In this episode, Andrew Perry, MD, interviews Richard Bach, MD, director of the Hypertrophic Cardiomyopathy Center at Washington University School of Medicine in St. Louis, about hypertrophic cardiomyopathy (HOCM). The conversation covers everything from diagnosis, risk of exercise, and medical management to indications for myectomy and alcohol ablations.
Bach previously was a guest on the APCardiology episode debating on the ORBITA trial with David L. Brown, MD. Bach is also medical director of the Washington University cardiac intensive care unit, and as Perry says, “probably one of the better clinician educators that I’ve encountered.”
A transcript of the podcast follows:
Perry: To start our discussion, I’d like to start with a case. This is actually a personal friend of mine. She’s about 28 years old, and actually, it was about a year ago her father passed away from heart failure. He had passed away from, the cause of his heart failure being hypertrophic cardiomyopathy. One of her questions was that she had never undergone screening at 28 years old. I think her father passed away around his late 50s, around 56 or 58, in there. One of her questions [was] about whether she should be screened for it and at what age and the kind of symptoms that may develop and how it gets diagnosed. Maybe just as a segue from them, for a internist everyday in their clinic, what are the triggers that then should have someone suspect hypertrophic cardiomyopathy?
Bach: With that specific example and I see individuals not unlike your friend, that they have had a family member diagnosed with hypertrophic cardiomyopathy. That kind of tragic example where a family member has died and the diagnosis was hypertrophic cardiomyopathy and they’ve never been screened highlights one of the problems with sort of community approaches to hypertrophic cardiomyopathy. I think there needs to be awareness in the community, particularly whether it’s primary care or cardiology, that all first degree relatives of someone with the diagnosis deserve screening. That screening requires a high-quality echocardiogram to look very carefully for signs of the phenotypic expression of hypertrophic cardiomyopathy and an awareness that the genetics are not as straightforward as someone might think. A family member, a child of an affected person has a 50% chance of inheriting a gene for hypertrophic cardiomyopathy, and so it’s not unlikely that family members may carry the gene.
The expression phenotype for the heart is something that can appear at any time in life, and so some individuals have been screened at a younger age and though they didn’t have it or they were told they didn’t have it when, in fact, it could develop later and they need regular screening, which is all defined in our guidelines. It’s sad to me to hear that someone has had knowledge that a family member had hypertrophic cardiomyopathy and had never been screened, and they come to attention when a sad event like the death of a family member prompts their paying attention to it.
But as far as awareness of when to look for the diagnosis, I’d first say that it’s much more prevalent than even physicians are aware of and certainly the lay population who believe that it’s a rare disorder. Prevalence is estimated somewhere between 1 in 200 to 1 in 500 individuals. We include those that are genotype positive, but not yet phenotype positive. It’s not uncommon, and in an office setting, hearing a murmur, hearing symptoms that might at least be within the universe of symptoms for hypertrophic cardiomyopathy like dyspnea on exertion, syncopal episodes, chest discomfort should at least prompt some consideration of the possibility and the characteristic murmur doesn’t even have to be present, but a systolic murmur that accentuates with standing or Valsalva maneuver should be a strong impetus to be looking carefully with an echocardiogram, which is the mainstay of the diagnosis.
Perry: Just along those lines, I’m curious. Do you know how common that exam finding is, the change in the murmur from standing to sitting or with squatting? Do you know?
Bach: I can’t tell you how common it is. I would say that, although it’s characteristic like many things, finding that specific murmur and waiting for that is probably neglecting many people who might have a murmur that doesn’t necessarily have those characteristics or the large proportion of individuals who may not, in fact, have much murmur and yet still have hypertrophic cardiomyopathy. There are patients without obstruction, left ventricular outflow tract obstruction, who have no murmur and yet still have bona fide, phenotypic hypertrophic cardiomyopathy. The murmur is just one aspect of a clue towards evaluating the patient and looking for it. Sensitivity to the diagnosis, I think, has to go well beyond just hearing the murmur.
Perry: Now kind of circling back. As you mentioned, it’s a very common disease and a very common genetic disease. I think the prevalence of that gene is like 1 in 500 or so, and correct me if I’m wrong. It’s inherited autosomal dominant, correct?
Bach: It’s autosomal dominant. It’s fairly complex genetics from a cardiologist’s perspective in that there’s incomplete penetrance. If we look for the gene, it’s not as if we can detect it in every individual who has phenotypic hypertrophic cardiomyopathy. 30% to 50% of individuals with a frank diagnosis establish well by imaging studies will turn out to not necessarily have a genetic marker that is identifiable, but this prevalence recently reassessed with considerations about genotype-positive, phenotype-negative individuals really has landed in the range more like 1 in 200 to 300 than 1 in 500. It’s even more common than we thought before.
I think that rings true that there are many individuals who don’t necessarily have phenotypic expression and many individuals who are asymptomatic and haven’t been diagnosed who nevertheless have hypertrophic cardiomyopathy. I think we need to be a little more sensitive to that as a possible diagnosis. My own experience, I do not uncommonly see individuals referred to the cardiac cath lab for chest pain syndromes where no consideration has been made of hypertrophic cardiomyopathy. In that setting, if we’re simply looking at the coronaries and neglecting the myocardium or the possibility that there’s hypertrophic cardiomyopathy, we’re sending the patient out with a diagnosis of non-cardiac chest pains sometimes because their coronaries are clean, when, in fact, we’ve missed the true etiology when it’s something like hypertrophic cardiomyopathy.
Perry: Gotcha. That’s a good point, because the cardiac cath is an insensitive marker to looking at the phenotype for hypertrophic cardiomyopathy.
Bach: That’s true. There are some clues there for the cardiology community and especially our fellows here when we see, for instance, septal milking, which is a sign that’s characteristic of hypertrophic cardiomyopathy if it’s present. There are some clues on the angiogram, even just the coronary angiogram, that could be helpful. But we should be considering it in many symptomatic individuals even though those symptoms are probably more commonly related to other conditions. Especially when a test like a coronary angiogram is negative, we have to consider hypertrophic cardiomyopathy. I would say another common presentation to me in the office is a consultation where an individual has had two or three cardiac caths. They’ve had a chest pain syndrome for years. It’s a recent echo that finally established or MRI scan that finally established the diagnosis when they’ve been symptomatic for years, and we’ve been essentially barking up the wrong tree and looking for a coronary etiology for their symptoms.
Perry: Gotcha. Now back to the penetrance. You’d mentioned that a lot of people can be genotype positive and phenotype negative. Do we know what influences the phenotypic expression?
Bach: No, we don’t. It’s a bit of a mystery, and I think it’s one of the bigger mysteries in the advances we’ve had in the last 25 years or so in understanding the genetics of hypertrophic cardiomyopathy, that there’s wide phenotypic variability even within families that carry the same genetic abnormality, which is not only surprising but somewhat counterintuitive. Within a single family that carries the same pathogenic mutation for hypertrophic cardiomyopathy, there can be different phenotypic expressions from one individual who carries the gene to another. [It] just highlights the complexity of the genetic expression of this disease. There’s a strong belief there are additional modifier genetic influences, whether it’s genetic or epigenetic influences that are modifying the expression of that pathogenic mutation. But our understanding of that is in its infancy. In fact, it’s still a mystery as to why one individual will have a very different phenotypic manifestation or not. It could not show signs of the disease. Why is there incomplete penetrance? One might think there should be another influence, either genetic or epigenetic, that’s masking or preventing the expression of that pathogenic mutation, but we don’t yet have a clue as to what that is. There’s a lot of active research going on, but it’s very challenging research in a phenotypically-variable illness. Because there is a wide spectrum of disease manifestations of hypertrophic cardiomyopathy, various locations of the maximal hypertrophy, varying degrees of outflow tract obstruction, and varying symptomatic manifestations. So being a very variable illness makes it challenging to try to hone down on what the particular influences are on gene expression.
Perry: That kind of is a segue when you’re talking about the variable characteristics. It raises a question about whether you can have a less than diagnostic thickness of the myocardium with still obstruction of the outflow tract. Is that still diagnostic? Maybe what are some of the principles that are going through your mind when you’re looking at someone’s clinical profile and their echocardiogram to make that diagnosis? What are the variables that then you’re like, “We can fudge a little bit on here, but these characteristics are really the most important to diagnose it?”
Bach: That’s a good question and fudge is not a word I like to use when we’re talking about diagnosing something this important. But there are challenges and many of the challenges are quite clinically significant, especially when we’re dealing in populations of elite athletes, where there are other reasons to consider myocardial hypertrophy and the phenotype and trying to differentiate individuals who have a benign form or an adaptive form of hypertrophy due to elite training versus an individual who has bona fide hypertrophic cardiomyopathy. That’s still a conundrum for many young individuals who are competitive athletes.
But if you take it at its fundamental, the definition of hypertrophic cardiomyopathy requires hypertrophy and myocardial hypertrophy to a degree that exceeds certain standards in the absence of other secondary causes, the most common likely being hypertension. We’re talking about wall thickness that’s diagnostic would be 15 mm Hg and typically asymmetric, not concentric hypertrophy, but asymmetric hypertrophy that exceeds 15 mm Hg is sort of at the root of the diagnosis for most individuals. There’s a gray zone between 13 mm and 15 mm Hg, so there is some gray zone, especially in young individuals where those benchmarks of 15 mm apply to adults, so a teenager or a child, it’s harder to know those standards and how exactly they apply poses an additional challenge. Sometimes look at the Z score, the difference compared to the expected wall thickness. But the bottom line is wall thickness is the fundamental feature and the pattern of that wall thickness, so asymmetry being very important.
The presence of outflow tract obstruction is an additional marker, but not necessarily diagnostic because, in fact, there are individuals who do not have outflow tract obstruction, and yet have bona fide hypertrophic cardiomyopathy. The typical mechanism being a combination of systolic anterior motion of the mitral valve and excessive septal thickening at the basal interventricular septum. It’s not present in all individuals with hypertrophic cardiomyopathy. Some individuals have more apical hypertrophy that’s currently termed the apical bearing to hypertrophic cardiomyopathy. There have been descriptions of individuals with lateral wall hypertrophy only, so I think the fundamental characteristic one should be sort of sensitive to is asymmetric hypertrophy of the ventricle with a maximal wall thickness that exceeds 15 mm. But even concentric LVH, at times, should be investigated for the possibility that it represents hypertrophic cardiomyopathy.
Perry: Gotcha. Another question about diagnosis and suspicion. How common is it that you see someone without a non-family history of hypertrophic cardiomyopathy coming in with that diagnosis?
Bach: That’s very common. In fact, I think the majority of individuals that I see in the office have no family history before their diagnosis is made, and very often their diagnosis is made incidentally on an echocardiogram done for other reasons or to evaluate symptoms. Although we believe that it is most commonly a familial disease, either no one else in the family has yet been diagnosed, which is not uncommon because sometimes screening family members will then pick up other members who do have the diagnosis, or there’s no trackable or identifiable family members who also have the disease.
There are sporadic cases. I think from the practical, clinical perspective we should always consider that it is more likely a familial disease to prompt the screening of family members and not neglect that screening. This is a disorder that has important clinical implications even for the asymptomatic individual who’s otherwise healthy. We establish the phenotypic diagnosis. We need to be looking very carefully at risk factors for premature sudden cardiac death, and given that risk amongst this population, although as far as the population is concerned, the vast majority do not have an excessive risk of sudden cardiac death by identifiable risk markers. Because there is a small percentage who do, preventing the possibility of unexpected sudden death is one of the most important aspects of screening. When we identify an individual, their family members should be screened as if there’s a possibility it’s a familial form until proven otherwise.
But there are a large number of individuals who are the only member of their family thus far identified. The challenge there being, of course, other family members may develop it at a later time in life or, as you’ve alluded to earlier, there’s enough incomplete penetrance that someone may be a carrier, but not necessarily show the phenotypic manifestations.
Perry: Are there other clues on family history that you’ve seen come up in your practice, that seem to be common trends? I mentioned, “Yeah, we have a family history. I’ve had a couple uncles who suddenly dropped dead and we don’t really know why.”
Bach: You bring another very common, at least in my practice and I think it’s not uncommon anywhere, is that other family members may have died suddenly, but the family was told or a death certificate is created that says it was due to coronary heart disease or myocardial infarction. The most common thing I see is a family member, maybe even a parent died and they’re at a relatively young age, perhaps in their 40s and 50s, suddenly, and the family was told they died of a massive heart attack without an autopsy. I’d say that’s as common as no family history, in fact. And it’s disturbing because no one has been clued in to the possibility that there was an underlying familial substrate for sudden death in that person’s family. And sometimes they’re even describing that multiple family members, as you’ve just alluded to, uncle died suddenly, parent, grandparent died suddenly, and yet, the family is not aware the potential that hypertrophic cardiomyopathy as the diagnosis may be present.
It just highlights that we have to be careful about the family history of sudden death that it may have been misattributed to other things. But likewise, there’s not a small number of individuals who have just no family history of any prior cardiac disease or cardiac illness, and they’re showing up as the first identified member of the family who has hypertrophic cardiomyopathy phenotypically expressed.
Perry: Does the prevalence or the expression of this vary across race?
Bach: Not in a way so far identifiable. Race has not turned out to be a differentiating factor for this particular disease. It happens in any race. It happens in any ethnic population, so there’s no particular stratification there that I can say that we have enough data to give you an answer that says, “It’s more common in this particular population.”
Perry: Okay, now I think we’ve alluded to this before, but one of my questions about how hypertrophic cardiomyopathy can cause sudden cardiac death, and then you started mentioning about how in regards to elite athletes and differentiating between those two. However, there are cases we hear about where a young, elite athlete then dies suddenly from hypertrophic cardiomyopathy. And this is maybe a bit of a side topic, but about screening for these populations who are a bit higher risk, engaging in strenuous exercise on a daily basis putting them at a higher risk for a fatal event from that disease. Is there a role for screening or do we have any data to suggest whether screening with an ECG or an echocardiogram in those populations is useful or not?
Bach: You bring up a topic that’s very controversial right now. This week’s New England Journal of Medicine has an article about screening soccer players, elite soccer players in Great Britain.
Perry: Yeah, I just read that last night.
Bach: Yeah, it’s fascinating. Let me say a couple of things that I think are relevant as we’re discussing this particular topic. First of all, any family with a family history of hypertrophic cardiomyopathy, the young individuals in that family should be screened on a yearly basis before they participate in sports at high school, for instance, and anyone, when we’re talking about screening for that population, would require a yearly echocardiogram.
If we’re talking about the general population of young athletes, the AHA [American Heart Association] and ACC [American College of Cardiology] recommendations, and in fact, with a whitepaper that looked very carefully at this a few years ago coming out of a taskforce that looked at it, they do not recommend routine screening with echocardiograms or even electrocardiograms. Simply the problem of finding the needle in the haystack is kind of the difficulty there. But they do recommend pre-participation examination by a physician, which is required, in fact, in most states for high school athletes before they’ll participate in the next year’s sports, that they have a pre-participation screening exam. That’ll include taking a history and asking them questions about whether they’ve had symptoms, chest pain, shortness of breath, syncope, very important symptoms that could be the first sign of hypertrophic cardiomyopathy, for instance. But looking for any condition that might propose or promote a risk of sudden death in competitive sports.
They have a physical examination that obviously includes examining the heart and looking for a heart murmur. From that screening exam, identifying individuals that may go on to need an electrocardiogram or echocardiogram from the sort of fundamental screening exam. That’s what’s recommended in the U.S. for pre-participation screening, but not a routine EKG, which is done in Italy and has been, in some publications of their experience, associated with a reduced risk of sudden death. That’s been controversial enough that extrapolating that data to the U.S. population is not felt to be compelling yet to this point.
But as you saw in that article in Great Britain, at least for the elite soccer players who are going on to professional careers, at around age 16, they do undergo a fairly rigorous screening examination with an echocardiogram and electrocardiogram. The results of which, this is very fresh data, the interpretation of those outcomes we have to look at very carefully before we can extrapolate it to an experience here in the U.S. But it is, as you read in that article, it’s very interesting that there were, unfortunately, some sudden deaths amongst those young athletes. The rate was very, very low. Eight out of 11,000 or more than 11,000 over a period of several years. Amongst those that died suddenly, unfortunately, there were several where the pre-participation screening evaluation they had didn’t identify the condition.
It just poses the conundrum of how difficult it is to screen the many athletes that we have and kids who are participating in high school sports here in the U.S. to identify those that are at increased risk and trying to prevent that very rare, but tragic event of a young person dying suddenly. We need more data on how to go ahead and do that in a cost-effective way and even in a clinically effective way. We should say for the sake of this podcast that if a young person is identified to have phenotypic hypertrophic cardiomyopathy on a pre-participation screening, the recommendation is that they should be prevented from participating in competitive sports. That would be proscribed for them. But it does pose that dilemma that there are young individuals who are elite athletes who might have a borderline evaluation, and it’s very challenging to be certain that they have hypertrophic cardiomyopathy to evaluate whether or not medically they should be disqualified from participation.
There are some cardiologists in the country who have argued that not all athletes with some phenotypic cardiac abnormality of concern should be prevented from participating in sports. But it’s a controversial enough topic that I think it’s probably more than we can talk about today, but one that will probably affect policy and physicians’ behavior in the future with respect to interacting with young, elite athletes.
Perry: What are the risk factors for sudden cardiac death in hypertrophic cardiomyopathy? What are those things that you look for?
Bach: We’re fortunate that we have a short list that helps identify those individuals, and some more recent data in the last several years, at least observational studies that suggest the vast majority of individuals do not have an increased risk of sudden death. But the risk factors, the short list is a family history of sudden cardiac death, premature sudden cardiac death, again, with the challenges of always knowing that in a first-degree family member, challenges of always knowing was that really sudden arrhythmic death, but not withstanding. Wall thickness, maximal wall thickness greater than 30 mm is considered an additional strong risk factor, but the reality there is it’s a continuum. So should you not be concerned at 29 mm, but more concerned at 31 mm? That’s a judgment call to some degree. Yes, always these risk factors have some sense of judgment associated with it. The third is syncopal episodes, especially if they’re recent, multiple, and unexplained by other etiologies of syncope. A drop in blood pressure with exercise on an exercise treadmill test is another marker. Then episodes of non-sustained ventricular tachycardia seen on a Holter monitor, especially if they are multiple. That is another factor, although that one may be somewhat mitigated.
The question of how many risk factors do you need to have before one intervenes — and the intervention being a primary prevention defibrillator — that’s a very important question that’s also controversial. The European recommendations are that one should calculate a risk, and when the risk is greater than the range of 6% risk of sudden death based on risk prediction on an equation that incorporates these risks…
Perry: 6% per year?
Bach: That’s considered a high enough risk to justify a defibrillator. But in the U.S. population that has been studied and some retrospective observational studies are pretty powerful in this regard, even one risk factor. Or let’s put it this way, the majority of individuals who have an event have just one risk factor. So that takes away necessarily the onus to be relying on a calculation of percentage risk, but we should be looking very carefully. This is one of the most important aspects of identifying individuals who have hypertrophic cardiomyopathy at an early point is to adequately risk stratify whether they have an increased risk of sudden death. And shown quite well in retrospective series, a primary prevention defibrillator can save lives in that circumstance.
One of those cardinal risk factors or if it’s borderline or there are questions, some supportive evidence now, some work done by Marty Maron, one of our former residents, actually, who is a leading expert on hypertrophic cardiomyopathy at Tufts. He’s looked at some very well-described information about late gadolinium enhancement on an MRI scan. When there is a large degree of it, more than somewhere in the range of 15% late gadolinium enhancement of the myocardium, that’s another supportive factor that helps risk stratify individuals and might support a defibrillator even though the other risk factors may be considered borderline.
We have some information in the last 20 years from these risk factors that has defined the population better that have an increased risk of sudden death. When it comes to the competitive sports question, one should realize that we don’t restrict those individuals only who have those risk factors. Any diagnosis of hypertrophic cardiomyopathy prompts a recommendation to avoid strenuous exertion and not solely defined by those risk markers. It is just one of those gaps in our knowledge, Is everyone at risk? There is a belief that certainly high-level, strenuous exertion does promote the potential for arrhythmic sudden death independent of these risk factors that we’re talking about that are more markers for whether or not a defibrillator is an important preventive strategy.
Perry: Sure. There’s individuals that are at higher risk, but still even just the diagnosis, itself, should preclude you from those competitive sports,
Bach: Right, and in fact, it’s part of our job to be counseling individuals to, perhaps, modify their lifestyle if they are extreme athletes. Even adults, master athletes, need to be careful about the vigor of their exercise with a diagnosis of hypertrophic cardiomyopathy. Again, countered by the belief and recommendation that regular, aerobic, moderate exercise is still worthwhile for patients with hypertrophic cardiomyopathy, and some recent data that suggests that’s absolutely true, that patients will have better exercise capacity, better overall health if they continue to exercise, but strenuous exertion in competitive sports are proscribed.
Perry: Say we’ve met somebody and make the diagnosis of hypertrophic cardiomyopathy. When do you initiate treatment and what do you start treatment with? Is that the asymptomatic stage you start them on? Do you wait till they start having symptoms? What do you start with?
Bach: Good question and let me put in a plug for the Hypertrophic Cardiomyopathy Center because I don’t think any of these questions are simple ones. One thing I believe very strongly in and the way we’ve created our own center here is that any individual at any stage needs a very comprehensive evaluation to determine what, if any, treatments are needed. When we’re talking about treatments, we’re not just talking about medical therapy or decisions on invasive interventions. We are talking about that question and determining the need for a primary prevention defibrillator for some of the population. Because these questions are not simple even at the initial diagnosis, there is some value in a hypertrophic cardiomyopathy center that has this comprehensive approach to management.
But when it comes to medical interventions, for instances, medical therapy being the first line of treatment for symptomatic hypertrophic cardiomyopathy. It really is symptoms that prompt that kind of decision. It is not recommended and typically not felt to alter the disease process necessarily to initiate medical therapy prophylactically for the asymptomatic individual who has the diagnosis. Medical therapy probably should be reserved for symptomatic individuals, but the most common symptoms being symptoms of congestive heart failure, shortness of breath, although angina pectoris, chest discomfort, is another common complaint.
The first-line treatment typically would be a consideration for a beta-blocker. The most common beta-blocker employed is probably metoprolol, although which beta-blocker has probably not been adequately studied to say there’s any difference to suggest it’s not a class-action effect. So beta-blockers are the first-line choice for most symptomatic individuals. I would say it’s not uncommon that we are not using therapeutic doses for many individuals that I see, so even achieving a therapeutic level of beta-blocker is probably important if we’re trying to mitigate symptoms for these individuals. But there are many individuals who, even with adequate beta blockade, simply don’t have enough responsiveness or have limiting side effects from the beta-blocker. For those individuals, we’d probably say the second-line agent is a calcium channel blocker and the most common one being verapamil.
We didn’t discuss it earlier, but one of the very fundamental aspects of hypertrophic cardiomyopathy is that the left ventricle is hyperdynamic. The ejection fraction is typically higher than a normal ejection fraction. It’s likely that at a very fundamental level the interaction between myosin and actin is overly vigorous for the myocardium for somebody with hypertrophic cardiomyopathy. These agents, beta-blockers, calcium channel blockers, we’re probably getting some benefit out of the negative inotropy that they also have as one of their characteristics. Verapamil being the most negatively inotropic calcium channel blocker is probably the agent of choice if the patient fails to respond to beta-blockers.
The third-line agent and I would use it as a third-line agent, although that might be considered too conservative, is disopyramide, which is a type 1a anti-arrhythmic agent in its original iteration, but a powerful negative inotrope as well. There are individuals and this has been described in some observational series that I think are very worthwhile taking a look at if one considers using disopyramide, that a significant proportion of a population that has, perhaps, failed to respond to beta-blockers and/or calcium channel blockers does have response to disopyramide. But it has to be used carefully. It is an agent that should be started during a hospital stay so that one can examine whether or not there’s change in the QT interval that portends some proarrhythmic risk for those individuals.
In the end, unfortunately, a significant proportion of individuals don’t really tolerate disopyramide. It has a side effect profile that is difficult for many patients. It’s not an easy medication to use. It’s probably is that third-line agent for symptomatic individuals. Just so that we sort of bring it up and don’t forget to talk about it today, there’s a new medication on the horizon. Here at the HOCM Center at Wash. U. we’re about to and we started one and about to start a second trial of this new medication. It’s called mavacamten, just to be aware of it. It is investigational. It’s a designer agent, which makes me quite excited about the fact that there’s some “precision medicine” behind it. It interacts with this excessive interaction between myosin and actin. We’ve learned a lot about the physiology of the myocardium in ways that, to me, are very exciting so that we understand it a little better than we did even 10 years ago, but in the normal circumstance, there’s this conformational state of myosin where it’s so-called in its super-relaxed state. Some of the myosin heads are folded over and not accessible to binding with actin. In the normal circumstance, they’re sort of held in reserve, so to speak. That state seems to be affected by some of the mutations on the myosin head or by the lack of breaking that happens from myosin-binding protein.
There’s an excessive interaction between myosin and actin, so to speak, which affects both the strength of the contraction, so it is hyperdynamic phenotypically when we look at it by imaging studies, but it also affects the relaxation phase. Those are both fundamental components of the abnormal physiology of HOCM. This new agent that binds to and sort of unhooks the state of myosin from its active binding and restores some of that super-relaxed state to the molecule seems to affect both the systolic hypercontractility and the diastolic dysfunction that are fundamental to HOCM.
It’s a very exciting agent. Let’s put it that way. It really has only been studied in a small number of individuals so far, but we’ve embarked with an FDA-approved clinical trial that’s multicentered that’s going on here and at many centers around the country and soon around the world to assess its effect on physiology using echocardiography and MRI to evaluate the patients and its effect on symptoms and physical functioning by exercise testing. It’s going to be a very, I think, important addition to our armamentarium for treating these individuals if it turns out to be safe and effective, as any clinical trial needs to prove first, but it’s our first agent to really look at prospectively, perhaps, that attacks one of the sweet spots of the abnormalities for hypertrophic cardiomyopathy, if I can put it that way.
We’re very excited about that and the individuals who are symptomatic with hypertrophic cardiomyopathy can volunteer to participate in the study here or at many of the hypertrophic cardiomyopathy centers around the country.
Perry: Very cool. Then back on the beta-blockers and calcium channel blockers. They treat symptoms. Do they have any impact on mortality as well?
Bach: None of them have been proven to impact mortality. The encouraging information that we’ve had recently that says that the mortality rate with modern interventions that include defibrillator implantation has dropped substantially over the last 25 years to match the general population. One has to take any such observational data a little bit with a grain of salt because it’s selected populations that have been examined. But it is encouraging that I think we’ve changed the history of the illness to some degree by intervening early. But if you were to ask the specific question, “Does beta blocker therapy or verapamil or disopyramide reduce mortality or increase longevity?” no such data exists.
When we get to if you want to talk about the invasive therapies, there’s even some controversy about that. But when one talks about myectomy for individuals with severe obstruction or alcohol septal ablation for the same population, patients, again, who are symptomatic and refractory in medical therapy may qualify for those procedures. The level of evidence is not great that we can say that they extend longevity. In a retrospective analysis very carefully done of individuals with severe obstruction who underwent a myectomy, compared to individuals who had severe obstruction but did not, the mortality was lower. But one has to realize that that’s a select population, and the biases may be large in that comparison to conclude that reducing gradients by intervening on septal fitness, whether that actually reduces mortality.
There are many of us who we certainly see great symptomatic benefit by those interventions and expect that it’s not unlikely that changing the physiology of the ventricle that way should impact long-term prognosis, but I would never promise to a patient that they’ll live longer based on one of those interventions with the level of evidence we currently have.
Perry: I think you highlighted this already. I did want to go into those invasive procedures, but who do you consider to refer towards either surgical myomectomy or an alcohol septal ablation? I’m sure the decision is probably first, “Yes, we should try to relieve some of this obstruction,” and then the next decision is, “Which way do we go, surgical versus the alcohol ablation?”
Bach: It shouldn’t be neglected that there are many individuals quite symptomatic at initial presentation whose symptoms may be well-controlled with medical therapy. That is still the first line for treatment and very successful for many individuals. But the proportion of individuals who remain symptomatic and we generally say severely symptomatic, meaning at least class III symptoms, who have the proper anatomy and physiology to consider it and what am I referring to there? Asymmetric septal hypertrophy as their fundamental manifestation of the hypertrophic cardiomyopathy and outflow tract obstruction, which is typically dynamic, meaning it’s due to the systolic anterior motion of the mitral valve interacting with that septum. Sorry.
Perry: That’s okay.
Bach: That cause what’s considered a “severe degree of outflow tract obstruction.” That means either at rest or with provocation, and the most physiologic provocation being an exercise-stress test, a systolic gradient across the outflow tract typically measured by the Doppler velocity of at least 50 mm Hg or greater. That qualifies as severe outflow tract obstruction. Fulfilling all of those criteria, that may be an individual, if refractory to medical therapy, who can benefit from septal reduction therapy as a general term for these two interventions.
Now that is very important, and in fact, I think one of the important roles of a hypertrophic cardiomyopathy center is to try to adjudicate what is the optimal treatment for each individual, comparing septal myectomy, a surgical approach that requires a sternotomy, a pump run, and an experienced surgeon. It is an operation that should be done in a center of excellence where the surgeon specializes in septal myectomy. But whether that approach versus a what might be considered minimally-invasive approach by catheters, by alcohol septal ablation, which of those should be recommended quite individual, so to speak, with respect to preferences and features.
It’s not a simple algorithm to discuss. I should reflect that the guidelines from 2011, I think which are very fair in this regard, suggest that based on the fact that septal myectomy has been in clinical use since the 1960s, so it has a very long track record, that the surgical approach has improved over the last 25 years to the degree that the risk of the surgery, the mortality rate is relatively low for isolated septal myectomy. That it is the “gold standard” for septal reduction therapy for appropriate individuals. When I see individuals, there are other factors that can affect whether or not we would recommend surgery as a primary approach. Is the individual young, and therefore the data that we’ve had in operation available for more than 40 years can affect one’s recommendation to a young individual, that, perhaps, we should be deferring surgery for younger patients. The thickness of the septum. A very thick septum, easier to thin by surgery than it is by alcohol ablation. Then comorbid conditions. If a patient has, for instance, atrial fibrillation as an additional condition, the ability to do maze surgery, which in our institution, Dr. Ralph Damiano, does our septal myectomies. He’ll also combine that, when feasible, with a maze operation to reduce the likelihood of recurrent atrial fibrillation, which, by the way, is very poorly-tolerated arrhythmia for individuals with hypertrophic cardiomyopathy.
These are reasons to, perhaps, prefer and recommend septal myectomy for the individual. When individuals have a higher risk from surgery and that’s not uncommon that we may see older patients or patients with comorbidities, COPD or other comorbidities that increase the risk of open heart surgery, then we prefer and recommend transcatheter alcohol septal ablation as a technique for septal-reduction therapy for those individuals. Then certainly, I believe very strongly in shared decision-making for this population. Generally, I have a long discussion about the differences between the procedures, the potential risks versus benefits, so to speak, and the patient’s preference is very important in which of these procedures may be chosen. Both procedures are very successful, probably in excess of 90% effectiveness in reducing symptoms with low morbidity and mortality rates on the order of 1% to 2% for both procedures for the average individual. So patient preference is an important component as long as they’ve been adequately informed about both procedures. I believe that very strongly.
Perry: Very good. Unfortunately, I’m running out of time. There’s a lot more that I would want to talk to you about, though.
Perry: But I really appreciate you coming by. Any last words or thoughts on this topic?
Bach: This was great. No, I’m very happy to get a chance to discuss hypertrophic cardiomyopathy. I do think we need more awareness, both in the lay community and in physicians’ offices to be looking for it. We’re eager to see more patients here at the Hypertrophic Cardiomyopathy Center so that we can have this comprehensive approach to them, to their families, and to keeping them healthy and keeping them happy.
Perry: Great. Again, thank you for your time.
Bach: Thank you, Andrew.
Perry: Thank you for listening to this episode of AP Cardiology. This series is cosponsored by MedPage Today and by the Division of Medical Education at Washington University in St. Louis School of Medicine.
Andrew Perry, MD, is a resident physician at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis.