Key result
Sex differences shape heart failure mechanisms and outcomes, with SGLT2 inhibitors showing sex-neutral efficacy while ARNI and MRA benefits in women rely on unconfirmed subgroup signals.
Why the study?
Sex is a consistent yet clinically underexploited determinant of heart failure phenotype, mechanism, and outcome, and the underlying mechanisms of recognized sex differences remain only partially defined.
Heart failure exhibits distinct sex-differentiated mechanisms, epidemiology, and therapeutic responses, necessitating sex-calibrated trial enrollment, sex-specific biomarker and ejection fraction thresholds, and menopausal stratification for personalized care.
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.
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Papp et al. (2026) conducted a review in Heart failure. Sex differences and sex-specific mechanisms/therapeutics was evaluated. Sex differences shape heart failure mechanisms and outcomes, with SGLT2 inhibitors showing sex-neutral efficacy while ARNI and MRA benefits in women rely on unconfirmed subgroup signals.
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