Clinical characteristics and prognostic impact of multiple pathogenic variants across the genetic spectrum of arrhythmogenic and dilated cardiomyopathies.

BACKGROUND

Arrhythmogenic and dilated cardiomyopathies (ACM and DCM, respectively) are genetically heterogeneous disorders of the right and/or left ventricles 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 or 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

This study aimed to evaluate the impact of single vs multiple P/LP variants on arrhythmic and heart failure outcomes across the ACM/DCM genetic spectrum.

METHODS

We retrospectively analyzed 1054 genotype-positive patients with ≥1 P/LP variant in a definitive or strong evidence ARVC- or ALVC/DCM-causative gene. Primary endpoints were MAE (sustained ventricular tachycardia, ventricular fibrillation, aborted cardiac arrest, appropriate implantable cardioverter-defibrillator therapy, and sudden cardiac death) and ESHF (transplant or heart failure death).

RESULTS

Of the 1054 patients, 27 (3%) harbored >1 P/LP variants (21 with ≥1 ALVC/DCM gene; 6 with >1 ARVC gene). 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 hazard ratio [HR], 2.46 [1.28-4.72]; P = .01 and ESHF HR, 3.15 [1.35-7.37], P = .01) and >1 ARVC-susceptibility gene(s) (MAE HR, 2.67 [1.28-8.72], P = .03) were independent predictors of the primary endpoints.

CONCLUSION

Multiple P/LP variants confer an increased risk of arrhythmic events and heart failure across the ACM/DCM spectrum.