Sex Differences in Dilated Cardiomyopathy: Evidence Gaps and Future Directions (JACC February 2026-2)-Article: Sex Differences in Dilated Cardiomyopathy: Evidence Gaps and Future Directions

Article: Sex Differences in Dilated Cardiomyopathy: Evidence Gaps and Future Directions

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This comprehensive state-of-the-art review in JACC examines sex differences in dilated cardiomyopathy (DCM), a prevalent heart muscle disease affecting about 1 in 250 people and a leading cause of heart failure and transplantation. The review highlights that DCM is roughly twice as common in men as women, a disparity partially explained by underdiagnosis in women due to sex-neutral diagnostic thresholds and by biological differences such as increased genetic variant penetrance in men.<br /><br />Genetically, around one-third of DCM cases have a genetic basis, with male predominance in most pathogenic variants (e.g., TTN, LMNA, RBM20), except desmoplakin (DSP) variants which are more frequent and penetrant in women. Sex hormones modulate cardiac remodeling and immune responses; testosterone tends to exacerbate hypertrophy and fibrosis whereas estrogen is cardioprotective. Female-specific reproductive factors, including pregnancy complications (notably hypertensive disorders and peripartum cardiomyopathy), influence disease onset and prognosis. Menopause’s cardiovascular impact remains understudied.<br /><br />Clinically, women often present later with less severe structural disease but report worse symptoms and quality of life, possibly reflecting underrecognition. Biomarkers also differ by sex. Outcomes generally favor women with lower long-term mortality and arrhythmic risk, though early heart failure outcomes may be worse. Genetic subtype and sex interact importantly in risk: men with LMNA variants have notably higher arrhythmia risk compared to women, while women with DSP variants face higher arrhythmia risk. Heart failure events are highest in both sexes with PLN and LMNA variants.<br /><br />Treatment guidelines remain largely sex-neutral but women may benefit from lower drug doses and higher left ventricular ejection fraction (LVEF) thresholds for therapy initiation. Despite similar or greater therapeutic benefits, women are underrepresented in trials and often undertreated in clinical practice. Device therapies like cardiac resynchronization and ICDs show some sex-based differences in efficacy and utilization, highlighting disparities in care access.<br /><br />Key knowledge gaps include understanding female-specific risk modifiers (e.g., hormonal contraception, menopause), refining sex- and genotype-specific risk stratification models, and optimizing treatment protocols accounting for sex differences. The review advocates for increased inclusion of women in research, development of sex-specific diagnostic and therapeutic guidelines, and comprehensive investigation into biological and environmental sex influences, to improve equitable, personalized DCM care.

Keywords

dilated cardiomyopathy

sex differences

genetic variants

TTN gene

LMNA gene

desmoplakin (DSP)

sex hormones

pregnancy complications

heart failure outcomes

sex-specific treatment