. Could you describe for us some of the background information that really went into the preparation of your study and what was the hypothesis that you wanted to address?

Dr. Amil Shah:

Well, thanks very much, Greg, and let me start by thanking you and the circulation team for the interest in this paper and the opportunity to discuss it with you today.

So I think in terms of background, we know that the prevalence and incidence of valvular heart disease increases with age, and that severe valvular heart disease is associated with substantial morbidity and mortality.

Sub-severe valvular heart disease is, of course, even more common and has also been associated with worse cardiovascular outcomes. So I'm thinking of earlier studies that have associated even aortic sclerosis in the absence of stenosis with worse outcomes.

Acknowledging the progressive nature of valvular heart disease, the ACCHA valve guidelines adopted this framework of valvular heart disease stages, where stage A was really defined as at risk for valvular dysfunction based on valve morphology in the absence of hemodynamic perturbation.

Stage B is progressive valve dysfunctions. This is commonly what we would clinically consider mild or moderate valvular lesions. And then stage C, severe asymptomatic valve dysfunction. Stage D, severe symptomatic valve dysfunction.

And we believe that looking at valvular heart disease in the context of these stages, as opposed to just as the hemodynamic severity of the lesion, can provide important insights into the burden of valvular heart disease. And especially sub-severe valvular heart disease in at-risk individuals, and in particular in older individuals.

But the prevalence of these stages in the community and their progression over time really prior to this, to our knowledge, hasn't been described. And so really our aims and our hypotheses in this paper was to understand the prevalence of valvular heart stages amongst older adults.

And really what we anticipate is that a large proportion of individuals in late life would have at least stage A, if not stage B, valvular heart disease.

To describe the prognostic relevance of these stages, and particularly the sub-severe stages, and we anticipated that even stage A or stage B relative to no stage would be associated with worse outcomes, based on the prior literature. And finally, to characterize the rate of progression in late life.

Dr. Greg Hundley:

So rather than just the hemodynamic significance, it sounds like we're going to investigate the stages of valvular heart disease in an elderly population and associate that with prognosis. So how did we do that? What was your study design and can you describe for us also your study population?

Dr. Amil Shah:

Sure, of course. So we ended up using longitudinal data from a large cohort of older adults who are participating in the Atherosclerosis Risk in Communities, or ARIC study. So ARIC is an NHLBI funded longitudinal epidemiologic cohort. It's actually been following participants from four communities in the US since 1986. So Maryland, Mississippi, North Carolina, and Minnesota.

Echocardiography was performed in just over 6,000. So 6,118 individuals are participants in 2011 to 2013. And at that time the mean age was 76. Just under 3,000 of those individuals underwent a repeat echocardiogram in 2018 to 2019. So that's a time elapse of about six and a half years, at which time the mean age was 81. So we're really looking at how things are changing between the ages of 76 to 81 years of age.

We really focused on the mitral and aortic valves and determined or ascertained the stage of regurgitation or stenosis in those valves using a combination of quantitative and qualitative criteria based on the study echocardiograms, which are all read and interpreted centrally.

And of course, each valve gets its own stage. And so for the purposes of this paper, we classified individuals as an overall valvular heart disease stage based on whichever valve had the highest grade lesion.

Dr. Greg Hundley:

Very nice. So using the ARIC study and then following the stages. So describe for us, Amil, what were your study results?

Dr. Amil Shah:

So at the first assessment, so amongst these approximately 6,000 individuals who had imaging in 2011 and 2013, the prevalence of stage A valvular heart disease was about 39% of individuals. Stage B, which again would be progressive, was about 17% of individuals. And stage C or D, which is really severe valvular heart disease, which was just over 1% in this community based population. And again, another 1% had previously undergone valve replacement or repair.

And not surprisingly, even amongst this older cohort, older age was associated with a higher prevalence of each one of these stages. Then over a median follow up of about six and a half years, we looked at the association of each one of these stages with incident cardiovascular events relative to that group of individuals who were free of valvular heart disease stage in this cohort.

And in each one of these stages, including stage A, was associated with a higher risk of incident heart failure, incident atrial fibrillation, coronary heart disease, which is largely MI, and then all-cause mortality. And that was true after accounting for many of common cardiovascular risk factors we usually think about as being related to risk for these outcomes.

Interestingly, there was not an association with incident stroke in this study, although I will say our numbers for incident events were modest.

Dr. Greg Hundley:

Now, did you find similar results for men and for women?

Dr. Amil Shah:

So these results were fairly consistent for men, for women. And then the other demographic subgroup we looked at is... One of the unique features of ARIC is that it is a biracial cohort. And so when we looked at demographic subgroups based on both gender and race group, these trends were similar.

Dr. Greg Hundley:

And I know, Amil, right at the beginning you were discussing the importance of the stages versus the hemodynamic consequences. Did you do any comparisons, for many of us that are following patients, for example, with aortic stenosis? Did you find a discrepancy between using the stage as the defining term for a patient as opposed to the hemodynamic significance of one of these valve lesions?

Dr. Amil Shah:

Yeah, that's an excellent question. And so I think the first point to make is the valvular heart disease stages, of course, that we are assigning are based on the highest stage lesion, and so, of the four lesions we assessed. And part of this is a little nuanced, I guess, based on how the guidelines have defined these stages.

So interestingly, if you look at stage A valvular heart disease, the majority of those individuals are getting in due to mild mitral regurgitation, because mild mitral regurgitation is considered stage A. In contrast, if you look at stage B, the majority of those individuals are getting in because of mild aortic regurgitation, because mild AR is considered stage B. And then stage C/D is really driven by aortic stenosis, probably not surprisingly.

So what we can do is look not only overall, but also by stage within lesion. And certainly for aortic stenosis and mitral regurgitation, which are the most common valvular lesions we encountered, we saw similar findings.

For mitral stenosis we had very few cases. So I don't think we can really comment on that based on this study. And for aortic regurgitation, we largely had individuals with no regurgitation or mild regurgitation, only a few with moderate. So again, we're a little bit limited in commenting on that.

Dr. Greg Hundley:

Very nice. Well, thank you so much, Amil.

And listeners, now we're going to turn to our associate editor, Dr. Ntobeko Ntusi from Cape Town, South Africa. Ntobeko, you have many papers that come across your desk. What intrigued you about this particular paper?

Dr. Ntobeko Ntusi:

Thanks, Greg. I'd like to start by congratulating Amil and his co-authors on this paper, which as an associate editor was an absolute pleasure to handle.

And the reason why we liked it are two-fold. Firstly, it's a large study, simple science of over 6,000 people. Very well characterized cohort clinically. We also liked its prospective design, as well as the protocolized nature of the echocardiograms.

We liked that there was a central facility for core reading of all of these echocardiograms. And the use of a well-validated system of categorizing valvular heart disease. And importantly, we also liked the fact that it is a very representative study in terms of ethnicity and sex.

And for me, there were three important takeaway messages from this study which advance our concepts of valvular heart disease. The first is that we've known for a long time that most severe valvular heart disease is associated with poor outcomes. But for the first time, this study provides us with data that shows a clear created association between the valve stage and outcomes related to mortality incident at fila and incident AF. So this is a new contribution.

The second important novel contribution from the study is the data they provided on disease progression between stages of valvular heart disease.

And then thirdly, I really liked the figures, in particular figure three and figure four, which I think are going to be highly cited and used in many presentations.

So figure three demonstrates the Kaplan-Meier curves and shows survival rates dependent on the stage of valvular heart disease. And figure four, beautiful alluvial plot showing disease progression. And for these reasons we thought this was a piece that we would like to include in Circulation. Thanks, Greg.

Dr. Greg Hundley:

Thanks so much, Ntobeko. Well Amil, based on all this work, where are you going next? What do you see as the next study to really be performed in this sphere of research?

Dr. Amil Shah:

So two major findings I think that may have downstream consequences for future studies, first relate to identifying a subgroup A. That these valvular heart disease stages progress fairly substantially over fairly limited periods of time in late life.

And really identify older individuals with certainly stage B, but even stage A valvular heart disease as a group, not only that we should screen with follow up, as recommended by the guidelines when we do detect sub-severe valvular lesions. But also potentially for therapeutics to prevent progression as those become increasingly available. And so I think one place where this data may be very helpful is in thinking about at-risk groups to evaluate therapeutics in.

I think the second place is this relationship of even stage A valvular heart disease with adverse outcomes, which I think suggests that when we see valve deformation on imaging, that is likely a marker of risks that we're not fully capturing using our other traditional cardiovascular risk factors. And potentially could begin to become incorporated into how we think about risk stratifying our patients.

Dr. Greg Hundley:

Very nice. Ntobeko, do you have anything to add?

Dr. Ntobeko Ntusi:

Indeed. So I think in terms of future directions, there are probably three questions that I think would be important in taking this work forward.

The first one is that this is clearly a descriptive epidemiological study. And for me it would be interesting to look at some of the mechanisms that underlie the adverse clinical outcomes associated with different stages of valvular heart disease.

Two, the follow-up is relatively short and I think that it will be interesting as these individuals continue to be followed up long term, to see how these observations are either strengthened or evolve over time.

And then finally, which is probably not going to be possible with the ARIC cohort. I think it would be useful to also look at rates of disease progression, but also the associations with outcomes in a younger cohort. And so for me, those would be interesting future ways of taking this work forward in the future. Thank you, Greg.

Dr. Greg Hundley:

Very nice. Well, listeners, we're going to wrap up and we want to thank Dr. Amil Shah from Brigham and Women's Hospital in Boston, Massachusetts, and our associate editor, Dr. Ntobeko Ntusi from Cape Town in South Africa, for bringing us this study highlighting that subclinical valvular heart disease is common in older adults with 39% at risk for stage A, and 17% with progressive valvular heart disease, or stage B. And they are independently associated with the risk of incident cardiovascular events.

Well, on behalf of Peder, 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 2023. 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 Circulation Senior Associate Editor Sana Al-Khatib and Associate Editor Mercedes Carnethon as they discuss the seventh Go Red for Women issue of the journal.

Dr. Sana Al-Khatib:

Hello and welcome to the Special Circulation on the Run podcast focused on the seventh 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 had the pleasure of co-leading this issue with a colleague and friend, Dr.

Dr. Mercedes Carnethon:

Well, I am so pleased to be with you today, Sana. My name is Mercedes Carnethon from the Northwestern University Feinberg School of Medicine. I'm an associate editor at the journal Circulation and extremely excited to join you this year on the seventh issue, as a guest editor for our Go Red for Women Issue. And we've got so many great pieces today, so let's get going.

Dr. Sana Al-Khatib:

Wonderful. So we're very excited to provide you with some highlights of the issue that covers a broad range of topics related to cardiovascular disease in women. In this particular issue, the content is presented as five original research articles, three research letters, five online articles, and one in-depth review article. And like prior podcasts, this year's podcast will only focus on the original research articles, so let's get to it.

The first original research article is titled Exercise for the Prevention of Anthracycline Induced Functional Disability and Cardiac Dysfunction. This was the breast cancer randomized exercise intervention Brexit study. In this trial, the investigators enrolled 104 women who were between 40 and 75 years old and had stage one to three breast cancer. And these women were scheduled for anthracycline based chemotherapy and they randomized them to three to four days per week of aerobic and resistance exercise training for 12 months and they were randomized in one-to-one ratio to either do the exercise or really usual care. Very interesting study Merci, don't you think?

Dr. Mercedes Carnethon:

Absolutely. This is such an important issue, particularly for survivors of breast cancer.

Dr. Sana Al-Khatib:

Exactly. And in this trial, they focused on looking at the following measures, cardiopulmonary exercise testing to quantify the peak VO2 and functional disability, cardiac reserve, quantified using exercise cardiac magnetic resonance measures to determine changes in left and right ventricular ejection fraction, cardiac output stock volume, standard-of-care echocardiography-derived resting LVEF and global longitudinal strain.

And exercise training was found to attenuate functional disability at four months, which was really interesting, but not at 12 months. But when they looked at it, Merci, in a per protocol analysis, functional disability was found to be entirely prevented at 12 months among participants who adhered to exercise training.

Dr. Mercedes Carnethon:

That is so exciting to hear, especially with the potential to intervene for better outcomes.

Dr. Sana Al-Khatib:

Exactly. And then listen to this, as compared with usual care at 12 months, exercise training was associated with a net plus 3.5 milliliter per kilogram per minute improvement in the peak VO2 that coincided with improvements in cardiac output, stroke volume, LVEF and RVEF reserve, all of them improved, Merci.

Dr. Mercedes Carnethon:

That is such great news. What did the authors have to say about these findings?

Dr. Sana Al-Khatib:

Well, of course they were really excited about these findings because hopefully this will help a lot of patients. Now, when they looked at the exercise training in relation to resting measures of LV function, there didn't seem to be an effect. So they concluded that in women with early stage breast cancer undergoing anthracycline based chemotherapy, 12 months of exercise training did not attenuate functional disability, but it certainly provided clinically meaningful benefits in relation to the peak VO2 and cardiac reserve. So really interesting findings. Obviously I personally would like to see these findings replicated by other studies, but I think these results are promising.

Dr. Mercedes Carnethon:

I'm so excited to be able to feature that important piece in here, especially as more women are living and being treated for breast cancer.

Dr. Sana Al-Khatib:

Indeed. So Merci, I'll turn it over to you to tell us about a couple of your articles.

Dr. Mercedes Carnethon:

Well, I'd love to do two of mine back to back if that's okay with you because they address similar issues. So in one of the first from Dr. Yuan, Liu, and colleagues, they studied the influence of maternal exposure to particulate matter, small, fine, particular matter, and how that influenced the risk of congenital heart defects. We certainly know that congenital heart disease is a significant problem. And what's even more interesting is that the author's site that more than 80% of congenital heart disease has no known cause.

However, prior research does suggest that particulate matter is a plausible environmental exposure that could damage follicular development, disrupt hormone homeostasis, cause inflammation and glucose intolerance. All of those processes could lead to abnormal placentation and fetal development. And so I thought it was really exciting that they would pull together this very large study. And in fact, this isn't the first study to ask this question, but it is one of the largest. It was carried out in China, which is an area with relatively higher levels of pollution.

And the authors did some really cool things. I can't wait to tell you Sana, because I feel as though I rarely get to say NASA was involved in a study that we're featuring here in Circulation. So let me tell you about it.

Not just cardiologists, not just obstetricians and gynecologists, but environmental scientists were involved here and the mean monthly measures of PM 2.5, which is small fine particulate matter, were made via satellite, NASA satellites, and imputation procedures were used that combined a number of meteorologic variables, land use types, road network information, elevations and emissions to train models using machine learning to make estimates of the burden of PM 2.5. Isn't this cool?

Dr. Sana Al-Khatib:

Wow. How interesting. Absolutely.

Dr. Mercedes Carnethon:

Yes. It's probably not something you do every day in your cardiology practice, but it's particularly important for us to be able to get these precise measures of PM 2.5 exposure and what the authors were doing were matching up these units of exposure with the preconception period three months before pregnancy, the first trimester three months after pregnancy, and the entire window to determine how exposures to PM 2.5 during those critical periods for fetal development influenced congenital heart disease and they studied the major causes of congenital heart disease, the major classes using ICD 10 codes.

Dr. Sana Al-Khatib:

Wow. Well, I can't wait to hear the results.

Dr. Mercedes Carnethon:

So the results suggested that in general, the risk of delivering a baby with a congenital heart defect increased by 2% for each 10 nanogram per meter cubed in maternal exposure to PM 2.5 during the preconception period. And this relationship was even stronger preconception than it was during the first trimester. And when they studied different types of congenital heart diseases, the strongest associations were with septal defects. And this was regardless of the exposure window, this was preconception, the first trimester and the entire peri-conception window. I think another really compelling thing about a study of this size, and did I mention that it was 1.4 million births that were studied here during a period of time between 2014 and 2017? 1.4 million births.

Dr. Sana Al-Khatib:

That's a very large study.

Dr. Mercedes Carnethon:

Yes, and one of the benefits of having a study of that size is that you have the opportunity to look at subgroup effects to determine whether there are other characteristics that modify the relationship of the exposure and the outcome in this case PM 2.5 exposure. And what they found was that the relationship of PM 2.5 exposure with congenital heart disease was even stronger for births that took place in northern China or births that happened in areas with a low per capita disposable income. And even more surprising, and I'm not sure if this surprised you, but the relationships were even stronger in births to mothers who were younger than age 35. And that's particularly telling given that many births are obviously happening when women are below age 35.

So I think these findings are just so compelling. I think they are important certainly for our cardiology community, but I think they're also important for policy makers as they consider the implications of air quality and how that affects our long-term health.

Dr. Sana Al-Khatib:

Yeah, no, absolutely. Very important implications here, Merci. I agree.

Dr. Mercedes Carnethon:

Yes. Well, so I was really pleased to feature that article and then in the same issue, if I can continue to hold the microphone here.

Dr. Sana Al-Khatib:

Yes, please.

Dr. Mercedes Carnethon:

In the same issue, we have another paper led by authors from China, Zhang and colleagues, who carried out a study of what happens when women grow up with congenital heart disease and they have their own pregnancies? And so the goal of this particular paper was to look at the influence of pulmonary hypertension, which is a common complication of women with congenital heart disease when they become pregnant, to see how the severity of pulmonary hypertension influences pregnancy outcomes in these women.

Dr. Sana Al-Khatib:

A very important topic. Yeah, I agree, Merci.

Dr. Mercedes Carnethon:

Yes. And so this was carried out in over 2000 pregnant women with congenital heart disease who had completed pregnancies. This was a retrospective analysis. And of those a significant portions, 729 women, had pulmonary hypertension. And these range from mild to moderate to severe. And unfortunately, maternal mortality was an outcome in this study along with birth outcomes among the babies. And what the authors found, I guess, consistent with what one might hypothesize, is that the severity of pulmonary hypertension was associated with adverse outcomes. Those women who had more severe pulmonary hypertension were more likely to experience maternal mortality. They were more likely to experience heart failure and other cardiac complications.

And unfortunately, those risks were as well passed along to the babies where there were more obstetric complications and other adverse events. So it's an unfortunate finding, but I would say that there were a number of bright spots and a few bright spots to this particular study. And their findings were that those women who had follow-up care with a multidisciplinary team, strict antenatal supervision, tended to have a lower likelihood of these adverse events.

Dr. Sana Al-Khatib:

That is so good to know. Of course, I mean, we have thought of that to be the case, but now to have a study showing that is really impactful.

Dr. Mercedes Carnethon:

It certainly is. And especially such a well done study. These aren't common. And so this team managed to find a relatively large sample size so that they could produce robust estimates that we can use and consider when we consider helping women with congenital heart disease manage their developing families. So I really thank you for letting me talk about two of these studies back to back, but I can't hog the microphone. We have so much good work in this episode.

Dr. Sana Al-Khatib:

Yeah, no problem. But it's so good to see more work being done on the adult congenital heart disease, by the way, because this is a growing patient population, and it's great that we were able to feature it in two articles, Merci. So let me present the second paper that I had the pleasure of handling in many ways, this particular paper. First of all, it is a topic that's near and dear to my heart as I am an electrophysiologist and the paper provides data on the comparative effectiveness of left atrial appendage occlusion versus oral anticoagulation bisects in patients with atrial fibrillation. And not only am I interested in the topic, but I actually was the senior author on this paper, and so I really need to acknowledge that and would like to share some highlights of the paper with you.

So in this particular paper, Merci, we analyzed Medicare claims data from 2015 through 2019, and we really focused on patients who were deemed to be eligible for left atrial appendage occlusion.

And we divided them into sex subgroups. And of course, we had to apply robust statistical methodology first in terms of making sure that patients with left atrial appendage occlusion were well-matched in one-to-one ratio to those receiving anticoagulant therapy. Obviously, a lot of selection bias goes into those assignments in clinical practice, and so we needed to make sure to match those groups, and we did that for women and we did that for men. And we were really interested in looking at the risks of mortality stroke or systemic embolism as well as bleeding between these matched groups, so we wanted to compare those risks.

And so among females, we had 4,085 left atrial appendage occlusion recipients, and those were again matched in one-to-one ratio to women who were receiving anticoagulant therapy. And if you look at the subgroup of males, 5,378 were left atrial appendage occlusion recipients. And again, those were similarly matched to men who received oral anticoagulation.

And so of course, after doing the matching, we applied the further adjustment to take care of remaining differences between the groups. So what did we find? We found that left atrial appendage occlusion was indeed associated with a significant reduction in the risk of mortality as well as stroke or systemic embolism and this was true for females and males. And when we looked at the bleeding risk, we found that that risk was significantly greater in left atrial appendage occlusion recipients early after implantation, because as you know, Merci, those people for the first six weeks have to be treated either with anticoagulation or a combination of aspirin and Plavix, and so it's not surprising that bleeding was actually high early on, but really lower after the six week per procedural period for both females and males.

And so what we concluded in this study, which was a real world study, and that's the significance of this because several trials had been conducted, but many of us always raised the questions of, well do the results of the clinical trials apply to the average patient that we see in clinical practice? So many of us would like to see comparative effectiveness analysis being conducted in real world populations, and here we were able to show that left atrial appendage occlusion was associated with a reduction in the risk of death, stroke, or systemic embolism as well as long-term bleeding both in females and males. So really very interesting results that I think should help inform shared decision making discussions with patients.

Dr. Mercedes Carnethon:

Oh, absolutely. I have to say I'm not biased. It's not because you are the senior author, it's because this is just truly excellent work, really a creative design. And I agree with your assessment that doing this sort of real world work is critically important because sometimes we don't have the representation in clinical trials of a distribution of people who would ordinarily be the targets of these types of therapies. And so I really applaud you and your team for really leading an excellent study that I hope people will find extremely useful.

Dr. Sana Al-Khatib:

Well, thank you very much, and I really want to give a lot of credit to the first author, Dr. Zeitler, who has been mentee of mine for many years and has done a great job and really a lot of credit to the rest of the co-authors.

Dr. Mercedes Carnethon:

Well, that's fantastic. I'm glad that I chose the ordering that I did because the final study that I'd like to talk about is in fact a randomized trial. And I think similar to the one that you just described, this is another study that's comparing sex differences. So this particular study led by Coughlan and colleagues describes sex differences in 10-year outcomes after percutaneous coronary intervention with drug-eluting stents. And given the positive impact that drug-eluting stents have had on improving coronary artery disease, I think it's critically important for us to find out whether or not there are any disparities by sex and the types of outcomes that occur following percutaneous coronary intervention. And so in order to address this question, what the authors did was to carry out a pooled analysis of five individual patient data from trials of drug-eluting stints that had at least 10 years of follow up.

And the objective here was to really address the controversy in the field about whether the outcomes were worse for women, which was observed in some studies versus in other studies where there was no difference. And the benefit of using this pool design, again, this sample size, I'm an epidemiologist, I love big samples for what can be done. And in the 9,700 patients that were included in this trial, 24% of them were women. So really it required this type of a meta analytic design in order to have enough women to answer these questions. So the outcomes of interest here included death from all causes, death from cardiovascular disease, MI, stent thrombosis, and revascularization of the target lesion, the target vessel, and the non-target vessel.

So one of the challenges in interpreting findings from prior studies of this question are the concerns that the clinical characteristics of men versus women who underwent PCI were different.

And in fact, in this particular pooled analysis, men were more likely than women to have three vessel disease, and they had a lower, lower mean ejection fraction coming in the characteristics following angiogram and the procedure also showed some differences by sex groups, namely that women had smaller vessel reference diameters before PCI and a smaller minimal luminal diameter after PCI. But men had a longer total stinted length as compared with women. So I'm sure you want to know what ended up happening.

Dr. Sana Al-Khatib:

Please.

Dr. Mercedes Carnethon:

Yes. So when the authors tested their primary hypothesis of sex differences in tenure outcomes, they found that some of the very minor differences in the proportion of women versus men who experience the outcomes of interest were eliminated following adjustment for relevant characteristics, or in fact that women were slightly less likely to experience the outcomes of interest. Specifically women were less likely to experience death from any cause over 10 years, but there was no difference in cardiovascular death as compared with men.

Women though were significantly less likely than men to require repeat revascularization of the target legion, the target vessel, and the non-target vessels over 10 years. But unfortunately, the findings weren't all good. A notable exception was that when the offers examined the one-year event rates, women had a significantly increased likelihood of MI in the first 30 days after PCI. And I'm not sure why this is, but the authors did advance numerous hypotheses to explain their findings. One was that baseline and procedural characteristics varied markedly between men and women, and that the age was a primary confounder of these findings. And this was because they carried out a series of sensitivity analyses where they didn't account for age and when they didn't account for age, women had an increased risk of cardiovascular death through the entire 10 years of follow up. And it's curious why this would happen.

And the observation was thought to be attributable either to women developing CAD later than men in life, or because they're diagnosed later because of decreased physician awareness among women. And that's shocking to hear since we all know that cardiovascular disease is the leading cause of death among women. So I really think that the observations in this large pooled analysis do warrant further study and investigation. And a point that I think we discussed earlier is that the representation of women in clinical trials, we have to have more women in these trials and this was an argument that the authors advanced because then without more women in these trials, we don't have adequate power to investigate these sex differences and to explore reasons behind these sex differences. And so I hope that investigators will really heed these calls so that we can generate the best possible science to inform treatment options for women so that we can maximize our health outcomes.

Dr. Sana Al-Khatib:

No, absolutely. Those are excellent points, Merci, that you make. And we certainly need to make sure that we have more women participating in clinical trials and that to the extent that we can, that patients enrolled in clinical trials are representative of patients that we see in clinical practice. You bring up excellent points. Thank you for that great summary.

Dr. Mercedes Carnethon:

Thank you so much, and thank you really for letting me join you in this special issue. I'm so excited about all of our pieces, not just these original research pieces, but as well our research letters and the rest of our content. I think there's just a lot for our readers to dig into here.

Dr. Sana Al-Khatib:

Yeah, no, absolutely. Merci, it's been a pleasure for me to co-lead this issue with you and I agree while we focus this podcast on the original research articles, the other articles are equally interesting and impactful. So a lot for our readers to enjoy here. So in closing, we want to wholeheartedly thank Dr. Joe Hill, the editor-in-chief for Circulation, Dr. James De Lemos, the executive editor of the Journal and all authors who submitted the research for this issue. We also want to thank the Circulation associate editors and staff who worked so hard to deliver what you are about to experience. We're very excited about this issue and know you will find it very informative and interesting.

This concludes our Go Red for Women issue Circulation on the Run podcast. Thank you so much for listening.

Dr. Mercedes Carnethon:

Thank you.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2023. 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.