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

Abstract

BACKGROUND Women are at greater risk for heart failure with preserved ejection fraction (HFpEF). OBJECTIVES The aim of the study was to compare sex differences in the pathophysiology of exertional breathlessness in patients with high vs low HFpEF likelihood. METHODS This 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. RESULTS The 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 O(2 )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/m(2) [95% CI:-8 to-11 mL/m(2)]) and mass (-12 g/m(2) [95% CI:-9 to-14 g/m(2)]) and more often iron deficiency (55% vs 33%; P < 0.001). CONCLUSIONS Women with unexplained dyspnea had significantly lower peak VO2, regardless of HFpEF likelihood, attributed to both lower peak exercise O-2 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. (JACC Adv 2024;3:101039) (c) 2024 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).