Circulation March 14, 2023 Issue

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.