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Cardiovascular Health and Outcomes in Carriers With Genetic Variants of Hypertrophic Cardiomyopathy

Nirav Patel1, Mokshad Gaonkar1, Akhil Pampana1

  • 1Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL.

Mayo Clinic Proceedings
|July 24, 2025
PubMed

Insights

Genetic variants in sarcomere-encoding genes for hypertrophic cardiomyopathy (SARC-HCM-P/LP) significantly elevate cardiovascular risk. This risk persists even with favorable cardiovascular health (CVH) metrics, underscoring the primary role of genetic predisposition.

Area of Science:

  • Cardiovascular Genetics
  • Cardiomyopathy Research
  • Public Health Genomics

Background:

  • Hypertrophic cardiomyopathy (HCM) is often linked to genetic variants in sarcomere-encoding genes.
  • Understanding the interaction between genetic predisposition and modifiable cardiovascular health (CVH) factors is crucial for risk stratification.

Purpose of the Study:

  • To investigate the combined impact of pathogenic or likely pathogenic variants in sarcomere-encoding genes (SARC-HCM-P/LP) and cardiovascular health (CVH) on adverse cardiovascular outcomes.
  • To determine if favorable CVH mitigates the risk associated with SARC-HCM-P/LP variants.

Main Methods:

  • Retrospective cohort study utilizing UK Biobank data (n=159,375) with whole exome sequencing.
  • Participants stratified by SARC-HCM-P/LP variant status and assessed for CVH using the Life's Essential 8 score.
  • Cox proportional hazards models analyzed the association between genetic status, CVH profiles, and a composite outcome of heart failure, arrhythmias, and cardiovascular mortality.

Main Results:

  • SARC-HCM-P/LP carriers (n=446) exhibited a significantly higher risk of adverse cardiovascular outcomes compared to non-carriers (SARC-NEG).
  • This elevated risk was consistent across all CVH profiles (favorable, intermediate, unfavorable) in SARC-HCM-P/LP carriers.
  • The adjusted hazard ratio for the primary outcome in SARC-HCM-P/LP carriers ranged from 2.12 to 2.30, irrespective of their CVH status.

Conclusions:

  • Individuals with SARC-HCM-P/LP variants face a substantially increased cardiovascular risk.
  • Favorable cardiovascular health metrics do not eliminate the heightened risk conferred by SARC-HCM-P/LP variants.
  • Genetic predisposition plays a dominant role in cardiovascular risk for individuals with SARC-HCM-P/LP variants.
Abstract

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