The Oxygen Cascade According to HFpEF Likelihood: A Focus on Sex Differences

BackgroundWomen are at greater risk for heart failure with preserved ejection fraction (HFpEF).ObjectivesThe aim of the study was to compare sex differences in the pathophysiology of exertional breathlessness in patients with high vs low HFpEF likelihood.MethodsThis cohort study evaluated consecutive patients (n = 1,936) with unexplained dyspnea using cardiopulmonary exercise testing and simultaneous echocardiography and quantified peak oxygen uptake (peak VO2) and its determinants. HFpEF was considered likely when the H2FPEF or HFA-PEFF score was ≥6 or ≥5, respectively. Sex differences were evaluated with the Student’s t-test or Mann-Whitney U test and determinants of exercise capacity with a multivariable linear regression.ResultsThe cohort included 1,963 patients (49% women and 28% [n = 555] with a high HFpEF likelihood). HFpEF likelihood did not impact the magnitude of sex differences in peak VO2 and its determinants. Overall, women had lower peak VO2 (mean difference −4.4 mL/kg/min [95% CI: −3.7 to −5.1 mL/kg/min]) secondary to a reduced O2 delivery (−0.5 L/min [95% CI: −0.4 to −0.6 L/min]) and less oxygen extraction (−2.9 mL/dL [95% CI: −2.5 to −3.2 mL/dL]). Reduced O2 delivery was due to lower hemoglobin (−1.2 g/dL [95% CI: −0.9 to −1.5 g/dL]) and smaller stroke volume (−15 mL [95% CI: −14 to −17 mL]). Women demonstrated increased mean pulmonary artery pressure/cardiac output slope (+0.5 mm Hg/L/min [95% CI: 0.3-0.7 mm Hg/L/min]) and left ventricular ejection fraction (+1% [95% CI: 1%-2%]), while they had smaller left ventricular end-diastolic volumes (−9 mL/m2 [95% CI: −8 to −11 mL/m2]) and mass (−12 g/m2 [95% CI: −9 to −14 g/m2]) and more often iron deficiency (55% vs 33%; P < 0.001).ConclusionsWomen with unexplained dyspnea had significantly lower peak VO2, regardless of HFpEF likelihood, attributed to both lower peak exercise O2 delivery and extraction. This suggests that physiologic sex differences, and not HFpEF likelihood, are an important factor contributing to functional limitations in females with exertional breathlessness.