Genetic determinants of severity and recurrence in arrhythmia-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.