Background: The terminology "end-stage" has been used to describe hypertrophic cardiomyopathy (HCM) with left ventricular systolic dysfunction (herein referred to as HCM-LVSD), defined when left ventricular ejection fraction (LVEF) <50% is present. The prognosis of HCM-LVSD has reportedly been poor, but due to its relative rarity, natural history remains incompletely characterized.

Methods: Data from eleven high-volume HCM specialty centers comprising the international Sarcomeric Human Cardiomyopathy Registry (SHaRe) were used to describe the natural history of patients with HCM-LVSD. Cox proportional hazards models were used to identify predictors of prognosis and incident development.

Results: From a cohort of 6,793 HCM patients, 553 (8%) met criteria for HCM-LVSD. Overall, 75% of HCM-LVSD patients experienced clinically relevant events and 35% met the composite outcome (all-cause death (n=128), cardiac transplantation (n=55) or left ventricular assist device implantation (n=9). After recognition of HCM-LVSD, the median time to composite outcome was 8.4 years. However, there was substantial individual variation in natural history. Significant predictors of the composite outcome included the presence of multiple pathogenic/likely pathogenic sarcomeric variants (Hazard Ratio (HR) 5.6 [95% Confidence Interval 2.3-13.5]), atrial fibrillation (HR 2.6 [1.7, 3.5]), LVEF <35% (HR 2.0 [1.3, 2.8]). The incidence of new HCM-LVSD was ~7.5% over 15 years. Significant predictors of developing incident HCM-LVSD included greater LV cavity size (HR 1.1 [1.0-1.3] and wall thickness (HR 1.3 [1.1, 1.4]), LVEF 50-60% (HR 1.8 [1.2, 2.8]-2.8 [1.8, 4.2]) at baseline evaluation, the presence of late gadolinium enhancement on cardiac magnetic resonance imaging (HR 2.3 [1.0, 4.9]), and the presence of a pathogenic/likely pathogenic sarcomeric variant, particularly in thin filament genes (HR 1.5 [1.0, 2.1] and 2.5 [1.2, 5.1], respectively).

Conclusions: HCM-LVSD affects approximately 8% of HCM patients. Although the natural history of HCM-LVSD was variable, 75% of patients experienced adverse events, including 35% experiencing a death-equivalent with an estimated median time of 8.4 years after developing systolic dysfunction. In addition to clinical features, genetic substrate appears to play a role in both prognosis (multiple sarcomeric variants) and in the risk for incident development of HCM-LVSD (thin filament variants).