Clinical Characteristics and Prognostic Impact of Multiple Pathogenic Variants Across the Genetic Spectrum of Arrhythmogenic and Dilated Cardiomyopathies.

BACKGROUND: Arrhythmogenic and dilated cardiomyopathies (ACM/DCM) are genetically heterogenous disorders of the right and/or left ventricle associated with an increased risk of major arrhythmic events (MAE) and end-stage heart failure (ESHF). In arrhythmogenic right ventricular cardiomyopathy (ARVC), the presence of >1 pathogenic/likely pathogenic (P/LP) variant is associated with worse outcomes. Whether this phenomenon occurs for non-desmosomal arrhythmogenic left ventricular cardiomyopathy (ALVC)/DCM genes is unknown. OBJECTIVE: To evaluate the impact of single versus multiple P/LP variants on arrhythmic and heart failure outcomes across the ACM/DCM genetic spectrum. METHODS: We retrospectively analyzed 1,054 genotype-positive patients with ≥1 P/LP variant in a definitive/strong evidence ARVC- or ALVC/DCM-causative gene. Primary endpoints were MAE (sustained ventricular tachycardia, ventricular fibrillation, aborted cardiac arrest, appropriate ICD therapy, sudden cardiac death) and ESHF (transplant or heart failure death). RESULTS: Of 1,054 patients, 27 patients (3%) harbored >1 P/LP variants (21 with ≥1 ALVC/DCM gene; 6 with >1 ARVC genes). MAE occurred in 20% of single-variant patients compared with 48% and 50% of those with >1 P/LP variants in ≥1 ALVC/DCM- and >1 ARVC-susceptibility gene(s), respectively. ESHF occurred in 9%, 29%, and 17% of patients, respectively. On adjusted analysis, >1 P/LP variants in ≥1 ALVC/DCM-susceptibility (MAE HR 2.46 [1.28-4.72], p=0.01; ESHF HR 3.15 [1.35-7.37], p=0.01) and >1 ARVC-susceptibility gene(s) (MAE HR 2.67 [1.28-8.72], p=0.03) were independent predictors of the primary endpoints. CONCLUSION: Multiple P/LP variants confer increased arrhythmic and heart failure risk across the ACM/DCM spectrum.