Sex Differences in HFpEF: Mechanisms, Manifestations, and Therapeutic Target Identification

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome that accounts for more than half of heart failure cases and disproportionately affects older women. Biological sex is a key determinant of HFpEF, influencing epidemiology, comorbidity profiles, cardiac structure, clinical outcomes, and therapeutic responses. Women more commonly exhibit concentric left ventricular remodeling and diastolic dysfunction, frequently in association with obesity, hypertension, diabetes, and anemia, whereas men more often present with ischemic heart disease, renal dysfunction, and right ventricular involvement. These sex differences extend to prognosis, quality of life, and responses to therapies such as spironolactone and sacubitril/valsartan. At the mechanistic level, women exhibit greater metabolic dysregulation, heightened inflammatory responses, and more pronounced ventricular–arterial stiffening, whereas men show more prominent ischemic and cardiorenal perturbations. Emerging evidence indicates that these sex-specific features arise from distinct but interconnected pathophysiological pathways, including mitochondrial dysfunction, renin–angiotensin–aldosterone system (RAAS) imbalance, microvascular inflammation, impaired NO–cGMP–PKG signaling, and extracellular matrix remodeling. These pathways are differentially regulated by gonadal hormones, sex chromosome dosage, and X-linked gene escape from inactivation, which together shape cardiac stiffness, fibrosis, oxidative stress, and immune activation. Overall, these findings highlight the complex interplay between hormonal, chromosomal, and molecular mechanisms underlying sex differences in HFpEF. A better understanding of these processes may help explain disease heterogeneity, guide the rational identification of sex-dependent therapeutic targets, and support the development of sex-informed prevention and therapeutic strategies.