Sex differences in the peripheral determinants of oxygen transport and utilization in patients with heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) disproportionately affects females; however, the influence of sex on peripheral contributors to exercise intolerance remains poorly understood. Forty-three patients with HFpEF (71 ± 7 yr, 28 females; 38.3 ± 6.7 kg/m2) performed incremental single-leg knee extension (SLKE) exercise to determine peak leg blood flow (BF; duplex Doppler ultrasound), arterial-to-venous oxygen content difference (a-vO2) (femoral venous catheter), leg oxygen consumption (V̇o2), and muscle oxygen diffusive conductance (DMO2). Whole body and thigh adiposity and lean mass (TLM) were determined by DXA, and myosteatosis (TLM/fat ratio) by MRI. After adjusting for differences in TLM, females had ∼30% lower peak exercise leg V̇o2/TLM (P < 0.001) and ∼15% lower BF/TLM compared with males (P = 0.024). However, when normalized to V̇o2, the leg BF/leg V̇o2 slope was higher in females (9.5 ± 2.3 vs. 8.1 ± 2.1, P = 0.017) and was associated with markedly lower a-vO2 difference (P < 0.001) and ∼40% lower DMO2 (3.6 ± 1.6 vs. 6.4 ± 1.7, P < 0.0001). Metrics of muscle adiposity were not correlated with peak leg V̇o2 or its determinants (P > 0.150 for all). Females with HFpEF have lower muscle oxygen diffusive conductance during peak SLKE compared with males. However, peripheral determinants of aerobic capacity were not differentially related to adiposity in males and females with HFpEF. Interventions to improve muscle quality and diffusive capacity are of particular importance for improving peripheral limitations to exercise in females with obesity and HFpEF. This study was registered as a clinical trial on https://www.clinicaltrials.gov (NCT04068844).NEW & NOTEWORTHY Females with heart failure with preserved ejection fraction have lower muscle oxygen diffusive conductance during peak exercise compared with males. Interventions to improve muscle quality and diffusive capacity are of particular importance for improving peripheral limitations to exercise in females with HFpEF.