Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe)

Abstract

Background: A better understanding of the factors that contribute to heterogeneous outcomes and lifetime disease burden in hypertrophic cardiomyopathy (HCM) is critically needed to improve patient management and outcomes. The Sarcomeric Human Cardiomyopathy Registry (SHaRe) was established to provide the scale of data required to address these issues, aggregating longitudinal datasets curated by eight international HCM specialty centers.

Methods: Data on 4591 HCM patients (2763 genotyped), followed for a mean of 5.4±6.9 years (24,791 patient-years; median [interquartile range] 2.9 [0.3-7.9] years) were analyzed regarding cardiac arrest, cardiac transplantation, appropriate implantable cardioverter-defibrillator (ICD) therapy, all-cause death, atrial fibrillation, stroke, New York Heart Association Functional Class III/IV symptoms (all comprising the overall composite endpoint), and left ventricular ejection fraction (LVEF)<35%. Outcomes were analyzed individually and as composite endpoints.

Results: Median age of diagnosis was 45.8 [30.9-58.1] years and 37% of patients were female. Age of diagnosis and sarcomere mutation status were predictive of outcomes. Patients <40 years old at diagnosis had a 77% [95% confidence interval: 72%, 80%] cumulative incidence of the overall composite outcome by age 60, compared to 32% [29%, 36%] by age 70 for patients diagnosed >60 years. Young HCM patients (20-29 years) had 4-fold higher mortality than the general United States population at a similar age. Patients with pathogenic/likely pathogenic sarcomere mutations had two-fold greater risk for adverse outcomes compared to patients without mutations; sarcomere variants of uncertain significance were associated with intermediate risk. Heart failure and atrial fibrillation were the most prevalent adverse events, although typically not emerging for several years after diagnosis. Ventricular arrhythmias occurred in 32% [23%, 40%] of patients <40 years at diagnosis, but in 1% [1%, 2%] >60 years.

Conclusions: The cumulative burden of HCM is substantial and dominated by heart failure and atrial fibrillation occurring many years following diagnosis. Young age of diagnosis and the presence of a sarcomere mutation are powerful predictors of adverse outcomes. These findings highlight the need for close surveillance throughout life, and the need to develop disease-modifying therapies.

Keywords: Genetics; Hypertrophic Cardiomyopathy; Natural history; Registry; Risk.

Figure 1.

Age at diagnosis is associated with the lifetime cumulative burden of events. These curves depict the cumulative incidence of events from birth for outcomes of interest, stratified by age at diagnosis <40, 40 to 60, and >60 years. Earlier age at diagnosis is associated with a higher burden of adverse events. Shaded areas indicate 95% CIs. A, Overall composite outcome. B, Ventricular arrhythmia composite. C, Heart failure composite. D, Atrial fibrillation.

Figure 2.

Age-specific mortality in hypertrophic cardiomyopathy (HCM) compared with the general US population from 1999 to 2014. Data from US SHaRe registry (Sarcomeric Human Cardiomyopathy Registry) sites were compared with the Centers for Disease Control and Prevention Wonder database (http://wonder.cdc.gov/) to estimate US general population mortality rates from 1999 to 2014. A, Compared with the general US population, patients with HCM have significantly increased mortality in the youngest and older age groups. B, When the comparison was restricted to the nonfamilial HCM cohort (no sarcomere mutation and no family history of HCM), overall mortality appears similar to that of the general US population. Error bars represent 95% CIs.

Figure 3.

Association between sarcomere mutations and clinical outcomes. Kaplan-Meier survival analyses were performed in the genotyped hypertrophic cardiomyopathy (HCM) subset. Compared with patients with HCM without sarcomere mutations (SARC−), sarcomere mutation carriers (SARC+) have earlier and a higher incidence of adverse outcomes, particularly those with pathogenic and likely pathogenic variants. A, The risk of developing the overall composite outcome by age 50 years is 29.1% for SARC+ patients vs 24.9% for carriers of a variant of unknown significance (SARC VUS) and 14.2% for SARC− patients. B, Ventricular arrhythmia composite outcome. C, Heart failure composite outcome. D, Atrial fibrillation.

Figure 4.

Forest plots showing hazard ratios (HRs) for the composite end points and their individual components, comparing sarcomere mutation carriers (SARC+), patients with hypertrophic cardiomyopathy (HCM) without sarcomere mutations (SARC−), and carriers of a variant of unknown significance (SARC VUS) cohorts. A, SARC+ vs SARC−: Sarcomere mutation carriers have a higher risk of all individual components of the composite end points compared with patients with HCM without sarcomere mutations. B, SARC VUS vs SARC−: SARC VUS patients have a higher risk of the overall composite end point, death, appropriate implantable cardioverter-defibrillator (ICD) firing, atrial fibrillation, and heart failure (HF) with ejection fraction (EF) >55%. C, SARC+ vs SARC VUS: SARC+ and SARC VUS patients have similar risks except for a markedly higher hazard for left ventricular (LV) EF <35% and need for cardiac transplantation or ventricular assist device (VAD) in SARC+ patients. NYHA indicates New York Heart Association.