Sex-Specific Mechanisms and Therapeutics in Heart Failure: Translating Biology into Personalized Care

Abstract

Sex is one of the most consistent, yet clinically underexploited, determinants of heart failure phenotype, mechanism and outcome. Building on landmark reviews and the 2024 scientific statement of the Heart Failure Association, which documented well-recognized phenotypic differences but noted that their mechanisms remain only partially defined, this review examines how sex differences in heart failure arise and how firmly they should guide practice. Epidemiologically, female predominance in heart failure with preserved ejection fraction is age- and menopause-dependent rather than lifelong. Mechanistically, sex-divergent hormonal signalling, autonomic tone, coronary microvascular dysfunction and myocardial fibrosis often produce similar phenotypes through different mechanisms: microvascular dysfunction is similarly prevalent in both sexes but linked to fibrosis in women and to atherosclerotic risk factors in men, and oestradiol regulates collagen synthesis in opposite directions in female and male cardiac fibroblasts. Clinically, comorbidities carry divergent prognostic weight by sex. Graded against the strength of evidence, sodium-glucose cotransporter 2 inhibitors show established sex-neutral efficacy, whereas the greater benefit of angiotensin receptor-neprilysin inhibition and mineralocorticoid receptor antagonism in women rests on subgroup signals that await confirmation. Natriuretic peptide concentrations are substantially sex-dependent, yet diagnostic thresholds remain sex-neutral, although sex-specific calibration is methodologically achievable. Women remain underrepresented in heart failure trials and less often referred to specialized care. Heart failure is therefore best understood as a sex-differentiated syndrome whose frameworks were built largely around male-pattern disease. Sex-calibrated trial enrolment, sex-specific biomarker and ejection fraction thresholds, and stratification by menopausal stage are concrete next steps towards personalized care.