Sex Differences in Heart Failure With Preserved Ejection Fraction (HFpEF): A Narrative Review

Heart failure with preserved ejection fraction (HFpEF) now accounts for over half of all heart failure cases and represents the most prevalent subtype, particularly among older adults. Its clinical heterogeneity and limited therapeutic options have posed persistent challenges in management. Importantly, sex-related differences have emerged as a critical-yet underappreciated-dimension in HFpEF, with substantial implications for prognosis, treatment response, and quality of life. Women are disproportionately affected by HFpEF and frequently present with worse self-reported quality of life, a greater comorbidity burden, and higher rates of hospitalization than men. Despite such burdens, they paradoxically demonstrate better long-term survival. Evidence from large trials and their subsequent post hoc analyses suggests that women may experience greater benefit from certain therapies, particularly in terms of mortality, heart failure hospitalization reduction, and symptom improvement. However, few of these trials were adequately powered to detect sex-specific treatment effects, and women remain underrepresented in most HFpEF studies. As HFpEF continues to dominate the heart failure landscape, recognizing and understanding sex-specific differences are essential. These insights not only improve clinical interpretation of trial data but are also crucial for guiding the development of tailored, equitable treatment strategies that address the unique needs of women and men living with HFpEF.