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Pathogenic Cardiomyopathy-Associated Gene Variants and Prognosis in Atrial Fibrillation: Results in 18,000 Clinical

Sean J Jurgens1, Giorgio E M Melloni2, Shinwan Kany3

  • 1Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam UMC location University of Amsterdam, Amsterdam, the Netherlands.

Journal of the American College of Cardiology
|September 3, 2025
PubMed

Insights

Rare genetic variants linked to cardiomyopathy increase heart failure risk and cardiovascular death in atrial fibrillation (AF) patients. These genetic markers do not elevate stroke risk, according to large clinical trial data.

Area of Science:

  • Cardiovascular Genetics
  • Clinical Cardiology
  • Genomics

Background:

  • Genetic variants in cardiomyopathy genes are known risk factors for atrial fibrillation (AF).
  • However, data on the clinical outcomes for AF patients carrying these specific genetic variants are limited.
  • Understanding these associations is crucial for risk stratification and patient management.

Purpose of the Study:

  • To investigate the prognostic significance of rare cardiomyopathy-associated pathogenic variants (CMP-PLP) in patients diagnosed with atrial fibrillation.
  • To analyze outcomes in a large cohort from well-characterized clinical trials.

Main Methods:

  • Exome sequencing was used to identify CMP-PLP carriers across five multinational trials (ENGAGE AF, FOURIER, SAVOR, PEGASUS, DECLARE) and replicated in the EAST-AFNET-4 trial.
  • Logistic and Cox regression models were employed to assess associations with adjudicated outcomes in AF patients.
  • The study included 17,190 patients with a history of AF, identifying 421 (2.4%) CMP-PLP carriers.

Main Results:

  • CMP-PLP carriers showed a higher prevalence of heart failure (HF) history (OR: 1.66) and were at increased risk for incident HF hospitalizations (HR: 1.75).
  • Dilated, hypertrophic, and arrhythmogenic right ventricular cardiomyopathy variants were notably associated with these HF outcomes.
  • A nominal association was found with increased cardiovascular death risk (HR: 1.46), primarily driven by dilated cardiomyopathy variants, but no significant association with ischemic stroke risk was observed.

Conclusions:

  • Rare cardiomyopathy gene variants in AF patients are linked to elevated risks of heart failure hospitalizations and cardiovascular death.
  • These genetic variants do not appear to increase the risk of stroke in AF patients.
  • The findings highlight the prognostic importance of identifying cardiomyopathy-associated genetic variants in the management of atrial fibrillation.
Abstract

Keywords:
atrial fibrillationgenetic testinggenetic variantheart failureoutcomes

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