Perimenopause as a potential window of cardiometabolic remodeling in heart failure with preserved ejection fraction: a missed opportunity for prevention

Abstract

Heart failure with preserved ejection fraction (HFpEF) disproportionately affects women and has emerged as one of the most prevalent forms of heart failure worldwide. Although the marked increase in HFpEF incidence after menopause is well recognized, the biological events that initiate disease development remain poorly defined. Most mechanistic and clinical investigations have focused on postmenopausal women or established HFpEF, leaving the menopausal transition comparatively underexplored despite growing evidence that it represents a period of accelerated cardiometabolic change. This review synthesizes current evidence on reproductive aging, cardiometabolic remodeling, and the pathophysiological mechanisms underlying HFpEF to examine whether perimenopause represents a critical window in the development of the female HFpEF phenotype. Evidence from longitudinal cohorts and mechanistic studies indicates that visceral and epicardial adiposity, insulin resistance, adverse lipid remodeling, systemic inflammation, endothelial dysfunction, coronary microvascular impairment, arterial stiffening, and early cardiac remodeling emerge or accelerate during the menopausal transition. These biological alterations closely parallel established mechanisms implicated in HFpEF pathogenesis. Building on prior clinical and experimental evidence identifying the menopausal transition as a period of cardiovascular remodeling and increasing cardiovascular risk, we develop a temporal framework for female HFpEF. This framework considers whether, in susceptible women, HFpEF-relevant biological changes may begin to accumulate during perimenopause, become progressively amplified after menopause, and ultimately contribute to clinically manifest disease. We further examine how reliance on binary reproductive classifications, recruitment of predominantly postmenopausal cohorts, and the limited integration of reproductive staging into cardiovascular research may have contributed to this early phase of disease remaining largely unrecognized. Reframing perimenopause as a critical period of cardiovascular remodeling shifts attention from treating established HFpEF to identifying opportunities for earlier prevention. Prospective longitudinal studies incorporating standardized reproductive staging, comprehensive cardiovascular phenotyping, and biomarker profiling are now needed to determine whether the menopausal transition represents the earliest identifiable window for preventing HFpEF in women.