Genotype Independently Predicts Heart Failure in Hypertrophic Cardiomyopathy Patients, Beyond LVEF and NT-proBNP

Hypertrophic cardiomyopathy (HCM) is a prevalent genetic heart disorder characterized by left ventricular hypertrophy and a significant risk of progression to heart failure (HF). While approximately 40% of HCM cases are linked to variants in sarcomere protein genes, current clinical predictors like left ventricular ejection fraction (LVEF), peak VO2, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels don't fully capture individual HF risk. There's a critical need for more precise risk stratification tools to identify HCM patients most vulnerable to HF, enabling earlier and more targeted interventions.

This observational, single-center cohort study enrolled 505 genotyped HCM patients (median age 52 years, 33% women). Patients were categorized into gene-positive (G+) and gene-elusive (G-) groups based on genetic testing for sarcomere variants. The primary endpoint was a composite of HF-related death or cardiac transplantation. Secondary endpoints included cardiac death, arrhythmic events, and all-cause mortality. Researchers utilized proportional hazards models to evaluate the independent predictive value of genetic status, log-transformed NT-proBNP levels, peak VO2, and LVEF for these outcomes.

During a median follow-up of 10.6 years, 34 patients (6.7%) experienced the primary outcome (HF-related death: 22 [4.4%]; heart transplantation: 12 [2.4%]). The HF endpoint occurred in 12.8% (28 of 219) of the G+ group, significantly higher than the 2.1% (6 of 286) observed in the G- group. In multivariable Cox analysis, G+ status emerged as a powerful independent predictor of HF outcomes.

G+ status demonstrated a hazard ratio (HR) of 5.86 (95% CI: 2.26-15.25; P < 0.001) for HF-related death or cardiac transplantation. Other factors independently associated with HF outcomes included log NT-proBNP (HR: 2.46; 95% CI: 1.59-3.80; P < 0.001), peak VO2 (HR: 0.90; 95% CI: 0.82-0.98; P < 0.001), and LVEF (HR: 0.74 per 5% increment; 95% CI: 0.63-0.86; P < 0.001). For secondary endpoints, 60 patients (11.9%) died of cardiac causes, 34 (6.7%) experienced arrhythmic events, and 115 (22.8%) died of any cause.