Sex differences in long-term arrhythmogenic and mortality outcomes in patients with hypertrophic cardiomyopathy: a 20-year longitudinal observational study

Background Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiomyopathy and has a wide heterogenous clinical presentation with variable age of onset, cardiac remodeling, disease expression, progression, and complications. Despite known sex differences in HCM outcomes, there remains a paucity of data regarding the long-term arrhythmogenic and mortality outcomes stratified by sex in HCM patients. Purpose To assess the sex-based differences in long-term incidence of arrhythmic events and mortality in HCM patients. Methods We performed 20-year longitudinal observational study of patients with HCM at a quaternary referral HCM center. Data were collected from electronic health records (EHR), with mortality information sourced from the National Death Index (NDI). Arrhythmic events (AEs) were defined as sustained ventricular tachycardia, implantable cardioverter-defibrillator shock, appropriate anti-tachycardia pacing, aborted cardiac arrest or SCD, extracted by previously validated natural language processing algorithms and supplemental EHR review. Cardiac death was defined based on NDI description combined International Classification of Diseases codes. Risk of events was estimated using Kaplan-Meier survival analyses or cumulative incidence (cardiac death). Results Overall, a total of 5,099 patients median age at diagnosis of 58.4 years (IQR 47.1, 68.0), 2,246 (44%) were female. Females were, on average, 5 years older at baseline than males. The median maximum left ventricular wall thickness was 18 mm (IQR 15–21) in females and 19 mm (IQR 16–22) in males (p <.0001). At baseline, females had a higher prevalence of LVOT obstruction (81% vs 75%, p <.0001), moderate/severe mitral regurgitation (24 % vs 15%, p <.0001), heart failure (20% vs 16.0%, p <.0001) and hypertension (40% vs 37%, p 0.009), but lower rates of atrial fibrillation (21% vs 25%, p 0.002). During median 0.6 year arrhythmic event follow-up, 69 females and 177 males experienced at least 1 AE. The 10-year risk for an AE was 8.7% (95% CI: 6.2–11.2%) in females and 13.8% (95% CI 11.3–16.1%) in males (Figure). A total of 699 females and 590 males died from any cause over a median of 12 years of follow-up with a 10-year risk of all-cause mortality of 23.3% (95% CI: 21.4–25.2%) for females and 15.6 % (14.2-17.0%) in males. Of these, 253 (11.3%) females and 233 (8.2%) males died from a cardiac-related death. The 10-year risk for cardiac death was 8.7% (95% CI 7.5-10.0%) and 6.5% (95% CI 5.6-7.6%) for females and males, respectively. Conclusion In this large cohort of patients with HCM, females had a lower long-term risk of AEs but higher risks of all-cause mortality and cardiac death. These findings highlight the importance of further research evaluating the causes and risk factors of the differential outcomes underscoring the need for continued improvement in risk prediction models and outcome management based on sex in HCM patients.