Genetic Determinants of Severity and Recurrence in Arrhytmia-Induced Cardiomyopathy

Background Arrhythmia-induced cardiomyopathy develops unpredictably in a subset of patients with atrial fibrillation, with marked interindividual variability in severity and recurrence risk. Whether genetic susceptibility contributes to this heterogeneity remains uncertain. Objectives To determine the prevalence and clinical impact of deleterious variants in cardiomyopathy-associated genes among patients with arrhythmia-induced cardiomyopathy. Methods In this retrospective, multicenter study, patients with arrhythmia-induced cardiomyopathy underwent genetic testing targeting cardiomyopathy-associated genes. Individuals carrying pathogenic or likely pathogenic variants were classified as genotype-positive. Baseline characteristics, clinical severity and follow-up outcomes were compared between genotype-positive and genotype-negative patients. Results In 100 patients (mean age 59.9±11.1 years, 18% women, baseline left ventricular ejection fraction 28.2±7.3%), 16 (16%) were genotype-positive, with TTN truncating variants accounting for 75% of variants. Compared with genotype-negative individuals, genotype-positive patients more frequently had a family history of cardiomyopathy (31.2% vs 4.8%, p=0.005) and sudden death (25% vs 6%, p=0.034), presented with more severe disease -including lower ejection fraction (24.6% vs 28.8%, p=0.034) and higher incidence of cardiogenic shock (25% vs 3.6%, p=0.012)- and exhibited a higher risk of recurrence (18.8% vs 2.4%, p=0.028). Conclusions Arrhythmia-induced cardiomyopathy patients exhibit a substantial prevalence of deleterious variants in cardiomyopathy-associated genes, particularly TTN truncating variants. Genotype-positive individuals represent a high-risk subgroup with greater familial burden, more severe clinical presentation and increased recurrence risk. Genetic testing may identify at-risk patients, refine prognostic stratification and guide therapy and follow-up.