Abstract 4367634: Genetic Variants and Prognosis in Hypertrophic Cardiomyopathy: A Systematic Review and Meta-analysis

Background: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease, frequently associated with sarcomere gene variants. While genetic testing is key for diagnosis and family screening, the prognostic relevance of sarcomere-positive versus sarcomere-negative status remains unclear. Clarifying this relationship is increasingly important with the emergence of genotype-informed therapies. Hypothesis: We hypothesized that HCM patients with pathogenic sarcomere variants have a higher risk of major adverse cardiac events (MACE), including sudden cardiac death (SCD), heart failure hospitalization, appropriate ICD therapy, and need for heart transplantation or LVAD. Methods: We conducted a systematic review and meta-analysis according to PRISMA guidelines, searching PubMed, Embase, and Cochrane through May 2025. Eligible studies included adult HCM patients with genetic testing and defined clinical outcomes. Two reviewers independently screened and extracted data. Risk of bias was assessed using the Newcastle-Ottawa Scale. Pooled hazard ratios (HRs) or risk ratios (RRs) were calculated using random-effects models. Subgroup analyses were performed by mutation type (e.g., MYH7, MYBPC3), age group, and endpoint category (arrhythmic vs HF-related). Results: Seventeen studies comprising 7,860 HCM patients were included. Of these, 4,180 (53%) were genotype-positive. Sarcomere-positive patients had significantly higher risks of SCD or appropriate ICD therapy (HR 2.12, 95% CI 1.48–3.02, p<0.001) and HF hospitalization (HR 1.67, 95% CI 1.21–2.34, p=0.002). Among mutation carriers, MYH7 variants were associated with higher likelihood of progression to transplant or LVAD compared to MYBPC3 or genotype-negative cases. Heterogeneity was moderate and resolved in subgroup analyses. Sensitivity analyses confirmed result stability. Conclusions: Pathogenic sarcomere gene variants in HCM are associated with increased arrhythmic and HF-related risks. These findings support the role of genetic testing in prognostic stratification and clinical management. Genotype may inform timing of therapy and guide future personalized approaches.