Arrhythmic genotypes and risk of major ventricular arrhythmia in dilated cardiomyopathy: a multicentre japanese cohort

Background Current European Society of Cardiology (ESC) guidelines recommend implantable cardioverter defibrillator (ICD) implantation for patients with dilated cardiomyopathy (DCM) carrying arrhythmia-associated pathogenic variants. However, evidence from large East Asian cohorts remains limited. Purpose To investigate the incidence of major ventricular arrhythmia (MVA) by genotype among patients with DCM. Methods We analyzed data from a multicentre retrospective study of genetically tested probands with DCM from 22 cardiovascular centres in Japan. Patients were categorized as (1) pathogenic variants in high-risk genes (LMNA, PLN, FLNC, TMEM43, RBM20, DSP, or DES), (2) other pathogenic variants, and (3) pathogenic variants negative. The primary outcome was MVA, including sustained ventricular tachycardia, ventricular fibrillation, or sudden cardiac death. Event rates were summarized with Kaplan–Meier estimates and Cox proportional-hazards models. Results Among 1,240 patients analyzed, pathogenic/likely-pathogenic variants were identified in 332 (26.8%) patients, of whom 88 (7.1%) patients had pathogenic variants in high-risk genes. Patients with high-risk genotype were younger at diagnosis and had a higher prevalence of a family history of cardiomyopathy compared with the genotype-negative group. Median (IQR) follow-up was 2,209 (1,001–4,111) days. MVA occurred in 10 (14.7%) patients with high-risk gene variants, 11 (5.1%) patients with other pathogenic variants, and 31 (4.2%) patients with pathogenic variants negative. The high-risk genotype group had a higher risk of MVA (hazard ratio 3.11 [95% CI: 1.67–5.80, p<0.001]) compared to the genotype-negative group. The risk of MVA was similar across baseline left ventricular ejection fraction in the high-risk genotype group. Conclusion In this East Asian DCM cohort, ESC-defined high-risk arrhythmia-associated genotypes had a markedly increased risk of MVA. These findings support the applicability of current ESC genotype-based risk stratification to East Asian populations and may help refine ICD decision-making.