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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
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Clinical characteristics and prognostic impact of multiple pathogenic variants across the genetic spectrum of

Cyrus M Nouraee1, Matteo Castrichini2, William H Swain2

  • 1Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.

Heart Rhythm
|August 11, 2026
PubMed

Insights

Multiple pathogenic variants in arrhythmogenic cardiomyopathy (ACM) and dilated cardiomyopathy (DCM) genes significantly increase risks for major arrhythmic events and heart failure. This finding applies across the ACM/DCM genetic spectrum, highlighting the importance of variant burden.

Area of Science:

  • Cardiology
  • Genetics
  • Molecular Biology

Background:

  • Arrhythmogenic and dilated cardiomyopathies (ACM/DCM) are genetic disorders affecting heart ventricle function.
  • Increased risk of major arrhythmic events (MAE) and end-stage heart failure (ESHF) are key concerns.
  • While multiple variants worsen outcomes in arrhythmogenic right ventricular cardiomyopathy (ARVC), their impact on other ACM/DCM genes is unclear.

Purpose of the Study:

  • To investigate the effect of single versus multiple pathogenic/likely pathogenic (P/LP) variants on MAE and ESHF outcomes.
  • To analyze these outcomes across the entire spectrum of ACM/DCM-associated genes.

Main Methods:

  • Retrospective analysis of 1,054 patients with at least one P/LP variant in ARVC or ALVC/DCM genes.
  • Primary endpoints included MAE (ventricular arrhythmias, cardiac arrest, ICD therapy, sudden death) and ESHF (transplant or heart failure death).

Main Results:

  • Only 3% of patients (27/1054) had multiple P/LP variants.
  • Patients with multiple P/LP variants showed significantly higher rates of MAE (48-50%) and ESHF (17-29%) compared to single-variant patients (20% MAE, 9% ESHF).
  • Multiple P/LP variants in ALVC/DCM and ARVC genes were independent predictors of adverse outcomes.

Conclusions:

  • Multiple P/LP variants are associated with increased risk of arrhythmias and heart failure in ACM/DCM.
  • This finding extends across both ARVC and ALVC/DCM genetic categories.
  • Variant burden is a critical factor in ACM/DCM prognosis.
Abstract

Keywords:
Arrhythmogenic cardiomyopathyArrhythmogenic left ventricular cardiomyopathyArrhythmogenic right ventricular cardiomyopathyDilated cardiomyopathyEnd-stage heart failureSudden cardiac deathVentricular arrhythmias

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