Abstract Body (Do not enter title and authors here): Background:
The impact of genotype on the risk of arrhythmia and heart failure in dilated and arrhythmogenic cardiomyopathy (DCM/ACM) is not well defined. Better understanding of genetic risk factors is needed to improve patient risk stratification, management, and outcomes.

Methods:
In this observational study, we leveraged the international Sarcomeric Human Cardiomyopathy Registry (SHaRe) to analyze the effect of arrhythmic gene variants on clinical events in patients with DCM/ACM (excluding arrhythmogenic right ventricular cardiomyopathy). Patients were stratified by the presence of pathogenic variants in 8 genes most commonly associated with ACM (AR(+): LMNA, DSP, FLNC, RBM20, PLN, SCN5A, DES, and TMEM43). We assessed for risk of clinical events including ventricular arrhythmia (VA), atrial fibrillation (AF), heart failure (HF), death, and the overall composite of any of these events. Analyses were adjusted for age at diagnosis, sex, and baseline left ventricular ejection fraction (EF). Patients were also stratified by EF ≥50% in subgroup analyses.

Results:
A total of 1373 genotyped adults with DCM/ACM from 6 centers were included with median follow-up of 5.5 (IQR 2.4-10.4) years. Mean diagnosis age was 48 (± 15) years, and 39.5% were female. The cohort included 185 (13.5%) AR(+) patients. AR(+) compared to genotype-negative patients (N=486, 35.4%) had increased risk of VA (HR 5.02, 95% CI 3.46-7.29) and AF (HR 3.02, 95% CI 2.20-4.10). Risk of HF (HR 2.32, 95% CI 1.55-3.49) and the overall composite (HR 2.12, 95% CI 1.68-2.67) were also increased (Figure). Risk of each event remained significant after adjusting for age, sex, and baseline EF (Table). AR(+) patients with EF ≥50% also had increased risk of VA (HR 4.56, 95% CI 2.16-9.63), AF (HR 2.94, 95% CI 1.72-5.03), and the overall composite (HR 2.15, 95% CI 1.41-3.28).

Conclusions:
Genetic testing enables powerful risk stratification for both arrhythmias and heart failure in DCM/ACM independent of age, sex, or EF.