Sharlene Day, Associate Professor of Medicine and Genetics at Penn Medicine Princeton Health elaborates on updates, diagnostic modalities, and preventative health in the clinical care of patients with hypertrophic cardiomyopathy.
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35th anniversary last night. Uh, more Europe. A lot of you have been alive. So, uh, just think about that for a minute. We're delighted to have Dr Charlene days. You could see Associate professor of medicine and genetics and director translational research at the Pen Cardiovascular Institute. Dr. Day spent most of her career, Mr Gunn, where she did her training, I guess 24 25 years there, Sherleen and is a graduate of M i t. So you can ask for all kinds of advanced calculus questions afterwards when you finish up, uh, with their per business school and M d from New York University and then training and, uh, academic medicine at Michigan before being wooed. Here she is, Uh, well, no researcher in this area of hypertrophic cardiomyopathy and the genetics associated there with, and we're thanks so thankful for you making the trip today, Dr Day, and nothing to disclose for today's talk. And welcome to 10 medicine, Princeton. Thank you so much. And thank you so much for the invitation. It is really delightful to be here in person. I was just saying this is the first time I've given a talk in person since February. Um, eso It's really nice to meet some of the people that I've spoken to on the phone and emailed with, um so be patient with me if I try to navigate using both zoom and it in person format. E think using the laser pointer here will work. Hopefully everybody. We'll be able to see it in both formats, but I may have to switch back and forth in order to play videos. Um, so just a little bit of my background this Dr Preston said, eso I was at the University of Michigan for all my career until I moved to Philadelphia to Penn last July. When I was there is Junior Faculty in 2006 started a program to treat patients with hypertrophic cardiomyopathy, which then grew into, um to expand it to treating patients with other types of genetic cardiovascular diseases, including other cardiomyopathy dilated with majestic and inherited arrhythmia syndromes. You know, it's fortunate to work with wonderful team there and have left the program in exceptional hands. Adam Helms and Sarah Sabari are now the co leaders of the of the program. Um, and I moved to pen a year ago, Um, enjoying the pen center for inherited heart disease. And that's my clinical home on then I also have a role. Is director translational research in the pen C B. I. Part of the, um, motivation for recruiting me was also to grow and expand the scope of the patients that we see in the pen center for inherited heart disease on Garage Dio, who is one of the electro physiologist with particular expertise and interest inherited arrhythmia syndromes will be leading an effort to really formalize that program and roll it into the center for inherited heart disease. I'm sure many of you know Anjali Owens has been the medical director since the center was first formed. Ken Margolies has a very seasoned, advanced heart failure and transplant physician, Um, in the notion raised, just finished her fellowship and you're gonna heart failure, enjoying the faculty in July. And then we're joined by a team of amazing nurse practitioners, nurses, program managers, genetic counselors and so forth. Um, so it's really delighted to be a pen. It's been a great year has in the pandemic. Um, but but other than that, it's it's really it's been a great move both for me, professionally and also for my family. Eso hypertrophic cardiomyopathy is the most common genetic heart condition. It was the condition which the very first gene was identified for any cardiovascular disease. Now 30 years ago by John and Cricket Seidman at Brigham and Women's Hospital. Really pioneers in the field, the disease is defined by unexplained hypertrophy of 15 millimeters or greater in any wall segment. Um, that's a fairly simple definition, but in practice, I think many of you know this is not always so straightforward. And, um, you know, it's often hard to differentiate hypertrophic cardiomyopathy from other forms of hypertrophy like acquired hypertrophy from hypertension, obesity and and many other how morbid conditions. So that's ah, lot of what we do is trying to make that differentiation and make the correct diagnosis. The age of onset hypertrophic card math is highly variable, as as the disease course itself, So symptom severity varies considerably from really people who are completely asymptomatic. And even professional athletes are very, you know, elite athletes to those who are very debilitated by their symptoms and may have advanced heart failure even advancing to needing heart transplantation and there a number of major complications, of course, including heart failure. Atrial fib, relations very common in ventricular arrhythmias. HTM, of course, is famous for that can lead to sudden death. But there are subsidy patients that have no or mild symptoms on normal longevity, So it really is incredibly heterogeneous condition. I'm not going to show too many graphs here today, but I just wanted to show a couple of slides to give you a flavor for the natural history of this disease. Um, so although many patients can experience normal longevity, what we have found from amassing a very large number of patients now in a registry called the Share registry, which is an international registries now grown 10,000 patients with HCM. And one of the earliest things that we published a couple years ago was mortality and outcomes data. Um, and so what we found is that people with HCM had a 3 to 444 Sorry, three to fourfold higher mortality across all age strata compared to the general population. And this is a cumulative incidents plot, looking at the cumulative risk of all adverse outcomes, sort of a composite of everything. Heart failure arrhythmias, death and stroke. And what you can see is that those who are diagnosed at a younger age here on this curve have about a 90% chance of developing one or more adverse outcomes in the course of their life. Compared to those a little bit lower for those who are diagnosed in midlife. Onda lower still for those who were diagnosed over the age of 60 for Yeah, So that's what this light, actually. So this is the breakdown of the three major composites? Yep, eso ventricular arrhythmias. So this is a composite of appropriate I C D discharge, sudden death and cardiac arrest and sustained ventricular tachycardia. Um, what you can see here is that if you're diagnosed at a young age, pediatric or young adult, you have about about a third of those patients Will experience ventricular with me in their lifetime on many, fairly early on is the most vulnerable period. Um, in contrast, if you're diagnosed at the age of 60 it's a 1% or last chance. So on. This really has bearing on making decisions about primary prevention defibrillators, heart failure a favor. Actually, the more common complications of H. P. M on again. Those who are younger experiences complications at a high rate. So in addition to the heterogeneity of symptom severity of disease course HTM looks ah lot of different ways on DSO. There's a very wide range of more apologies. The most common is asymmetric septal hypertrophy shown here, um, these air, all cardiac memorize from patients s O. This is the most typical morphology. About 70% of patients. A pickle hypertrophy, um, comprises probably about 5 to 10%. This is a less common form called the men ventricular. Um hey, big ventricular variant, which predisposes to a pickle aneurysm formation. And then we also see other sort of focal areas of hypertrophy here, shown in the anterior wall and anterior septum left ventricular outflow. Tract obstruction is a common. So I'm gonna have to take a laser pointer off to play the video. I think here we go. Left ventricular obstruction out. Protracted structure. The cruise in about a half to two thirds of patients, either at rest or with some type of provocation like El Salva, is the most common one squad to stand on and also exercise. So what you can see here is that the flow accelerates around the septum dragging the mitral valve leaflet. Now, you can't see that, because now I don't have a laser pointer. Eso, um dragging the mitral valve leaflet that's working okay in towards the septum on that creates turbulent flow in high velocity flow. And we calculate the Grady int by the equation four times the velocity squared. Um, you can see this is a typical dagger shaped radiant, which is the late peak ingredient you see, without a tract obstruction because it gets worse as a sisterly progresses on. This is in contrast to fix stenosis like aortic stenosis in this Grady int can often be contaminated with my career agitation. So you have to be aware of that over us. Make the grade yet. So I'm always very scrupulously, um, looking through all of these stop tracings myself on the echoes to make sure that we're getting an accurate measurement. So how might all of you see a patient with hypertrophic cardiomyopathy? How may they come to your office? So about half the time there'll be asymptomatic at the time that you make a diagnosis. Um, and you either pick up a murmur on exam. Or they might have an incidental finding that abnormally kg done for some other reason, preoperative or some health physical. Or they might be screened systematically because they have a family member with hypertrophic cardiomyopathy. You know the other half the time they'll present with some symptoms thes air. Fairly non specific symptoms. Destiny. A chest pain usually exertion all. Sometimes after heavy meals. Think of the precinct, API fatigue and palpitations. So we have a number of diagnostic modalities. We rely most heavily on echo. That's really our mainstay, so we can learn a lot From the echo. We can look at systolic and diastolic function, outflow tract radiance at rest and with fell Salva, mitral valve, systolic anterior emotion and also whether there's intrinsic disease of the mitral valve leaflets or the sub valvular structures as well. When we use this really for serial surveillance, Azzawi follow patients. Um, logic friendly Um, CMR or cardiac Emery is helpful for a lot of patients. I would say the vast majority of patients we do it last at least one CMR unless they have a device and there isn't a strong indication for doing it. Otherwise, it can be very helpful in terms of diagnosis and differentiating other conditions from hypertrophic cardiomyopathy, prognosis and treatment. And I'll show you something later. Um, in the talk of how we use late Catalonian enhancement, for example, Thio potentially influence decisions around sudden death with stratification. We also do stress testing very routinely. I'd like to do cardiopulmonary exercise testing in all our patients. Um, it's very helpful to assess their cardio respiratory fitness at Baseline and then to follow them as their symptoms make progress over time, particularly for those patients who present with class two or three heart failure symptoms. Um, and you'd be surprised often at how low people's cardiac cardio respiratory capacity is, despite the fact that they may not really describe very debilitating symptoms, because this progresses so slowly that they adapt over time and stop doing some of the things them that caused them to get breathless. We can also assess provoke herbal outflow, tract obstruction with exercise, human dynamic response, such as blood pressure response on whether they developed arrhythmias with exercise. In addition, the peak fio two carries very throne prognostic value, So I'm going to show you a couple of cases these air to patients who presented to me since I've been at Penn. This is a 33 year old woman who presented with effort Disney A and chest heaviness for a year. As the trial adolescent, she had difficulty keeping up with her peers playing sports. When she was 24 she developed post partum heart failure a time. Her echo was reportedly normal in the heart failure resolved. But he still continued to have palpitations and presentable episodes, and then she'd had about a year's worth of Disney on exertion chest, having this with about 4 to 5 blocks or two flights of stairs in her family. Her mother and father both had atrial fib relation kind of a younger ages. But there was no known hypertrophic cardiomyopathy and no sudden death in the family. So here's your E K G, which I don't know how well you can see this, but she has Sinus rhythm. She has some premature atrial complexes. There's some small Q waves in A and L, and otherwise from non specific T wave abnormalities. There isn't like a classic e k G for HCM. You sort of. It's often abnormal, but it's abnormal in different ways. Um, here's her echocardiogram. Okay, so there's asymmetric septal hypertrophy, um, and and a little bit of facility and promotion of the my travel, but it doesn't cause obstruction. Here's her critic Emery here. Um, and this is a still frame of a late cannellini, um, and have a nimitz taken after gallium injection so you can see uptake of battle any, um, um, into the hypertrophy. Stepped, um, in the sort of patchy mid myocardial pattern that's typical for hypertrophic cardiomyopathy. Okay, next case, this is a 44 year old woman with an abnormally piggy on a preventive health physical. Um, so he was just She just got this physical is part of her work, but because of her family history of her father having HCM, they didn t k g um, she reports as a child and adolescent. She played basketball volleyball. No, she's keeping up with her with her peers. She's currently completely symptomatic and does regular aerobic exercise with some interval training. And then, as I mentioned, her father has HCM diagnosed age 50 with the primary prevention I, C. D and process milling defibrillation. Greco wasn't terribly impressive. It's not playing again. but she has some septal hypertrophy that looked fairly mild. Both with that? Yeah, the wall motion was normal. I just can't get it to play again. For some reason, I don't know why. Um, but here you can hear Emery. She has this very focal area of hypertrophy in the mid septum. And it's a lot more pronounced on the Emory than you can really appreciate on echo and actually a fair amount of delayed enhancement in the mid Septimus. Well, eso that confirmed the diagnosis. Okay, so before I go into clinical management, I just want to see if there are any questions about that diagnosis. Um, and not really linked. Mhm. Yeah. So it affects about one in 500 people. So it's the most common man DeLeon genetically. Of course, everything's genetic to some degree, but yeah. Okay, so we're gonna go into the cornerstones of clinical management. Eso go through treatment of symptomatic patients, which is primarily what we use medical therapy for recognizing and managing advanced remodeling and heart failure. Re stratification for sudden death. And what's the threshold for primary prevention I CD? I read my management particularly for fib relation. We'll talk about genetic evaluation and family screening. And then all finally will go over lifestyle in terms of exercise recommendations and treatment of co morbid conditions. So first we'll start with treating symptomatic patients so in the symptomatic, so it depends on whether they have obstruction or not. Um, although we have kind of a limited number of drugs that we can use in terms of medical therapy for either but conventionally and those that have symptoms and have outflow tract obstruction, which is defined by Grady in greater than equal to 30 at Raster with provocation, we start with negative aina tropes, usually beta blocker calcium channel blockers. First line you can add dice a pyramid. It's not my favorite, Um, I personally use it extremely rarely. Um, just has a lot of anti Colin ergic side effects that aren't well tolerated, but it is safe, you know, it's been shown to be effective in a subset of patients who don't respond to negative and entropic therapy. But we have something better now, and I'll tell you in a minute, um, good hydration is really important. Minimizing caffeine and take You'd be surprised at how much caffeine people drink or maybe not. Um, And if there's still symptomatic, despite medical therapy in the Grady inches over 50 then that's typically the threshold at which we would consider sector reduction therapy that comes in two forms. And I wasn't going to go into a lot of detail about this, but stepped on my ectomy is a surgical procedure where muscle is shaved off the septum, and often the mitral valve might need to be repaired as well to prevent the systolic inter emotion and my trigger education and alcohol. Septal ablation is a catheter based procedure where alcohol is injected down into a septal perforated branch to basically, my father is controlled infection in tow them and started that in the system. Okay, so selection of patients for one of these procedures, um, it has to take into account. A lot of factors include include patient factors. So their age, whether they have co morbid conditions, how good surgical candidates they are, what their morphology is, where the obstruction is, how accessible it would be by one or the other procedure their court anatomy, whether suitable for alcohol ablation, um and then ultimately, of course, patient Well, a pretty small number um, you know, when I was at Michigan, we did about 32. Started to 40 my activities a year, and we did very few alcohol relations. Um, but we're also a referral center. Um, my activities, its overall pretty small percentage. And I think the number is going to get smaller. And I'll tell you why in the next slide. So we actually have a new drug. Finally, after many, many years and decades of observation and really fairly ineffective medical therapy for treating obstruction, it's a drug called Mavi Campton. It's in a class of drugs called liasson modulator. SERM Eliasson inhibitors, Um, and there are others that are in development. And there's another that's in a clinical through a different company called Side of Kinetics. Have a captain is, um, was developed by a company called my Cardia. And probably none of you know this, but my cardio was just acquired yesterday by Bristol Myers Swim, um, for $13,000,013 billion. Sorry. In cash? Yes. So, um, and that reflects the success of this drug in clinical trials to date and the likelihood that it will probably be FDA approved in 2021 So what this drug does is it binds to my a sense of the major, um, motor protein in the heart. And it kind of dampens down the activity because the hyper contract il ity is really what contributes to the obstruction on dso. They've tested this drug now in phase two, clinical trial. Initially last year it was published The Pioneer Trial. This was a non randomized open label trial of very small number of obstructive patients. Um, go back to my laser pointer on what you can see here is pretty dramatic. Drop in both resting and provoke a ble Grady INTs with only a slight drop in l V ejection fraction, which you do have to be very careful of. This drug has to be tight, created very carefully on there are some patients in the trial that did drop their E f transparently down into the thirties or forties. The Explorer trial has made a pretty big splash. It was published in The Lancet just in August, Um, coinciding with presentation, the late breaking clinical trials, the European Society of Cardiology meeting. This is a phase three clinical trial of 251 obstructive eight stand patients that was randomized, double blind and placebo controlled. Both pen and Michigan were among the top enrolling sites. Mom, for this trial, um, the results were really quite striking. That mav a captain dramatically reduced outflow Tract radiance. This is resting, Grady, and I'm showing here compared to placebo, this is a kind of a complicated graph. I tried to pull something that would kind of give you the overall kind of impression of the trial. Essentially, what this is is showing you the transition of patients from New York Heart Association classes. Generally from have a Campton was very favorable. Moving from class two and three, two more people in class one who are completely symptomatic by the end of the trial on this compared with placebo. So there's basically less blue in the placebo group and still more for boys and pink, reflecting that there is still more symptomatic kitchen. So on day also had improvements in their peak photo to in New York Art Association of class combined. So that was the primary and point, And this was met in 37 versus the City Council. Um, very striking result, I think. Exciting. Okay. Moving to the non obstructive patients. These patients are notoriously really challenging to treat you Think about Hef, Hef to an extreme, and that's pretty much what you're dealing with with these non obstructive patients. Um, so we try negative aina tropes to flow the heart rate down and, you know, prolonged diastolic filling. It has a variable effect, and it's kind of a trial and error thing. I've personally had more success with calcium channel blockers for treating these patients, but not great if there's still symptomatic, and particularly if they're really having any heart failure symptoms at all. I move pretty quickly to doing cardiopulmonary exercise testing if they have reduced exercise capacity for human mimic assessment. And I'm often I'm not anymore. But I used to be very surprised because often patients really hide very well. Um, you know, increased right and left side of filling pressures. Um, and we really don't have other treatment options right now for these patients unless they progressed to the point that they need transplantation. So Mavi Campton has been trialed in non obstructive patients. This is a much smaller study. This was a Phase two trial that was published in fact, earlier this year, um, 60 patients were randomized to the placebo. Lower high dose knave. A camp in the results were not nearly as promising is for the obstructive patients, but it shows potentially a signal. Um, which waas, um that there was a decrease in BMP levels, Um, in those patients that were treated with man versus placebo, but they didn't see a significant difference in Peak Vo two or New York Art Association class between groups, which was their primary and point. So I think, you know, a larger study is now being planned. I think patients elections really critical for this because the patients that seemed to benefit the most in kind of a pre specified subgroup analysis were those with the most severe symptoms. Um, so I think there is potential for benefit. But we have toe really think about patient selection and who would benefit? Um, okay, So I wanted to give one example of of sort of the most extreme case. This is somebody that I recently took care of in the hospital and is now, like now assumed care in my continuity clinical. That has mostly been in the hospital now since August So this is a 40 year old with longstanding hypertrophic cardiomyopathy and is now presenting with refractory heart failure. He was diagnosed when he was 14 years old. You know, my acting at age 29 and then had a by the I c D placed, um, a year later, because of the f was down to 45 to 50. Um, they had advanced heart failure symptoms within the presence of left bundle from the McNamee, of course. And around that time, he had multiple shocks for ventricular tachycardia. It's actually been fairly quiet since then in terms of ventricular arrhythmias, but has had 10 years very progressive. Disney A had a ablation for a fib and may have very complicated course following that. This was all done elsewhere, I think, um, outside of pan. And then he ultimately was referred to pen for advanced heart failure and with transferred in because, um uh of D compensated heart failure. Um, it was in love up. My actually was. Yeah, that's a great question. So you know so about Well, no coronary disease. So e mom for the while. Yeah, that's a great question. So about 8% I can tell you that from our from our share registry. 8% of patients with HCM progress to develop systolic dysfunction. It is part of the natural history and the advanced remodeling stages. So they can progress down a couple different pathways either more of a restrictive FINA type where they get these massive Atria. And this is garlic function is basically at least the F is intact. Um, but they get restrictive filling and low output on that basis. Or they progressed to systolic dysfunction with more dilated cavity. Now he has gone down that path. Um, and so it's hard to know whether the my ectomy had anything to do with it or not, you know, are our senses. It probably didn't, you know, did the left bundle do something? I think if it did, by v i c d should have helped to improve this function. You know, anecdotally, I've seen a couple of patients cause they all get left bundles after my act to me, um, who responded well to buy the pacing and their function is recovered and they feel great and other people who it's really not help. So I think those are people who are kind of down that path already. Um, you know, and I think it brings up an important point about that window of opportunity. Also, um, we've seen a number of patients referred in really too late. Thio have benefit from my act to me. And I think, um, you know, we want to jump on those patients along earlier. Um, yeah. So he is now in the, uh, re admitted to hop for diaries is because he failed outpatient. Um, uh, and, you know, continue to accumulate weight and going to progressive heart failure. So he is now being evaluated for heart transplant. Okay, so I'm gonna move on to sudden death with stratification. This is incredibly challenging algorithm to navigate with patients very individualized, and I'll kind of give you the landscape of where things are at, but we certainly need a lot more refinement of this, um, stratification. So it's very hard for us to predict those who are going to die suddenly We're pretty good now, predicting those who aren't going to die suddenly. So people are low risk. They in every, you know, in every sense of the way they have no risk factors whatsoever. I generally feel very good about them and incredibly rarely see events in those patients. But we put in a lot of I C ds We unnecessarily trying to refine this, Um, I think is really, you know, a major priority for the field. So conventional risk factors we consider hypertrophic burden. Classically, it's been this sort of somewhat arbitrary threshold of massive hypertrophy greater than 30. I really prefer to think of this in more is a continuous variable, um, non sustained ventricular tachycardia captured on event monitoring family history of sudden cardiac death. Um, in the first degree, relatives and the non vagal thing could be those were really the four conventional risk factors. Several years ago, your large European study of several 1000 patients developed and then later validated this five year risk score. This is an app for anybody who is interested. You could go toe HCM, STD risk calculator. I pull it the app out every time I'm in clinic, and I show the patient exactly, and I go through their whole risk score with them, so I think it could be very useful. So in addition to these four factors, it also considers age which is very important. So older age, um, individual is much less likely to have a sudden death. I mean, they lived this long with HCM presumably and, um, you know, and not had an event, so age is important. Um, left atrial size is also in there. A Zwelithini LBO Teague, radiant. The most influential factors of the family history of sudden death. Non sustained VT in sync. API. So what you end up with is a number. So it spits out this number that says, you know, 4% and that's a 4% risk over five years, and that sort of considered an intermediate risk. Then it will tell you a recommendation. So between one and 3% is low risk. Between three and 6% is intermedia than about Iran. I personally find that stratification not as useful because I think it really depends on the patient and other factors. Um, but at least it puts them into sort of a category in terms of, um, research studies and looking further, for example, um, there a number of other novel risk factors that are being considered, including high burden of left, uh, sorry. Late Catalonian enhancement on cardiac memory in this study. What they did they get my laser pointer back was to, um, look at patients who had intermediate risk scores, which means they were between three and 6% five your risk aan den. They stratified them according to whether they had 15% or greater than 15% or less than 15% of Lake Atitlan enhancement and in terms of its percent of total LD Mass. And so they found that there was a small but statistically significant difference in terms of the proportion of primary composite arrhythmias. Um, in those patients who had more. Lake Adeline IAM enhancement There's a large study called HCM Are, which is in its final year of follow up. That's about 2000 patients with a Sam who have had cardiac memories. Onda. We will know much more about this when the results of that study come out a Z, you know, determining whether it's truly an independent risk factor. Lower ejection fraction, I think, appears to be a risk factor for sudden death. Um, very uncommon, um, morphology. That's a pickle aneurysm. They tend to be very scarred. Um, they're also a risk for stroke because of the, um, Stasis in the in the apex and then also genetics. And what we found is that those that carries our community mutations and I'll explain in a minute, um do have a higher risk in in sort of a multi variant model. So this is really still a process and evolution. Um, but something that you know definitely captures Ah, lot of time, um, in clinic in terms of counseling for patients. So I'm going to be an example of how I used this risk. Or actually just last week, a 20 year old, 21 year old male with recent diagnosis of HCM hey described decreased endurance compared to his peers in high school. Um, he had a murmur that was heard on a recent physical that led to the diagnosis. He is pretty mild. Sometimes he still works out pretty regularly now at home. He wasn't the gym. Um, he has a family history that's quite strong on the maternal side. Maternal uncle with HCM, who had a cardiac arrest, several other maternal relatives with HCM and then another instance of seven cardiac death in a second cousin of age 28 and on his event monitor. He had two episodes of non ST BT, so his risk or calculates to 7% over five years, which puts him in the high risk category. And I think, you know, meets the threshold by probably anybody's criteria, particularly given his young age. So just showing you quickly his images here. Here's his echocardiogram. He has typical asymmetric septal hypertrophy, this so called reverse curvature. Um, morphology. You can see that here also in the cardiac emery on you have some. Like any limit enhancement. It's not. It's not a lot, but mostly at the RV insertion points. Okay, um, I just have one slide on management of atrial fib relation, although this definitely consumes a lot of our time because about 25% of HD and patients have a have a fib. A. Some point in their lifetime, Um, it reflects definitely a more advanced stage of L B remodeling that's associated with increased daily pressure. It's often very refractory, requires multiple relations, you know, you know, the management is not unlike a fib and other patients, except I tend to be more aggressive sending patients for ablation because I think they don't tolerate it as well because of their stiff ventricle. Their need for, um, for more active l a filling they don't tolerate they fed because they need their atrial kick. Yeah. Yeah. So that's the most important thing that you're bringing up. This is a stroke risk, and their annual stroke risk is 2% which is which is similar to valvular a fib on DSO. The most important thing in this algorithm that I know is a little bit hard to see because of the small print. Um, is that the Chad score does not correlate it all with risk of problem. Bill is, um so all these patients should be in a coagulated on. That is an absolute class one recommendation and in all the guidelines, okay, we'll talk a little bit about the genetics before we go into lifestyle. And that'll be the end. Um, so the genetic basis of HCM for 30 years now has been the cardiac stark Amir. This is a contract of apparatus of the cardiac Maya site. So there's mutations in thick filament proteins, mice and binding protein C and mice, and most commonly and then here are friends that proponents everybody knows proponent, right? That's those air components of the thin filament mutations in this gene. Also. Kenly Tate, Sam. So there's eight core jeans. Um, that air tested the gene testing panel, and there's others that contribute a small amount that when you send off genetic testing well, it will encompass these eight genes, plus a variable number of others, depending on the company in the panel. In terms of logistics of genetic testing, is performed by primarily by external laboratory is really not. Many academic centers do this internally. Um, it's typically Dunas. A panel of known genes can be done, asshole Exxon sequencing and so forth. But typically we send these office panels insurance. Prior authorization is typically conducted by the testing. Labs will notify patients of any copay that they would have before the samples run so they get the sample and they hold it until they've got the authorization and verify cope. The copay typically is not very much. This is generally covered by insurance, um, recommendations that patients should receive priest test genetic counseling. This can be done in the clinic, so we, of course, do it in our clinic because we have genetic counselors embedded within us. Um, it can also be done by telemedicine. Genetic counseling, which is actually what we're doing now, anyway. Um, but it's also it often offered by testing companies. So they have genetic counselors, and they could be telemedicine counseling. Um, if that's not available to you in your clinic? Yes. Uh, all liquid biopsy. Yeah. Zuba, Blood. That's it? Yeah. They're specialized company. They're specialized companies. And there's essentially three of them that do it. Yeah. Yeah. And beat aging Jackson Emery. Um, so just in terms of fundamentals and what you want to know about genetic testing for patients, um, the genetic evaluation and counseling a comprehensive family history and offering genetic testing is really become standard of care for treating these patients. So it's not a research thing. It is, really is standard of clinical practice. Now, um, you should always tested clinically affected. Individual first is testing somebody who is unaffected. Um, yield Very confusing results. Um, And in those individuals in whom a pathogenic variant is identified, Cascade testing of family members should be offered and facilitated the way we do. This is our genetic counselors put together a family letter detailing what the results are. And they say you can now distribute this to family members, and then they'll probably information, and they can call us, and we can help help them figure out where to go. So I'm just gonna be an example. This a patient that I'd seen at Michigan many years ago. I followed this guy right here who have been diagnosed with HCM when he was quite young. He was 35 at the time. I started seeing him in this family trees. This is a four generation pedigree. This is generated a nice program called progeny. Um, so the black squares air clinically affected, read news. They carry the mutation and blue means they had a sudden, uh so in his family, his sister had had aborted cardiac arrest and had 900 placed. His father died suddenly. His brother suddenly So not a good family history. Um, so we gene test him region tested him, we found, um this is what this is kind of the read out. This is what it looks like. So it's this. The name of the gene is this is my ass. And this is the symbol for bison. And then this is Argentine a position four or three which changes to go tannic acid. So that's the mutation. So then we were able to test his sister. Of course. She carried it a swell. We knew that would be true. And then we tested her three Children, who at the time hadn't been clinically screened, Um, to her two sons. Carried it. We did clinical testing and identified them is both having a diagnosis of HCM. Her daughter was clinically screened as well, with negative, and her gene test was negative. And then there two sisters were negative, which meant that there were seven people, Um, that seven kids that no longer had to head of any ongoing screening. So they were released screen. So cascade testing could be very efficient. Um, way of screening family members. So genetic testing also sometimes turns up some things that are not HCM. So we call these mimics. So here's an example of an 18 year old who is asymptomatic had an abnormal preoperative e k g. Before knee surgery, you can see how dramatic um is e. K g was in terms of l V H. With deep polarization changes. And I'm sorry this eco doesn't play, but this is you can see the concentric appearing hypertrophy on his echocardiogram. He was initially diagnosed with HCM, But when we saw him, um, his family history was remarkable. The fact that his mother had died of complications after heart transplant in her mid forties. Um, and nobody else in the family had had any disease, except there wasn't learning disabilities over here on things. So we tested him and Hindi. A mutation in a gene called lamp you So lamp to, it turns out, causes a disease called Dannon disease, which is the glycogen storage disease. Um, and here you can see his Emory where there is massive uptake of cattle. Any, um And then here is the logically we did a biopsy and who was well to confirm, Um, there was a vacuole, ization and scarred deposition. And so this is where they like it and stores are. There's a multi system license, almost language and storage disease. It's excellent, very rapid progression for prognosis and males. There are currently no existing therapies, but there is a phase one clinical trial underway with gene replacement therapy just looks very promising. Here's another mimic There's a 25 year old male with left ventricular hypertrophy concentric on DNA or apathy. This is a case of transferring amyloidosis, which you can pick up on a technique empire Phosphates can. This is a very scan that is highly sensitive and specific for translating amyloidosis. He had a mutation known pathogenic mutation in the translating gene, and they're now specific therapies for this disease. The feminists and patisserie in, um, two families is a drug that stabilizes the non amyloid amyloid. A genic form of the protein and patisserie in is an S i R N a. That knocks down the translation gene. Um, so this is a very exciting um, um, this is very exciting progress, um, and discovery in the field that we now have therapy to treat transferring amyloidosis so very important to distinguish it from HCM. So I'm going to finish up here in the last few minutes. Probably. Yeah, probably within within the next 10 minutes. Um, talking about lifestyle in exercise, which is really important, Thio Every patient that gets diagnosed with HCM. There's a lot of uncertainty and there's a lot of things out there. A lot of misconceptions. The guidelines have recommended disqualification from sports participation for any individual with HTM for decades now, um, yet it's actually unclear whether exercise at any level increases risk of sudden death. And that may seem surprising to you because it's it's sort of been written into the text books at this point and every review article that you read, Um, that sudden death is increased with vigorous exercise, but actually they're accumulating data now that suggests that that may not be true. In fact, there there really isn't anything other than anecdotal evidence, um, to point to that. And in the meantime, we have an obesity epidemic not only in the general population, but very much so in patients with HCM. 70% of patients they see em are either overweight or obese. Um, here's some outcome data, um, that we published from the share registry where we looked at, um, stratified based on B m I. And these are all patients with HCM um, their overall composite outcomes, sort of. That whole mixture of all the all the heart failure and arrhythmias and everything that could happen was, um, higher, higher risk and those who are obese, um, in heart failure really stood out as a a now outcome that those who are obese experience more frequently. So when I was at Michigan actually very early on when we first started the program and I'm sorry Saberi joined the program as a, um, training through cardiology fellow is a cardiology fellow and then junior faculty. We had the idea to do a randomized study of exercise training because there was really no data at all of the time. We called it the Reset Age Sam trial. Um, we randomized 136 patients to either usual activity or exercise training. And I should mention we did this in collaboration with Stanford. A. So, um, the exercise training was moderate intensity exercise. It wasn't anything crazy, but it was a structured, home based exercise program where they built up over four weeks and then, um and then maintained, um, for the next three months. So our primary endpoint was changed in Peak Co two or exercise capacity at the end of the four months, and we did see a significant increase in those who exercise versus those who did their usual activity with an absolute increase in peak feel to 6% which is about what you would expect in other populations with this type of an exercise stimulus and importantly, we saw no major adverse arrhythmic events in either group. Eso This was very encouraging and I think reassured many of us that at least moderate intensity, recreational exercise, you know, it's something we should be encouraging our patients to Dio. We now have an ongoing observation study which we expect to publish probably the end of 2021. Um called the live trial. This is a lifestyle and exercise, um focus study in patients with HCM and also a companion study and long QT syndrome. So we've enrolled about 2000 patients in each arm ages 8 to 60 all levels of activity, including some who are doing competitive sports. Um, and what we're going to do then is stratify according to activity levels, um, and look a clinical outcomes and quality of life. So stay tuned. So in the meantime, I think we're really, um, advancing towards a new paradigm. Recreational exercising, competitive sports participation where we're encouraging patients who are inactive Thio thio to engage in light to moderate recreational activity. Um, that we know benefits everybody but including those with HCM. And then for those who wish to do more vigorous or even competitive sports, engaging in more of a shared decision making model as opposed to more of a paternalistic kind of exclusionary model. Eso. I'll give you an example of a girl. Actually, I saw her through telemedicine. She lives in Texas andan Interesting story, given the pandemic that I got a license to practice medicine in Texas in less than 24 hours, and it took six months for me to get a license in Pennsylvania just a year earlier. So that's pretty remarkable. Eso She's a 17 year old competitive high school swimmer and the Division one college recruit. Um, I don't have a picture of her echo, but here is her m r I S O. She just had not been a one kg picked up on routine screening is part of an athlete screening, and she's completely symptomatic and exercising the high level. Um, she has a focal area of pretty marked thickening here in fibrosis. Um, so ultimately she saw me and then Mike Ackerman also Mayo Clinic to make decision about whether to go on and continue to compete in high school and go on to college swimming. Um, and through shared decision making discussion, she's decided she wants to consider continue to pursue swimming. Um, and we also decided for her defibrillator was indicated, given her hypertrophy burden and scar. Um so So at this point, I think I'd like to conclude And then I'd be happy to take questions. Um, I think the most important take home points are that HCM is a really highly heterogeneous disease with a huge spectrum of disease, onset and severity. The diagnosis can be very challenging and differentiating weather conditions. Offering requires some advanced imaging on genetic testing. The clinical management is really multifaceted, as you've seen, it's often very nuanced int individualized. So there's not really kind of a one size fits all approach, and the genetic evaluation sorry and family screening are really now considered standard of care. And I think we're finally now seeing, um, you know, on the horizon, this precision medicine therapies like Maverick camped in these other minds and modulators. And I think there's other things that air behind it and development that air hopefully not too far off and Finally, I wanted to announce that the new Age A CC guidelines for HTM will be coming out in November. They'll be, um, co published in circulation and Jack. It was really an honor for me to be a member of the guideline committee and a wonderful experience. And I think, um, for those who are really interested, I think this guideline document has, um, you know, has really captured the spirit of patient autonomy. Andi, um, you know, in the expertise of everyone on the committee and the hard work, I think is really paid off. We also had a patient on the committee, which is wonderful. Um um, to get her input as well as many a pediatrician. So the pediatric management of HCM has also been, um, very well addressed in this document. And then here's all the contact information for the four of us. The four faculty members in the Center for Inherited Heart disease at Penn. Um, we're very happy to take your questions when I won cases by us refer patients to us. Um, you know, we'd love for you to reach out personally. Um, there are a few clunky things in terms of just with the resurgence in terms of the referrals going through our system and long waits in the call center, which I know everyone's working hard on. But the call volumes have increased so much, um, that sometimes the referrals might be slower than they have been. Historically, eso we'd love for you to reach us trust directly because we can facilitate that for you. So I'd be happy to take any questions. Welcome comment, but I guess the General Cardella Hendricks Yeah, right on. Yeah, I've been trying today. Something every care center, think a lot of time. Uh huh. Yeah, I appreciate this was very Yeah, I okay, both bond e o e. We would like to see anybody. Yeah, it's a question. I'm sorry. Yes. So the question is really regarding. Sort of What patient Population? To refer for specialty care and who, you know, would be managed by general cardiologists in practice. Um, Andi, First of all, I think I see this is a partnership. This is not a sort of an either or situation. We Very much. When I work with any of you in managing these patients and we can do, we can do any kind of model that involves ah, following them continuously, particularly. They have sort of a, you know, sort of high maintenance in terms of symptom management or other things on. And we can also do one time consultations, um, you know, and then send them back and very much want to continue to do a co management strategy. That's something that you know that Angela is really embraced and I know has, you know, worked with a lot of referring physicians, and they have great relationships, So we want to continue to foster that. So in terms of which patients should be managed in specialty clinics, I think like you said, I think patients that have, um, you know, younger patients those were more likely developed complications who have already developed complications. We certainly don't want to miss Windows of opportunity for stepped a reduction therapy or for use of now the campaign. Now that that that's available. Andi, I have seen some patients who really, I think could have had my act to be five or 10 years ago, who now have very severe pulmonary hypertension. We have somebody who's we've struggled after their my act to me um, now it's been the hospital for three weeks, managing or pulmonary hypertension. And I think that could have been avoided had she been referred earlier when she had the lowest VO two I've ever seen with 9.5, you know, which is well within the transplant range. So, um so certainly when we want to see people as early as possible. If there's any hint if they have any symptoms or or outflow tract obstruction, you know, there's also now you know, the capacity and roll patients in clinical trials, um, mavi camped in and another mice and modulator or they're too active clinical trials going on with those and those air both for obstructive patients, there will be a non obstructive study. At some point with Navid camped in, we'll have to see how things shake out after the acquisition. But, you know, I think they acquired the company. Thio, you know, to bring this drug up, Thio FDA approval. Eso those patients for sure. Those with a family history and so forth. So if they can get genetic evaluation, um, and we can do again telemedicine. So that's an option as well. Yeah, no. The prevalence by a prevalence by age. So the question is so you mean the prevalence of the disease by age? So it's a little hard to answer because the age of onset so variable um you know, I think, or the the studies that have been done that we quote that 11 in 500 comes from adults, um, where they just did echocardiograms on the general population and found that one in 500 had criteria. Unexplained hypertrophy. I don't exactly remember. But there were adults, so probably 18 to middle age sometimes, and so that that number has really never been sort of re evaluated. So it's kind of hard to know, and it depends on the family history. Um, so I don't know if I could tell you what the prevalence is in the pediatric population. Overall, it's probably lower, though, because the disease can often not manifest until adult life. So there may be, you know, kids that carry the mutation and don't yeah, pre clinical. Yes. Lisa. Yeah. Mhm these things. Yeah. And you know, it's really interesting. So I can't I can't. I'm, like, sworn to confidentiality, and I can't I e getting these emails don't talk about the guidelines, but I'll tell you that this was one of the topics that generated the most discussion. We're all sort of surprised by it, because the pediatrician's had a very different view of how often we should be screening than the adults did. I mean, adult cardiologists are not there. Everybody was adult. Mm. And you know, So I think it really just It's so individualized and it really depends on the family. Um, you know, if you've got, I think Children should be screened more often because the chance of emergence, I think, within a year's time is greater than in somebody who's in their thirties or forties s o. I think it depends on whether or not they carry gene mutation. If they have familial disease than I do screen more often for kids, I would definitely screen every year. I generally start by age 10, but there's some families I would start earlier If there's early manifestation of disease or sudden death in the family, I would start, you know, pretty much age like, you know, three or five, Um, and then if there's for those that don't carry star community mutations about 50% of patients with HCM who have a clinical diagnosis of HCM. We can't find a gene mutation. And many times those patients also don't have a family history. Um, and there's been a couple of studies. Now they've shown that that, you know, if you do systematic family screening, just there's not that many people that turn out to have disease and those that do have really good outcomes. And so it's sort of hard to imagine that we should be screening everybody every child in every for every family member every year and every adult every 3 to 5 years. So I don't actually even remember exactly how it came out in the guidelines. But I would just say it's very individualized, and it just depends on the family on And then the genotype status. Yep. Remember, almost with commercial, um, genetic testing, commercial product. Brooke and I Wow. Very yeah, Yeah, their genetic tests. Thank you. That they're free in a Is that? Yeah. Yeah, yeah, yeah, yeah, yeah, yeah, absolutely. So that I mean, commercial testing is what we do too. So we and if they're all clear approved laboratories eso we don't do any internal testing or very rarely over a chopped. They do have some sequencing more often in the kids, but they also tend have more syndrome, a disease and things. Um, so we use the same commercial laboratories that you would use? Um, you know, I think if the patients can't get down to come see us to get in person genetic counseling, we may be able to do telemedicine counseling because our counselors can do counseling only visit. So that's an option. And then also through the testing companies, they do have genetic counselors that they can, and they can reach out to the patients and do telemedicine counseling through the testing company as well. Um, three. Interpretation of the test is not always that straightforward. Um, particularly these variants of uncertain significance. I didn't get into all the nuances, but, um, they can be pretty tricky. We don't always agree with the interpretation of the testing company. We're also happy to look at any results that you get that you're not sure about. And we can, you know, see those patients. If there's the quick the protest about, you know, I think, yeah, I think. But I'm a little biased because, you know, I've been because I do this for a living. But I think that, you know, I do think that it's probably best the ideal circumstances to probably bring the patient into the clinic and have a full genetic counseling. Visited a full family history and then and then to have the genetic testing done, Um, with our ability for us to be able to interpret the results because we have experienced to understand, you know, what the different types of results mean. Some of them are very straightforward, but some of them are more complicated. But you know it's not. You can't always do that in patients may not want to travel. And, you know, so we could work with you. And, you know, if you wanted to or the testing from here. And you know we can help with interpretation and then maybe see those patients who are more confusing. Yeah, content less nice. Three. No, Although there's a little country, it depends as long as the the gene test result is a diff ERM affirmative positive so definitively pathogenic and not some varying of uncertain significance. But if it's clearly pathogenic, there's no question about it. And family members test negative. They don't need to be clinically screen anymore. Thank you very much. You're very welcome. Yeah, The presentation. Thank you so much. Yeah, it's been great. Well, thanks so much. Thanks so much for the invitation.
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