Sex-specific impairment of cardiac functional reserve in HFpEF: insights from the HFpEF-Stress trial

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): DZHK Background Heart failure with preserved ejection fraction (HFpEF) has been observed to have a twice as high prevalence in women compared to men.(1,2) While predisposing risk factors are quite similar between the sexes(2,3), this study aimed to identify sex-specific pathophysiological features in HFpEF using state-of-the-art diagnostic approaches. Methods 75 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 right heart catheterization (RHC), echocardiographic and cardiovascular magnetic resonance (CMR) imaging at rest and during exercise stress. HFpEF was defined according to pulmonary capillary wedge pressure in RHC (rest ≥ 15mmHg, stress ≥ 25mmHg), below these thresholds patients were classified as non-cardiac dyspnea (NCD). Results Main results are displayed in Figure 1. Compared to men, women with HFpEF revealed lower right ventricular (RV)-stroke volumes during exercise stress (f 38.1 vs. m 50.4 ml/m2 BSA; p = 0.011) but not with NCD. This was accompanied by a decreasing left atrial (LA) EF in women but not men comparing resting to exercise conditions (f −2.7 vs. m 2.5%, p = 0.020) and an impaired left ventricular (LV) filling (f 35.5 vs. m 44.2 ml/m2 BSA, p = 0.017) in women with HFpEF during exercise stress. These sex-specific differences were not present in NCD. The exercise-induced decrease in LA EF emerged as a predictor for HFpEF in women (OR 13.67 95% CIs: 3.03 – 62.14, p<0.001) with high diagnostic accuracy (AUC 0.83 95% CIs: 0.7–0.95). Conclusion Women with HFpEF demonstrate sex-specific functional alterations of RV, LA, and LV function during exercise-stress. The biventricular impairment suggests a complex interplay of both sides of the heart during the progression of HFpEF in women. This unique pathophysiology represents a sex-specific diagnostic target, which may allow early identification of women with HFpEF for future individualized therapeutic approaches.