Underpinnings of heart failure with preserved ejection fraction in women - From prevention to improving function. A co-publication with the American Journal of Preventive Cardiology and the Journal of Cardiac Failure

Abstract

Heart failure with preserved ejection fraction (HFpEF) represents a major clinical challenge with rising global prevalence. Women have a nearly double lifetime risk of developing HFpEF compared to heart failure with reduced ejection fraction (HFrEF). In HFpEF, sex differences emerge both in how traditional cardiovascular risk factors (such as hypertension, obesity, and diabetes) affect cardiac function and through distinct pathophysiological mechanisms triggered by sex-specific events like menopause and adverse pregnancy outcomes. These patterns influence not only disease development, but also therapeutic responses, necessitating sex-specific approaches to treatment. This review aims to synthesize existing knowledge regarding HFpEF in women including traditional and sex-specific risk factors, pathophysiology, presentation, and therapies, while outlining important knowledge gaps that warrant further investigation. The impact of HFpEF spans a woman's entire lifespan, requiring prevention and management strategies tailored to different life stages. While understanding of sex-based differences in HFpEF has improved, significant knowledge gaps persist. Through examination of current evidence and challenges, this review highlights promising opportunities for innovative research, therapeutic development, and clinical care approaches that could transform the management of HFpEF in women.

Keywords: Cardiovascular disease; Heart failure with preserved ejection fraction; Sex differences; Women.

Fig. 1

Obesity-mediated mechanisms for development of HFpEF in women, with associated preventative and treatment strategies. Caption: Overview of obesity-related mechanisms in women with heart failure with preserved ejection fraction, highlighting neurohormonal activation, visceral adiposity, inflammation, and oxidative stress, which drive cardiac remodeling and reduced exercise tolerance. Prevention and treatment strategies target key effects like reducing inflammation, myocardial stress, and blood pressure, while improving glucose uptake and promoting weight loss. HFpEF: heart failure with preserved ejection fraction; RAAS: renin angiotensin aldosterone system; BNP: brain natriuretic peptide; EAT: epicardial adipose tissue; RA: right atrial; RV: right ventricular; LA: left atrial; LV: left ventricular; TNF: tumor necrosis factor; IL-6: interleukin-6; GLP-1: Glucagon-Like Peptide-1; SGLT2: Sodium-Glucose Cotransporter 2.

Fig. 2

Estrogen Signaling in HFpEF Development. Caption: Synopsis of estrogen signaling in the development of heart failure with preserved ejection fraction. Reduced estrogen levels trigger four proposed pathophysiological pathways that ultimately lead to cardiac structural and functional changes. HFpEF: heart failure with preserved ejection fraction; ANP: atrial natriuretic peptide; BNP: brain natriuretic peptide; RAAS: renin angiotensin aldosterone system; LV: left ventricular.

Fig. 3

(Central Illustration): Mechanisms Underlying Traditional and Sex-specific Risk Factors for HFpEF in Women. Caption: Summary of pathophysiological mechanisms underlying the female predisposition to heart failure with preserved ejection fraction, integrating traditional risk factors, sex-specific factors, and social determinants of health. These elements contribute to altered cellular physiology, and cause a cascade that leads to remodeling, reduced functional reserve, and abnormal hemodynamics and a variety of clinical manifestations. HFpEF: heart failure with preserved ejection fraction; LV: left ventricular; RV: right ventricular; CAD: coronary artery disease; BP: blood pressure; HTN: hypertension; Ca: cancer.