HCM in the modern era: low mortality and predominantly predictable sudden cardiac death under systematic risk stratification

Background Hypertrophic cardiomyopathy (HCM) is associated with significant morbidity and mortality. We aimed to characterise clinical outcomes in a modern HCM cohort managed according to current ESC guidelines in an expert centre. Methods We conducted a prospective analysis of a single-centre HCM cohort with follow-up from 2017 to 2025. All-cause mortality was ascertained through the national electronic health records platform (Greek National Network, icardiacnet), ensuring complete capture of deaths. Mode of death was determined through communication with relatives and forensic services. Risk stratification used the ESC HCM score alongside modifying factors, including left ventricular ejection fraction (LVEF) <50%, myocardial fibrosis >15%, and apical aneurysm. End-stage HCM was defined as LVEF <50%. Results A total of 551 patients with HCM were included (66% male, mean HCM Risk-SCD score 3.2 ± 2.6%, mean age 41.5 ± 17 years, 32% obstructive). Genetic testing was performed in 161 patients (29%), of whom 50% harboured a pathogenic/likely pathogenic variant. The most frequently implicated genes were MYBPC3 (48%) and MYH7 (32%), together accounting for 80% of P/LP variants. Most patients (79%) were classified as low risk, with 9% intermediate and 12% high risk. An implantable cardioverter-defibrillator (ICD) was implanted in 81 patients (15%). Additional modifying risk factors were present in 10.3% of the cohort (8% significant LGE, 2.3% apical aneurysm). During follow-up, 27% developed diastolic HF and 4.2% progressed to end-stage HCM. A total of 25 patients died (4.5% - 0.57% per year): SCD in 9, HF-related in 11 and non-cardiac in 5 patients. SCD occurred at a significantly younger age compared with HF-related death (38 ± 17 vs. 73 ± 9 years). Among the 9 SCD patients, 6 had been previously identified as high-risk including 3 patients who died suddenly with an ICD in situ. Of the 3 SCD patients without identifiable high-risk features, 2 had clinical features suggestive of a syndromic phenocopy: one with borderline systolic function and syndromic facial characteristics, and one with early-onset HF, a borderline risk score (3.5%) and near-significant LGE (14%). There was no significant association between the presence of a P/LP variant and the combined outcome of SCD, HF progression or end-stage disease. Conclusions In this contemporary real-world HCM cohort, overall mortality and SCD rates were low, supporting the effectiveness of modern risk stratification tools and guideline-based management. SCD not captured as high risk by current models was rare (0.5% of the cohort) and may partly reflect limitations in differential diagnosis and phenocopy recognition rather than inadequacy of the models themselves. Taken together, these findings reinforce that, in the current era, HCM can be a relatively low-mortality condition when managed with systematic risk assessment, timely ICD implantation and structured HF surveillance.