Mar 13, 2023
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.