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[how to lower myostatin]House of Cards Journal Club presents: EXPLORER-HCM
source:Sky forum Release time:2021-10-10 typeface:large in Small

  On May 25, 2021, the House of Cards Journal Club and the Department of Internal Medicine hosted a Clubhouse event on the efficacy and safety of Mavacamten in symptomatic obstructive hypertrophic cardiomyopathy.

  Nona Jiang, MDDaniel Jacoby, MD

  This event was moderated by Zaniar Ghazizadeh, MD, PGY-3 Internal Medicine resident. Below are some highlights from the event. The conversation has been edited for brevity.

  Zaniar Ghazizadeh: My name is Zaniar, I’m an Internal Medicine Resident at Yale and also one of the founders of the Yale House of Cards Journal Club along with Dr. Golsa Joodi and Dr. Justin Pacor. Today we’ll be discussing the EXPLORER-HCM trial. Dr. Jacoby graciously accepted to participate in this event, and I’m joined by Drs. Nona Jiang and Golsa Joodi, who are also my co-residents. As some of you may know, the EXPLORER-HCM trial evaluated a new medication called Mavacamten on patients with symptomatic hypertrophic cardiomyopathy (HCM).

  Q: Tell us more about the science behind discovering this new medication.

  Nona Jiang: The hallmark of this disease is unexplained left ventricular (LV) hypertrophy, growing at 1.5 cm, and this is in the absence of any other etiology for increased afterload and in the absence of any other systemic cardiac or a metabolic disease states. And HCM actually remains the most common genetic cardiovascular disease and affects between 1 in 500, to up to 1 in 250 people in the U.S., and there are actually 1,500-plus variants that are linked to HCM. 90% of these genetic variants are in genes that basically encode thick and thin filament proteins in the cardiac sarcomere.

  To understand Mavacamten, when there are mutations in either thin or thick filaments, there is fundamentally dis-regulation of the cross-bridge cycling, this then leads to hypocontractility, and then that eventually, which is still by an unknown mechanism, this then triggers hypertrophy, which is the hallmark of the disease. Mavacamten was… It’s actually this first-in-class myo-blocker, that is a selective allosteric inhibitor of the cardiac myosin ATPase. Originally in biochemical studies, they have found that Mavacamten has actually decreased myosin ATPase activity, and decreased maximal tension generation in cardiac muscle in mice, and this was done in a dose-dependent fashion.

  Interestingly, Mavacamten was found to actually have a lower affinity for skeletal muscle, this made it a very good drug for potentially treating HCM. So fast forward to 2016, there was an in vivo study, a seminal study, published in Science where Mavacamten was used to treat mice, established mouse models of HCM. And in the study they found that Mavacamten in young mice actually decreased fractional shortening and also prevented hypertrophic remodeling of mouse hearts. This drug was then trialed in patients, there was a phase II Pioneer HCM trial where patients were treated with Mavacamten for 12 weeks, and they were followed for changes in post-exercise left ventricular outflow tract (LVOT) gradient, and with several secondary exploratory endpoints with variable effects. EXPLORER-HCM is now the largest perspective double-blind placebo-controlled study ever conducted in patients, who have symptomatic obstructive HCM.

  Zaniar Ghazizadeh: Thanks Nona. I wanted to give more information about the study design and inclusion criteria, exclusion criteria and the outcome.The trial was a phase III multi-center randomized double-blind placebo-controlled trial, and it took place in 68 clinics in 13 countries. The trial was sponsored by Myocardia. The key inclusion criteria were, age more than 18 years, and also having hypertrophic obstructive cardiomyopathy which was defined as LVOT or left ventricular outflow tract gradient of more than 50.

  Other inclusion criteria were left ventricular ejection fraction of more than 55%, and a New York Heart Association class two or three symptoms of heart failure. The other important criteria was the patient being able to perform an upright cardiopulmonary exercise testing and with respiration ratio more than one at screening. The exclusion criteria included syncopy, or sustained ventricular tachycardia with exercise within six months. So plans for the duration was about 43 weeks, and it had three periods. The first was screening, which was up to five weeks prior to the actual treatment, and the second step was a double-blind treatment. The length of the treatment was for 30 weeks.

  Post-treatment follow-up was eight weeks. So patients could have continued beta-blockers or calcium channel blockers if it was started before the trial participation, but Dysopyramide was not allowed while the patients were in the study.

  During the eight-week post treatment period, the study drug obviously was discontinued, and if patients were willing they could return for key assessment at 38, and after they may have elected to consent for continuing the long-term extension study of Mavacamten.

  The primary endpoint of this trial was a composite functional endpoint at week 30 of treatment, and defined as achieving an improvement of at least 1.5 ml per kg per minute in peak oxygen consumption, or pVo2 as abbreviated, and as determined by that cardiopulmonary exercise testing and the reduction of more than one heart failure class. The second criteria was improving at least three cc per kg per minute. The first one was 1.5, now this one, 3 cc per kg per minute, without worsening in heart failure functional class.

  Secondary endpoints include analysis of change from baseline to week 30, in treatment group versus placebo in these parameters, which were post-exercise LVOT gradient, pVo2, NYHA class, and two patients reported outcomes, which were Kansas City Cardiomyopathy Questionnaire, and HCM core symptoms, as assessed by a newly developed instrument, and the hypertrophic cardiomyopathy symptom questionnaire.

  To characterize the change from baseline to week 30 in multiple parameters involved assessing cardiac function, hemodynamics, myocardial structure, cardiac rhythm, and for treatment versus placebo. The study included 12 visits with serial assessment of cardiac structure, function, and symptom using EKG, echo, New York Heart Association function class, and lab tests such as… Including biomarkers, CPET, and recording of daily physical activity as the patients were using wrist worn accelerometer, and they had the data for analysis.

  The participant characteristics were roughly equal number of men and women. So about 43% of the people who received Mavacamten which were 98, 43% were women, 57% were men, and of the placebo group, which was also 96, 35% were women and 65% were men, and 94% of the Mavacamten group. About 46% of the patients were enrolled in US, and fairly similar BMIs, close to 30 in both groups, and the heart rate in treatment group was an average of 62 and for placebo was also 62, very similar. And similarly, the rest of the criteria were consisted of randomization were very close, 10% of the population of the people who get Mavacamten and 14% in placebo. Hypertension, 52% in Mavacamten and 45% in placebo.

  Q: Discuss the results and the findings of the study.

  Nona Jiang: Overall in the Mavacamten group, so there’s 125 patients. In the placebo group there’s 128. 97% of the patients ended up completing the treatment. Five patients discontinued the treatment prematurely. Three were due to adverse events, and then there was one sudden death actually in the placebo group, and then no patients were lost to follow-up, which is pretty impressive. And then I guess the main punchline is, as Zaniar alluded to a the primary endpoint in the study was defined as either a 1.5 milliliter per kilo per minute or greater increase in peak oxygen consumption with at least one New York Heart Association class improvement, or a 3.0 milliliter per kilo per minute or greater increase in peak oxygen consumption with no worsening. So basically this was a composite primary endpoint that was designed really to capture both an objective and subjective way to measure impact, or improvement in the lives of patients with HCM. So with the Mavacamten group of those 123 patients, 45 patients out of 123, which is 37%, met the primary endpoint after 30 weeks.

  And this is compared to 17% of patients on the placebo, and this was a significant difference. And furthermore in terms of the secondary endpoints, Mavacamten treatment was also associated with a significant improvement in all secondary endpoints as compared with placebo. So there was almost a 50 millimeter hydrogen, not hydrogen, mercury reduction in post-exercise LVOT gradient, so this translated into an improvement in peak oxygen consumption of almost 1.4 milliliters per kilo per minute on average. And as Zaniar alluded to, there was also subjective symptoms measured as an outcome using the Kansas City Cardiomyopathy Questionnaire, which is a self-administered questionnaire that evaluates patients with heart failures… Heart failure and their health status. So there was also improvement in the subjective symptoms. And based on these metrics, nearly 75% of these patients with obstructive hypertrophic cardiomyopathy study, they would no longer actually be eligible for septal reduction therapy, and 56% actually showed complete relief of obstruction.

  And as I mentioned before, great completion rate. 97% completed therapy through 30 weeks, and in terms of the adverse effects of therapy compared to placebo, there was no significant difference. So all these data and aggregate show that Mavacamten, as compared to placebo, was superior to placebo with respect to exercise capacity as measured by the peak oxygen consumption. Also superior with respect to relieving LVOT obstruction and improving New York Heart Association functional class and also subjective health status. And actually, by virtue of these data, the FDA has actually granted breakthrough therapy designation for this drug, which is really exciting.

  Awesome, thanks so much, Nona. The findings of this trial are very exciting, and a lot of opportunities for the clinicians and to understand the future clinical applications. And we saw that the new analysis came out in the most recent ACC as well.

  Q: What are your thoughts about the current status of the treatment and how it’s being used, and also the future directions and how the FDA process is going?

  Daniel Jacoby: Thanks so much for having me. For those of you who are interested in hypertrophic cardiomyopathy, I’ll pitch something we call HCM Club, which occurs on Thursday mornings from 8:00-9:00 a.m. It was started by Srihari S. Naidu, MD, who’s at Westchester Medical, and it’s topics in hypertrophic cardiomyopathy, so it’s an interesting Clubhouse channel to plug into if you’re interested in this kind of thing.

  A couple of quick thoughts since this is a journal club format, it’s worth pointing out some opportunities for further thought. Obviously, the data is very powerful and suggests very significant benefit. One of the things that people have asked questions to that, and I think it’s a legitimate topic to talk about is, what does it mean when you give a medication that lowers the ejection fraction for patients that requires close monitoring? And how many of those patients get ejection fractions that are actually sub 50% and what does that mean for the long term for these patients.

  Number two is equally effective in patients who receive beta blockers and calcium channel blockers, versus just primarily getting Mavacamten. And number three, and I think probably the most interesting question is what are the sort of longer term remodeling type effects that might be apparent from this drug that might have a longer term effect on the disease over and above the the acute treatment of left ventricular outflow tract obstruction. And actually, there is a number four, which is that the representation for minority populations is really limited in this study, and highlights the need for more inclusiveness and access in clinical trials.

  That’s a chronic problem in clinical trials. And unfortunately, although this was a very well ran trial, there obviously are systematic barriers. And my feeling is that some of those barriers occur, even in the diagnosis and treatment of hypertrophic cardiomyopathy before people get to trials. And we have a paper out on access and outcomes in hypertrophic cardiomyopathy that we did, that I did with Alex Thomas, last year, to kind of expose some of these root cause issues. So with that, I’ll address the specific questions that came up about FDA, the drug is before the FDA. Currently, they’re in process, I anticipate that we’ll see and I don’t have any inside information about how it’s being approved at this point. But I do think that we’re gonna see it come to market either in Q3 or Q4 of this year. And with that, I’m very interested to see how it lands in the marketplace. The last major new advancement in cardiac specific disease specific medications, which was tafamidis to be approved by the FDA, which is a treatment for TTR Amyloidosis is the most expensive medicine, cardiovascular disease has ever seen at over $200,000 a year.

  I’m really curious to see if this medication will cost a lot to develop, The company MyoKardia was ultimately sold for over $13 billion to Bristol Myers Squibb. I’m interested and curious to see what the cost of the medication is. We as investors have been advocating for transparency and for patient-centered activities to be foremost as this medication gets launched, and I have total confidence that our partners in the industry.

  Q: What’s going to happen and how will the follow-up go when this drug is introduced to the public? Will they have to have echoes every two months to make sure that it’s not harming them and make sure there’s improvement? If so, that means six the first year. Who’s going to pay for all that?

  Daniel Jacoby: Obviously, safety has to be monitored. There’s a five year long-term extension study, that’s including patients who’ve been in all the Mavacamten obstructive studies, so PIONEER and also EXPLORER and also MAVERICK, to look at sort of long-term exposure and longer term exposure of the drug. This study has less intensive monitoring and a 30 week treatment trial because patients were in long-term extension. And I’m fairly certain that data from that and also from the clinical phase, the clinical trial will drive the level of oversight for how this medication is going to be utilized. I don’t have any inside information, but my guess is that there will be clear recommendations for guidance around initiation of the dose and monitoring. And then there will be some kind of ongoing monitoring process.

  It’s a critical issue for our overall health care system, but the progress from treatment of the disease with non-specific therapy, such as calcium-channel blockers, beta blockers or disopyramide, and/or septal reduction therapy, to being able to use disease-specific therapy that significantly improves outcomes over even a short treatment period, and might have remodeling effects as well. It’s a profound step forward in terms of treatment for patients for hypertrophic cardiomyopathy. I’ll just say, there have been no other prospective phase III clinical trials of this magnitude in hypertrophic cardiomyopathy. None of the other treatments that we use have been looked at in this fashion, not even septal myectomy. And so, one can make an argument that this is the only tested effective therapy for treatment of obstructive hypertrophic cardiomyopathy that we really know the effect, the downsides, the outcomes, and how to monitor it.

  So, I think, yes, is it an issue? Absolutely. Is payment gonna be something we’re gonna have to work through? Absolutely. Is this a massive step forward for patients with hypertrophic cardiomyopathy? Without a doubt.

  I want to touch on patient outcomes. We live in a world in cardiovascular medicine where, in general, we have humongous studies, multiple thousands of patients with really well-defined outcomes, typically cardiovascular mortality, very frequently major adverse cardiac events are really well-documented, and we’re looking at areas where there’s multiple different therapies. This is unique in that regard. And to that end, we need to look at what the results are. Data that was presented most recently at American College of Cardiology is really profound in terms of the Kansas City Cardiomyopathy Questionnaire. The level of benefits seen in this patient population from a patient-reported outcome perspective is absolutely astonishing for a medication. We’re at the level of benefit that you only see in terms of life-changing interventional therapies such as LVAD or TAVR, things that immediately and acutely massively change the structure or function of the heart and cardiac output. And you don’t see this in other areas. There is no heart failure therapy that comes anywhere close to the effectiveness of this in terms of patient-reported outcomes.

  I’ll tell you one quick story about a patient of mine. When I first started in PIONEER Phase 2, who got the medication. He came back the next week and he said to me, “This stuff is magic. I never knew that my heart wasn’t supposed to be pounding in my chest at night when I lay down to go to sleep.” Imagine, his heart was pounding, it was a constant drumbeat in his chest that never went away. And for the first time in his memory, he laid down to go to sleep at night and he didn’t feel his heart pounding in his chest. It was just quietness, which was this profound experience. How do you capture that experience of being able to suddenly have that experience and having normal heartbeat in your chest? And how much more relief that might feel for someone who doesn’t even know the difference? These individual patient experiences is something that’s hard for us to put too much value on as we think about the use of Mavacamten in this population.

  Zaniar Ghazizadeh: Thanks so much, Dr. Jacoby. It’s very exciting to see that it’s making a change in people’s lives and people’s efforts over the years has come to a great result.

  Q: When you were analyzing the rhythms and the EKGs, Holter monitors and things like that, did it decrease the rates of any benign arrhythmias or anything like that?

  Daniel Jacoby: We haven’t come up with the official data analysis yet, but it seems to be relatively balanced between groups over the three-week period of time, their arrhythmia burden seems to be relatively balanced. But I would be curious to see ongoing, over the long-term extension study, whether we see any reduction in ventricular HL arrhythmias, ’cause there’s a significant drop in BNP and troponin. We know both BNP and troponin are associated with adverse outcomes, both arrhythmic and heart failure outcomes.

  There is data from the MRI sub-study that was published in circulation in November, and at the same time was presented at the American Heart Association, that there’s reduction in the left ventricular mass. We know from basic science, or from translational science, that there’s reduction and in hypertrophy in animals as well. There’s a lot of good data to suggest that over the longer term, we’re gonna see either a halt or slow down in adverse remodeling, or potentials in beneficial remodeling. There’s a good chance that we may see reduction in these outcomes that we see with HCM of AFib ventricular arrhythmias, and certainly heart failure. And I’m wondering whether even some reduction in progressive fibrosis and dysfunction.

  If I can introduce a colleague of mine Wendy Borsari, who has been involved in the field of hypertrophic cardiomyopathy and is also patient advocate and a patient who really understands this disease from the inside out.

  Wendy Borsari: I’m excited about Mavacamten. I tried to get into the next non-obstructive trial, but because I’m on verapamil and disopyramide, it didn’t work for me to participate in the trial, but I do know people who participated in the obstructive in the EXPLORER trial, and one particular woman who is a good friend of mine who is now on the long-term extension because she felt so terrible after that wash-out period, but one of the effects that she’s had, recently she was diagnosed with. Her A1C was, I think, 6.5, so she was pretty close to being diabetic, and she asked the doctor if she could just exercise and try to eat right, to bring that number down instead of going on a medication, and she was able to, in about six weeks time, bring her A1C down to 5.4, so I think that’s another thing that we’re gonna see as people start taking this medication is you’ll have people with HCM who for years have been told don’t exercise or have been afraid to exercise, who now feel as though they can and now have the energy and just overall, feel so much better, so that they’ll be getting out and doing the exercise, that’s gonna help so many other things.

  Wendy Borsari: So I think the long-term effects we’re gonna just see a ripple effect in terms of what Mavacamten can even do for other conditions that are not related specifically to the drug.

  Daniel Jacoby: That’s really a great point, Wendy. I wanted to say because people listening might ask, Why doesn’t your friend just get a myectomy? I want to point out that over two-thirds of the patients in the study were New York Heart Association Class II. So remember that New York heart Association Class II on medical therapies are not candidates for septal reduction therapy by guidelines unless they’re having episodes of syncope, or refractory whether symptoms progress, and so those patients were not indicated for alcohol ablation or myectomy.

  So the majority of patients in this study would actually have at the time of enrollment in the study, no other treatment option available to them, prior to them being enrolled in the study, no other reasonable treatment. So these are patients who have had substantial improvement on best therapy with no alternative, frequently people have talked about EXPLORER. There’s been this question, “Well Geez, why don’t you just get a myectomy?” Remember, a lot of these patients would not have been candidates, if you wanna talk about a comparison between treatment with Mavacamten versus myectomy, that study’s ongoing is called the VALOR study, and it’s differently designed and it’s specifically for class III patients or a class II with syncope who are in hemodynamic syncope or indicated for surgical therapy or septal reduction therapy of some kind or another, and they go on placebo versus Mavacamten, over, I believe, 12 weeks then are re-assessed for their candidacy for septal reduction therapy, and they can either choose to go forward with that or not to see whether Mavacamten will play a role for patients in general who are selecting septal reduction therapy versus not.

  So this is a more complicated question but very important to know that what we’re doing now is we’re palliating patients with chronic symptoms who end up with diseases like diabetes and obesity, difficult to treat hypertension and all kinds of quality of life issues that we underestimate all the time, and giving them an opportunity for an improved quality of life, and we don’t know about quantity yet, but I certainly hope so.

  I think we have a word of caution, we should always have a word of caution, this is although very large study for hypertrophic cardiomyopathy only 257 patients enrolled, and that’s a relatively small number of patients in the exposure days. So we have 30-week study, there’s obviously, that’s why a long-term extension is so critically important, and why the launch of it needs to be associated with developing of a registry hopefully, and with some very careful monitoring, but it’s just a hopeful time, it’s just a way of looking as Dr. Ghazizadeh said, it’s just a way of looking at a disease over 50 years with first clinically characterized, then genetically characterized and then with tremendous basic science work by the sides things and others, then with translational work, and ultimately commercialization, and then a very well-run phase two and phase three projects, and finally a drug that’s now going to be available to our patients, it’s really a happy story of the ability of science to come face-to-face with inherited disease and do something helpful for our patients.

  Zaniar Ghazizadeh: Thanks to Wendy for joining, I think Golsa had a question that she wanted to ask.

  Q: I was going to ask about part of the study that talks specifically about the imaging findings. And Dr. Jacoby alluded to how the remodeling is being affected. How are we doing in that regard? And are there any more ongoing imaging studies that we’re looking at?

  Daniel Jacoby: Yeah, this is one of the most important issues that the echocardiography paper is, will be forthcoming shortly, which will give us additional information about remodeling. But remember, talking about it’s a 30 week exposure, three zero weeks, over the course of average patient age, somewhere in the late 50s. Mid to late, I think maybe mid to late 50s. So you’re talking about disease that’s probably been present for years and years, even decades, and only with only 30 weeks of exposure to detect remodeling is quite astounding. I think, the indications that we’re getting some kind of remodeling again, go back to biomarkers, and maybe some of the translational sciences, some of the imaging data we’re getting now, long-term extension study does not have MRIs built into it, but it does have echoes. So we’ll see if we can see any remodeling in that.

  Ahmad Masri, MD, MS, who’s a hypertrophic cardiomyopathy and amyloid doctor at Oregon Health & Science University, is working to put together an investigator initiated MRI study for the long-term extension, with a number of investigators, possibly looking primarily at the PIONEER patients who’ve been, had the longest period of exposure. But obviously, that’s the most hopeful issue. There’s trials that have already been forth and there’s a phase three, an obstructive, Wendy, that that’s under planning and I know, not to get too off topic, but Cytokinetics, which is my modulator company, muscle dynamics company, which has produced recently, the Galactic HF study, which if anybody follows that literature recently came out at the American Heart Association, I believe.

  And they have a drug called CK-274. That’s in phase two now, and already the phase three is being launched. And they’ll certainly be coming with a non-obstructive study too, as well. And then I think the question that’s sort of a corollary to that is, do these drugs that we come to call modulators. Are there certain phenotypes that associate heart failure with preserved ejection fraction? Are those patients candidates for mild modulation with the allosteric inhibitors of myosin ATPAs, or other mild modulators that will lead to potentially benefit in that population? I think that’s a really interesting question, and one, that’s certainly going to be worth looking at over the coming years.

  Maybe I have a question Dr. Jacoby, do you think the type of mutation that the patients might have might have any effect on the effect of drug or you think the endpoint of the mutation is malfunctioning version and the medication will fix it by the mechanism as normal, or you think like sequencing may have a role in future in stratifying patients?

  So there were only 20 to 30% of patients in each arm of the study placebo and treatment that had sarcomere mutations. The majority of patients were genotype negative. The forest plot in the paper shows no difference in effect and efficacy by sarcomere mutation status, yes or no? What we don’t have, we haven’t done a deep dive into the, whether there’s a difference between, in responsiveness, between those patients who have thin filament versus thick filament disease, there are biological reasons to think that perhaps there might be a difference there. The most interesting piece to me is that we don’t see a significant differential in treatment effect between those who are phenotype negative and phenotype positive. But we know that these two diseases have different natural histories and different presentations and different heritability from data from the SHaRe registry and other large cohort studies. And so the question comes up about a final common pathway. In other words, similar to many diseases, has the target of looking at myostatin interaction been identified by identifying a genetic mechanism for a specific type of underlying hypertrophic disease, but has that been able to be utilized to treat what I would call oligogenetic or multigene, or sporadic cases of hypertrophic cardiomyopathy that don’t have a sarcomere origin.

  There’s lots of reasons to think that there’s a final common pathway to hypertrophy associated with energetics at the level of the cardiac sarcomere. In many cases, although it won’t be all cases, and that those cases may respond particularly well to modification and interaction and energetics at the level of the sarcomere. So I think there’s a lot to explore in that space, we tend to be really caught up in hypertrophic cardiomyopathy is a monogenic disorder of sudden cardiac death and hypertrophy of the young. We know that that’s the case in many patients. But we know that it’s not the case in many patients, and that their hypertrophic cardiomyopathy occurs both also sporadically, in the absence of sarcomere mutations, but has similar and overlapping natural histories similar and overlapping imaging. And obviously similar and overlapping response to this myosin modification.

  Some of that translational work can be done in the lab but a lot of it’s going to be done in the clinic, as we start to learn what the responsiveness is to these medications. We should not be surprised by this, however, because the dilated cardiomyopathy studies that have been done non-ischemic, dilated cardiomyopathy or heart failure studies have never screened for inherited disease. And yet, we know that in populations with non-ischemic cardiomyopathy, upwards of 25% of patients have significant family histories of dilated cardiomyopathy and probably have a genetic predisposition to the condition. I would say at least a quarter of all dilated cardiomyopathy are probably strongly genetic in origin, and yet we treat everybody with a beta blocker or an ACE inhibitor because there’s a common mechanism for decompensation and hear failure, just a common mechanism for remodeling. And it seems to be equally effective.

  In fact, in titin, which is the most common inherited type of genetic dilated cardiomyopathy accounting for over around 12% of patients with dilated idiopathic dilated cardiomyopathy, those patients are particularly responsive to medical therapy and unloading, and are overrepresented LVAD heart failure with recovered ejection fraction. So there seems to be a pathway by which certain mutations are super responsive in some level to guideline directed medical therapy for dilated cardiomyopathy, I think we’re gonna find out a lot more as we move forward.

  This idea that genetic cardiomyopathies are something different and special, it’s probably the reverse, I think, probably genetic cardiomyopathies are the tip of the iceberg. They teach us the underlying pathophysiologic mechanisms of the so-called non-genetic or environmental or sporadic cardiomyopathies. And that there’s a final common pathway. After all, when you stub your toe, you prick your finger, you break your arm, you bonk your head, there’s only one response the body has, and that’s pain. It’s common for the body to have a single response to multiple different stimuli. So a final common pathway.

  Zaniar Ghazizadeh I love the analogy. Yeah, I agree. It’s interesting. I know that a lot of questions in genetics, or translational research has been figuring out the mechanism, but now we see the endpoint. And the final common pathway is the one that we can learn a lot more from. We appreciate you guys joining the discussion and for all your comments and input. Hopefully to see you all in our next meeting. Thank you all.

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