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Michelle Kittleson, MD, PhD: Welcome to Medscape InDiscussion: Heart Failure. I'm your host, Dr Michelle Kittleson. This is the eighth episode in our 12-part series. Today we're talking about special concerns related to diagnosis and management of hypertrophic cardiomyopathy (HCM), one of the most common forms of genetic heart disease. We'll talk about everything you need to know about diagnosis, clinical manifestations, and treatment, including exciting new strategies here and on the horizon. For expert guidance on these questions, we've invited Dr Carolyn Ho. Dr Ho is the medical director of the Cardiovascular Genetics Center and associate professor of medicine at Brigham and Women's Hospital in Boston, Massachusetts. Welcome, Carolyn. We're so lucky to have you.
Carolyn Ho, MD: Thank you so much, Michelle. It's great to be with you.
Kittleson: Your academic focus has been on characterizing early phenotypes of sarcomere mutations and inherited cardiomyopathies, and developing clinical trials to diminish the progression of HCM. What was it that sparked your interest in cardiovascular genetics and HCM, and what keeps you engaged today?
Ho: I've always been fascinated by human genetics. By identifying the genetic basis of disease, we can start to study its molecular basis and get clues about how and why disease develops. If we can leverage these insights, we have remarkable opportunities to develop specific rational therapies that can truly be disease-modifying — slowing progression and then ultimately preventing the emergence of disease altogether.
Kittleson: I love it. So, you take your initial natural curiosity and you parlay it into something practical to help patients. That's the definition of a true scientist. Let's start with the diagnosis of HCM. What are the key requirements to make the diagnosis, and what are the common pitfalls you see in clinical practice?
Ho: Right now, HCM is defined by unexplained left ventricular hypertrophy (LVH). That means LVH that develops without pressure overload, which could cause hypertrophic remodeling, or LVH that develops without infiltrative/storage diseases, such as cardiac amyloidosis or Fabry disease, which could result in increased left ventricular wall thickness. The key challenge typically centers around patients on the bubble in terms of LVH — trying to decide whether there's enough hypertrophy, if 15 mm or more is the standard threshold for invoking the diagnosis of HCM, and then also trying to figure out if there are enough or not enough background medical issues to account for this if it's truly unexplained. For example, a common diagnostic challenge is patients who have some degree of hypertension and mild to moderate hypertrophy, in whom you're trying to decide if that's enough hypertension to cause that amount of LVH and also trying to differentiate HCM from hypertensive heart disease. You want to look for other features that might suggest the underlying cardiomyopathy. You might want to see if there are more marked EKG abnormalities beyond voltage criteria for LVH — dramatic repolarization abnormalities or other abnormalities in intraventricular conduction. You want to look at cardiac morphology. HCM is typically demonstrated by having asymmetric septal hypertrophy, in which the hypertrophy is focused in the intraventricular septum and leads to reversed septal curvature; that's stereotypical primary HCM.
If you have concentric hypertrophy, that's a bit more ambiguous. That can be a primary cardiomyopathy; that can be pressure overload. What is nonspecific and probably more likely to be a secondary hypertensive or hypertrophic remodeling, not primary HCM, is that discrete upper septal thickening, in which you have that upper septal bulge. This is particularly common in older patients, in whom there's some background hypertension. So, if I see just that, it kind of shifts me away from thinking about primary HCM and shifts me more toward thinking about a secondary hypertensive or hypertrophic remodeling — some other type of secondary remodeling. You also want to keep in mind that cardiomyopathy and LV outflow tract obstruction are nonspecific. They can develop with any small hypercontractile heart, suggesting that that doesn't clinch your diagnosis. You can also use multimodality imaging and see greater degrees of what things look like at a gadolinium enhancement on cardiac MRI. It can also tell you more about a primary cardiomyopathy. Then finally, you want to remember the family. You want to take a good family history that ideally spans over three generations, to see whether there's any kind of pattern of familial heart disease. Look at the mom's side of the family, the dad's side of the family, the grandparents on each side, and then also your patient's siblings and their children. Or, you shift that, depending on how old your patient is, and look for evidence of familial disease.
Kittleson: That's super-helpful, because patients can come to you for so many different reasons. They might have had a weird EKG and they're referred to a cardiologist. They might have had chest pain and shortness of breath, and they're referred to a cardiologist. They might have gotten a screening echo because a family member is diagnosed. They funnel to you in so many ways. I love how you highlight the importance of not just what an echo may show you but incorporating the family history and the other imaging parameters to help you make the diagnosis. I'm curious how many times you feel confident making the diagnosis based solely on an echocardiogram vs getting that confirmatory MRI.
Ho: Much of the time, I would say. You must think about the clinical context. Make sure that you're considering everything, see what else is going on with your patients; see if there's anything going on with their family. If you have a healthy person who doesn't have much going on and they have striking hypertrophy, then that's straightforward. But it's always the people on the edges — the slightly older person with some comorbidities and hypertrophy that's present but not that striking — in whom you really must dig deep. And it's those people about whom we may never feel fully confident and about whom you just want to keep your eyes or your mind open to different possibilities.
Kittleson: That is the theme of this podcast series. It boils down to the art of medicine. Now, when we were happy enough to have convinced ourselves that the patient has HCM based on all those important parameters, the next question generally, when you're going down your management algorithm, will be, "Is it obstructive or nonobstructive HCM?" So, tell us: What is your approach to identifying whether obstructive HCM is present?
Ho: It's important to look hard for obstruction because we have more effective treatment options for symptomatic obstruction, and you don't want to miss an opportunity to leverage these in your symptomatic patients. You must roll up your sleeves and look for it. So, on physical exam, we need to do provocative maneuvers and not just listen to the heart with the patient resting quietly but do something to try to provoke obstruction. You want to decrease preload, increase afterload, or get the heart rate up — all those things that might cause the heart to be a little bit smaller and cause the hydrodynamic features that can cause obstruction to be more prominent. My favorite maneuver is having a patient stand from squat, because I find that to be more reliable than Valsalva. It's sometimes hard to know what somebody is doing when you try to instruct them to do a Valsalva maneuver, but you can get your patient to jump off the exam table, stand in front of you, get your stethoscope on them, squat down with them, and then have them stand up. I find that to be a very helpful maneuver.
You want to make sure that your echo lab knows to do provocation with patients with suspected HCM. There, you typically do Valsalva, because it's a little much to get people to jump off the echo table. You need to make sure that the echo lab knows to take a couple passes to make sure that they are careful to discriminate it from mitral regurgitation and get very well aligned to the outflow tract. I also routinely do stress echocardiograms — and when I say "stress," I mean exercise, not vasodilator, stress. So, I want to do exercise echocardiograms; they're the best, most physiologic, and most practical provocation to try to figure out what's going on. It can also help you tease out what might be contributing to symptom burden. You get all the other good information that we get from exercise testing, such as functional capacity, hemodynamic response, and symptom threshold, and that can really help you find those people who have latent obstruction.
Kittleson: Beautiful. What a perfect summary. You can start out with your physical exam. And if you're a little worried that you're not so coordinated, you can start by squatting with the patient with your stethoscope on their chest and pop up together, so you don't fall over. Hold on to the patient if you squat together.
Ho: Yes, I tell us to both hold on to the exam table.
Kittleson: Safety first in the HCM clinic. And then don't forget about Valsalva, but don't stop at Valsalva in the echo lab. Do a stress echo. Don't rely on dobutamine, because it can lead to false positives. They need to exercise. I love those pearls. So, now we're going to move on. Let's take a dive into treatment and let's focus on obstructive HCM, because there's so much excitement in this space. What do you try first? What do you try next? How do you tell if it's working? Give us all your wisdom.
Ho: Yes, it is such an exciting time to be in HCM. I remember a few years ago being envious of my friends who were involved in amyloid, because there were so many interesting and effective therapies being developed. Now this is happening in HCM. It's a dream come true. First line, I still use beta-blockers or nonvasodilating calcium channel blockers — meaning verapamil or diltiazem; I avoid the dihydropyridine calcium channel blockers. Because what we're trying to do is slow down the heart rate, to allow more time for filling and get the heart as plump as possible, to try to decrease obstruction. Also, to somewhat take the edge off hypercontractility. Beta-blockers and calcium channel blockers are easy, safe, and affordable. I typically start with those, and you can adjust your strategy based on side-effect profile and what seems to be tolerated best by your patients. Younger patients may find it easier to be on calcium channel blockers than beta-blockers. If symptoms are not sufficiently improved, or if these agents are not tolerated or can't be uptitrated, the standard approach, as of a couple of years ago, was to try disopyramide as a more potent negatively inotropic agent and/or to consider invasive septal reduction therapy, and to pose those as options to your patients. Disopyramide can be effective, and it can be a bit more effective in terms of decreasing gradients than beta-blockers and calcium channel blockers. But it has a lot of anticholinergic side effects that can be very difficult to tolerate, including dry eyes, dry mouth, and urinary retention. And there are also frequent manufacturing shortages, especially for the long-acting formulations. We're all constantly scrambling, trying to find a pharmacy that has them in stock, having to switch over to TID — three-times-daily — formulations with the short-acting as a bridge.
But now we have the luxury of more medication options, so we have a detailed discussion with patients about the availability and the high efficacy of invasive septal reduction therapies, such as septal myectomy — a surgical procedure — or catheter-based alcohol septal ablation vs cardiac myosin inhibitors. The cardiac myosin inhibitors are a brand-new class of medications that were developed specifically for HCM based on a better understanding of the underlying pathophysiology. Animal models and in vitro models of HCM, particularly HCM caused by sarcomere mutations — the most common form of genetic HCM — showed that there were fundamental effects of these pathogenic sarcomere variants, including, among other features, increased contractility, impaired relaxation, a shifting of the balance of a more disordered relaxation from a more super-relaxed state of the cardiac myosin, and also inefficient myocardial energetics.
The cardiac myosin inhibitors target the myosin adenosine triphosphatase (ATPase) that is needed to initiate the power stroke and therefore decrease the hypercontractility that's characteristic of HCM. They also, at least in models, improve the proportion of that super-relaxed state of myosin. One of the most obvious impacts is reducing cardiomyopathy and obstructive physiology. The left ventricular outflow tract (LVOT) gradients can be decreased far more than what we see with beta-blockers, calcium channel blockers, or disopyramide, and almost as much as what we see with the invasive septal reduction therapies. Clinical trials have shown improvement in peak VO2 [oxygen consumption] and New York Heart Association class, as well as a variety of secondary endpoints, including a decrease in NT-proBNP, decrease in troponin, improvement in diastolic parameters, and improvement in left atrial enlargement. But it comes with the potent pharmacologic effect of these myosin inhibitors, which is to decrease contractility. So, left ventricular ejection fraction (LVEF) will decrease a little bit; you expect that. That's one of the pharmacologic effects. And typically, the EF is reduced by about four EF percentage points. So if you start at 70%, you end up at about 66%; nobody is really going to notice that. Patients can have a more substantial reduction in LVEF; it's also dose-dependent but reversible. We must keep an eye on LVEF. And because of that, there is a specific strategy in place that's FDA-mandated.
Backing up a little bit, there are two basic ways that patients can access these cardiac myosin inhibitors. One is using the FDA-approved agent, which is mavacamten. This was approved about a year ago, in April 2022, and it's therefore clinically available, although with a rigorous Risk Evaluation and Mitigation Strategies (REMS) program. This was mandated by the FDA because there is still relatively modest overall clinical human experience with mavacamten and because it can reduce LVEF a little bit more than we want. Patients must come in on scheduled visits at 4 weeks, 8 weeks, and 12 weeks after starting, and then every 12 weeks thereafter, to monitor for EF and obstruction. There's also an ongoing phase 3 clinical trial for symptomatic obstruction using another agent, aficamten, so patients can seek out a center that's enrolling in those trials. There's still a lot we need to learn about long-term efficacy and consequences, but it's great to have another tool in the toolbox medically. Some people may still want to go forward to the most definitive strategy, which is invasive septal reduction therapy. We can talk to them specifically about whether myectomy or ablation would be the best strategy for them individually. Others may wish to use medicine to avoid the procedures and the inherent risk associated with recovery. Overall, it's great to have more effective options.
Kittleson: That was the best tour de force ever of the landscape of the management of obstructive HCM. It also highlights why I love managing patients with HCM so much, because it really comes down to two incredibly important points, which are (1) talk to your patient about their symptoms and (2) talk to your patient about their wishes. Because when a patient has obstructive HCM, you just want to help them feel better. It's a very subjective thing. How is your chest discomfort and shortness of breath with exertion? Is it getting better or is it not? If you slap on that beta-blocker, you're not tracking serially the LVOT obstruction, because that's dynamic. Once you know it's there, you don't have to really care about it in the sense that you titrate your beta-blocker to your symptoms. If that doesn't work, then you have that amazing discussion with your patient. Is it disopyramide? Is it mavacamten? Is it an invasive strategy? Figure out the patient's desires, goals, preferences. I love the art of medicine that is inherent in HCM. As you said, we don't have to be jealous of those amyloid people anymore. Now we have a disease-directed therapy based on the beautiful translation of understanding of pathophysiology and tiny molecules. Incredible. You mentioned aficamten, so we're getting toward the future. Now I'm going to ask you to predict the future. Tell me the greatest unmet needs and what advances we can expect in the next few years.
Ho: We still have so much to learn about HCM itself. The patient experience is incredibly varied. It ranges from patients who have essentially no symptoms and no real impact their whole lives, to others who have a cardiac arrest when they're teenagers or others who need a heart transplant when they're in their 40s. Why are some people more susceptible and some more resilient to these adverse consequences? Can we be better about stratifying patients into more coherent subcohorts? Not all HCM is created equal. Can we bucket people into more defined categories, and can we really understand what's driving that risk? We can focus our aggressive therapies on those people whom we can more confidently predict to be at higher risk and allow a lot more latitude on the people whom we can confidently predict to be at lower risk.
Furthermore, can we better understand how disease develops? Why is the penetrance of sarcomere variants incomplete? Again, some people can peacefully coexist with this variant that causes HCM in their own family without developing HCM themselves. Can we figure out why they're able to do that, and then bottle it and give it to other people who are at risk? And related to this, we need to be more sophisticated about diagnosing HCM. This is how we started the whole conversation. Can we evolve beyond just relying on LV wall thickness? If your wall thickness is 15 mm, you have HCM; if your wall thickness is 14 mm, you don't. But it's so muddy, as we talked about; there are a whole lot of other things that influence your wall thickness that are just a primary cardiomyopathy. The LV wall thickness doesn't capture the full spectrum of the cardiomyopathy that is HCM, and it's not sufficiently discriminating from other hypertrophic heart diseases. So, can we move toward integrating the underlying pathophysiology and include the molecular underpinnings to become much more precise about how we make this diagnosis?
Kittleson: Incredible. I think that's a good glimpse into the future. So, what we've learned today is to look at your patient. Incorporate everything from their physical exam, their EKG, their echocardiogram, plus or minus their MRI and family history, to put together the diagnosis. Figure out if they have an obstruction. Titrate your therapy accordingly. And for all of you out there saying, "But wait, there's so much more about HCM," don't forget about your incredible resource, the American College of Cardiology/American Heart Association Hypertrophic Cardiomyopathy Guideline, which is currently undergoing an update for which Dr Carolyn Ho is the vice chair. So, plenty more wisdom to come. Thank you so much, Carolyn. It's been a delight to have you.
Ho: Thank you so much, Michelle.
Kittleson: Thanks for joining our discussion with Dr Carolyn Ho. There's much more ahead in the coming episodes, so be sure to check out the Medscape app, and share, save, and subscribe if you enjoyed this episode. I'm Dr Michelle Kittleson for Medscape InDiscussion.
CY 6031 Study Will Evaluate the Effects of Treatment With Aficamten (CK-3773274) Over A 24-Week Period on Cardiopulmonary Exercise Capacity and Health Status in Patients With Symptomatic oHCM (SEQUOIA-HCM)
2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines
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Cite this: An Espresso-Shot on Hypertrophic Cardiomyopathy - Medscape - Jul 06, 2023.