Author + information
- Received December 17, 2018
- Revision received January 23, 2019
- Accepted January 27, 2019
- Published online April 15, 2019.
- Barry J. Maron, MDa,
- Martin S. Maron, MDa,
- Bradley A. Maron, MDb and
- Joseph Loscalzo, MD, PhDb,∗ (, )@BrighamWomens
- aHCM Institute, Division of Cardiology, Tufts Medical Center, Boston, Massachusetts
- bDepartment of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
- ↵∗Address for correspondence:
Dr. Joseph Loscalzo, Department of Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115.
• Single sarcomere gene mutations are insufficient to explain the full clinical and endophenotypic profile of HCM.
• Limitations of the single sarcomere gene hypothesis include failure to identify pathogenic mutations in the majority of patients with HCM or account for the disease’s mechanistic complexity.
• Innovative research methods can be useful for identifying novel determinants of HCM and clarifying the mechanisms responsible for disease heterogeneity.
Hypertrophic cardiomyopathy (HCM) has been considered a heterogeneous cardiac disease ascribed solely to single sarcomere gene mutations. However, limitations of this hypothesis suggest that sarcomere mutations alone do not adequately explain all HCM clinical and pathobiological features. Disease-causing sarcomere mutations are absent in ∼70% of patients with established disease, and sarcomere gene carriers can live to advanced ages without developing HCM. Some features of HCM are also inconsistent with the single sarcomere gene hypothesis, such as regional left ventricular hypertrophy and myocardial fibrosis, as well as structurally abnormal elongated mitral valve leaflets and remodeled intramural coronary arterioles, which involve tissue types that do not express cardiomyocyte sarcomere proteins. It is timely to expand the HCM research focus beyond a single molecular event toward more inclusive models to explain this disease in its entirety. The authors chart paths forward addressing this knowledge gap using novel analytical approaches, particularly network medicine, to unravel the pathobiological complexity of HCM.
Dr. Bradley A. Maron has received support from National Institutes of Health (NIH) grants R56HL131787, 1R01HL139613-01, R21HL145420, and 1U01HL125215-01, and the National Scleroderma Foundation. Dr. Loscalzo has received support from NIH grants R37HL061795, U54 HL119145, U01 HG007690, and P50 GM107618, and American Heart Association grant D700382; and he is a cofounder of Scipher Medicine, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.
- Received December 17, 2018.
- Revision received January 23, 2019.
- Accepted January 27, 2019.
- 2019 American College of Cardiology Foundation
This article requires a subscription or purchase to view the full text. If you are a subscriber or member, click Login or the Subscribe link (top menu above) to access this article.