The Female Phenotype of Heart Failure with Preserved Ejection Fraction: Diagnosis, Trials, and Treatment Gaps

Epidemiology and Diagnostic Ambiguity

Heart failure with preserved ejection fraction (HFpEF) represents a rapidly growing clinical challenge, with incidence rates climbing significantly among aging populations. This condition exhibits a pronounced female predominance; lifetime risk estimates indicate that women face nearly double the risk compared to men with heart failure and reduced ejection fraction [8]. Despite this disparity, clinical management often proceeds without accounting for sex-specific pathophysiology, leaving a critical gap in care.

Diagnostic protocols currently rely on a left ventricular ejection fraction (LVEF) threshold of ≥50%. This "sex-neutral" cutoff may obscure diagnosis in women, who typically possess smaller cardiac cavities and higher baseline ejection fractions than men [24]. Consequently, reliance on a uniform threshold risks misdiagnosis or delayed recognition of diastolic dysfunction in the demographic most affected by the disease. The potential for under-recognition underscores the need to reevaluate diagnostic algorithms that do not adjust for anatomical sex differences.

Phenotypic Divergence and Comorbidity Profiles

Women with HFpEF frequently present with comorbidity profiles distinct from men, suggesting divergent biological pathways. Men are more commonly associated with ischemic heart disease and coronary artery disease as primary drivers. In contrast, women are more frequently linked to systemic inflammation, microvascular dysfunction, and obesity-driven phenotypes. Recognizing these distinctions is essential for targeted therapeutic selection, yet current guidelines often treat HFpEF as a monolithic entity, obscuring the unique contributions of inflammation and vascular health in female patients.

Clinical Trial Representation and Design Bias

The evidence base guiding HFpEF therapy suffers from systemic underrepresentation of women. While women constitute the majority of HFpEF patients, meta-analyses indicate that female participation rates in cardiovascular trials frequently lag behind population prevalence. Recent data highlights authorship bias within the field; a 2025 analysis revealed that while subspecialty teams are becoming more inclusive, principal investigator roles and overall authorship remain skewed male, potentially influencing trial design priorities and endpoint selection [12].

The exclusion of multimorbid patients in HFpEF trials creates a significant gap between evidence-based recommendations and real-world practice. Older women, who often manage concurrent conditions such as renal impairment or cognitive decline, are systematically filtered out during enrollment due to restrictive inclusion criteria. This results in therapeutic guidelines derived from a population that does not mirror the typical patient presenting with HFpEF, necessitating extrapolation that carries inherent safety and efficacy uncertainties.

Therapeutic Uncertainties and Emerging Data

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are now standard of care, yet their sex-specific efficacy in HFpEF remains a subject of scrutiny. Conflicting data exists regarding the magnitude of benefit. Some analyses suggest that reductions in death and hospitalization may be less pronounced in women compared to men, whereas other real-world studies indicate significant advantages for female patients [49]. Current consensus positions generally affirm consistent relative efficacy across sexes, though absolute risk reduction may vary due to baseline demographic differences. For clinicians, interpreting trial data requires caution; individualized assessment is warranted as a woman's absolute benefit profile may differ substantially from pooled averages.

Newer agents targeting metabolic drivers offer promising insights. The STEP-HFpEF program evaluated semaglutide in obesity-related HFpEF, demonstrating improved exercise capacity and symptom relief. Notably, women achieved significantly greater weight loss than men during treatment [108]. A detailed analysis by Verma et al. (2025) confirmed superior weight reduction outcomes in women, raising critical mechanistic questions regarding whether cardiac benefits in females are driven primarily by adiposity reduction or direct anti-inflammatory modulation independent of body mass index [47]. If women derive disproportionate structural or functional benefits unrelated to weight loss, it suggests underlying sex-differentiated tissue responses to glucagon-like peptide-1 receptor agonism.

Patient-Facing Implications

• Adopting a phenotype-first approach rather than treating HFpEF as a monolith may improve diagnostic accuracy and align management with underlying biology.
• Clinicians should consider sex-specific fluid distribution patterns and comorbidity burdens when managing diuretic therapy and monitoring response.
• Recent GLP-1 agonist data validates the importance of addressing metabolic drivers in women, though providers must distinguish between weight-mediated effects and potential direct cardioprotective mechanisms to optimize long-term outcomes.