TY - JOUR
T1 - Pathogenic Cardiomyopathy-Associated Gene Variants and Prognosis in Atrial Fibrillation
T2 - Results in 18,000 Clinical Trial Participants
AU - Jurgens, Sean J.
AU - Melloni, Giorgio E.M.
AU - Kany, Shinwan
AU - Fabritz, Larissa
AU - Rämö, Joel T.
AU - Goette, Andreas
AU - Kamanu, Frederick K.
AU - Berg, David D.
AU - Magnussen, Christina
AU - Choi, Seung Hoan
AU - Bonaca, Marc P.
AU - Giugliano, Robert P.
AU - Scirica, Benjamin M.
AU - Wiviott, Stephen D.
AU - Bhatt, Deepak L.
AU - Steg, Philippe Gabriel
AU - Raz, Itamar
AU - Braunwald, Eugene
AU - Pirruccello, James P.
AU - Sabatine, Marc S.
AU - Marston, Nicholas A.
AU - Kirchhof, Paulus
AU - Ellinor, Patrick T.
AU - Ruff, Christian T.
PY - 2025/9/9
Y1 - 2025/9/9
N2 - 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.
AB - 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.
KW - atrial fibrillation
KW - genetic testing
KW - genetic variant
KW - heart failure
KW - outcomes
UR - https://www.scopus.com/pages/publications/105013666196
U2 - 10.1016/j.jacc.2025.06.052
DO - 10.1016/j.jacc.2025.06.052
M3 - Article
C2 - 40903137
AN - SCOPUS:105013666196
SN - 0735-1097
VL - 86
SP - 738
EP - 753
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 10
ER -