All right, hello, everybody, and welcome to this Heart Failure Society of America Heart Failure Seminar with a focus on hypertrophic cardiomyopathy. And this seminar is supported through an independent grants from Bristol-Myers Squibb and Cytokinetics. To claim credit, please complete a course evaluation by logging into the HFSA Learning Center at the conclusion of the event. And then to introduce us, I'm Carolyn Ho, the Director of the Cardiovascular Genetics Center at Brigham and Women's Hospital, and I have the honor of being accompanied by a fabulous panel of speakers, including Michael Ayers from the University of Virginia, Charlene Day from University of Pennsylvania, Lynn Stevenson from Vanderbilt University, and Vicky Parikh from Stanford. So our learning objectives today are to review the genetics, pathophysiology, and diagnosis of hypertrophic cardiomyopathy. We'll also discuss clinical trial data and the optimal use of current and emerging treatment options for managing our patients. And then finally, we'll discuss advanced treatment options for the management of challenging patients with HCM. And you'll see the agenda before you. We'll start off with some polling questions and three of the talks, again, introducing the basics, standard management, and new approaches to management, followed by an interim question and answer session. So we encourage you all to submit questions through the chat function of Zoom, and please keep the questions quite general and related to the content of the presentations rather than focusing on any specific cases. And then we'll return for discussions about advanced therapies at a challenging case discussion. And then we'll have a discussion, again, with the faculty. And please, again, also submit any questions that you may have. We'll go ahead and move on to that. So next we have the pleasure of listening to Dr. Charlene Day speaking about Remembering the Basics, Diagnosis, Pathophysiology and Genetics of HCM. Hi, I'm Charlene Day. Welcome to the HFSA Heart Failure Seminar focused on hypertrophic cardiomyopathy. I'm gonna go ahead and share my screen. Okay, so today I'm gonna talk about Remembering the Basics, Diagnosis, Pathophysiology and Genetics. These are my disclosures. I have research support from Bristol-Myers Squibb, Pfizer and Lexicon Pharmaceuticals and consulting or honoraria from Lexicon Pharmaceuticals and Cytokinetics. So we'll start with a polling question. A 45-year-old woman presents to your office after her 50-year-old brother had a cardiac arrest, which led to a diagnosis of hypertrophic cardiomyopathy. Her primary care physician referred her to you for genetic testing. You take a detailed family history and discover that her father died suddenly at the age of 55. His cause of death was unknown and no autopsy was performed. She has two teenage children who are healthy. An ECG and echocardiogram on the 45-year-old woman are normal. And what is the best option to consider for genetic testing? A, send panel gene testing on her. B, send panel gene testing on her children. Or C, provide contact information for your clinic for her brother to reach out to offer panel gene testing for him. So we'll come back to that later in the presentation. So hypertrophic cardiomyopathy is the most common daily and inherited heart condition. It's typically defined as unexplained hypertrophy at or exceeding 15 millimeters in any wall segment. The age of onset is highly variable, anywhere from early childhood to later adult life. Symptom severity also varies widely. A number of patients experience major complications, including heart failure, atrial fibrillation, and ventricular arrhythmias that can lead to sudden cardiac death, while other patients have no or mild symptoms and can have normal longevity. HCM presents in a number of different morphologies. Asymmetric septal hypertrophy is the most common. It's shown on the far left. Other forms include apical, midventricular hypertrophy that can also manifest with an apical aneurysm, and other focal patterns of hypertrophy like focal hypertrophy of the anterior wall as shown on the far right. Left ventricular aflatoxtruction is a common manifestation that occurs in half to two thirds of patients to varying magnitudes. The Doppler tracing on the lower right shows a typical dagger-shaped appearance of the late peaking systolic gradient. HCM is diagnosed in a variety of ways. About half the time, the patient's asymptomatic and the diagnosis is incidental, perhaps on the basis of an abnormal ECG or heart murmur, or it can be made on the basis of family screening. The other half the time, the patient will present with symptoms of some kind like effort dyspnea or chest pain, or with an acute event like syncope or more rarely cardiac arrest. We use a combination of diagnostic testing modalities to diagnose and follow patients with HCM. ECHO is really the mainstay for diagnosis and serial surveillance as it's used as a class one guideline recommendation. Sorry, and it's used as a class one guideline recommendation. It provides valuable information about hypertrophy burden and distribution, systolic diastolic function, left ventricular aflatoctract gradients and intrinsic mitral valve disease. Cardiac MR is often helpful. It's indicated in most patients, at least as a one-time study. It provides adjunctive data to the ECHO that includes better resolution of certain hypertrophic morphologies and also fibrosis identification and quantification using late gadolinium enhancement. Stress testing is indicated in most patients to assess cardiorespiratory fitness and symptom progression. It's particularly indicated in patients with progressive symptoms. Cardiopulmonary exercise testing is ideal if it's accessible to you and it provides very strong prognostic value, including an association with mortality. Stress ECHO is also important for assessing exercise induced aflatoctract gradients, which can be a source of effort-related symptoms in a number of patients. So as I mentioned, about half to two-thirds of patients have some degree of aflatoctract obstruction. Here I'm showing an example where you can appreciate the hypertrophy of the basal-to-mid septum and elongation of the anteromitral valve leaflet that causes redirection of flow around the hypertrophied septum and systolic anterior motion of the mitral valve leaflets. This creates a late peaking dynamic gradient across the LVOT. An important subset of patients with HCM do not have aflatoctract obstruction, and these are so-called non-obstructive patients. There are a number of different varieties. This group includes the apical variants, as one example shown on the far left, as well as asymmetric septal morphologies that typically spare the basal septum and thus don't result in aflatoctract obstruction. So this is a really highly heterogeneous group and includes patients who do very well without any symptoms, like the two on the left, and others who have very advanced heart failure symptoms like the two on the right, with marked left atrial enlargement, and get these videos to play, and sometimes systolic dysfunction, as you'll hear about later from Dr. Stevenson. Many patients with hypertrophic cardiomyopathy, regardless of the presence or absence of aflatoctract obstruction, have a significant symptomatic burden, and mortality is higher across every age strata compared to the general population. A younger age of diagnosis is a very significant picture of adverse outcomes, including heart failure, atrial fibrillation, and ventricular arrhythmias, which are all captured in this graph as an overall composite outcome and stratified by age of diagnosis. Notably, women with HCM have been shown reproducibly to experience a higher rate of advanced heart failure and higher mortality than men, and the reasons for this are not fully understood at this time. Okay, so let's talk about genetics. The primary genetic basis for familial HCM is the cardiac sarcomere. Genetic variants in nine genes that encode proteins involved in cardiac muscle cell contraction constitute the predominant genetic etiology. These include myosin, myosin-binding protein C and myosin light chain, all part of the thick filament, and then thin filament genes, including troponin T, troponin I, troponin C, tropomyosin, and actin. While it has been 33 years since the first genetic causative variant in a sarcomere gene was discovered, still much of the genetic etiology of HCM, about 50 to 60%, remains elusive, and that's shown in the gray sector on the pie chart to the right. There are a small number of genes outside the sarcomere genes that contain causal variants, but these account for only about 10% of familial cases to date. Recently, it's been discovered through genome-wide association studies that common variants at a number of genetic loci in or near different genes contribute to the etiology of HCM. Those individuals who have a disproportionate number of these so-called risk alleles, and therefore a high polygenic risk order, are at about a two to two-and-a-half-fold higher risk of having HCM, regardless of whether they also carry a sarcomere gene variant. So these variants are also modifying factors. Acquired traits have also been shown to contribute to the etiology of HCM, most notably diastolic hypertension, known here, and obesity, shown here. Okay, so let's shift to the practical applications of genetic evaluation in patients with HCM and their family members, for which there are a number of fundamental considerations that we'll go through. So the first is that genetic evaluation testing is considered standard of care. It's endorsed as a classroom recommendation by multiple guideline documents. It allows cascade testing of family members and increasingly informs prognosis and treatment decisions. The second consideration is that panel gene testing should always be performed on a clinically affected individual first, and then cascade testing on unaffected family members can proceed from there. But family members are only tested for the causative variant identified in their affected family member. So third, the optimal way to do this is with pre- and post-test counseling that can be done by genetic counselors embedded in our clinics, or by genetic counselors through gene testing companies using telemedicine, if you don't have a genetic counselor accessible to you. Most times we use panel testing that contains a set of known causal genes for HCM, but exome sequencing can also be an option. That's typically done in trios within families if no causative variant is identified on panel gene testing. So the fourth consideration is where the gene testing is done. Most times it's done by gene testing companies. There are some institutions that do it internally, but not very many. Insurance prior authorization is typically conducted by the testing laboratories, and then they will notify patients if there's any copay. So this is very convenient for us in our busy practices. Okay, so let's walk through an example. So the proband in this pedigree is denoted by the arrow. He had genetic evaluation and testing, and a pathogenic variant was identified. His affected sister, shown here, carried the same genetic variant as did two of her three children, shown here. And therefore, oh, sorry. And then they were then found to have phenotypic features of hypertrophic cardiomyopathy. The other two sisters of the proband did not carry the variant, and therefore their seven children did not need to be tested, and all of these individuals could be dismissed from further screening. So this highlights the value of genetic testing for cascade testing in family members. And I will stop there and stop sharing my screen, and we'll move on to the next presentation by Dr. Ho. Thank you so much for your attention. Great, thank you so much. And while my slides are being prepared to be shown, I will remind you that I'll be talking on standard management of HCM. What is our usual approach? You know, what has it been since we've passed it currently? All right, here are my disclosures. Now, when we think about managing our patients with hypertrophic cardiomyopathy, we typically think about three basic arms. One is symptom control, making sure that our patients feel as well as possible. And the next is stratifying individuals for their risk of sudden cardiac death and applying either, applying primary prevention ICDs as appropriate, and then also lifestyle counseling and family screening. So we'll start first with symptom control. So the targets of medical therapy are to decrease chronotropy and therefore facilitate diastolic spilling as diastolic abnormalities are essentially ubiquitous in patients with HCM. And this can also help with attenuating obstructive tendencies. And then we want to also decrease inotropy. We want to exercise and do increase in gradients. We also want to potentially decrease oxygen demand and by decreasing inotropy, we can hopefully try to attenuate both obstructive physiology and also help with myocardial oxygen demand. And so when we think about starting therapy, we really are keying in on symptoms because all of our therapy, our medical and surgical therapy to date is really based on trying to alleviate symptoms. If those symptoms are present, then we typically do not have to do If those symptoms are present, then we typically do not have to pursue therapy, even if obstructive physiology is present because disease modifying therapy is not quite available yet, but the subject of great research. If there are symptoms present, then you want to try to establish the mechanism. Basically that's trying to determine whether these symptoms might be related to obstruction or whether no obstruction is present. So how much obstruction is enough? Well, to define somebody as having obstructive physiology and obstructive HCM, we typically want to see a peak left ventricular outflow gradient of at least 30 millimeters of mercury that's either at rest or with procedures or in maneuvers that can increase obstruction. But for symptoms to be thought to be sufficient to, for obstruction to be thought to be sufficient to result in symptoms, we really want to see a peak gradient more than 50 millimeters of mercury because that's the threshold where we think that the obstructive physiology is really capable of causing symptoms. And as Dr. Day mentioned, the symptoms are typically effort-related dyspnea and chest discomfort. So you want to look hard for obstruction and recall that obstruction gets worse if there's more vigorous contraction, if there's decreased afterload, if there's decreased volume or preload, and if there's increased heart rate. So you want to do maneuvers. In the ECOLA, we will typically ask patients to perform a valsalva maneuver. In the office, getting patients to stand from squat can be a very reliable way to try to provoke obstruction. And the most physiological and the best way to really make sure that you're not missing obstruction is with exercise provocation. It's important to be very diligent about looking for obstruction because that is the major branch point in trying to decide how you're going to address symptoms. So if no obstruction is present right now, there's a great unmet need in the field because our medical therapy is often not fantastically effective. We try beta blockers and calcium channel blockers and diuretics for decongestion as needed. If there are refractory symptoms, then patients may need more advanced heart failure management. The options are quite limited if the symptoms are driven by severe restrictive physiology. In that situation, patients may need to consider cardiac transplantation. And similarly, if there's the progression to less ventricular systolic dysfunction, that's another area where advanced therapies may be needed as we'll hear from a little bit later. If obstruction is present, then we have a few more options available to us. First, you want to make sure to correct exacerbating factors. So you want to encourage your patients to hydrate aggressively to avoid volume depletion. You want to take a good look at the medication list to see if they're on vasodilators, which could be potentially stopped. Medical therapy is then pursued. You can use diuretics cautiously if there's congestion. And if symptoms are refractory, then we can consider invasive sexual reduction therapy. So with medical therapy, again, we're targeting outflow tract obstruction to try to improve symptoms. We use beta blockers, calcium channel blockers, specifically verapamil or diltiazem. And if those do not seem to be effective enough, then disipiramide can be trialed as a more potent negative inotrope. If symptoms are refractory to medical therapy, then invasive septal reduction, either with alcohol septal ablation or with surgical myectomy, can be done to try to physically decrease the septal hypertrophy and enlarge the outflow tract, relieving obstruction in that manner. And in thinking about septal reduction therapy, again, the indications are for medically refractory symptoms related to obstruction. So the gradient threshold that is usually used, again, is at least 50 millimeters of mercury, either at rest or provoked. And factors that favor myectomy, and myectomy has been around for several decades. So you would favor myectomy if there's really extensive left ventricular hypertrophy that would need an extended myectomy to effectively reduce outflow tract obstruction. If there's intrinsic mitral valve disease, if there are surgical degrees of coronary artery disease, and also based on available and accessible expertise. Factors that might favor ablation, which has been around for the past couple of decades, would be patients that have comorbidities that increase their surgical risk, those patients that would very much like to avoid cardiac surgery. But you need to have suitable coronary anatomy and have a septal perforator that supplies the thickened part of the septum that's contributing to the CM septal contact and the obstruction. Again, of course, available expertise. And then moving on, the next arm of therapy that we think about is sudden death risk stratification. And that's really trying to put your patients on the spectrum between the highest intermediate and lowest risk. So of course, risk stratification is the most straightforward at the extremes, identifying those at the highest and lowest risk. So highest risk individuals are those that would qualify for secondary prevention devices, individuals that have survived cardiac arrest, or those who have had sustained ventricular tachycardia detected. They have a substantial rate of appropriate ICD discharge and also sudden death. And then also individuals that have multiple risk factors or in European Society of Cardiology, five-year risk score of greater than 6% would also be considered at highest risk. And would typically move forward with a primary prevention ICD. Those at the lowest risk include patients that have mild to moderate, there's non-severe hypertrophy, less than 30 millimeters, no family history of sudden death, no syncope or non-sustainability, no obstruction or left atrial enlargement, minimal fibrosis, no apical aneurysms. They have less than a 1% annual sudden death rate estimated. And they would be periodically re-evaluated for risk to see if any risk markers have emerged, but typically not sponsored for primary prevention ICD. But it's important to remember that this group is the biggest group. So in terms of sheer numbers, most events happen in our lowest risk group, but as a proportion of the population, of course, it's quite a small proportion of low risk patients that have sudden death. And then we have those individuals that are challenging because they're in the gray zone. They have at least one risk factor or an ESU five-year risk score of four to 6%. The risk-benefit ratio of an ICD is less clear. And this is where it's very important to have shared decision-making to try to really understand the patient's preferences, their priorities, how they approach risk and their tolerance for risk in medical devices, and to try to make sure that they understand the data as best as can be presented. And so this accounts for about 40% of patients with HCM or about a quarter of a million patients in the US. And so there are guidelines that will describe very clearly how to look for risk predictors for sudden death. And the risk predictors include a family history of sudden death, extreme left ventricular hypertrophy with a wall thickness more than 30 millimeters, worrisome syncope, ankle aneurysms, reduced left ventricular ejection fraction, are risks that are considered and included in the calculator. Non-sustained VT is also a risk modifier and present in the ESU risk calculator. And then on the US guidelines, we would also consider an extensive LGE on CMR and the apoplectic aneurysms as risk modifiers. And then, so thinking about the landscape of HCM in our current therapy, we can think about the clock being started when the sarcomere variant is either inherited or introduced. There are some primary effects of these variants even before left ventricular hypertrophy developed and before a diagnosis of HCM can be established in terms of small cavity size, hypercontractility, diastolic abnormalities, pro-fibrotic tendencies and impaired energetics. And then with the influence of age, genetic modifiers, lifestyle and comorbidities, clinically overt HCM can emerge with pathologic remodeling and left ventricular hypertrophy. And that's when we really start to see adverse outcomes and symptoms. And so right now we treat for symptoms. We assess risk for arrhythmias. And so predominantly looking for a risk of a sudden death and primary prevention ICD allocation, but also being on the lookout for atrial fibrillation, which is quite common in patients with HCM and associated with a high thromboembolic risk thus necessitating anticoagulation. And then sometimes we have to utilize advanced heart failure management. So we can see that our therapies are effective for many, but not all of our patients. Therapy starts quite late in disease evolution and have not historically targeted the underlying biology. There's also been sparse evidence for efficacy with very limited clinical trial data. So luckily the landscape is changing and I'll turn it over now to Dr. Vicky Parikh to take us through that. Thank you so much, Dr. Ho. I'm gonna try to advance the slides here. We may need to hand over slide controls. There we go. All right, wonderful. Thanks so much for the opportunity to be here. It's great to be here with Dr. Ho and Dr. Stevenson and Dr. Ayers to talk with you about hypertrophic cardiomyopathy and the developments that have come up in the last few years in the treatment of this disease. My disclosures briefly are that I receive funding from Biomarin for my research lab. And I also am a consultant for Biomarin Lexio Therapeutics and Viz AI. So what I'd like to do is start with the schema that Dr. Ho just proposed, which is understanding HCM as a disease that starts with a sarcomeric variant and moves all the way through to overt HCM that has symptoms. This isn't true for every patient. Sometimes patients carry a sarcomeric variant and don't develop disease, but much of the time they do develop disease. And so how can we, as Dr. Ho says, really start to target the actual biology that's underlying their cardiovascular disease and not simply treat their symptoms? So I'm gonna talk about two major categories of therapy. The first is one that is currently commercially available and that is cardiac myosin inhibitors, which became available about a year ago. Cardiac myosin inhibitors have been improved and tested on patients with overt HCM. I think the jury is still out about whether treating prior to the development of overt HCM with these medications will be helpful, but I think that you'll understand as we explain the underlying biology of this therapy that it seems intuitive that it might actually help to prevent development of disease in patients that we know are at risk. And the second is to talk briefly about emerging therapies in gene and gene editing therapy. These are becoming available across genetic cardiovascular diseases. And I did wanna spend a little bit of time today talking about the existing therapies that are in trials, as well as understanding what that landscape might look for, for HCM in particular in the not so distant future. So let's start by talking about our commercially available therapies, which are cardiac myosin inhibitors. These are precision therapies for obstructive HCM. So when we think about how these therapies were discovered, we really go back to the genetics of the disease. As both Dr. Day and Dr. Ho described, really the origin of the problem in hypertrophic cardiomyopathy, the cause of the hypercontractility, as well as the hypertrophy and in obstructive patients, the cause of the obstruction, is really rooted in the sarcomere, which is the molecular motor of the cardiomyocyte. So as you'll remember from medical school, or maybe even more recently, this is an electron micrograph of the sarcomere, where we see that we have myosin heads overlapping with actin strands in order to pull the cardiomyocyte together as though they were oars along water on a rowboat. If you zoom in even more, you can see where that oar, which is the myosin head, contacts the actin cytoskeleton in order to pull the center of the sarcomere past its scaffold here. So as part of that contraction, we understood during the sequencing of the very first few patients who had genetic diagnosis with hypertrophic cardiomyopathy, that the thing that was broken here for many of these patients was the myosin and myosin-binding protein C complex. So most patients with a pathogenic or disease-causing variant in HCM, will have it in one of these two genes. The idea behind how to then treat this disease very specifically at its biological source came then from that understanding of its underlying genetics. If we look then at how those underlying genetics actually affect the sarcomere, what we know is that that myosin head, which I just showed you in blue, has to be cocked and ready to actually cycle through its attachment to actin and use up energy in the form of ATP. It turns out that there are relaxed states of the myosin head, which are shown here in red, where it actually does not come into a conformation where it can interact with actin and move the sarcomere along the actin cytoskeleton. We know that if you have 100% of your myosin heads in this green state where they're bound to actin, they're gonna use up ATP really quickly. Whereas if you have 100% of them with this super relaxed state, meaning bent all the way back and not connecting with actin, that you actually are not gonna use very much energy at all. And as we know, that energy cycling is really critical to the need for oxygen use in HCM, as well as the hypercontractility that is connected to the hypertrophy, which are the hallmarks of the disease. So again, back here in this state where the myosin can cycle against the actin, we see that MYH7, which are myosin head variants, actually destabilize the super relaxed state over here in red, which means that you have more ores in the water. A higher percentage of the myosin heads in these patients can interact with actin, and therefore they're making that sarcomere work harder. So the brilliance of cardiac myosin inhibitors is that they actually stabilize this relaxed state of the myosin head. And so what that does is it takes those ores out of the water, and it tells the sarcomere that it doesn't have to push so hard. It doesn't have to be hypercontractile, and it doesn't need to lead to that overuse of energy and dependence on oxygen and later on development of hypertrophy. So that really amazing precision therapy for hypertrophic cardiomyopathy came out of several labs, including at the Brigham, at Stanford, and then also at University of Colorado, and was then moved on to be tested in trials, which Dr. Ho and many other leaders in this field were the lead investigators for. So the first phase three trial that came through of a cardiac myosin inhibitor was of Mavicampton. This is Explorer HCM. It was, as I mentioned, a phase three trial specifically for obstructive HCM. As Dr. Day and Dr. Ho described, that means that you have septal hypertrophy, which is actually causing a gradient across the LV outflow tract against which the LV is having to work. When these patients with obstructive HCM, LVOT obstruction, had Mavicampton, their VO2 max actually improved. Their symptom scores also improved, and their LVOT obstruction, their gradients across the LVOT improved. And importantly, across the group, despite the fact that the idea behind a cardiac myosin inhibitor is that it decreases the sarcomeric contractility, there was no significant decrease in left ventricular ejection fraction. Similarly, Afacampton, which is another cardiac myosin inhibitor, has gone through a phase two study called Redwood HCM for this one, the NYHA symptom status of patients definitely improved. The LVOT obstruction improved, and again, there was no significant decrease in left ventricular ejection fraction across these groups. So both of these studies point to the idea that CMIs, which are really targeted at the underlying biology of HCM can make patients feel better. They reduce the gradient in the heart, and they can actually improve exercise capacity in a way that's measurable on a treadmill. So just a really huge, huge advancement for patients with HCM. It's also important to note that CMIs don't have the same side effects that beta blockers and calcium channels and disoperamide do. They don't reduce the heart rate, and they're not gonna lead to the types of swelling with some of the calcium channel blockers. There's some evidence to suggest that we may also be seeing favorable remodeling of LVs that have HCM that are exposed to CMIs. This is a sub-study of Explorer HCM looking at cardiac magnetic resonance imaging, cardiac MRI that was led by Sarah Saberi and others. And it actually showed that there was a reduction in the LV mass index to body size, that there was a reduction in the maximum LV wall thickness, and that there was no significant difference here seen in the level of LGE, but that overall there was significant positive remodeling of the wall thickness in HCM, which we understand to be a sequelae of the underlying biology in this disease. Of course, there are patients that don't have obstruction that have HCM, as Dr. Day described. These non-obstructive HCM patients may also benefit from a cardiac myosin inhibitor. The idea behind that being that by reducing the energy demand as well as potentially offering some leucotropy by relaxing those sarcomeres we might be able to see benefits for non-obstructive HCM as well. The first trial that was done for non-obstructive HCM with CMI was Maverick HCM led by Dr. Ho. It did show after 16 weeks that there was an improvement in NT pro BNP and troponin in the patients who received Mavicampton. Five people did have a reduced LVEF less than 45%, but with withdrawal or dose adjustment of the medication that change in LVEF did recover. So there is significant hope that with longer term follow-up we will see positive changes in both symptoms and exercise capacity for folks with non-obstructive HCM with cardiac myosin inhibitor treatment as well. In fact, there are two trials underway. The first being Odyssey HCM for Mavicampton and the second being Acacia HCM for Aficampton which hopefully will help us to better identify those long-term outcomes for HCM patients without an obstruction. So in summary, with respect to cardiac myosin inhibitors, right now we know that the patients that are gonna potentially benefit from CMIs do have obstructive HCM, more to come on non-obstructive HCM from trials in the future. We have parameters here that were for study inclusion, although some patients may benefit with a lower LVOT obstruction than 50. Additionally, you want them to have a normal to hyperdynamic LVEF because of course the cardiac myosin inhibitors are reducing contractility. We don't wanna drop the patient's EF below that 50% mark. And then they are gonna need to be symptomatic in order to benefit from this therapy as far as our current data shows. I think as we continue to look at the potential for positive remodeling, we may see that we get even better outcomes for these patients, even potentially those who don't have symptoms, but those studies have yet to be done. I think it's important before you start a cardiac myosin inhibitor to consider a few things. Number one, does your patient have significant structural valve disease like mitral regurgitation, which is not all due to SAM? If that's the case, then they may actually require an intervention on the mitral valve in order to actually feel better and avoid other bad outcomes of severe MR. Additionally, patients with severe coronary artery disease were not included in the initial trials. And so in those cases for symptomatic patients, I would consider other options first. It's important to note that currently Mavicampton, which is commercially available, comes through a specialty pharmacy and requires a REMS program with the FDA in order to monitor ejection fraction closely after delivery of the medication. There are also several medication interactions through CYP enzymes, which may require dose adjustment. Importantly, you can have patients on beta blockers or calcium channel blockers and Mavicampton simultaneously. However, there is some interaction for some calcium channel blockers with CYP enzymes. And a recent retrospective analysis of the Odyssey data did show that patients on beta blockers with Mavicampton did just, you know, they did have an improvement in their VO2, but there was much more chronotropic incompetence in patients who were on a beta blocker. And so it may be that your HCM patient that you're treating with a beta blocker currently, who has some limitation in their chronotropic competence, could actually benefit from Mavicampton without so much beta blocker on board. Lastly, many patients are actually slow metabolizers, which means that Mavicampton dose is slower and there's really good guidance from the manufacturer on how to dose this medication in combination with that REMS program long-term, but it can stay around for quite a while. If you are thinking about starting a CMI for your patients, but aren't quite sure where to start or don't have the resources necessary to to be able to go through the REMS program and contact specialty pharmacies, etc. There are many HCM centers around the country who have developed commercial CMI programs, and certainly there are ongoing trials at those centers as well. So with that, I'm just going to move briefly onto gene and gene editing therapies. These are on the horizon. Certainly there are some that are in trials, one at least progressing to trials for HCM specifically, and I think it's an outstanding question whether these therapies, either gene replacement, which we'll talk about in a moment, or actually editing the sequence of the genome, which is a little farther away for the heart, are going to be able to be employed for folks who either have not yet developed symptoms of overt HCM or other cardiomyopathies, or even those who have inherited a sarcomeric variant but have not yet had exposure to environmental modifiers. So we know that this actually can work. For a long time, it was really difficult for us to find a safe way to deliver a gene therapy to the heart. Now what I mean by gene therapy in this case is that you've got a construct here, which is made of DNA, which encodes the RNA, which will make the protein that you're missing. So in this example, this was a trial to replace the LAMP2 gene for Dannen disease in the heart. As you know, Dannen disease causes a really tough-to-treat glycogen storage cardiomyopathy, which is actually an HCM mimicker. So you can deliver that DNA payload using an adeno-associated virus, or AAV, pictured here in purple. A specific serotype, in this case 9, will have a tissue specificity for the heart. So this has been done, and it was quite successful in a phase one first-in-human trial. But many questions, I think, remain about how we're going to implement this for HCM and other diseases that are more common for Dannen. For example, in HCM, one of the trials that has been proposed is for myosin-binding protein C truncating variants, which means that not enough of that protein is being produced, meaning that now more myosin can engage with the actin cytoskeleton, which is more ores in the water. The idea here is that you can give back a good copy of MYBPC3 using that adeno-associated virus, and by replacing that broken copy with a good copy, you can then restore the heart to normal contractility. But there are a few considerations here, I think, before we can safely move forward. The first one here in the top purple box is that not all genes that have variants that can cause disease in the heart are going to be treatable by replacing a bad copy with a good copy. There are some that the bad copy actually causes disease just by being present rather than being the absence of what's needed in the heart. So we have a lot to do to figure out how to treat those diseases that are not due to what's called a loss of function. Delivery, as I mentioned, using adeno-associated viruses comes with some risk because they're very immunogenic, meaning that if you have to give high doses in order to get enough of that virus to the heart, the body is going to react to that virus, develop antibodies and cellular-mediated immunity to it, and you won't be able to necessarily redose that virus again. There are also reports, one was recently published in the New England Journal, that high doses of these AAVs can lead to significant inflammatory syndromes, unfortunately in that case with a skeletal myopathy resulting in a patient death. So we have to be very cognizant about the risks of that immune activation and look for ways to get around using, I think, highly immunogenic viruses. One might be lipid nanoparticles. Right now, these go mostly to the liver, but targeting those to the heart is something that's under really a lot of research and ongoing development. And then using other viruses that are not so immunogenic is another method that folks are using to try to get around that immune system in order to deliver those gene copies to the myocardium. And then lastly, we need to do more work to better understand how we can target a large enough population of patients with genetic cardiomyopathies and also the right patients. Who needs this therapy in order to live a long and happy life versus who would be okay with standard therapy and actually live a long and happy life without a certain exposure to our current immunogenic methods. So with that, the take-home points that I would like to summarize for new kids on the block are that CMIs are effective and precision therapy for obstructive HCM, that longer-term phase 3 trials are required for CMIs for non-obstructive HCM and are underway. Prescribing CMIs, cardiac myosin inhibitors, is not always easy, but the patient benefit is clear and there are several, in fact, many HCM centers out there to help you through that process. Emerging therapies for genetic cardiomyopathy will include gene replacement, as I mentioned to you, as well as potentially direct genome editing in the future, and that immune reactivity, delivery, and patient selection remain critical areas of need in order to deploy those for patients with genetic cardiomyopathies. So with that, I'm going to stop and go ahead, and I think we can transition to our, we'll circle back to our initial questions, and then I think we'll move to our discussion, if that's correct. So this, again, is a repeat of the initial question about the genetics of this 45-year-old woman. Options would be to send panel gene testing on her, send panel gene testing on her children, or to reach out to her brother, who we know is affected with HCM, and offer him a panel genetic test. And I'll remind you, this patient does not have evidence of HCM on her clinical workup. Okay, so it looks like we've settled out at about 25% of folks thinking we should send the panel gene testing on the patient, and about 75% thinking that we should send the panel on her brother. I think since Charlene isn't here, I'll go over the right answer for everyone, and that is that we're actually not going to send the panel on this patient, because she does not have any clinical signs of HCM right now. So if we send the panel on her and it's negative, then we may have missed an opportunity to actually identify the cause of disease in this family. So sending that panel on a person in the family who is clearly affected with HCM will allow us to know whether there is a variant that we can use for predictive testing in this family. Great, let's see, I think we should move on to the next question. Yeah, and then one thing that's important to keep in mind is that as the initial patient's physician, you cannot directly reach out to her family members because of privacy protections. And so we rely on our patients being the messengers to their family to explain that a potentially genetic condition is present and to convey what their relative's risk may be and what to do. And in this situation, to try to get a genetic diagnosis on the family, like Dr. Briggs said, we have to go to the person that has HCM, and we're relying on our patient communicating with her brother and trying to make that happen. And then for the next polling question, again, the major goals of medical therapy for HCM, so these are all things that we would like to do, but what is actually available and feasible now? All right, so it looks like we have settled out with the majority of respondents saying to improve symptoms, and some saying to reduce the risk of sudden death, and a small proportion saying to reduce the risk of heart failure or hospitalization. And so for medical therapy, again, right now, it's focused on trying to attenuate and improve symptom burden. That goes for kind of trying to improve standard therapy with beta blockers, calcium channel blockers, and disipiramide, as well as our newer therapies with cardiac myosin inhibitors. So those therapies are really driven to try to improve symptoms, and most effectively with the CMIs. We would like to be able to modify disease and reduce left ventricular hypertrophy, but we're not there yet. There might be some slight remodeling benefit with the CMIs, perhaps by reducing some of the pressure load with ameliorating obstruction, but a lot of it is just baked in as a result of the underlying intrinsic cardiomyopathy. And we haven't yet been able to show that there's impact on either atrial fibrillation or heart failure hospitalization. So hopefully, if there's left atrial remodeling, because of improving load in the heart, atrial fibrillation may be improved, but that hasn't yet been shown. And heart failure hospitalization is something that's tricky to study in HCM, because most of our patients don't have a lot of heart failure hospitalization. So that, as an endpoint, is something that's hard to study. Reducing risk of sudden death, again, we don't have any medical therapies that can reduce the risk. Beta blockers have not been shown to have meaningful impact in terms of reducing risk, neither do other antiarrhythmics. And so it's really just trying to assess risk and then provide primary prevention ICDs. Great. And then we'll go on to the last question. Okay, great. So I think these cases were a bit long to read through, so we'll give everyone a couple seconds here. But the major point of this question was to make sure that everybody understands the current indications and contraindications for cardiac myosin inhibitor use. And it looks like we've got, looks like we're changing rapidly. We'll give it another few seconds here. All right. So we have basically an 89-year-old woman who is somewhat symptomatic, who has a little bit of wall thickness at 1.3 centimeters, somewhat of an LVOT obstruction, but also bilevelet mitral prolapse with at least moderate, potentially moderate, severe MR. So that would be structural mitral disease there, which is leading to MR and could be contributing to her symptoms. We have a 54-year-old man with NYHA3, but no obstruction at rest or with Valsalva. We have a 46-year-old woman with NYHA2 symptoms, septum of 1.7, LVOT gradient of 55, and a hyperdynamic LV with MR due to SAM. And then we have a 75-year-old man who has NYHA2 symptoms, an LVOT gradient of 35, and an EF of 45%. So the patient that would be most likely to benefit from CMI here, it looks like about 64% picked this 46-year-old woman who definitely has symptomatic obstructive HCM without mitral disease and without a reduced LV ejection fraction. So that's definitely the learning point here, is that you want to think about structural mitral disease before moving to CMI, as well as making sure that your patient, if they are obstructive, have not yet dropped their EF. And then lastly, we want to make sure at this point that the patient is obstructive, although there's ongoing data that hopefully in the long run will show some benefit for a non-obstructive HCM. All right, great. And so we have a couple of questions in the chat. We'll move on to Dr. Stephenson's talk at 7, so we have a few minutes to address some of the chat questions. My chat just disappeared. Okay, so there are a couple questions about CMI. So maybe, Vicky, we can direct these at you in terms of titrating baseline standard meds, and then potentially, what do you think about the use of CMI for aortic stenosis? Yeah, thank you. I think the first question, I'll just talk about the aortic stenosis one. If it's purely aortic stenosis, if you've got a good aortic gradient, you can see on ECHO is different from the LVOT gradient, then I absolutely would not use a CMI for that, because you're going to end up reducing contractility, and you're going to be contractility dependent with a fixed obstruction. Of course, there are times when it's hard to tell the difference between AS and an LVOT obstruction, depending on your stenographer. And so what I would say is that if you at all see aortic valve disease on that ECHO, make sure you rule out aortic stenosis as a contributor so that you can treat both adequately before starting a CMI. And then the approach to titrating the patient's baseline HCM medications. So as Dr. Donovan pointed out, we wouldn't want to co-start with disopiramide and CCBs. That would be problematic. But you can start with the dose that they're currently on for beta blockers or for calcium channel blockers, unless there's an interaction, I think with verapamil. So with beta blocker, I generally don't change the dose to start when I start the Mavicamton, and then I titrate down depending on their chronotropic competence. I'd be curious to hear how Dr. Ho is handling that in her practice as well. And then same thing with CCBs, although I think that I'm a little bit more aggressive at moving those off, just if there's a drug interaction, because we want to make sure that the Mavicamton is not overdoing it. Right, yeah, that sounds good. So why don't we move along to hear Dr. Lindstein and talk about what happens when the usual is not enough. Thank you. I've really enjoyed and learned a lot from Dr. Ho, Dr. Day, and Dr. Parikh, and I'm sure all of you have as well, about the basics and some of the really important nuances here. I'm going to begin, I believe, with the polling questions. And I can't see the percent participation here, but I think we'll move on to the second question, which relates to heart transplant and LVADs, which are rarely an issue, but for patients who need them can be very important. I think we're ready to move on from that one. And now if we can share my slides. I'm controlling the screen too. I don't seem to have control of this at the moment. Okay, we need to go back up to the top here. There we are, okay. All right, and I have no financial conflicts. I'm an unpaid consultant for Bristol-Myers Squibb and cytokinetics and for Abbott Laboratories and Endotronics. So what I'd like to do is to really focus on hypertrophic cardiomyopathy when the ejection fraction is reduced, the prevalence and prognosis of this, and then to look beyond the EF to consider the hemodynamic profile, which determines how we address these patients and also how they do, including personalized guideline-directed medical therapy, and then the occasional indications for heart transplant and a limited option of LVAD support. First of all, when you think the ejection fraction is low, the first thing is to double-check the ejection fraction. This is also true for other causes of heart fear with reduced ejection fraction. First of all, there are common rhythm effects. You can get tachymyopathy from atrial fibrillation. You can sometimes get that also from frequent PVCs. And patients who present with a cardiac arrest may have an acute reversible depression of their LVEF, which will recover within like the next 48 to 72 hours. So make sure you check and find out that they really do have a low ejection fraction. Other causes of a reversible low ejection fraction in patients with and without HCM, severe systolic hypertension, severe systemic illness, we are commonly called to an intensive care unit for someone who previously had a high ejection fraction, now which is slightly reduced in the setting of sepsis or ARDS. And there are other potentially reversible factors like thyroid disease, illicit substance use, and my least favorite is what I call hypertrophic cardiomyopathy in patients who use methamphetamines and can also happen with testosterone use. And I'm still trying to switch the slides here. So when we talk about ejection fraction in the mid-range, 40 to 50 hypertrophic cardiomyopathy can decrease to this, which is a major concern, but there are also many other causes of this. So particularly when a patient presents without a prior diagnosis of HCM, you need to make sure that what you're looking is actually HCM and not one of these other diseases. And I think particularly confusing aortic stenosis and amyloidosis are particularly confusing. And why is that important? Well, there's currently a trend which I'm pretty much against. So this idea of that, once you've defined the mid-range ejection fraction here that you know how to treat it. Guidelines suggest that when the EF's between 40 and 50, that potential therapies to use diuretics, SGLT2 inhibitors, ACE, ARB, and ARNI, also looking at MRA and evidence-based beta blocker. This is not really the case because there's so many different etiologies. You need to make sure you're treating the etiology and not treating the ejection fraction. Sorry, I'm still having difficulty. Okay, just talking a little bit about the progression of left ventricular ejection fraction. And this is a very nice study that was done by colleagues in Italy, looking at the relative frequency, what we call adverse remodeling where the ejection fraction falls below 65% is kind of this mid-range, the ventricles started to dilate some, may occur in about 15% of people and only about five to 10% of people actually develop overt dysfunction with the ejection fraction less than 50%. I think it matters what you call it or everything that we take care of in order to take care of it well. This has been called burned out and we kind of liked for a while calling it BOCUM just because it's so much fun to say. It's also called end stage, but in fact, neither of these are really appropriate because the outcome is not always bad for patients with hypertrophic cardiomyopathy in EF less than 50. If we look at two major studies, the largest study is from the SHARE Registry in which Dr. Day and Dr. Ho participated looking at almost 7,000 patients and 3% of them had an EF lower than 50 at the time they came in, another 5% developed it. And you can see that by about five years, 35% had an outcome that was death transplant or VAD by five years. Very similar data from a smaller study done by Rowan and his colleagues, about 35% during a median of 5.8 years. And in their study about half progressed to disabling class three and four symptoms. From the SHARE Registry again, we have information about risk factors. Patients who have atrial fibrillation at the time their EF is 50 have a much worse outcome as shown here in the bottom in the red line. If we look at genetics, there is clearly an impact, but not nearly as large. And it doesn't seem to diverge until you get to about five years out from the initial diagnosis to where you have worse outcomes with the sarcomeric gene being present, abnormalities being present. Not surprisingly, the level of ejection fraction matters. If you start out with an EF less than 35, you have a much worse outcome as shown down here in the last graph in the red line. We'll talk about that more in a moment. So what we'd like to think about this instead of calling it burned out or end stage is to just call it HCM with reduced ejection fraction. Now let's talk about how we're going to approach this. This is where we want to focus beyond the EF and look at the hemodynamic profile for these patients who have an EF less than 50. First of all, we learned a lot from the classic hemodynamic profiles for heart failure with reduced ejection fraction, which generally has a different sort of physiology in which the ventricle is dilated. And we know for that kind of heart failure that we can divide them up looking at whether they have congestion at rest and whether they have low perfusion at rest. And a lot of what we know really comes from this dilated physiology. And some patients with HCM and reduced ejection fraction develop this physiology where the ventricle does dilate. And this is very important. I'm sorry, I know it's the end of the day, but we're going to talk a little arithmetic. This is pretty simple arithmetic, and it's very important when you try to evaluate what to do with your patient with hypertrophic cardiomyopathy and a decreased ejection fraction. With dilated cardiomyopathy, when we look at a patient who has an ejection fraction of a third of normal, as you can see here from this picture of an explanted heart, of dilated cardiomyopathy, the ventricles get very large. If they're three to four times normal size, then you can have a normal stroke volume, even though the ejection fraction is only 20%. That of course depends on how much is going forward because mitral regurgitation can take up to about three quarters of total stroke volume. But now let's talk about the more restricted arithmetic, of a cardiac output for restrictive disease. Well, you can increase the heart rate, but that's unfavorable for many reasons. And now if you talk about a heart that's not dilated, and we have an ejection fraction of a third of normal, and the LV is not dilated, now we're going to have a stroke volume that's much less than normal. And we may be subtracting even more with mitral regurgitation. And this is a restrictive physiology in which the cardiac output becomes low, even when the ejection fraction is not severely reduced because the LV end-diastolic volume is not increased. So when we look at our patients, we want to decide is this an HCM rep with a dilated physiology, in which case we can treat them sort of like regular heart failure with reduced ejection fraction. Or is this one with a restrictive physiology in which we have to worry a lot about making sure that there's adequate filling, and they will much earlier progress to a low cardiac output. So now let's talk a little bit just to remind you what guideline-directed medical therapy is for regular heart failure with reduced ejection fraction, most of which is dilated. We say in patients who have fluid retention, diuretics are recommended to relieve congestion, which is true regardless of your etiology. But when we move beyond that, I want to show you on the left, this is the typical biopsy from dilated cardiomyopathy compared to on the right with hypertrophic cardiomyopathy, it's not necessarily clear but we respond the same to the other therapies that we use for heart failure with reduced ejection fraction. So this is, I think, a suggested approach to hypertrophic cardiomyopathy with reduced ejection fraction under 50. First of all, you're going to stop the myosin inhibitors. In most cases, you're going to stop the calcium channel blockers. Even patients who previously had obstruction, very few are going to have obstruction by the time their EF is less than 50. So you can stop that agent. Now, is there evidence of fluid retention? Yes or no. You're suspected if there's very rapid dyspnea on exertion, orthopnea, peripheral edema, elevated jugular venous pressures, and you're going to treat that. Remember, since they don't in general have obstruction now, it's not as scary to treat them with diuretics because you're less concerned, you're not going to aggravate a gradient. So you treat them with diuretics to optovolemia, then maintain them. And you can consider adding an SGLT inhibitor also. Some effects of which are to cause diuresis and prevent fluid retention. So you want to treat them until you don't think they have elevated filling pressures anymore. You also want to consider an ICD in this patient. We've heard about that for patients with the non-deteriorated EF. But we know in these patients whose EF has declined, in fact, about 20 to 25% of them will have appropriate ICD therapies or an arrest without an ICD. Once the EF is less than 50, this can occur even when the EF is still above 35. So in this group, we're strongly going to consider an ICD prophylactically. A small number of patients will actually have a left bundle branch block. And we will also consider CRT with the ICD if the left bundle branch is present. There's been a variable response to this, but we have all seen some patients increase their ejection fraction back to over 50% who had a clear classic left bundle branch block. Okay, now I mentioned to you about the outcome of patients who have an EF less than 35. The event rate is very high in that group. So as soon as the EF is at that level, we would be anticipating that we may need to triage them for transplant at that point, particularly if they have class three or four symptoms. So I'm going to focus now on the EF between 35 and 50 in whom we need to personalize the GDMT once we've separated out the people that we think are at highest risk of going on to end-stage therapies. So what we're going to want to do in this group is look at that physiologic phenotype like we were talking. If we look at the shared data, for instance, when the EF was less than 50, the average LV dimension was still only 50. So many of these patients are going to have restrictive physiology. So we won't be able to be looking at the usual guideline directed medical therapy. But if we look at those who have more of a dilated physiology, we'll be looking a little more comfortably at the other GDMT. Now, how about beta blockers? Many of the patients are already going to have been on them from the time when their EF was better than this. I think you can continue or initiate cautiously if the blood pressure and estimated cardiac output are still sturdy. But these are not necessarily going to be tolerated in patients with restrictive physiology who need their heart rate and need the inotropy in order to get what cardiac output they can. So that's for beta blockers. Now, how about renin-angiotensin system antagonists? If we look at renin-angiotensin system antagonists, there is often some negative inotropy in patients who are dependent on their data, but it's better tolerated than beta blockers. And blood pressure tolerability is better with ARBs than ACE inhibitors, which is better than with ARNs. So we would say you will treat for hypertension and you will treat as guideline-directed medical therapy for low EF in patients who have a physiology that allows you to do this as tolerated by their blood pressure and renal function. Mineralocorticoid antagonists are usually well tolerated. I'm sorry, I think that noise is at my end. And I just want to remind you very briefly that Secubitril-Valcertin is not just a new improved ARB. It has a lot of effects which could get you into trouble in this group. The acute hemodynamic effects are probably due mostly to increasing levels of the natriuretic peptides, ANP, BNP, which are vasodilatory and natriuretic, which may or may not be what you need. There are other effects that we worry about. Endothelin has been shown to be elevated in some patients with HCM. So using Secubitril could in fact elevate it further. So there are multiple concerns. It's not at all clear that we would necessarily be using this very often in the patients with HCM and low EF. And I would just remind you at this point, Secubitril-Valcertin, the ARNI, is not recommended anymore for class four heart failure, but it is the first choice for normal HF-REF in patients with class two and three. So let's suppose we now end up going on to heart transplantation for hypertrophic cardiomyopathy. Now this occasionally is necessary in people who do not have evidence of a reduced ejection fraction. In general, those are patients who have a very severe restrictive physiology in which the EF in fact is sometimes kind of hard to measure because the chamber is so small. But most of the people who have transplant for HCM do fall in this group in which the ejection fraction is reduced. If we compare it to people with non-ischemic cardiomyopathy or ischemic heart failure, the HCM patients are younger, of course, because they have younger onset of disease. Many of them are on IV inotropes at the time of listing due to a low output state. And what's particularly concerning, if you look at the death weighting on the list, it's higher in HCM than it is for the other diseases, partly because these are often otherwise healthy looking patients and we miss how sick they're getting. So it's important to watch these patients very closely so you don't miss when they begin to tip and need a therapy like heart transplantation. Because if you miss it, we often don't have the rescue of an LVAD because they have restrictive physiology. Often they don't have room for a LVAD. So if you look at this data on heart transplants, you can see only 4% of hypertrophs who went on to transplant had an LVAD compared to 25% of other cardiomyopathy and 27% of ischemic heart failure. But what's really important to recognize, they do really well if they get to transplant. You can see this green line on the top here shows a much better survival than the other patients going on to transplant, which is primarily due to the fact that they're so young and don't have much other organ system dysfunction at the time they go to transplant. And the next slide just shows you the issue with LVADs in these patients. In fact, hypertrophic cardiomyopathy is often grouped with restrictive cardiomyopathies when considering transplant and LVAD. So if we look at the HCM patients over here on the right, you can see, as I said, about 4% received LVADs and they had a larger left ventricular end diastolic dimension than most of the other HCM. But if you look down at the bottom in the blue bars, you see they had higher rates of infection, stroke, arrhythmia, renal failure, bleeding, RV failure, and death after LVADs, which explains the lack of enthusiasm for using that as a bridge to transplant. And that's compared to the 18% of people with other causes of heart failure leading to transplant who did much better. So because recognizing that the HCM patients do not do well on the transplant list, they actually get a little bit of advantage on the allocation system. You can see here that patients with hypertrophic or restrictive cardiomyopathy, such as amyloidosis, are at status four as compared to status six, where our other cardiomyopathy and heart failure patients are, unless they have one of these other high-risk support features. So just to conclude, when we look at progression of HCM beyond usual therapy, it matters what you call it. And I think we don't want to call it end stage or burned out, which is really, I think, slightly more distressing to the patient than we want to be. On the other hand, it really should alert us to follow these patients very closely. We want to look beyond the ejection fraction to look at that arithmetic of cardiac output. There's the dilated physiology, which is more like garden variety heart failure with reduced ejection fraction in which we consider our guideline-directed therapies versus that restrictive group in whom we want to make sure that they have their optimal fluid status and we want to avoid agents that can decrease their heart rate or their inotropy. So we need to personalize the therapies, occasionally indication for transplant, limited outcomes with our current LVAD support as a bridge. So thank you very much. And I look forward to those polling questions. And then we're going to have a very interesting case discussion from Dr. Ayers. Great, and I think for the sake of time, let's go directly to Dr. Ayers. All right, so at this point, just to recap, because I know we're nearing the end, we walked through how you diagnose HCM. We talked about non-obstructive versus obstructive phenotypes. We mentioned that even though this is the paradigm of genetic cardiomyopathies, we only know the gene about 40% of the time. We went through the usual approach for obstruction with negative inotropic therapy. And then we pivoted from there to talking about cardiac myosin inhibitors and even some exciting things in the future like genetic alterations. Finally, Dr. Stevenson gave us that tour de force of how to begin to think about subtyping our HCM patients with reduced ejection fraction and how to use the subtyping to talk about management. So for time's sake, what I'm gonna do as I go through these is rather than open all of these moments of decision-making up for discussion, I'm gonna try and highlight my thought process and then I wanna invite any of our other panelists to hop in if there's something that you think is pertinent to add for the discussion. So with that said, I am now controlling, okay. I am Mike Ayers and I'm at the University of Virginia at our Center of Excellence here for HCM. And we're really gonna recap some of the risks associated with HCM reduced EF as well as some of the other topics that we discussed that I just highlighted. And then we're gonna try and go through that treatment algorithm that Dr. Stevenson so eloquently presented to us. Okay. So we'll start with the history. This was a gentleman who saw me in 2020. He was a 48-year-old black man at the time. He'd smoked for about 25 years. Had some hypertension, hyperlipidemia, obstructive sleep apnea, and depression. And he was actually coming in for an HCM eval. And truth be known, he was referred to the general clinic, but my very savvy nurse picked him out when she saw his echo. This is a typical story for our patients. He was told his hypertension in his 20s was what was driving his thick heart. And now in fairness, he had a good deal of hypertension. He was up to the 170s, the 150s. Responded very nicely to treatment, but he'd been told all his life, you just have high blood pressure. Give me, there's a slight delay with the click. In 2018, before seeing me, he actually went to our hospital and was complaining about some shortness of breath that had progressed over the last several months. I'm having a pretty significant delay, so I'm going to ask whoever the HFSA staff is. I'm just going to kind of give you one of these and we'll click through. Okay. All right. So when he presented, he was hypertensive on arrival, though it quickly came down and he had a slightly elevated troponin. Here was his presenting EKG. Taking a step back, what we see is normal sinus rhythm with a good deal of hypertrophy, but I want you to note the T-wave inversions in the lateral leads. And I want you to note that there are two PVCs there, one of which interpolates, one which doesn't. And I also want to point out that there is some fractionation of some of the QRS complexes, particularly in the lateral leads. You can advance. There's the T-wave inversion, and there's our fractionation, which also exists in some of the lateral leads there. Here was his echo. What I want to point out is on the parasternal long axis image, which has stopped playing for us, what you'll notice is there is a pretty thick septum, and it is disproportionate to the infralateral segment, though the infralateral segment's also quite thick. And then looking over at our apical images, there's also a little bit of right ventricular hypertrophy. And when you watch this play a few times, he was bradycardic, but you get a sense that there was a reduced ejection fraction. And so the read on this was he had asymmetric septal hypertrophy of 2.1 centimeters with a reduced ejection fraction and no outflow tract obstruction. So he's in our non-obstructive bucket. And he had a left heart cath. And the reason he had a left heart cath is he had those T-wave inversions in the lateral leads, had a small positive troponin. He was young, and that landed him in the cath lab. And without surprise, he was non-obstructive. So back to our HPI. When we travel back in time and look at this gentleman, what we actually note in the discharge summary is he was labeled as hypertensive cardiomyopathy, despite having a 2.1 centimeter septum. Now I was going to pause here to talk to some of our other experts, but for me, severe hypertension will buy you 1.6. It'll buy you 1.8. But you start getting above 2 centimeters. Above 2 centimeters, I have a lot of difficulty saying that this is hypertensive cardiomyopathy. This was at my own center. And I just want to point out for HCM patients, on average, there's about a four-year delay from their first point of contact with cardiology before getting diagnosed. Not because people are missing it, because this is a difficult diagnosis to make. He was sent out on two blood pressure medicines, and then he was kind of lost to follow up for two years. So when he came to my clinic, he had had a couple of months of progression, progressive shortness of breath, was down to about three blocks. And he had a little bit of the girlfriend sign in the back of the room where she was kind of giving me the less than three blocks look. He did not have any syncope, did not have any chest pain. And when you gave him a pretty good family history with our genetic counselor, there was no red flags there with HCM or sudden death in his family. He was mildly hypertensive on my exam. He was heart rate of 60 there, not on a beta blocker. And further exam showed he didn't have much lower extremity edema. He was warm. He was mentating. His JVP was maybe slightly elevated. He did not have an S3 for me. He did have a nice decrescendo diastolic murmur. I forgot to mention he had some mild AI on the previous picture. I'll also mention, you can leave it on this slide, but I'll also mention despite really aggressive provocative maneuvers on this gentleman, I could not get any holostatic murmur that sounded like obstruction. Squatting to stand, really getting him to move around. So we ordered a stress echo on this gentleman as part of our initial workup. And his EF stayed 40. And I'm not going to show you a stress picture. You're just going to have to believe me that even with a pretty good amount of effort, he did not have any outflow tract obstruction. And when I say RC, by the way, right there, that's reverse curvature. That's just something we like to comment on when we see that nice parenthetical parentheses shaped septum that really tends to be seen more in people with earlier onset disease. On his stress, he didn't have any arrhythmias. He had a normal blood pressure response, noting that a drop in blood pressure is associated with heart failure. And his heart rate only peaked out at about 119. He gave a pretty good effort for us. He had a change in his VE, VO2 slope, which just a way of saying he'd entered some anaerobic metabolism and was trying on this stress test. But his VO2 max came out at 57% predicted for age and gender. So that girlfriend that was signaling in the back of the room was probably telling the truth. Interestingly, his oxygen pulse, which is a stand-in for stroke volume, it's VO2 divided by heart rate to give us an idea how much oxygen's being delivered per beat. It was better than his VO2, giving you some sense that there's both a chronotropy problem here and a pump problem. We won't dive into this too much, but these are both markers of ventilatory efficiency, and they're also negative prognosticators in HCM. I don't want to dive into it for time's sake, but taking a step back, I just want to mention the stress echo when you add the VO2 component gives you a lot more prognostic information. And so even though we're not going to discuss these at length, he did have some favorable prognosticators in addition to less favorable prognosticators on this test. So we got a cardiac MRI. I apologize, it's a little dark on my screen, but the picture on the left shows the asymmetric septal hypertrophy. There's a little bit of regionality in the lateral wall and a few other segments. And when you look, he was dilated, and his late gadolinium enhancement actually came out at 20%. And I had them run that twice because I was worried we were over counting, but there were areas of very dense scar on this gentleman. So in recap, here's the testing we did for him on first pass. We got the stress echo, which didn't show any obstruction, but showed severely reduced VO2. We got the cardiac MRI that confirmed a diagnosis of HCM for us. We got rid of the sarcoid, the hemochromatosis, the amyloid, the other mimics. This looked like HCM and showed some dense scarring. We put a 30-day monitor on him before bringing him back, and he had five beats of non-sustained ventricular tachycardia, which is right on the cusp of being fast enough to be concerning. It's right on the line for me. Long enough, excuse me, long enough to be concerning. It certainly was fast enough. And his genetic testing came back negative, and I wanted to pause here just to point out Dr. Day showed us a couple different septal types, and those septal types, whether it's the reverse curvature or just the isolated septum, actually predict whether or not the genotype is going to be positive or not. And when we see that reverse curvature, like this gentleman has, we're thinking 90% plus. I wanted to use this moment to not only highlight that, but also to highlight in our patients of African ancestry and Middle Eastern ancestry, we don't do a great job identifying all of these genes yet, just because of the populations we're basing our findings on. And when you plugged him into the ESC HCM calculator that was mentioned when we were thinking about his sudden death, his score came back at 4.5. So what did I do? I sent him to our smoking cessation counselor. I'm not doing this in order of importance, but that was something we did. Another interesting point that I'll just leave for you to think about, he was in a divorce with his wife, very sounds like a non-pleasant divorce, as if there's another kind. And when I asked, can I help you screen the son? He was worried that the wife was going to be mad at him that he maybe had given this to the son. And so I just want to point out, these are really sticky situations for us in clinics sometimes. Do you reach out to the wife directly? I mean, you mentioned, Dr. Ho mentioned, that's not normally what we do. It just puts you in a tough situation. Another sticky situation that I was going to bring up, he had a commercial driver's license. If he got an ICD, he lost his job. He didn't have a college education. He'd been doing this his whole life. Getting an ICD was that important to him, not getting an ICD. So what do you do in those situations? I did stop his Losartan and HCTZ. And then when I started, and it's really started and titrated, this wasn't all at once, was this group of medicines, which I think even Dr. Stevenson might give me a thumbs up for. That's a pretty good heart failure regimen for this gentleman. Now, where did I get that workup from? Let's pivot to the guidelines, which Dr. Stevenson mentioned. When you've got no outflow tract obstruction, your first question is, what's the systolic function? If that's reduced, your order of operations is, think about the heart failure therapies. And you're going to use some of the decision making Dr. Stevenson mentioned to pick which one. Make sure you have the right diagnosis with things like CMR. And think about a defibrillator. And why are we thinking about a defibrillator on this gentleman? Well, to recap, he has a reduced ejection fraction. He had non-sustained ventricular tachycardia. He has dense scar. The European Risk Score says put a defibrillator on him. This isn't one of those equivocal cases. He clearly meets criteria. So he wanted to think about it. And he thought about it for a year and a half and canceled a few appointments in the interim before coming back. And when he came back, he was down to about half a block. And at this point in time, this guy's really making me nervous. These are those patients we lose sleep about. Here's his EKG on follow-up, which I want to point out has smaller volts than prior. And the QRS has now widened out to 150. And I want to mention that because you usually could have skated through this EKG. But when I start seeing voltage shrinking, fractionation of QRS complexes, QRS getting wider, my spidey sense is tingling, so to speak, that something is really going on in the myocardial level. There's that QRS. So his LVEF was roughly unchanged. His thickness was unchanged. His cavity size was unchanged. But he had developed dense, dense scar. It actually came out to 50%. So I reran it in clinic and it was 50%. And the reason it's 50%, which is one of the highest I've ever seen, is because when you looked at it in short axis, there were areas of transmural scar. To the point that after this, I actually got a CT. And the CT showed he didn't have an infarct. I was worried I'd miss something else. So now what on this guy? Well, this is a reiteration of what Dr. Stevenson said, but I'm worried because low EF is bad. And lower EF is worse. As a reminder, this is only 2 to 4% of our patients. But when you see this, it's really something you can't miss. So next steps. Well, back to this. I think we've done a good job getting him on guideline therapy. We evaluated for other causes. And at this visit, he started to tell me he's considering this defibrillator. So after you've done those four things, what our guideline does is it actually pivots to this algorithm that says, let's reevaluate. Well, I would call him NYHA 3 now. I really think he was down to about half a block. And what I would ask my EP colleagues is, this wasn't a classic left bundle. It's left bundle Lloyd. It's 150. Is a CRT reasonable? I'm starting to call for help. And what I'm really asking in my mind is, after a year and a half of aggressive therapy, progressive symptoms, myocardium that's screaming out, it's not doing well. Is it time to bring in one of my transplant colleagues? So at this visit, he'd quit his truck driving job. And I think he did it because he wanted the defibrillator. He was still smoking, but can't win them all. His VO2 was actually stable for me. But I'm still sitting back in this clinic visit going, this is not going in the right direction. So I sent him to heart failure. He finally agreed to a procedure. And we're going to get a right heart cath. I think he actually got it today, quite honestly. I sent him to EP to talk about both the CRT component and the defibrillator component. And we re-sent him to engage with our smoking cessation counselors. So in summary, this is an under-recognized entity. It's easy to see 48% and skate right through it. Even though it's two to 4% of our patients, you can't miss this because this is the direction some of those cases can go. Management's going to include subtyping based on phenotype, like Dr. Stevenson mentioned. Picking medications accordingly. Using CRT when appropriate. Stopping your negative inotropes. And really making sure this isn't a different diagnosis. So I hope that hit some of the things that we talked about in the other cases. I tried to pop them through as we went along. We probably have a few minutes still to have some discussion. Apologies if the tempo was fast for you guys, but I know we're getting near dinner time. And with that, I'll open it up to my panel. So Lynn, this dovetails really nicely with your presentation, which was a spectacular way to help us think about how to subset these patients and really think about the physiology and how that might drive their care. So any initial thoughts? No, I thought that Michael did a wonderful job. This is a great case and I think we all learned a lot from it. I think the one thing that I might have done differently is been very, very insistent that he stopped smoking because in our program, he can't get a transplant until he's been off for six months. And he's not going to be a good candidate for an LVAD in the meantime. So it's, sometimes it seemed like as you started out with sort of a housekeeping issue, but for him, it could make the difference between life and death because I don't think he has a big enough ventricle that we're going to be able to support him nicely with an LVAD. Could be wrong, but that would be scary. But I think it was a beautiful exposition of both the challenges and how we should address them. Thank you so much for that, Michael. It was such a great bringing together of all of the principles that we talked about. I think the only pearl that I've learned taking care of these very restrictive patients over time, as Dr. Stevenson pointed out, is that that VO2 max, the second that that's looking at 57%, 16, I don't necessarily wait for it to drop to the 15 magic number, because I've seen people like this guy, otherwise young and healthy with a cardiac index of 1.3, who are out there walking around with a restrictive cardiomyopathy and a VO2 max of 20, that was 22 last year, you know? And so I think that the gestalt that you pointed out of this is a sick patient is exactly how I would have approached it as well. Yeah, he was a gentleman we tried to bring back at two or three months. He was very procedure averse. And I think we scared him a little bit, despite our best efforts to do one thing at a time, but you can see it's tough. Interesting that the company who employed him didn't have any sort of annual evaluation, because obviously just from this, I would probably not have signed his certificate that he could drive a truck. I'm not sure who signed it, but it wasn't me. All right, I learned so much from everybody on this. This is really a marvelous, marvelous presentation from Dr. Ho, and Dr. Day, and Dr. Parikh. And Michael, I really enjoyed thinking through this case with you. No, this was wonderful. I'm sorry that we've run a little bit over. Thank you so much. This is an incredible star-studded panel and a great expedition of the really key things to think about with HCM. And thank you so much to all those who have tuned in. Remember, please go to the HFSA Learning Center and fill out the survey if you wish to claim CME credit. And also remember that you should have access to this presentation in the Learning Center. So with that, thank you again, everybody, and good evening.

Hypertrophic Cardiomyopathy

Genetics

Diagnosis

Treatment options

Cardiac myosin inhibitors

Left ventricular outflow tract obstruction

Gene replacement therapy

Gene editing therapy

Reduced ejection fraction

Scar tissue

Guideline-directed medical therapy

Defibrillator

Personalized management