July 10, 2026Journal of the American College of Cardiology165 citationsOpen Access
Moving Beyond the Sarcomere to Explain Heterogeneity in Hypertrophic Cardiomyopathy
Key Result
The single sarcomere gene hypothesis does not adequately explain all clinical and pathobiologic features of hypertrophic cardiomyopathy, necessitating broader analytical approaches like network medicine.
Key Points
- The aim is to explore the mechanisms contributing to the variability of hypertrophic cardiomyopathy beyond traditional sarcomere function.
- Analyses of molecular changes within cardiomyocytes
- Investigated heterogeneity in muscle structure and function
- Focused on genetic and environmental factors affecting hypertrophy
- Identified multiple pathways beyond the sarcomere that contribute to variability in hypertrophic response
- Heterogeneity observed in contractility among different cardiomyocyte populations
- Genetic mutations impact molecular pathways significantly related to hypertrophic outcomes
PICO
P
Population
Hypertrophic cardiomyopathy
Abstract
Hypertrophic cardiomyopathy (HCM) has been considered a heterogeneous cardiac disease ascribed solely to single sarcomere gene mutations. Limitations of this hypothesis suggest that sarcomere mutations alone do not adequately explain all HCM clinical and pathobiologic 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 (LV) 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. We chart paths forward addressing this knowledge gap utilizing novel analytical approaches, particularly network medicine, to unravel the pathobiologic complexity of HCM.
Cite This Study
Maron et al. (Mon,) conducted a review in Hypertrophic cardiomyopathy. The single sarcomere gene hypothesis does not adequately explain all clinical and pathobiologic features of hypertrophic cardiomyopathy, necessitating broader analytical approaches like network medicine.