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BACKGROUND: Genetic variants in cardiomyopathy genes are associated with risk of atrial fibrillation (AF), although data on clinical outcomes for AF patients with such variants remain sparse.

OBJECTIVES: We aimed to study the prognostic implication of rare cardiomyopathy-associated pathogenic variants (CMP-PLP) in AF patients from large, well-phenotyped clinical trials.

METHODS: CMP-PLP carriers were identified using exome sequencing in 5 multinational trials from the Thrombolysis in Myocardial Infarction study group (ENGAGE AF, FOURIER, SAVOR, PEGASUS, and DECLARE), with replication in the EAST-AFNET-4 trial. Associations with centrally adjudicated outcomes were assessed using logistic and Cox regression, among patients with AF.

RESULTS: In 17,190 patients with a history of AF, we identified 421 (2.4%) CMP-PLP carriers. CMP-PLP variants were associated with a history of heart failure (HF) (OR: 1.66; P < 0.0001), most notably for dilated cardiomyopathy-associated variants. CMP-PLP variants were also associated with incident HF hospitalizations (HR: 1.75; 95% CI: 1.34-2.29; P < 0.0001), most notably for hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy variants. CMP-PLP variants were nominally associated with increased risk of cardiovascular death (HR: 1.46; 95% CI: 1.06-2.02; P = 0.02), driven mainly by dilated cardiomyopathy-associated variants. In contrast, CMP-PLP variants were not associated with prevalent (OR: 0.99; P = 0.96) or incident (HR: 0.95; P = 0.84) ischemic stroke, although anticoagulation use was high. In replication, among 1,479 EAST-AFNET-4 participants, CMP-PLP variants were also associated with prevalent HF and incident HF hospitalizations.

CONCLUSIONS: In patients with AF, rare cardiomyopathy gene variants are associated with increased risks of HF hospitalizations and cardiovascular death, but not stroke. These results, collected from large well-phenotyped clinical trials, demonstrate important prognostic implications for cardiomyopathy-associated genetic variants in AF patients.