Sex Differences in the Peripheral Determinants of Oxygen Transport and Utilization in Patients with Heart Failure with Preserved Ejection Fraction

Background: Heart failure with preserved ejection fraction (HFpEF) disproportionately affects females, however the influence of sex on peripheral contributors to exercise intolerance remains poorly understood. Methods: 43 patients with HFpEF (71±7 years, 28 females; 38.3±6.7 kg/m 2 ) performed incremental single leg knee extension (SLKE) exercise to determine peak leg blood flow (BF; duplex Doppler ultrasound), a-vO 2 difference (femoral venous catheter), leg VO 2 , and muscle oxygen diffusive conductance (DMO 2 ). Whole body and thigh adiposity and lean mass (TLM) were determined by DXA, and myosteatosis (TLM/fat ratio) by MRI. Results: After adjusting for differences in TLM, females had ~30% lower peak exercise leg VO 2 /TLM (p<0.001) and ~15% lower BF/TLM compared to males (p=0.024). However, when normalized to VO 2 , the leg BF/leg VO 2 slope was higher in females (9.5±2.3 vs. 8.1±2.1, p=0.017) and was associated with markedly lower a-vO 2 difference (p<0.001) and ~40% lower DMO 2 (3.6±1.6 vs 6.4±1.7, p<0.0001). Metrics of muscle adiposity were not correlated with peak leg VO 2 or its determinants (p>0.150 for all). Conclusion: Females with HFpEF have lower muscle oxygen diffusive conductance during peak SLKE compared to 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.