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

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Sex-Specific Clinical and Genetic Factors Associated With Adverse Outcomes in Hypertrophic Cardiomyopathy. Circulation. Genomic and precision medicine Butters, A., Arnott, C., Sweeting, J., Claggett, B., Cuomo, A., Abrams, D., Ashley, E. A., Day, S. M., Helms, A. S., Lampert, R., Lin, K., Michels, M., Miller, E. M., Olivotto, I., Owens, A., Parikh, V. N., Pereira, A. C., Rossano, J. W., Ryan, T. D., Saberi, S., Stendahl, J. C., Ware, J. S., Atherton, J., Semsarian, C., Lakdawala, N. K., Ho, C. Y., Ingles, J. 2025: e004641

Abstract

Females with hypertrophic cardiomyopathy present at a more advanced stage of the disease and have a higher risk of heart failure and death. The factors behind these differences are unclear. We aimed to investigate sex-related differences in clinical and genetic factors affecting adverse outcomes in the Sarcomeric Human Cardiomyopathy Registry.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 females and males to find the sex-specific hazard ratio (HR).After a mean follow-up of 6.4 years, females 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 (HR, 0.74 [95% CI, 0.59-0.93]; P<0.0001) and ventricular arrhythmia (HR, 0.60 [95% CI, 0.38-0.94]; P=0.027) than males. No sex difference was observed for death (P=0.84). Sarcomere-positive males had higher heart failure (HR, 1.34 [95% CI, 1.06-1.69]) and death risks (HR, 1.48 [95% CI, 1.08-2.04]) not seen in females (HR, 0.85 [95% CI, 0.66-1.08] versus HR, 0.86 [95% CI, 0.71-1.21]). MYBPC3 variants lowered heart failure risk in females (HR, 0.56 [95% CI, 0.41-0.77]) but not in males (HR, 1.29 [95% CI, 0.99-1.67]). A sex difference appeared in moderate (4% to <6%) versus low risk (<4%) European Society of Cardiology hypertrophic cardiomyopathy risk score, with females at moderate risk more prone to ventricular arrhythmia (HR, 3.57 [95% CI, 1.70-7.49]), unobserved in males (HR, 1.13 [95% CI, 0.63-2.03]).We found that clinical and genetic factors contributing to adverse outcomes in hypertrophic cardiomyopathy affect females and males differently. Thus, ÌÇÐÄ´«Ã½ to inform sex-specific management of hypertrophic cardiomyopathy could improve outcomes for both sexes.

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