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

Area of Science:

• Cardiology and Exercise Physiology
• Sex Differences in Cardiovascular Disease
• Heart Failure Pathophysiology

Background:

• Women are disproportionately affected by heart failure with preserved ejection fraction (HFpEF).
• Understanding sex-based differences in the mechanisms of exertional breathlessness is crucial for effective treatment.

Purpose of the Study:

• To compare the pathophysiology of exertional breathlessness between sexes in patients with high versus low likelihood of HFpEF.
• To investigate the determinants of exercise capacity and identify sex-specific factors contributing to dyspnea.

Main Methods:

• A cohort study of 1,936 patients with unexplained dyspnea.
• Utilized cardiopulmonary exercise testing (CPET) and simultaneous echocardiography.
• Quantified peak oxygen uptake (peak VO2) and its determinants, assessing HFpEF likelihood using established scores (H2FPEF/HFA-PEFF).

Main Results:

• Women exhibited significantly lower peak VO2 compared to men, attributed to reduced oxygen delivery and extraction.
• Lower oxygen delivery in women was linked to lower hemoglobin levels and smaller stroke volumes.
• Physiological differences, including increased pulmonary artery pressure/cardiac output slope and higher prevalence of iron deficiency in women, were observed.

Conclusions:

• Sex, rather than HFpEF likelihood, is a significant determinant of reduced peak VO2 and exertional breathlessness in women.
• Physiological sex differences in oxygen delivery and extraction play a key role in functional limitations experienced by women.