Sex-Specific Clinical and Genetic Factors Associated with Adverse Outcomes in Hypertrophic Cardiomyopathy

ABSTRACT Background Women with HCM present at a more advanced stage of the disease and have a higher risk of heart failure and death. The factors contributing to these differences are unclear. We aimed to investigate sex differences in clinical and genetic factors associated with adverse outcomes in the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Methods Cox proportional hazard models were fit with a sex interaction term to determine if significant sex differences existed in the association between risk factors and outcomes. Models were fit separately for women and men to find the sex-specific hazard ratio. Results After a mean follow-up of 6.4 years, women had a higher risk of heart failure (HR 1.51; 95% CI 1.21-1.88, p=0.0003) but a lower risk of atrial fibrillation (0.74; 0.59-0.93; p<0.0001) and ventricular arrhythmia (0.60; 0.38-0.94; p=0.027) than men. No sex difference was observed for death (p=0.84). Sarcomere-positive men had a higher risk of heart failure and death, not seen in women (p-heterogeneity=0.006 & p-heterogeneity=0.035, respectively). MYBPC3 variants were associated with lower heart failure risk in women than other HCM subgroups, with no significant change for men (p-heterogeneity <0.0001). Women with moderate risk of ventricular arrhythmia (4% to <6% ESC risk score) were at a higher risk of ventricular arrhythmia than those scoring <4%, not observed in men (p-heterogeneity= 0.019). Conclusion Clinical and genetic factors contributing to adverse outcomes in HCM affect women and men differently. Research to inform sex-specific management of HCM could improve outcomes for both sexes.