Hypertrophic Cardiomyopathy With Left Ventricular Systolic Dysfunction: Insights From the SHaRe Registry

Abstract

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

Methods: Data from 11 high-volume HCM specialty centers making up the international SHaRe Registry (Sarcomeric Human Cardiomyopathy Registry) 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 6793 patients with HCM, 553 (8%) met the criteria for HCM-LVSD. Overall, 75% of patients with HCM-LVSD 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% CI, 2.3-13.5]), atrial fibrillation (HR, 2.6 [95% CI, 1.7-3.5]), and left ventricular ejection fraction <35% (HR, 2.0 [95% CI, 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 left ventricular cavity size (HR, 1.1 [95% CI, 1.0-1.3] and wall thickness (HR, 1.3 [95% CI, 1.1-1.4]), left ventricular ejection fraction of 50% to 60% (HR, 1.8 [95% CI, 1.2, 2.8]-2.8 [95% CI, 1.8-4.2]) at baseline evaluation, the presence of late gadolinium enhancement on cardiac magnetic resonance imaging (HR, 2.3 [95% CI, 1.0-4.9]), and the presence of a pathogenic/likely pathogenic sarcomeric variant, particularly in thin filament genes (HR, 1.5 [95% CI, 1.0-2.1] and 2.5 [95% CI, 1.2-5.1], respectively).

Conclusions: HCM-LVSD affects ≈8% of patients with HCM. Although the natural history of HCM-LVSD was variable, 75% of patients experienced adverse events, including 35% experiencing a death equivalent 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 the risk for incident development of HCM-LVSD (thin filament variants).

Keywords: cardiomyopathy, hypertrophic; genetics; heart failure; prognosis; ventricular dysfunction.

Figure 1.

Kaplan-Meier curves for reaching the composite outcome from the time of diagnosis of hypertrophic cardiomyopathy with left ventricular systolic dysfunction (HCM-LVSD). A, The estimated median time to occurrence of the composite outcome is 8.4 years (95% CI, 7.4–9.3 years). Patients with (B) pathogenic sarcomeric variants (SARC+), (C) atrial fibrillation, or (D) left ventricular ejection fraction (LVEF) <35% at HCM-LVSD diagnosis all have worse outcomes. LVAD indicates left ventricular assist device; SARC−, no clinically relevant sarcomeric variants; and Tx, cardiac transplantation.

Figure 2.

The natural history of hypertrophic cardiomyopathy with left ventricular systolic dysfunction (HCM-LVSD) is variable. Individual-level events are shown in 553 patients with HCM-LVSD from the time of presentation with HCM-LVSD to the time of event or last visit. The x axis represents the patient’s age at diagnosis of HCM-LVSD; the y axis represents years until death (red), cardiac transplantation (blue), left ventricular assist device (LVAD) implantation (purple), or last visit (green). Age at event or last visit is shown above mark for a limited number of patients.

Figure 3.

Forest plot depicting risk predictors for developing the composite outcome of all-cause mortality, cardiac transplantation (Tx), or left ventricular assist device (VAD) implantation in 394 genotyped patients with hypertrophic cardiomyopathy with left ventricular systolic dysfunction (HCM-LVSD) experiencing 136 composite events. Unadjusted number of events per variable is shown in the second column. Hazard ratios are adjusted for all included risk factors. The diamond symbol in the cohort with ≥1 pathogenic/likely pathogenic variant (SARC+) represents the composite effect of thin filament, thick filament, and multiple pathogenic/likely pathogenic (P/LP) sarcomere variants. LVEF indicates left ventricular ejection fraction; LVIDd, left ventricular diastolic diameter; NYHA, New York Heart Association; ref, referent; SARC−, no clinically relevant sarcomere variants identified on genetic testing; and SARC VUS, a variant of unknown significance in a sarcomere gene.

Figure 4.

Time from initial evaluation to developing incident hypertrophic cardiomyopathy with left ventricular systolic dysfunction (HCM-LVSD). Rates of developing incident HCM-LVSD were 1.7% (95% CI, 1.4–2.2) at 5 years, 4.5% (95% CI, 3.8–5.3) at 10 years, and 7.5% (95% CI, 6.5–8.6) at 15 years. SHaRe indicates Sarcomeric Human Cardiomyopathy Registry.

Figure 5.

Forest plot depicting risk predictors for developing incident hypertrophic cardiomyopathy with left ventricular systolic dysfunction (HCM-LVSD). Unadjusted number of events per variable is shown in second column. Cox proportional hazards model is based on 2816 patients, of whom170 developed incident HCM-LVSD. Hazard ratios are adjusted for all included risk factors. The diamond symbol in the cohort with ≥1 pathogenic/likely pathogenic variant (SARC+) represents the composite effect of thin filament, thick filament, and multiple pathogenic/likely pathogenic (P/LP) sarcomeric variants. LVEF indicates left ventricular ejection fraction; LVIDd, left ventricular diastolic diameter; ref, referent; SARC−, no clinically relevant sarcomere variants identified on genetic testing; SARC VUS, a variant of unknown significance in a sarcomere gene; and SRT, septal reduction therapy.