Pathogenic Cardiomyopathy-Associated Gene Variants and Prognosis in Atrial Fibrillation

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.