Sex-Specific Impairment of Cardiac Functional Reserve in HFpEF: Insights From the HFpEF Stress Trial

Heart failure with preserved ejection fraction (HFpEF) has been observed to have a twice as high prevalence in women compared to men with similar predisposing risk factors between both sexes.

This study aimed to identify sex-specific pathophysiological features in HFpEF using rest and exercise stress right heart catheterization (RHC), echocardiography and cardiovascular magnetic resonance imaging (CMR).

Seventy-five patients with exertional dyspnea, preserved ejection fraction (EF) (≥50%), and signs of diastolic dysfunction on echocardiography were prospectively recruited in the HFpEF Stress Trial. Patients underwent RHC, echocardiography and CMR at rest and during exercise stress. Patients were diagnosed with HFpEF and noncardiac dyspnea according to RHC measurements.

After exclusion, the final study cohort comprised 68 patients (females n = 44, males n = 24) with a mean age of 66.9 ± 9.7 years. Compared to men, women with HFpEF revealed lower right ventricular stroke volumes during exercise stress (females 38.1 vs males 50.4 mL/m² BSA; P = 0.011). This was accompanied by a decreasing left atrial EF in women but not men comparing resting to exercise conditions (females -2.7% vs males 2.5%, P = 0.020) and impaired left ventricular filling (females 35.5 vs males 44.2 mL/m² BSA, P = 0.017) in women with HFpEF during exercise stress. These sex-specific differences were not present in noncardiac dyspnea.

Women with HFpEF demonstrate sex-specific functional alterations of right ventricular, left atrial, and left ventricular function during exercise stress. This unique pathophysiology represents a sex-specific diagnostic target, which may allow early identification of women with HFpEF for future individualized therapeutic approaches.