Genetic testing enters cardiovascular-disease mainstream



Genetic testing is now part of routine practice in at least some U.S. centers for managing a short list of cardiovascular disease scenarios.

Although it remains well shy of ubiquitous for cardiovascular practice, for at least four important settings genetic testing has begun to play a key role: diagnosis of inherited cardiac conditions such as cardiomyopathies and channelopathies, diagnosis of homozygous and heterozygous familial hypercholesterolemia, treatment of stented coronary-disease patients with clopidogrel, and use when starting patients on warfarin.


Cardiomyopathies and channelopathies

Genetic testing of patients with any of the several inherited diseases that fall into these categories, including hypertrophic cardiomyopathy, dilated cardiomyopathy, long QT syndrome, and Brugada, received official recommendation from the Heart Rhythm Society and European Heart Rhythm Society in 2011 (Europace 2011;813:1077-109), and genetic testing for patients with hypertrophic cardiomyopathy and their first-degree relatives received a class I level B rating in guidelines for this specific cardiomyopathy released last year from the European Society of Cardiology (Eur. Heart J. 2014;35:2733-79).

Those endorsements put these cardiac diseases on the firmest ground for categorization as routine practice, a status that grew firmer still when researchers announced in January 2015 new evidence that better clarified the genetic underpinnings of dilated cardiomyopathy, the most common inherited cardiac condition.

Dr. Ray E. Hershberger

Dr. Ray E. Hershberger

“Genetic testing clearly contributes to risk assessment” of cardiomyopathies and channelopathies, Dr. Ray E. Hershberger said during a talk last November at the American Heart Association scientific sessions in Chicago. “Finding a plausible genetic cause for a condition lays the foundation for more durable intervention,” said Dr. Hershberger, professor and director of human genetics at Ohio State University in Columbus.

“Genetic testing for dilated cardiomyopathy is becoming increasingly important in clinical practice. Genetic testing is available, affordable, and efficient,” Dr. Luisa Mestroni, director of the Adult Medical Genetics Program of the University of Colorado, Denver, said during a separate talk at the AHA meeting. She cited three commercially available genetic tests for dilated cardiomyopathy that use next-generation sequencing and screen dozens of implicated genes. The genetic findings are available within about 10 weeks and cost in the range of several thousand dollars. Similar panels also exist for the other cardiomyopathies and channelopathies. Perhaps the most significant limitation on genetic testing for these patients is that it be done within the context of genetic counseling, said both Dr. Mestroni and Dr. Hershberger.

Dr. Luisa Mestroni

Dr. Luisa Mestroni

Genetic testing for dilated cardiomyopathy has been hindered by the disorder’s genetic heterogeneity, but understanding of the genetic picture grew much clearer in January with publication of genetic findings from 5,267 people representing the full spectrum of cardiac status, including fully-assessed healthy controls; 3,603 unselected community dwellers taken from the Framingham and Jackson Heart Studies; 374 unselected, ambulatory patients with dilated cardiomyopathy; and 155 patients with severe, end-stage dilated cardiomyopathy. The large, multicenter team of mostly British and U.S. researchers validated the findings in 163 additional patients with familial dilated cardiomyopathy (Sci. Transl. Med. 2015;7:[doi: 10.1126/scitranslmed.3010134].

The findings showed that mutations that produce truncated forms of titin, the body’s largest protein and a critical part of cardiac muscle, appear in about 2% of the general population, about 13% of ambulatory patients with dilated cardiomyopathy, and about 20% of patients with end-stage DCM. In addition, the truncations that occur in people who lack clinical disease tended to affect minor titin isoforms and produce mild functional changes, while the titin truncation mutations in people with severe disease were in the most commonly used isoforms and at sites that severely impaired function.

Until now, in the United Kingdom, “it would not have been standard of care to do gene testing [for patients with suspected dilated cardiomyopathy] unless there was a clear family history or some phenotypic indicator, but going forward we believe the yield from titin truncations [as well as from other, less common known mutations] is sufficient to include genetic testing in a patient’s work-up,” Dr. James S. Ware, a coauthor of the new report and a cardiologist at Imperial College, London, said during a press conference in January.

“The American College of Cardiology and American Heart Association guidelines for managing cardiomyopathy say that it is critical to perform longitudinal clinical follow-up on all first-degree relatives of patients with cardiomyopathy. The cost for longitudinal clinical screening is huge and also poses inconvenience for the family members screened. Genetic testing can now identify which family members really need clinical follow-up and which ones don’t need it,” said Dr. Cristine E. Seidman, a coauthor of the new titin-genetics report, professor of genetics and medicine at Harvard Medical School, and director of the Cardiovascular Genetics Center at Brigham and Women’s Hospital, Boston.


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