Key result
Multiple pathogenic variants in ALVC/DCM genes linked to ~2.5-fold higher risk of major arrhythmic events.
Why the study?
Whether the presence of multiple pathogenic or likely pathogenic variants affects arrhythmic and heart failure outcomes across the ACM/DCM genetic spectrum was unknown.
Does having multiple pathogenic variants increase the risk of major arrhythmic events and end-stage heart failure compared to having a single variant in patients across the arrhythmogenic and dilated cardiomyopathy genetic spectrum?
Cohort (n=1,054)
Does having multiple pathogenic variants increase the risk of major arrhythmic events and end-stage heart failure compared to having a single variant in patients across the arrhythmogenic and dilated cardiomyopathy genetic spectrum?
Hazard Ratio: 2.46 (95% CI 1.28–4.72)
Absolute Event Rate: 48% vs 20%
p-value: p=.01
In patients with arrhythmogenic and dilated cardiomyopathies, harboring multiple pathogenic genetic variants significantly increases the risk of severe arrhythmias and end-stage heart failure compared to a single variant.
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.
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Nouraee et al. (2026) conducted a cohort in Arrhythmogenic and dilated cardiomyopathies (ACM and DCM) (n=1,054). >1 pathogenic or likely pathogenic (P/LP) variants vs. Single P/LP variant was evaluated on Major arrhythmic events (MAE) for >1 P/LP variant in ≥1 ALVC/DCM-susceptibility gene (HR 2.46, 95% CI 1.28-4.72, p=.01). Harboring >1 pathogenic variant in ALVC/DCM genes was associated with a significantly increased risk of major arrhythmic events (HR 2.46; 95% CI 1.28-4.72; P=.01) compared to a single variant.
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