Genotype and arrhythmic risk in dilated cardiomyopathy

Background and Aims Dilated cardiomyopathy (DCM) presents with variable risk of life-threatening arrhythmias. Genetic diagnosis guides sudden death prevention strategies, but risk magnitude for arrhythmogenic genes remains unknown. This study leveraged the international Sarcomeric Human Cardiomyopathy Registry (SHaRe) to address this gap and improve risk stratification. Methods Effects of pathogenic/likely pathogenic (P/LP) variants in genes associated with DCM and ventricular arrhythmia on clinical events were analysed in DCM-SHaRe patients. Patients were stratified by presence of a P/LP variant in a high-arrhythmogenic risk gene (LMNA, DSP, FLNC, RBM20, PLN, SCN5A, DES, TMEM43), a low-arrhythmogenic risk gene (TTN, TNNT2, MYH7, others), or gene-elusive. Outcomes included age-, sex-, and baseline left ventricular ejection fraction (LVEF)-adjusted risk of major ventricular arrhythmia (MVA), atrial fibrillation (AF), heart failure (HF), death, and their composite. Results Among 2660 genotyped adults with DCM (mean diagnosis age 47 ± 15 years, 39.8% female), 434 (16%) had P/LP variants in high-arrhythmogenic genes, 451 (17%) in low-arrhythmogenic genes, and 1775 (67%) were gene-elusive. Compared with gene-elusive patients, patients with high-arrhythmogenic P/LP variants showed increased MVA [hazard ratio (HR) 3.25, 95% confidence interval (CI) 2.63–4.01], AF (HR 2.42, 95% CI 1.96–2.98), HF (HR 2.46, 95% CI 1.89–3.19), and composite (HR 1.97, 95% CI 1.69–2.29) risk, which remained significant after adjusting for age, sex, and LVEF. Patients with high-arrhythmogenic P/LP variants and LVEF ≥ 50% maintained increased MVA (HR 2.36, 95% CI 1.59–3.51) and composite (HR 1.63, 95% CI 1.25–2.12) risk. Conclusions Genetic testing enables powerful risk stratification for arrhythmias and HF in DCM independent of age, sex, or LVEF.