Mechanisms Determining VO2peak During Single Leg Knee‐Extension Exercise in Heart Failure with Preserved Ejection Fraction Patients: Peripheral vs. Central Phenotypes
Authors: Skow Rachel J. , Martin Zachary T. , Nandadeva Damsara , Hearon Christopher M. , Samels Mitchel , MacNamara James P. , Haykowsky Mark J. , Levine Benjamin D. , Fadel Paul J. , Sarma Satyam 
Published: May 2022

BackgroundHeart failure with preserved ejection fraction (HFpEF) is characterized by exercise intolerance, including a reduced maximal aerobic capacity that affects all aspects of daily living. The mechanisms responsible for the decreased exercise tolerance in HFpEF are incompletely understood. Our research group has characterized two unique HFpEF phenotypes based on cardiac output reserve relative to exercise metabolic work: those with either a “central” (Type A) or “peripheral” (Type B) limitation to exercise. We sought to investigate the peripheral limitations to exercise in these 2 phenotypes using single‐leg knee extension (SLKE) exercise, a modality that reduces the central limitations to exercise. Specifically, we tested the hypothesis that patients with the Type B phenotype would have lower leg VO2peak secondary to insufficient oxygen extraction (i.e., lower ∆a‐vO2diff) when compared to patients with the Type A phenotype.MethodsWe studied 20 HFpEF patients with either the Type A (n = 8; 68 ± 2yr; 5F) or Type B (n = 12; 70 ± 2yr; 7F) phenotype. Participants performed an incremental SLKE peak exercise test on a custom ergometer. Leg blood flow (LBF) was measured at the common femoral artery using duplex Doppler ultrasound. Average LBF (ml/min) at each workload was determined from measured blood velocity and vessel diameter. a‐vO2diff was calculated from hemoglobin and venous oxygen saturation directly from a femoral venous catheter, and arterial oxygen saturation via pulse oximetry. Leg VO2 (ml/min) was determined as the product of LBF and a‐vO2diff. All data are presented as mean ± SEM.ResultsParticipants with the Type A “central” phenotype reached a peak exercise workload of 20 ± 4 W and those with the Type B “peripheral” phenotype reached 15 ± 2 W (p = 0.18). Leg VO2peak was not different between the two phenotypes (Type A: 215 ± 23; Type B: 253 ± 34 ml/min; p = 0.42). The peak increase in LBF was ~ 50% greater in Type B (+1940 ± 243 ml/min) than Type A (+1309 ± 161 ml/min) patients, though this response was more variable (p = 0.07). Additionally, the ∆a‐vO2diff from rest to peak exercise was significantly lower in those with the Type B phenotype (Type A: +7.17 ± 0.87; Type B: +4.63 ± 0.46 ml O2/dl blood; p = 0.01). Finally, the ∆LBF/∆VO2 slope was lower in patients with the Type A phenotype (Type A: 6.78 ± 0.55; Type B: 8.72 ± 0.43; p = 0.01).ConclusionContrary to our hypothesis, there was no difference in leg VO2peak between phenotypes. Patients with Type B HFpEF had greater limitations in skeletal muscle oxygen extraction during exercise as evidenced by their diminished ability to increase a‐vO2diff during incremental SLKE, similar to the observed a‐vO2diff extraction impairments during whole body exercise. Importantly, by phenotyping HFpEF patients based on their limitations to exercise, we may be able to better individualize treatment strategies to improve exercise tolerance.