Are clinical trajectories in obstructive hypertrophic cardiomyopathy mutation-specific? A systematic review and meta-analysis of MYH7 vs. MYBPC3.

BACKGROUND

The clinical course of obstructive hypertrophic cardiomyopathy (HCM) is highly variable. Whether this heterogeneity reflects mutation-specific clinical trajectories remains a pivotal question for prognostication and personalized management.

OBJECTIVES

This study aimed to determine if pathogenic sarcomeric variants in MYH7 and MYBPC3 are associated with distinct clinical pathways in obstructive HCM, by comparing their associations with age at presentation, severity of hypertrophy, left ventricular outflow tract (LVOT) obstruction, and arrhythmic outcomes.

METHODS

We conducted a systematic review and meta-analysis following PRISMA 2020 guidelines. Four databases were searched up to October 2025 for cohort or registry studies reporting on sarcomeric variants and quantitative phenotypes in obstructive HCM. Data were extracted independently in duplicate, and effect estimates were pooled as odds ratios (OR), mean differences (MD), or hazard ratios (HR) with 95% confidence intervals (CI).

RESULTS

Ten studies comprising 192,361 participants were included, encompassing a large population sequencing cohort (UK Biobank/Mass General Brigham) of 184,511 and nine clinical/registry cohorts totaling 7,850. Carriers of MYH7 variants presented with a more obstructive and arrhythmogenic phenotype, demonstrating higher odds of LVOT obstruction (pooled OR range: 1.95-4.30) and a 70% increased risk of incident atrial fibrillation (HR: 1.7, 95% CI: 1.1-2.6). In contrast, carriers of MYBPC3 variants, while often presenting later, faced a significantly elevated risk of progressive systolic dysfunction (adjusted HR: 2.53, 95% CI: 1.09-5.82). MYH7 was also associated with greater interventricular septal thickness (MD: 1.30 mm, 95% CI: 0.06-2.54). Substantial heterogeneity (I 2 = 80.7%) was observed, reflecting real-world differences in phenotype ascertainment.

CONCLUSIONS

This analysis confirms that obstructive HCM follows mutation-specific clinical trajectories. Genotype provides critical prognostic insights, delineating an MYH7 driven path of early obstruction and arrhythmia from an MYBPC3 associated trajectory of long term systolic decline. These findings support the integration of genetic data into personalized surveillance strategies.