Sex differences in the peripheral determinants of oxygen uptake in heart failure with preserved ejection fraction
Authors: Skow R J , Wakeham D J , Samels M , Martin Z T , Nandadeva D , Balmain N , Macnamara J P , Brazile T L , Nelson M D , Babb T G , Levine B D , Sarma S , Fadel P J , Hearon Jr C M , Haykowsky M J 
Published: November 2023

Abstract

Background
A hallmark feature of heart failure with preserved ejection fraction (HFpEF) is exercise intolerance. Data from non-invasive, whole-body cardiopulmonary exercise testing indicates that females with HFpEF have reduced VO2 secondary to a to lower cardiac output and arterial-to-venous oxygen content difference (∆a-vO2) at maximal effort compared to males with HFpEF [1]. Thus, in addition to cardiac limitations, peripheral/non-cardiac limitations may be important contributors to reduced peak aerobic power (VO2) in females with HFpEF; however, these peripheral mechanisms of exercise intolerance are not fully understood. Given that HFpEF disproportionately affects older females, identifying sex differences in the limitations to exercise is especially important.

Purpose
Using dynamic single leg knee extension (SLKE) exercise to isolate peripheral determinants of oxygen transport and utilization, we sought to test the hypothesis that females with HFpEF have lower leg VO2 at peak SLKE resulting from smaller increases Δa-vO2 and muscle oxygen diffusive conductance (DMO2) compared to males.

Methods
Eighteen females (69 ± 7 years) and 13 males (73 ± 6 years) with HFpEF performed a maximal SLKE exercise test on a custom ergometer. LBF (duplex Doppler ultrasound) was measured at the common femoral artery and leg VO2 was determined as the product of LBF and ∆a-vO2 (femoral venous catheter). DMO2 was calculated as leg VO2/2x leg venous oxygen pressure (PvO2). Thigh lean and fat mass (TLM and TFM, respectively) was measured using dual energy x-ray absorptiometry. Group differences between the two sexes were compared using an unpaired t-test and significance was set at p&lt;0.05.

Results
Body mass, body mass index, and TLM were not different between groups (p &gt; 0.05 for all), however TFM was higher in females (p&lt;0.001; Table 1). At rest, ∆a-vO2 was lower in females (p = 0.001), whereas heart rate, mean arterial blood pressure, femoral LBF, and leg VO2 were not different between groups (p&gt;0.05 for all; Table 1). Peak workload was lower in females compared to males (13 ± 5 vs 20 ± 7 watts, p = 0.011). At peak SLKE, leg VO2 was lower in females (185 ± 57 vs 286 ± 91 ml/min, Figure 1) due to lower ∆a-vO2 (9.7 ± 1.8 vs 12.3 ± 2.5 ml O2/dl blood, p = 0.003) and LBF (1918 ± 576 vs 2382 ± 872 ml/min, p = 0.084). DMO2 at peak SLKE was also lower in females (3.6 ± 1.2 vs 6.3 ± 1.8 ml/min/mmHg, Figure 1) suggesting sex differences in both convective and diffusive oxygen transport. Moreover, when normalized to TLM, the difference in peak leg VO2 between the sexes persisted (28.2 ± 6.5 vs 41.5 ± 10.9 ml/kg/min; p = 0.004).

Conclusion
These data highlight that that the lower peak oxygen extraction (∆a-vO2) and diffusion (DMO2) in females with HFpEF contribute to sex-dependent differences in exercise intolerance. Further studies investigating potential sex-specific impairments in the muscle-vascular interface in HFpEF are warranted.Table 1Figure 1