Think about genetics in heart disease [PODCAST]

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“Despite these high numbers, we cardiologists often look to genetic screening last in our diagnostic workup. But without genetic screening, we can’t always see the whole picture in our cardiomyopathy patients. Once we’ve excluded coronary disease as an etiology, available diagnostic tools such as echocardiography and magnetic resonance imaging provide great insight into the symptoms and consequences of these conditions but not the specific underlying causes. Epidemiology studies support this notion. For example, in 2011, one study found that more than half of previously unexplained cardiac deaths in young people resulted from genetically-linked arrhythmia, as determined through postmortem genetic testing. Thus, our ability to advise patients and their families, and in some cases, take preemptive measures such as defibrillator implantation, is limited.”

Marc Semigran is a cardiologist and chief medical officer of a biotechnology company developing cardiac gene therapy.

He shares his story and discusses his KevinMD article, “It’s time to start approaching heart disease like breast cancer.”

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Transcript

Kevin Pho: Hi, and welcome to the show, where we share the stories of the many who intersect with our health care system but are rarely heard from. My name is Kevin Pho, founder and editor of KevinMD. Rate and review the show at KevinMD.com/rate. Subscribe at KevinMD.com/follow. Today on the show, we have Marc Semigran. He is a cardiologist, and he’s the chief medical officer of a biotechnology company developing cardiac gene therapy. His KevinMD article, which we’ll talk about today, is titled “It’s time to start approaching heart disease like breast cancer.” Marc, welcome to the show.

Marc Semigran: Thank you, Kevin, and thank you for inviting me.

Kevin Pho: We’ll get into the article in a little bit. First off, briefly share your story and journey to where you are today.

Marc Semigran: Sure, thanks. I grew up in New York City and Long Island, and I’m a public school graduate. I went on to Harvard and the Harvard-MIT Health Sciences and Technology program. I was a chemistry major, really interested in chemistry and physics, and that led me down the path to cardiology, where we think about the physics of blood flow and pump function all the time. Actually, for over 30 years, I was on the faculty at Harvard and in the heart failure and transplant program at Mass General.

At the end of 2016, I had the opportunity to rethink my career, as I was offered the chance to become chief medical officer at MyoKardia, a biotech in the San Francisco Bay Area, which was developing a precision approach to heart failure and cardiomyopathy. I thought the science was terrific, and it was based on the work of Jon and Kricket Seidman, who were friends and mentors. And I said, “This is an opportunity to really do something different than just take care of heart failure patients and do small-scale clinical investigations.”

We had some luck and a lot of fun at MyoKardia developing a drug for obstructive hypertrophic cardiomyopathy, and I realized that my passion was about thinking about the underlying mechanism of disease and how we could develop therapies that target that underlying mechanism. So when I was offered the opportunity to come now to Renovacor, where we’re working on gene therapy for cardiomyopathy, I took it, and I’m still having a lot of fun.

Kevin Pho: All right, and we’re going to talk more about the science and your article in a little bit, but I just want to ask you: When you were at that fork in the road, you were doing clinical medicine for decades, and you were at that fork where you had the opportunity to pivot into the biotech industry. Tell me the questions that you asked yourself, the questions that you talked about with your colleagues and family members, when you were going through that decision at that fork.

Marc Semigran: The major question was how I was going to really continue to have an impact on patients’ lives, and what would be the best way of doing that. I had reached an age where I was going to have really one more opportunity to make a career change, and I felt that being able to have the resources available in the biotech industry to really execute on good science was going to be invaluable in my making this type of change. It was both a geographic move, from Boston to San Francisco, as well as a career change. But what kept me going through all of it was my interest in cardiology and in heart failure and cardiomyopathy, and that’s really turned out to be a wise decision.

Kevin Pho: All right, so let’s talk more about your KevinMD article, titled “It’s time to start approaching heart disease like breast cancer.” Now, for those who didn’t get a chance to read your article, just walk my audience through it. Share the story and why you decided to write it.

Marc Semigran: Sure. It’s a little bit of a provocative title there, designed to catch people’s interest. In breast cancer, and in oncology in general, over the last 15 years or so, we’ve come to appreciate the importance of genetics, both in identifying patients at risk of developing cancers as well as in guiding their treatments. We haven’t really done that in cardiovascular disease to any great extent, and particularly not in heart failure. And I think segmenting the heart failure population, using genetics as a guide to understanding the mechanism of heart failure in a given patient, and then deploying an appropriate therapy based on that mechanism is really going to be critical to how we change the field over the next five to 10 or 15 years, much as it had been in breast cancer and in oncology in general.

I wrote the article just to bring the audience’s attention to the importance of genetics in heart failure: to ask about a family history when they see a patient with heart failure, and, if there’s a reasonable to high likelihood that there might indeed be a genetic cause of their heart failure, to do genotyping. Because it can really inform the patient about prognosis. It can inform about specific therapies for a given genotype that might be very appropriate for that patient. And perhaps most importantly, it can help inform family members whether they are at risk, and whether they should be monitored for the development of early signs of cardiomyopathy so that they can be treated preemptively in some cases, as well as be reassuring to family members who may not be at risk because they don’t carry the genetic variant.

Kevin Pho: So give us a little bit of a one-minute primer on heart failure. Give us examples of the different types, and which one of those types has a genetic component to it.

Marc Semigran: Heart failure, we learned in medical school, is defined as when the heart is not able to pump enough oxygenated blood to meet the needs of the body. And of course, that can occur at rest in severe heart failure, but most often it occurs when somebody tries to exert themselves and they feel limited by shortness of breath and fatigue.

You know, in the field, we segment the heart failure population very grossly by whether the ejection fraction, a measure of contractility of the heart, is depressed or normal. We call it heart failure preserved ejection fraction or heart failure reduced ejection fraction, most commonly, and our therapies are mostly determined by how we classify along that spectrum. What I’d like clinicians to start thinking about is how we can segment that population further, to develop and deploy much more powerful therapies than we have to date.

Kevin Pho: So what percentage of heart failure has that genetic predisposition to it?

Marc Semigran: We estimate, well, first of all, you asked just in terms of heart failure reduced and heart failure preserved ejection fraction: There are genetic predispositions to both sides of these. Now, among the patients with hypertrophic cardiomyopathy, a specific type of heart failure preserved ejection fraction, we estimate that it could be as many as half to two-thirds that really do have that readily identifiable genetic predisposition. For those patients with heart failure reduced ejection fraction, the majority are going to have it because they have coronary disease or a heart attack, but of the other 40 or so, again, perhaps half will have a genetic predisposition.

Kevin Pho: So if we have someone in front of us, and I’m a primary care physician, so in the exam room, who has a diagnosis of hypertrophic cardiomyopathy, and I do want to ask about a genetic predisposition, what kind of tests are available for that?

Marc Semigran: First, ask about a family history, Kevin. I think that, as I said, based on the statistics, more likely than not you’re going to identify other relatives who either may have had the diagnosis of hypertrophic cardiomyopathy or were told that they had an enlarged heart, for example. It’s very important to ask about a history of an unexplained sudden death that may well have been due to the arrhythmias that are associated with hypertrophic cardiomyopathy. Then I think one would want to send off a sample of either blood or saliva for genotyping. This is either readily available through your local institution, or there are genotyping companies that make this type of testing available, that can permit identification of a specific genetic mutation.

Kevin Pho: And then once we send those tests out, and let’s say there is a predominant family history and one of those tests does come back positive for a genetic predisposition for, say, hypertrophic cardiomyopathy, what would be the next steps after that?

Marc Semigran: I think that the next step would be to involve a genetic counselor who’s available to you at your local institution. I think that would be very appropriate, to help inform the patient and help dive further into the family, so that other members of the family who may actually indeed have the variant can be identified and seek out appropriate treatment.

There are a number of specialty centers around our country, most of them located at the major academic institutions, where they do have specialists in genetic cardiomyopathy who can then essentially see if this is a genotype that needs a specific targeted therapy, as well as who are up to date on the various therapies that should be considered for a patient with hypertrophic cardiomyopathy. Should they have a defibrillator implanted prophylactically, for example? What’s their medical regimen? Has it been optimized with the current standard of care? Are some of the newer procedures or medications appropriate for that?

Kevin Pho: So one of the reasons why you wrote the article was to bring attention to the genetic predisposition for various cardiomyopathies. So in general cardiology practice, how often do cardiologists ask about this genetic predisposition?

Marc Semigran: Kevin, it’s strikingly rare, and that’s a large part of why I did write the article: to make both primary care docs like yourself as well as cardiologists aware of the importance of asking about a family history. Most adult cardiologists don’t go into the field because we’re interested in genetics. We’re much more interested in pump function, and many of us work with our hands to intervene upon patients’ problems. But I think it’s very important to target the appropriate therapy to the appropriate patient by asking about the family history. There was a paper published about a year ago from the European consortium of cardiomyopathy that found that family history and subsequent genotyping were really being acquired in less than half of the patients that these specialists were seeing, and that was quite shocking to me.

Kevin Pho: So I know you mentioned a couple of conditions that would trigger a light bulb to ask about that family history. You mentioned hypertrophic cardiomyopathy, and you mentioned preserved ejection fraction cardiomyopathy. In a primary care setting, what would be the picture of some typical patients that a primary care clinician would see in front of them that should trigger, “Hey, maybe I should ask more about the family history”? What would some typical scenarios be?

Marc Semigran: Certainly hypertrophic cardiomyopathy in and of itself. I think that should prompt a question about a family history. I think among our heart failure reduced ejection fraction patients, again, about half of them are going to have coronary disease or a prior heart attack. While there certainly can be genetic causes of hyperlipidemia that might be important to ask about, in general, I’m directing my attention more to patients with the non-coronary dilated cardiomyopathies.

And it’s in those patients that I think, in essence, three or four simple screening questions should be asked. Is there anyone in your family with a history of a heart transplant or cardiomyopathy? Is there anyone in your family who died suddenly from something that could have been heart-related, like, for example, a motor vehicle accident that was a single vehicle that went off the road into a tree, or something like that? Is there any family history of a thick heart or an enlarged heart? And finally, and perhaps most importantly, a young person, because these cardiomyopathies tend to present when people are less than, say, 50 years of age. So asking about whether any of these events occurred in a family member who was younger than 50, or in particular whether the patient themselves is under 50, and I probably should have mentioned that first. It should be an important signal to the primary care doc that there could be something genetic going on.

Kevin Pho: Are there any other cardiac conditions outside the world of cardiomyopathy where genetic testing should play a role?

Marc Semigran: There is the phenomenon we talk about, premature coronary artery disease. Again, for somebody who develops significant coronary disease before the age of 50, you’re certainly going to be checking their lipid profile, and if they do have hyperlipidemia, I think it’s time to think about genetic testing there. There are some therapies, again gene therapies, targeting these specific subtypes of hyperlipidemia.

I’ve talked about cardiomyopathy mostly from the heart failure perspective, but there are what we call the arrhythmogenic cardiomyopathies, which present as arrhythmia, sometimes as severe as sudden cardiac death, which somebody can be resuscitated from, where I think obtaining a genetic family history and likely genotyping can be quite important.

Kevin Pho: We’re talking to Marc Semigran. He’s a cardiologist, and he’s the chief medical officer of a biotechnology company developing cardiac gene therapy. His KevinMD article is titled “It’s time to start approaching heart disease like breast cancer.” Marc, what does the future hold when it comes to that intersection of genetic testing and cardiac disease?

Marc Semigran: I think that it gets into what we call precision medicine: really taking a therapy and designing it to address the underlying mechanism of a patient’s cardiomyopathy or heart failure. Now, in the case of what we worked on for hypertrophic cardiomyopathy, we learned about the mechanism, the hypercontractility that leads to HCM, and designed a small molecule to treat it. But I think that gene therapy itself, in particular gene replacement therapy, has the potential to correct the underlying genetic defect in other cardiomyopathies where such a common mechanism may not be present, and really have a dramatic effect on patients’ lives. And a number of investigators and companies are developing gene therapies for specific cardiomyopathies that, my hope is, will lead to tremendous advances in the field.

Kevin Pho: And my final question: What are some of your take-home messages that you want to leave with the KevinMD audience?

Marc Semigran: I’d say two things. From a personal point of view, as you think about your career, follow your passion. You know, as physicians, there are many ways that we can help patients. We can help patients in the clinic one-on-one, and we can use our knowledge of science and of the unmet needs of patients to help design better therapies, and there certainly are a number of huge unmet needs. And the second point is that when you’re seeing someone with severe cardiovascular disease, think about what the underlying mechanism is. Is there a genetic cause?

Kevin Pho: Marc, thank you so much for sharing your time and insight, and thanks again for being on the show.

Marc Semigran: Thank you, Kevin.

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