Sharlene Day, MD , Associate Professor of Medicine and Genetics and Penn Medicine discusses hypertrophic cardiomyopathy and the new insights, guidelines, and directions surrounding the condition.
Related Links:
Twitter @PennMDForum New Paradigms in the Clinical Care of Patients with Hypertrophic Cardiomyopathy Gaining a Deeper Understanding of Inherited Cardiomyopathy - Podcast with Dr. Anjali Owens Dr. Day’s physician profile
So I'm really delighted to be here today to talk about a topic that's near and dear to my heart and something that I've focused on in my career for the past 15 years. Hypertrophic cardiomyopathy. The title might talk new insights, new guidelines and I'll touch on some of the highlights from the guidelines and talk about new directions that the field is moving in. So I also apologize actually have sort of a legitimate cold that's not covid. So my voice is a little scratchy. Hopefully it's um still audible. Okay. Um I have a few disclosures really. The only one that's relevant to the top today is bristol Myers Squibb who acquired my cardio. I am going to talk about the the first in class minus and modulator maverick Hampton and bristol Myers Squibb funds a patient registry. Um so as Samir said, I started my career at the University of Michigan about 15 years ago started inherited cardiomyopathy program and was really fortunate to have the support of um so many people there including surgery, cardiology and beyond. Um Sarah Siberian Adam helms now who came up through the fellowship and trained with me and joined the program as faculty. Now Khalid the program. Um And then when I came to Pen of course joined the Pen center for inherited cardiac disease under the medical direction of Anjali Owens. These are all familiar faces to you here. Um We have really a fabulous team that includes physicians um um nurse practitioners, nurses, genetic counselors, research coordinators and cardiology fellows who are in training to become the next HCM docks. Um So I also want to highlight here collaborators on some studies. I'll touch on the reset HCM study which was the exercise study. Um collaborators at stanford um the live HCM study, Rachel and Mike Ackerman. I'll touch on that a bit and then the share registry. I'm gonna show you a number of slides of data of natural history that we've cleaned over the years from compiling um very deeply Fiona typed and genotype patients across multiple centers around the globe. So the share registry um comprises all these centres currently. Um we now have close to 10,000 patients with HCM who are entered into the registry. Most of them are clinically genotype will not most, but more than half are clinically genotype. Um and we have very deep genotype data. So that's allowed us to really make some I think important insights um into the natural history of the disease and risk factors that predict adverse events and complications. Um I'm not really going to talk much about the are translational research program here today, but I did want to acknowledge the group, you know, it's really an amazing group of very dedicated individuals, many of whom are still back at michigan. I sort of have run a lab both at michigan and penn right now at least the next couple of years. Um and this is the last time we were all together. It was like these pictures are from keystone colorado the week before the pandemic really hit. And we were all kind of laughing about why, you know, they're telling us not to shake hands and and hug each other. So it's been a while and I'm looking forward to going back to see them in person. Um also just want to mention collaborators from other institutions as well as new collaborators um here at penn, both in the pen C. B. I. And penn vet cardiology. And finally, you know, I have, I'm so indebted to the patients who I've gotten to know over the years, who have shared their lives with me, who have trusted their care to me, um shared their stories and their inspirations um and their tragedies in many cases and and you know, really I just feel very privileged, you know, to be a part of their lives and to be able to care for them. Um and they're really the reason that the field moves forward. Okay, so with that as my Acknowledgments, um I will just do a brief introduction of this. I know everybody here on this call is very familiar with disease entity. Hypertrophic cardiomyopathy is the most common genetic heart condition that's inherited in a dandelion pattern um is to find somewhat simply as unexplained hypertrophy at or exceeding 15 mm in any segment. I think everybody knows here that that's not always such an easy call to make um particularly when there are many other conditions that can lead to LDH including hypertension, infiltrated conditions and so forth. Um So of the familial form of hypertrophic cardiomyopathy variants in the genes that encode proteins of the cardiac star career make up more than 90% of the genetic ideology. Um this is a disease with huge variation in terms of age of onset and disease severity. And we really see everything from patients with no or mild symptoms really. About half of the people who are diagnosed or asymptomatic at the time and are picked up as an incidental finding or on family screening. And many of those patients may have normal longevity, but we see a substantial number that suffer significant complications heart failure, atrial fibrillation and ventricular arrhythmias. And then I just wanted to show a few pictures. Of course you're all going to be familiar with these morphology is but you know, these are the varied morphology. Is that um that HCM can manifest as the most common is asymmetric septal. Um showed here in this cardiac MRI. This is sort of the classic reverse curvature, convex shape of the septum in the saarc americ forum of hypertrophic cardiomyopathy is probably about 70% of patients um have asymmetric septal hypertrophy smaller percentage have this atypical variant form forms like a spade shaped looking ventricle and then there's this mid ventricular form, which is much less common. These are not playing. But um and these are the types that can form an atypical aneurysm. This is a small subset but an important subset because we think there's some increased risk of ventricular arrhythmias and and potentially stroke from bill embolism. And then a substantial number of patients have left ventricular outflow tract obstruction here. You can see the systolic enter most of the mitral valve, contacting the septum. About a third of patients roughly at rest will have some obstruction um and about another third will have obstruction with provocations such as um el salva maneuver or with exercise. Um So again, while many patients with HCM can do very well with this condition and really live pretty normal lives. Um You know what we found when we um um compared patients in the share registry to those in the general population was that their mortality. While absolute mortality is really quite low, The relative mortality to the general population is about 3-4fold higher. Um And that's true across every age strata. And when we looked at the cumulative risk of adverse outcomes. And this is a cumulative incidence plot showing the incidents of any complications occurring from the disease. So this includes heart failure, atrial fibrillation, ventricular arrhythmias, stroke and death. Um and and in those in particular who are diagnosed at a young age shown on this curve here under the age of 40. Their cumulative risk of having at least one complication in their lifetime is close to 100%. And by far the two outcomes that are most prevalent are heart failure in atrial fibrillation. And again, these curves sort of mirror the cumulative sort of composite outcome I showed you in the previous slide um where those under the age of 40 have the greatest chance of developing these complications throughout their lifetime. But sometimes, you know, there can be quite a lag from the time of diagnosis, it may be years too many decades before they experienced these events. Um and then I wanted to point out that ventricular arrhythmia um curves here because you know, I think this is very informative patients who are diagnosed at a young age, particularly pediatric patients. Um you know, have a very high incidence of ventricular arrhythmias over the course of your lifetime somewhere in the 30 to 40% range. Whereas those that are diagnosed at an older age, these tend to be more non familial Types of forms of HCM have a very low lifetime incidence 1% chance. And I think that's really informs our sudden death risk stratification. So I wanted to just sort of briefly review the genetic architecture of this disease. Um you know, the first mutation for HCM was discovered more than 30 years ago now by john and Cricket Seidman by a family linkage analysis, you know, and since then, you know, it's it's still continues to be the star career that is the predominant genetic basis of hypertrophic cardiomyopathy with mice and binding protein C. And mice and heavy chain being the two genes that hold the largest number of variants. These are also the two largest genes in the Stark Amir. And then sort of the other six smaller proportions there are now about five genes outside of the Stark Amir that are well validated and clearly linked to disease. Um And then there of course the sort of metabolic and mimics um you know that cause like storage diseases like Dannon disease and so forth. But you know even to this date with all of the genetics um that's been done over the past 30 years still 50 to 60% of patients with H. G. M. Who are genetically tested who have a clinical diagnosis still do not have an identifiable genetic variant And you know well for many years I think we said well we just haven't figured out with all the genes are and we just gotta keep looking you know we've been looking for a long time many people and um you know I think we've reached the conclusion that probably about 40% of clinical HCM is really non-vandalia. Um And and so there's some genetic basis but it's probably more of apologetic thing where there's you know sort of risk leal's with very small effects that add up together. So somewhat you know I think apologetic risk or for this disease eventually as you know it will be something we're implementing And then there's of course acquired and modify some of these factors are modifiable um hypertension being one that's fairly obvious. So in terms of, you know, thinking about how the genetics influence outcomes. You know, this is one of the things that we were really interested in doing in the share registry is trying to define the sort of genotype phenotype correlations. And so this is a Kaplan meier curves, kind of the opposite of a cumulative incidence plot. Looking at the rate of complications, this is a composite endpoint of sort of all the bad things. And those patients that have Stark Amir gene mutations shown in green clearly have a much higher rate of developing complications than those who are stark amir negative and those are to carry so called variant of uncertain significance, which is sort of this category in the middle. We can't you know, definitively say it's disease causing, but it's rare enough that we can't say it's benign, they fall right in the middle. And I think that is just because this is a mixture of pathogenic and non pathogenic variants um that we're still have yet to sort out there are a number of non genetic factors that clearly influence outcomes. Obesity is one of them um you know, and we've all clinically recognized this for a long time that patients are obese have much higher rates of heart failure. Um and that really born out in in our analysis um as well as uh increased rate of sort of overall complications from the disease. Um uh Lauren neighborly who is a cardiology fellow here at Penn was at Brigham at the time when she did this study um showed that black race was associated with higher rate of heart failure in particular about a two fold higher rate compared to um took caucasian patients. And that held up in a multi varied analysis and then um subsequently Neil locked wallet Brigham. Um let a study looking at the influence of gender and clearly women seem to have a higher rate of developing heart failure and also have a higher mortality related to HCM compared to men. So I think these are really enlightening findings and and ones that will help guide, you know, our future risk stratification and trying to think about factors that is you know, whether these are biological factors or whether these are access to care factors um you know that we need to consider. So I just wanted to pause here uh and and show you a video for a couple minutes of a woman who has lived with HCM her whole life whose Children have HCM. Um and just hear from her what it's like to really live with this disease. So I interviewed her um and I did the video editing myself. It's quite amateur and so I apologize, it's a bit choppy but I think you'll get the major points from it. So I'm gonna play this, that's about 2.5. I was diagnosed with hypertrophic cardiomyopathy at the age of 24. So she sent me to a cardiologist who had never heard of her, never worked with anyone with hypertrophic cardiomyopathy. And during the appointment she got out her medical book and read to me what it was from her medical book. Um and at that point she told me you know, you could drop dead at any moment instead of cardiac death, You shouldn't drive, you will never be able to have Children. Um and kind of essentially, you know, almost stop living your life. Just just just sit back and wait for this to kill you, sort of thing. My mother had lost four brothers to sudden cardiac arrest and because I had these near fainting episodes that they couldn't really pinpoint exactly what had happened during those. Um they thought it was safer to go ahead and just um just put the implant in. I have good days and I have bad days, so I have days where I just don't, even if I didn't also work with HCM, I probably forget that I add it. Um But but then I have, you know, I'll have a bad day where Pushing a grocery card, an empty grocery card across the parking lot of the grocery store, you know, I struggled to do that. And my daughter was diagnosed for and um my son then was later diagnosed at the age of 15, but he has almost no symptoms, very, very mild thickening has absolutely no restrictions, does all the exercise. You know everything he wants to do. My daughter on the other hand, she had surgery right after kindergarten about nine years later she suffered a series of cardiac arrest in terms of the exercise. And you know and my kids, I had I had worked with enough other people, patients with HCM who had teenagers already when my kids were little who had had to take these things away from their kids. You know, the kid was a star football player and you know, getting ready to go to college and get a scholarship and suddenly they couldn't make football anymore. So um the restrictions in my mind made sense because you know that's just what the standard operating procedure kind of was at that point, luckily both of our kids are really nerdy so neither of them really wanted to be in sports. Some both of my kids are madly into exercises now. Her heart is not in good shape otherwise. And you know, the chances of her getting a transplant with. However, how many we've already had in the family are probably fairly significant. But I know she would be going into that as healthy as you can possibly be miss a day of exercises and we cannot get a little. My mother who had HCM had this idea that you know, knowledge and science were the key to everything I was asked to speak in front of Harvard and M. I. T. Classes for my cardiologist, Christine Seidman when she would teach these classes on genetics. This was when my son was a newborn baby. So I would bring him in the sling to the class with me or in the stroller or she would walk around the class with him. Well I answered questions, I think it's really important for patients to use their voice. Um HCM can make you feel very out of control. So Wendy is really an amazing advocate and she's someone that holds support groups and really is nationally involved in forwarding this field. So you know I think we learned a lot from her just in a couple minutes. Um you know the misconceptions among patients and physicians. You know this is not a historical perspective. I mean this still happens today, right? So patients come to us very scared um that they're going to drop dead um that they're you know that their life is over and you know they get this from the internet. They hear this from you know they're referring physicians various sources and I think you know it is really upon us to to really work on clearing up these misconceptions. I think you got a sense of the huge spectrum disease severity and her family is a great example right? Her daughter was diagnosed at birth, It has really severe disease and her son is asymptomatic with diagnosed at age 15. Um clearly that speaks to the fact that there's modifiers, both genetic epigenetic, who knows what, you know, that we still have to discover. Um and then she talked a lot about exercise and quality of life and how important that's been for their family. And this is something that, you know, that I've been very passionate about because I hear this time and time again. Um and she also talked about how education is really bi directional, right? It's really important for us to listen to our patients and what, you know, and what drives them and motivates them, what's important to them. Um and patients should feel empowered to use their voice and um to really advocate for their own health care. And so, you know, this was really a central tenant, you know, when we went into the um to the guidelines and we talked beginning about, you know, how we wanted to structure this. I think everybody was very much on the same page that we wanted to make sure decision making, really central. And it's something that would permeate across all of the recommendations. And, you know, that's certainly not a new concept, right? And this is something that's been around this is how we practice medicine. And it's not unique to HCM by any means, but I think, you know, in this disease where there are a lot of nuances to care. We still have very few randomized trials that guide our decision making and many of our recommendations are still based on expert opinion and limited data. Um and I think in that context we felt that it was even more important to emphasize um this concept of shared decision making. The other thing that we introduced in this guideline document that hadn't been present previously was this idea of multidisciplinary HCM centers um and both primary and comprehensive centers. Um and so we so we laid out a table with different competencies that we felt, you know would be important to sort of for a particular center to be recognized as either comprehensive or primary uh focusing on HCM um you know in the two things that I think we called out, where that set the reduction therapy really should be done by experience providers and it centers where there is a multidisciplinary care team and the decision is made as a group. Um And then the other thing is that, you know, consultation referral to a center for decisions that were really caught, we felt were like complex disease related decisions and you know for example really anything that's a to B recommendation um you know, we thought really should probably be um a reason for referral to a to a focus. Er So I'm going to go through just a few of the highlights of the different sections, there is you know, 130 different recommendations. I'm clearly not going to just walk through all those, but you know, I'm going to talk about the ones that I think had major updates in areas that there's always you know that there's been a lot of controversy. So sudden death risk stratification of course is one of the most challenging things that we do for these patients. You know it's like having that crystal ball and predicting who is going to drop. These are very stochastic events. Um But there are a number of risk factors that have stood up uh you know across the test of time held up across the test of time um aboard sudden cardiac arrest is still the only class one indication for a defibrillator. There are a number of class to a indications that include hypertrophic burden sort of in a linear scale. Um Non sustained V. T. Much stronger risk factor for Children than for adults. Um We actually downgraded that to a to be recognizing that there's of course different non sustained V. T. S. Right? There's the four beats at 100 and 30 and there's repetitive episodes of 26 beats at 100 and 80. Those are really different. Um Family history of sudden death and first degree relatives and non vagal sympathy. And I'm sure many of you are aware that there is this risk score that was developed by european group validated in thousands of patients incorporates these conventional risk factors and a couple other things I think are important age. Um uh Left atrial size in gradient the ages more influential than the uh than the L. A size in gradient. And the important thing is one that they're weighted. Um and they're weighted in such a way that I think is appropriate in terms of their predictive power. Um and that many of them are also non binary. So now getting away from this idea that 30 of wall thickness is like some magical threshold, you know, it really isn't right, that's a linear relationship. So um so that's a nice part of this calculation and it's and so there's an app for it. Here's the link if you wanted to search for and put on your phone and um I don't give you a number and say this is the risk at five years And I think that number is useful. It'll give you recommendations saying about 6% of high risk should get an STD but you know really more I use that just to kind of put people in the ballpark of and be able to give them some idea of what I think their risk is and different people have different perceptions of what that risk means to them. There are some new risk factors that we incorporated high burden of left late gadolinium enhancement on CMR. You know, we still have a lot to learn here. We don't quite know what the threshold is. We don't even know if we're looking at the right thing by just quantifying the amount of it whether it's location, whether we should be looking at interstitial fibrosis by T one that's all being studied. You know, Until then we consider this a class to be recommendation based on data such as these where in patients who are otherwise at intermediate risk. Um You know, based on this calculation um that those who had late gadolinium enhancement exceeding 15% of the LV mass had a higher risk of arrhythmic events. Um Either non obstructive or obstructive compared to those that had LG less than 15% other risk factors. Um Ejection fraction of 50% HCM patient is not normal. Um You know so they should be up and around 70% normally. So this really represents systolic dysfunction. Um And in that context we felt that that should be a threshold for an I. C. D. Um a pickle aneurysm really rare but we do have a subgroup with these and they at least in case series, they do seem to have a higher risk of ventricular sector reduction therapies. This is another um Long contested, long debated um Mostly this sort of idea of whether septal myomectomy or alcohol septal ablation uh you know should be done and um I think what everybody agrees on is that patients was severely symptomatic Outflow tract obstruction, at least 50 of mercury. Despite guideline directed medical therapy should be eligible for separate reduction therapy. So everybody agrees on that. Um And then whether to do surgery or alcohol ablation, I really think depends And I think the bottom line is, you know, it's really an individualized decision clearly for patients that have other surgical needs, other surgical lesions, the mitral valve, sell valvular apparatus, coronary disease or etcetera. Then those are patients who probably should go to surgery, those in whom who are sort of high surgical risk because of comorbidities. Um you know, those are patients who would be, you know, perhaps better served by alcohol ablation, you know, and and the guidelines used to say bye, ectomy is the gold standard and you should do my ectomy if at all possible. But I think we reached more of an equipoise here and said, you know, I think that these both of these are acceptable. Um and I think it really depends on patient preference. Um, once you go through all the data and and patients will tell you, they often come with a preconceived notion that they want one or the other. They definitely don't want something. So, you know, I think this is really just falls under, you know, quite squarely, the shared decision making model. Um and then, you know, we did define additional risk factors that we felt for patients who were less symptomatic, maybe class to that my ectomy would be reasonable. Um those with pulmonary hypertension with left atrial enlargement, Very poor functional capacity on objective testing or very high rest ingredients. So the genetic section really was completely revamped from prior and that's just because of the last 10 years of um of advances that we've made in terms of um the understanding of the genetics and the widespread availability of genetic counseling and testing. There are a number of class one recommendations here. I'm just highlighting a couple one. I think it's very important that genetic counseling be incorporated into this algorithm. Um and part of that is taking a three generation family history um and and providing pre test counseling to patients. And then you know, for the vast majority of patients. We do offer genetic testing unless the diagnosis really doesn't fit HCM or unless there is no living family members who would benefit from the information. Um We offer gene testing to patients and and many of them take it. We have um you know, there are mechanisms to get around insurance authorization. The companies really do work well with us and the patients to make it um affordable um with very low copays. So this is just an algorithm that kind of goes through what we do. I mean it's most important that you test an index case of somebody that clearly clinically affected with the disease, ideally someone in the family with the most severe form. And then if you just look at the colored boxes, You know those that are classified that have an identifiable pathogenic variant or then eligible for cascade genetic testing and the family which would then dismiss about 50% of family members. And this is really important because lifelong family screening is, you know, is quite a burden on patients and on the health care system. So this is a very efficient way of doing screening. Those that don't have a pathogenic variant. You have to resort to clinical surveillance in the family and regular follow up. And and I think the the frequency of follow up, you know, really depends on the longevity of follow up, depends on the individual families. Lifestyle considerations also has a section that underwent major revisions, major additions or a number of things that we added to this. I'm just highlighting a few um Samir pointed out exercises really, it was a big topic and something that we really um you know, heavily revised compared to prior guidelines. And for the first time we felt very comfortable saying that we recognize that recreational exercise at least in a modern intensity levels beneficial for patients and really are actively encouraging them to exercise rather than setting So all these limitations and listing all these things that they shouldn't do um pregnancy. A lot of recommendations for pregnancy. The bottom line is, you know, for the vast majority of women, it was really very safe, very low risk, um you know, we do uh consult with maternal fetal medicine and high risk will be and and do all that and you know, when we and we survey them during their pregnancy. But I think in general it's very reasonable to advise the pregnancy is safe for the vast majority of women? And then we address comorbidities um you know, and this may seem, you know, intuitive um that a lot of these patients have other health problems, but you know, it's surprising how many of them really aren't um either recognized or aren't like aggressively addressed. Um you know, obesity is a major problem, right? So we have 70% of patients with HCM are overweight or obese and I think that clearly contributes to their symptom burden. Hypertension. You know, is clearly contributing both to penetrates of the disease as well as probably that sort of apologetic plus environmental risk. Um and so we're really aggressive about managing their hypertension. Sleep disordered breathing is also prevalent. About 70% of patients with HCM have obstructive sleep apnea. So we send a lot of referrals to sleep medicine and again, this is something that probably um contributes to their heart failure and symptom burden. So, let me talk a little bit about exercise and smear pointed out this is something I've been kind of passionate about since the beginning and it it really stemmed from this. You know, these conversations with patients from the very start of our clinic. You know, all of them saying they're afraid to do anything, they shouldn't, can they get off the couch can they do this, can they travel with their families? And you know, there were just no data whatsoever. And so we had this idea of doing a randomized trial of exercise training HCM and at the time this is like a little bit controversial and people said, oh you'll never get external funding. So we sort of scrap this together And you know, we had a donor contribute, we collaborated with stanford um and you know, we did a very simple design, Right? So it was really just an exercise training arm. This was moderate intensity, home based exercise training. Individuals individualized exercise prescriptions versus their usual activity and they were randomized to one or the other. And not surprisingly, those people that exercised, you know, improve their exercise capacity. That was our primary in point was the change in Peak Vo two and a cardiopulmonary exercise test And the absolute increase of 6% is about what you would see for this level of exercise. Certainly get more if you do high intensity training. But we really wanted to start with something relatively modest and prove that this was, you know, so called safe. Um you know, that patients improved in terms of their physical functioning. Um and importantly, we didn't see any major adverse events. There was really no signal for an increase in arrhythmias. In fact, there was a decrease in PVC burden in those who are exercising. So this I think was very reassuring and and did provide a strong basis for a class one recommendation for exercise for patients with HCM. So the vigorous exercise and competitive sports on the other hand, um was probably the topic that generated the most discussion among the guideline committee um and rightly so. I mean we really don't have enough data to be able to inform these decisions. But you know, ultimately what we settled on was that this is an area where shared decision making. I think you know really plays an important role. Um you know, time and time again we heard from patients, you know that they were being disqualified and made ineligible and that was not their choice and that was not their preference. Um and so you know, that's really what drove this to be recommendation that participation in competitive sports may be considered with a lot of qualifiers important to have a comprehensive evaluation, a shared discussion that includes elements of there are uncertainties. This could increase your risk of sudden death. We don't know, we don't have enough information and provide the data that we have enough for them to be able to make their decision. And it was important that they follow up annually that there's an emergency action plan. You know, we work with the teams, we work with the athletic directors and trainers and so forth to make sure that they're in an environment where if there were an emergency that they would be prepared for that. Um So you know, the other thing that motivated this is this recommendation was you know, that was rarely recognizing that it may not be true that exercise induces there is a trigger for sudden death. I mean the absolute annual incidence of sudden cardiac arrest or death in patients with HCM is exceedingly low to begin with. And then, you know, the fact that HCM you know, has been touted as the most common cause of sudden death, has really been effectively disproven by a number of prospective studies um You know, in the last 10 years or so. And HTM really accounts for a small proportion in some studies, only 3% of sudden cardiac arrest and young people. And the other observation is important is that most events occur during routine daily activities at rest or while sleeping. Um and you know, very few are occurring with with ex strenuous or vigorous activity. Um you know, this really borne out in the sports. I see the registry where the HCM at least the vast majority events were not associated with exercise. And so I think at this point we can say it's uncertain um whether any level of activity increases the risk of sudden death. So in that context, we thought that it was very reasonable um for people to for patients to make the decision about whether they wanted to continue in their sport, you know, and we really need more prospective data here are a couple of studies. These are small numbers so far, you know, it's 12 to 20 years of follow up and this study was done in Italy. This was done at Mayo Clinic. Totalling just over 100 patients with HCM but all who were competitive athletes who either on their own decided to stop or continue sports. Um And what you can see here in the italian study is that there was no difference in terms of either arrhythmic outcomes sync api or symptoms. Um And then in this study there was actually patients who were continued in athletes who continued in sport had a lower rate of arrhythmic outcomes compared to those who stopped. So, um so I think, you know, this is again kind of very preliminary and small numbers, but you know, that doesn't show a signal um for increased rates of sudden death in athletes. So we need more information. And this is a study that we've been working on for a long time. We finally just completed the medium three year follow up period just a couple of months ago, or in the process of putting all the data together in adjudicating events. This is a registry. So it's an observational study where we enrolled about 2000 patients with HCM in 2000 patients with Long QT syndrome. Um And we enrich the study for those who are athletic and you know, some doing competitive sports that are doing recreational activity, but there are also a number of people who are, you know, not particularly active on a regular basis. So we'll be able to make some comparisons and look at outcomes, um arrhythmic outcomes and quality of life across the spectrum of exercise. So stay tuned for that. So at this point I just sort of like to pause and just, you know, to really reflect on the accomplishments in the field. And I think it's been really remarkable since I first started when I think about where we were when I started the clinic and where we are today. You know, we have large registries now, um, you know, 10,000 patients in one and and several others um that have really allowed us to make important insights into the natural history and to identify risk predictors for various adverse outcomes. Um, you know, I haven't talked about this explicitly, but you know, certainly the, you know, the advances in imaging have been tremendous and in our ability to now use M. R. I mean, like we got an MRI and extend patient like we get me kg right, um and our ability to be able to do that and to and to be at the resolution that the MRI is is really phenomenal and, you know, as I pointed out, genetics, you know, is really uh become standard of care now for patients with HCM. So, this is, you know, this used to be a research tool right and now we're using this daily in our practices and it's identifying patients who are genetically susceptible to developing HCM with the potential that we could eventually intervene. And at an earlier stage we've made enormous strides with sudden death with stratification. It's not perfect. But I would say we miss very, very few people right. There are exceedingly small numbers of people who die suddenly who have been comprehensively evaluated and is thought to be at low risk. Um I can tell you I only have three in my practice ever in 15 years. They were all middle aged men who didn't have an autopsy and I think probably a coronary disease. So we put in too many defibrillators for sure, you know, but I think we do error on the side of caution, particularly in the US separate reduction therapies have come a long way. And I think, you know, we've reached a state of equipoise in terms of surgery and and alcohol septal ablation a point where, you know, we can offer both both therapies to patients. Um and they're very effective at reducing symptom burden. And we've gone from exercise restrictions to prescriptions and I think that's a huge stride and one that will vastly improved patient's quality of life. But we still have a lot to do. Um and then this is really the major unmet need in our field is that we have nothing that interrupts the disease course. Right? So we're not treating HCM per se were treating the complications and we're trying to prevent complications from developing, but we're not really treating the disease itself. And so I wanted to kind of give you in the next few minutes. Just an idea of kind of where we are now and what the future holds. And bear with me a little bit on this analogy, I think it kind of works, you know? So I think about this question kind of like I think about getting married. All right. Um so what do we do when we are trying to think about new therapies for each stand? When we think about what are the old things that work and other diseases like heart failure? Can we borrow drugs from them? And then we try and develop new things that would be specific to HCM. So, I'm gonna give you some examples. So, here are some of the old borrowed things that we've tried beta blockers. You know, it's like this knee jerk response to put people in beta blockers that have HCM. There's actually zero evidence that they do anything other than improve symptoms. And in patients that have outflow tract obstruction. Ace inhibitors really never been studied systematically. There's no evidence of benefit. Angiotensin angiotensin receptor blockers are interesting. There have been six relatively small trials, no definitive benefit, but there's one that spending and results will be published soon. And I'm going to highlight that in the next slide. Spironolactone. There's one trial negative results, sodium channel blockers were proposed potentially to both decrease the rhythmic burden and also improve diastolic function, granola seen trial was negative uh L. A. Cuisine was the Liberty Sam trial. That trial was dr lee for lack of efficacy. So that was kind of a failure and then metabolic modulators per hex a lien. Um was it was toxic. So it actually potentially had some benefit in the heart but it was had too much extra cardiac toxicity and then try Matassa Dean was a trial that was published a couple of years ago and patients actually did worse on this drug and these are both inhibitors of fatty acid oxidation. So those seem to not be so promising. So exercise is actually stood up was really the only thing that's improved exercise capacity in patients with HCM of the old things. So what's new? So I think you've probably all heard about mice and modulators. That's you know, really a hot topic right now. Um And I'm going to talk about that for a couple of slides here. Um And then gene therapy is the other thing that I think is on the pike. Um and there's a lot of buzz about that. There's a lot of interest. Um You know, I'm not gonna talk about that explicitly except to say that, you know, I think it has great potential certainly for cure either replacing a defective gene or fixing a mutation using somatic gene editing. There are a lot of challenges um you know, and certainly we're in early stages but um you know they're going to be a lot of challenges to implementation of patient selection is going to be really key. Um So let me just talk about these two briefly. So the vanish trial has been going on for a while. We finally have results and they should be reported soon. Um This is a randomized placebo controlled two year trial of al certain early Stark America HCM in the way that it differs from these other trials that have been done previously. Um is that we selected patients that were much younger. Um So 22 is compared to people in their fifties mostly asymptomatic class one. All of them have Stark amir variants and less hypertrophy. The ideas here we're trying to target early. Right? And because once the disease is established I think it's less likely that some of these interventions are really going to have an effect. And the other thing this trial has done is to come up with a composite endpoint that sort of um totals like nine different measures and metrics of cardiac structure function and stretch like the Mp and troponin and things like that. So you know, stay tuned. I think you know the manuscript is um you know going to be submitted shortly and it has been submitted to E. S. C. Is a late breakers. So we'll see hopefully by august we'll have results from this trial. So Maverick Hampton is the first in class miocene modulator. So you know, if you kind of think about it simply what it's doing is binding Tobias and the heart's muscle motor and basically dampening contraction by decreasing the rate of 80 p turnover. So it's effectively preventing some of the mayas and heads from engaging with acting. Right? So you have fewer my assassins engaged with acting to generate a power stroke at any given time. And that effectively is reducing the hyper contract Illini. That's sort of part of HCM and particularly obstructive HCM. So there were they went through Phase one and phase two trials, you know very successfully and then went on to explore which is a phase three trial randomized double blind placebo controlled 251 patients across the world, mostly in the U. S. And the results were really, you know, very promising. Right? So Mavi Campton very effectively reduced resting outflow tract gradients compared to placebo. And they met their primary endpoint which was a combined one point of improvement in peak vo two and N. Y. H. A. Class. So you can see here graft is um you know, on the Mavi camping group on the left. Everybody was symptomatic at baseline by the end of 30 weeks, only 50% had 50% were totally asymptomatic Compared to only 20% in the placebo group. Um so the primary endpoint was met in 37% vs 17 placebo. So this is very promising data indeed. And a follow up sub study to that showed that maverick camped in this is a CMR sub studies show that Maverick campaign resulted in regression of hypertrophy. Both the reduction in LV mass index reduction in wall thickness and a reduction in left atrial volume. So these are very encouraging results showing that we're actually inducing structural adversary, sorry, reverse adversary modeling in these patients. So I think, you know, the results in non obstructive HCM are not as far along, you know, and certainly don't look, you know, quite a striking um but there will be a Phase three studies so stay tuned for that. But in the phase 2 60 patients were randomized to either placebo, lower high dose Maverick Hampton and the primary point was not met in this study. Um and that there was no significant difference in peak flow to N. Y. H. A. Class between groups, although some with more severe disease. Excuse me. Um did seem to potentially have a benefit. So there's a signal there there was a decrease in BNP that was significant in Mavi Captain. So we're hopeful this is a group for which we really don't have any effective therapy. So um So hopefully the Phase three trial will be will show some benefit. So in just the last couple of slides, I'm gonna show you a little bit about kind of what we're doing in in our research program here at Penn um to you know, to to think about new therapies and like really novel ideas and what we could apply um because my eyes and modulators right now are really kind of the only thing that's been successful. Sorry. So one way you can go about finding new pathways is to do this sort of ah mix approach. And so we have a lot of human heart samples that we've collected over the years from my ectomy specimens from patients with HCM and also from non failing donors. So these are hearts that are not usable for transplant for various reasons, often age or other things but are generally pretty normally functioning. And we use those as a comparison as a control and so what we've done is a proteomics analysis and also targeted metabolite analysis here at Penn. I'm just going to show you a couple slides, there's obviously oodles of data here but um you know, one of the things that we've really been intrigued by um was the difference in energy substrates that you know between the HCM hearts and the control hearts. And we divided these, you know, these groups, these HCM groups into different genotype but we really see that they completely overlap and so this, you know, vast difference in energy substrate availability um is really genotype independent um and very distinct from control hearts. Um this is a principal component analysis um that looks at basically all of the metabolites and separates the groups according to how different they are across about 100 different measurements. So this is really pretty striking to us and this is being driven primarily by the fact that the hearts from HCM patients are massively depleted of fatty acids and as you may know, fatty acids are really the primary energy source for the normal heart. The other observation we've made is that the the hearts are the HCM hearts are enriched in three hydroxybutyrate, which is a key tone body. Um and so this has been shown in heart failure um that increased increase in increasing ketone body metabolism um is an adaptive um sort of response of a failing heart to a reduction in fatty acid um substrates. And so we're really intrigued by this and you know, I'm here in the hotbed of cardiac metabolism with dan kelly and salt irani and ken Margolies surrounding me here in the C. B. I. And um I think we're really intrigued by the idea of doing some early clinical studies and in thinking about ways that we could modify and shift um these energy substrates back to a more adaptive, more adaptive and beneficial place. So I will end here with just some perspective and that is um you know, the You know, where the field has come since HCM was first recognized as a clinical entity more than 50 years ago And the genetic basis of HCM has been known now for more than 30 years and um you know, we're really at kind of as precipice and sort of a turning point I think where we're moving from observation to intervention and when we think about where the opportunity is, um you know, we can now identify patients at a very early stage before they ever developed a disease. And I think our opportunity for a disease modifying intervention is probably going to be pretty early on, you know, but there are a lot of challenges we face, right, we have to identify exactly what the right targets are, how to prioritize those when to start, are we going to treat lifelong? And if we're going to do that, we have to find treatments that are really safe long term and have a, you know, um you know, a good safety profile and don't have off target effects. Um and how are we measuring efficacy I think is another huge challenge because um you know, if you wait for a hard endpoint like mortality or sudden death, you know, we're all gonna be dead and buried by them, these are rare events. So we uh and they develop over years, two decades. So we really have to think creatively about how we can come up with composite endpoints that are really going to reflect a state of disease progression. But you know, despite these challenges, I think this is an incredibly exciting time to be in this field. Um you know, I feel like we're really starting to have a lot of fun and really have the opportunity to change patients lives for the better. So with that I'll stop and I'd be happy to take any questions Charlene. Fantastic talk. Thank you very much for that. There was a lot of material that you covered very very elegantly. Thank you. I'm gonna start with a couple of questions and I know there's a few that are kind of flowing in here. Um early in the talk you mentioned obviously we're seeing more patients with L. V. H. In terms of hypertension, obesity, diabetes, metabolic syndrome, all these risk factors. So can you comment a little bit about what is it on the echo that may prompt you to start thinking of HCM and when may you pull the trigger to get an MRI. Yeah that's a great question. And it really is a conundrum still I think um you know a lot of it is sort of um the morphology um you know the in hypertension, you know classically we think about concentric L. B. H. But also those sort of sigmoid symptoms. You know the upper septal thickening you know that reaches 16 or 17 millimeters. You know in patients who are older who have a long history of hypertension. You know those are patients whom I generally have been you know not calling HCM anymore. Um even with obstruction and I think that's another thing that people think well there's obstruction than it has to be HCM but it's not really true and it's it's really just physiology right? It's sort of the you know where the collect ation of point is in the sort of the positioning of the mitral valve and that can be influenced by things like that might ruin your calcium and other things like that. And then when you have a sigmoid septum the flow around the septum gonna drag the leaflets in. So it really does not necessarily have to be HCM if there's outflow obstruction. So I don't use that as distinguishing feature. So the morphology I think as a primary one. Um And also just whether the patient does you know how long their history of hypertension is whether they're obese other factors, diabetic and so forth, sleep apnea. So um so I think it depends on both clinical factors as well as um you know features on the echo. Um M. R. E. We use quite a bit. I mean we and often patients have already had an MRI before they even come to see us. So um you know we get the images to review. I think it can be very helpful in differentiating between the you know the sort of more familial type versus non familiar and then genetic testing obviously will help us to discriminate those cases. And at least put us into a category of whether it's non familial HCM or whether it's familial disease. So one question that came through I guess how how conclusive is MRI I'll defend the MRI for the diagnosis. Um I mean I think it's as good as we can possibly get the images. Quality is generally outstanding and we can really see the morphology, you can get all the mass index and and the L. G. Again doesn't distinguish necessarily from other pathologic Florence of hypertrophy. I think it is very useful in um in athletes, you know when we're trying to distinguish between athletic remodeling and pathologic hypertrophy. Um whether that's HCM or some other form. Um the MRI is really crucial I think in those cases. Um but I think just because it gives us a better idea of what the anatomy is, we can see the sub valvular structures and so forth. So um yeah, so I think it's very useful Charlene if you have a family member, that's the genotype pro band. Right? So they're the case. And now you have other family members coming in for screening purposes. I think we'll see this quite a bit. Um you know, some family members been diagnosed and they tell all of their family members you need to go see a cardiologist and get evaluated and we don't always have all of the gene, a typical Jenna, typical information of that pro band. So now they're in and let's say they get an echocardiogram and if that Fiona typically is negative, is that adequate in terms of screening or how often do they have to be screened? This is such a really surprisingly challenging question to answer. So we were actually very surprised in the guideline committee that this became a very controversial topic because we realize they're actually very different practices and what people were doing in terms of screening. I mean, I'll tell you what I do. So, you know, when someone is clearly Jeanette when their genotype and it's clear or there's clearly familial disease. I'm much more aggressive about screening family members about making recommendations. And I start earlier. Um, so I'll start in, you know, sarge America HCM. I'll start in kids generally before puberty, particularly in the family. If there's been young. Um, other cases of pediatric onset HCM or if there's sudden death in the family. Um, I'll start as young as, you know, you know, it's two or three or even sometimes at birth. Um, and then we will go every year because it can come up in kids, it can come up really from one year to the next. It can change pretty drastically. Once you get to adulthood then you can start to space out the screening and it becomes less and less likely that even if they carry the gene mutation that they're going to get it because it's the penetrates is still only 50%. So 50% of people carry a gene mutation never get the disease right. So, so I think about that. And as they get to be 40 and 50 we're going to keep screening them on and on and on. So um so that's one scenario, you know, the other scenarios we either don't have the genotype information or it's clearly like, you know, there's no family history, their genotype negative. Um you know, those are families in which I don't screen as aggressively. So I recommend screening and kids, maybe a puberty usually, you know, maybe yearly, maybe every 2-3 years. And then as adults, usually a one time screen. And if it's truly there's nobody else in the family, I usually stop or at least advise them to stop screening. So, um but it's really still an open ended question and and it's very individualized particular family does the agent which the the other case and the family manifested itself play a role. So if it does, I mean later in life. Sure. I mean, and while there's variation within a family in those that have had pediatric onset disease or sudden death at young ages, we definitely screen more aggressively and start earlier. Um questions about exercise, how do you individualize it? Is there a target heart rate? Is there a holter monitor? Do you do an exercise stress test in the office first? That's a great question. Yeah, I mean, ideally like in the study, we did it with an exercise physiologist where we everybody had a c pet, we gave them their heart rate sort of heart rate thresholds and get, you know, we wanted them in 60 to 80% of their heart rate reserve. So we made it very scientific for the purpose of the study in practice. Um You know, I do that for patients who really are very heart rate obsessed, but I do not give them heart rate threshold. I mean there really isn't any, I tell them if you want to work in your aerobic zone, I try and do a seabed on everybody um particularly if someone who wants to exercise, I always get an exercise test you ideally a CPAp because then you can really get a better idea of where their aerobic zone when they become it and go into their anaerobic threshold. And I say if you want to stay in aerobic threshold, this is where your heart rate should be. Um But for the vast majority of people, they're not really that you know kind of geared towards thinking about these things and they might just want to say, you know, I just want to go for a walk and I say we'll keep it at a conversational case if you want to keep it in a moderate intensity um you know and kind of back off, you know if you feel like you're gasping for air or you just need a break or you get lightheaded and um you know, I usually use more of like a kind of the board score perceived level of intensity, all right. Um moving on to treatment. Um in your slide of different treatments. I don't think I saw a calcium channel blockers and disappear. Um Yeah, I didn't put you know right. That was I should have put that in there. That's on that before we move on to because I was thinking about disease modifiers. I should have definitely including calcium blockers. But you know, they're really there's a small trial and you'll ties them in like 30 patients a while ago. That showed that there might be some benefit early on for like pre clinical HCM in a particular genetic subgroup. It's never been followed up, you know, So there's not really any study that's shown that there's disease modifying potential calcium blockers. You know, we used them to treat symptoms. Um You know, in patients particularly with obstruction and verapamil probably is more effective than guilt, but um dice of pyramid is strictly limited to patients with symptomatic outflow obstruction that you know that that are refractory to beta and calcium channel blockers. Um And if they don't want to move forward with such a reduction therapy for whatever reason, I use it pretty sparingly because it has a lot of unwanted side effects. All right. So now moving to the new kid on the block, which is what a lot of the questions coming in are about with magic Hampton. Um When will it be available? You use it on all patients. Symptomatic patients. Um Great question. So, yeah. So it's submitted to the FDA. It's anticipated that it will be if it's approved it will be the end of this year. Um This calendar you're probably fourth quarter. Um there's still a lot of open ended questions about you know, how it's going to be implemented, whether it's going to need to be, so patients are gonna need to be referred to a specific center that expertise, you know, it's a very potent drug um you know, and it has and you have to follow drug levels and so forth. And so I think, you know providers with some experience in using the drug particularly centers that have been involved in the clinical trials. I think at least early on if it's possible, I think it makes sense for patients to be referred in to initiate the drug. Um I don't quite know how it's going to be mandated um but I think it would be useful to at least have people with experience and involved in in in initiation. Um I don't I don't know whether it's going to be widely available to all centers. So um I think in terms of its it's going to be if it's approved it's going to be approved for treating symptomatic obstruction which is what the phase three trials showed um whether we would, you know consider using it for um you know for non obstructive select patients. You know, I think, you know will be, you know up in the air. Um You know hopefully the phase three trial will be ongoing by then. Um for the non obstructive HCM. So still a lot of questions. I don't know the cost. Um you know long term how are we going to play that up against S. R. T. I mean I think it's a great drug to at least use initially upfront. Um It's gonna be way better tolerated than beta blockers and calcium blockers and far more effective. Um But there will be patients that say you know I don't want to be on this drug forever. I'm 30 years old. You know I'd rather just have a definitive surgery and not be treated. So you know I think it's going to be an option but and it's not going to make us artie go away by any means side effects or toxicities of it is their concern for long term heart failure. Yeah. You know I know there was an editorial american general cardiology. I don't necessarily agree with that perspective. I don't think we can equate a reduction in injection fraction which is really very small percentage. We're talking about single digit less than 5% reduced E. F. Um and can equate that to sort of this you know like disease progression where the EF drops over time. You know those are really fundamentally different things. Um You know when we see this reverse remodeling which I think is really encouraging. Um you have to be careful with it. There were some patients in the trial who transit we dropped their es down to thirties to forties and had the study drug have to be withdrawn but it comes right back up. So there's nobody that's had any long term effects and they are now a number of patients that are followed in long term extension trials and so far it seems to be well tolerated. Alright, last set of questions have to do with genetic testing. If you could just give us a little bit of an overview of what's the best way to get that done. Uh cost refer to you and then practically speaking who should get it and how often patients get it if the initial ones negative. Yeah so great a lot of questions. So I think I think the bottom line is I really think the pretest counseling is important um And it also the counselors know how to work with the gene test companies as far as the insurance authorization. So it's just far easier um to do it in the context of you know of with working with the genetic counselor and if that you know and we can talk about that in terms of like you know logistical and practical things as far as referrals. Um you know our genetic counselors can do G c only visits they are now doing they've been doing video visits um you know patients can be referred in for an initial consultation. Certainly if there's any diagnostic questions um you know that you would want a physician to see them too. So we can work out a lot of different arrangements there. And I certainly would want to have an Julian of that conversation. I'm sure you've already had these discussions. So terms of practical things I think we can have a you know talk about that. Um You know we do offer testing to virtually everybody that has a diagnosis of HCM. We always you know always somebody who's clinically affected. Um It's important to start with them and not somebody who is a family member who is not affected. Um As far as how often the testing should be repeated. You know we're not doing that routinely. The number of genes that are getting added to testing panels That really are well validated to be disease associated is a pretty small number. I mean it really is five Over the course of like 20 years. So we don't often repeat testing unless you know there's a very strong family history and we really suspect that there's something that we missed and the panel was done a long time ago. Um I think that covers. I was a loaded question. I was trying to get it in at the end of our session here and not keep it too long. No I think again thank you very much. That was a fantastic talk fantastic overview thank you for all the work you've done in this field. I mean really lead the way for not only understanding hypertrophic cardiomyopathy, but also how to help these patients tried to live a normal life. And exercise and activity is a big part of that for so many folks. And it's always been so fearful in the minds of uh cardiologist, primary care doctors. Uh you know what's gonna happen if they drop dead on me so Well, I think you've done. Thank you so much. I mean we need a lot more data and I think everybody is working hard on it, so I really appreciate the opportunity to come talk to you today. Look forward to meeting people in person soon, definitely. All right, charlie have a great day and thank you so much. You too. Bye bye.
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