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Advances in Treatment of Obstructive Hypertrophic Cardiomyopathy - Episode 2

Role of Genetic Mutations in HCM Pathophysiology

Steve R. Ommen, MD, leads a review of common mutations seen in hypertrophic cardiomyopathy and the role of biomarkers and genetic testing in HCM.

James Januzzi, MD: Steve, we’ve heard that this is a genetic diagnosis, a disease based in genetic mutations. Could you give us a sense of the lay of the land as far as the mutations that you consider as a specialist?

Steve R. Ommen, MD: That’s a good question. HCM [hypertrophic cardiomyopathy] can be both familial and nonfamilial. When it’s familial, it’s generally due to mutations that encode for the proteins that make up the cardiac sarcomere. The most common ones are myosin heavy chain and myosin binding protein–C, but actin troponins and some others that are part of the cardiac sarcomere complex have all been implicated as variants that can result in HCM.

There are also a few variants outside of the cardiac sarcomere. To the point you were just making, there might be a polygenic etiology for some individuals, and there might be environmental factors or comorbidities that play a role in that. That’s part of the haziness that we have with HCM. But when it’s genetic, when it is sarcomeric in nature, the major pathophysiologic issue is that actin and myosin interact too strongly in the cardiac sarcomere. How that results in asymmetric hypertrophy in a heart vs ubiquitous hypertrophy is 1 of the unknowns we have about the condition.

James Januzzi, MD: Interesting. What role does genetic testing play here? Can we expect a different disease course based on individual mutations?

Steve R. Ommen, MD: The data on individual mutations aren’t robust, but that might be because there are so many different mutations. Many of them are family private variants. But if you have a sarcomeric variant identified, we have data that composite end points occur at a faster rate than in patients who are sarcomere variant negative. There’s some prognostic information from knowing a variant status.

James Januzzi, MD: Interesting. Is there a different amount of hypertrophy associated with 1 type of mutation vs another, or different rates of complications, such as arrhythmia vs congestion?

Steve R. Ommen, MD: We had a lot of hope for the idea of the genotype-phenotype correlation studies about a decade ago.

James Januzzi, MD: Yes. It used to be talked about.

Steve R. Ommen, MD: Yes. We don’t talk about that as much now. If you’re homozygous, or have 2 mutations, 2 variants, then complications are higher than for the pure isolated heterozygous individual. If you only have 1 gene, it’s better than if you have 2 genes.

James Januzzi, MD: That’s a useful summary. It provides information about the presence of the diagnosis. It may provide useful information for counseling families and screening children.

Steve R. Ommen, MD: Yes. Screening families is the primary role of our use of genetic testing. If you have a patient in your office—we’ll call that person the proband—we recommend that we do genetic testing in that individual. If we can find their disease-associated variant, then we do cascade screening, starting with their first-degree relatives, and follow the positives around the family tree.

James Januzzi, MD: These are all autosomal dominant.

Steve R. Ommen, MD: Yes, for all intents and purposes.

James Januzzi, MD: That’s useful information. I’ll turn to Dr Butler here. Generally speaking, in heart failure, genetic testing isn’t something that we do all that frequently, even in dilated cardiomyopathy. But when you think about evaluating someone with HCM, genetic testing might be informative for family information.

Javed Butler, MD, MPH, MBA: I’d like to ask Steve a quick question. Jim, you brought up something interesting: the disease modifier issue. If somebody who is obese and has high hypertrophic cardiomyopathy, or we think has hypertrophic cardiomyopathy, comes into the clinical picture but has hypertension, 1 of the things that you classically learn is that hypertrophic cardiomyopathy diagnosis requires that there’s no alternate reason for somebody having hypertrophy. If you have someone with hypertension, when do you suspect hypertrophic cardiomyopathy? In which patients with hypertension and LDH [lactate dehydrogenase] should you be doing genetic testing? Can you give us some idea?

Steve R. Ommen, MD: That’s a great question. The clinical diagnosis is hypertrophy in the absence of another stimulus that could cause that degree of hypertrophy. If you have mild long-standing hypertension, and your left ventricle is 20 mm thick, mild hypertension doesn’t explain that. On the other hand, if your ventricle is 15 mm thick and your blood pressure has been 170 over 100 mm Hg for a long time, that’s a diagnostic uncertainty. Genetic testing might play a role there. Cardiac magnetic resonance imaging may help us image the ventricle in a different way to make a clinical diagnosis differently from just measuring wall thickness.

Martin S. Maron, MD: I’ll add another point, too, because as Steve was saying, the most important role for genetic testing is probably for family assessment. Probably second to that is the opportunity with genetic testing to make the diagnosis of other phenocopies of HCM diseases that look like HCM in adults but aren’t. The common list there is Anderson-Fabry disease, potentially amyloidosis, and other glycogen/lysosomal diseases, which obviously have a different etiology, different natural history, and different treatment. Genetic testing could be helpful there.

James Januzzi, MD: Huge. In fact, in my practice at the Massachusetts General Hospital Heart Center, I’m on a crusade to get the echocardiogram reports rewritten to stop calling things left ventricular hypertrophy [LVH] because the frequency of transthyretin amyloidosis, for example, is a lot higher than we realized, especially when you start looking people who have mild LVH and 11- or 12-mm walls, especially in the absence of hypertension. That’s critically important. This is helpful, and I’m grateful you brought up the differential diagnosis because I was going to ask about that.

Transcript Edited for Clarity