Impaired oxygen uptake kinetics in heart failure with preserved ejection fraction

Abstract

Background The amount of time needed to increase oxygen utilization to sufficiently meet metabolic demand (V̇O2 kinetics) is impaired in heart failure (HF) with reduced ejection fraction, and is an independent predictor of HF mortality. However, it is not known if V̇O2 kinetics are slowed in heart HF patients with preserved ejection fraction (HFpEF). We tested the hypothesis that V̇O2 kinetics are slowed during submaximal exercise (equivalent to activities of daily living) in HFpEF patients, and that slower V̇O2 kinetics are related to impaired peripheral oxygen extraction. Methods Eighteen healthy controls (69±6 years, 10 females) and eighteen HFpEF patients (68±7 years, 10 females) were studied during submaximal (~30% predicted max) and peak treadmill exercise. Cardiac output (Qc, acetylene rebreathing), pulmonary oxygen uptake (V̇O2, Douglas bags), and arterial‐venous oxygen difference (a‐v O2 diff) were measured during exercise. Breath‐by‐breath V̇O2 uptake was measured continuously at the onset and throughout submaximal exercise, and V̇O2 kinetics quantified as the time needed to for V̇O2 to rise to ~63% of steady state V̇O2 (mean response time, MRT). Results During submaximal exercise, absolute oxygen demand was similar between groups (V̇O2: Control: 0.81±0.1, HFpEF: 0.85±0.2 L/min; P=0.54) however, HFpEF patients had substantially slowed V̇O2 kinetics (MRT: Control: 40.1±14.2, HFpEF: 65.4±27.7 s; P=0.002), and >50% greater accumulated oxygen deficit compared to controls (Control: 400±173, HFpEF: 693±392 mL; P=0.007). At peak exercise, HFpEF patients had lower relative V̇O2 (Control: 22.2±4.0, HFpEF: 14.6±3.1 mL/kg/min; P<0.001), preserved peak Qc (Control: 13.4±4.0, HFpEF: 13.9±3.5 L/min; P=0.68), and reduced peripheral oxygen extraction (a‐v O2 diff: Control: 12.7±2.9, HFpEF: 10.4±2.1 mL/dL; P=0.01). When stratified by MRT, HFpEF patients with a MRT >60s demonstrated impaired peripheral oxygen extraction that was apparent during submaximal exercise compared to HFpEF patients with a MRT <60s (submaximal a‐v O2 diff: MRT<60s: 9.7±2.1, MRT>60s: 7.9±1.1 mL/dL; P=0.03). Conclusions HFpEF patients have slowed V̇O2 kinetics during exercise that are due in part to impaired peripheral oxygen utilization. This finding supports growing evidence that peripheral oxidative capacity is a primary contributor to exercise intolerance in HFpEF leading to substantial oxygen deficit even during activities of daily living. Further, MRT can lend important insight into the pathophysiology of exercise intolerance in individual HFpEF patients, and identify patients with severe peripheral limitations to exercise capacity. Support or Funding Information NIH: AG017479, F32‐HL137285 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Priming the cardiodynamic phase of pulmonary oxygen uptake through voluntary modulations of the respiratory pump at the onset of exercise

“…These findings are in agreement with the contention that convective O 2 delivery is not limiting muscle O 2 consumption at the onset of moderate‐intensity exercise in healthy young subjects (Grassi, 2001). In contrast, this can be the case in cardiac patients in whom the ‐on kinetics are slowed to an extent that oxygen transport limits the progressive increase in muscle aerobic metabolism (Grassi, 2000; Hearon et al., 2019).…”

“…We examined how altering the relative contributions of the respiratory muscles for the act of breathing affects alveolar O 2 transfer in the early stages of exercise and whether mass oxygen transfer at the onset of exercise can be accelerated by increasing early venous return, thus priming muscle metabolic oxygen consumption. This would decrease the oxygen deficit accrued at exercise onset and could be of clinical use in cardiac patients in whom mass oxygen transport can be a limiting factor for metabolic oxygen consumption at the onset of exercise (Hearon et al., 2019).…”

Peripheral and pulmonary effects of inorganic nitrite during exercise in heart failure with preserved ejection fraction

“…It is now evident that peripheral abnormalities in O 2 uptake and distribution are common in HFpEF 2–6,8 . To date, exercise training has represented the only intervention proven to enhance peripheral O 2 distribution, extraction and utilization in HFpEF 12 .…”

“…To provide an independent assessment of the effects of nitrite on peripheral O 2 delivery and utilization, we also assessed O 2 uptake kinetics, which are known to be abnormal in HFpEF 8,27 . Briefly, the O 2 deficit was defined as exercise time multiplied by the change in VO 2 from rest to steady state exercise minus the cumulative VO 2 (determined by Simpson's method of multiplying breath‐by‐breath VO 2 by the number of seconds that transpire between each breath).…”

“…Heart failure (HF) with preserved ejection fraction (HFpEF) afflicts over half of all patients with HF, and there are few effective treatments 1 . HFpEF is associated with central cardiac reserve limitations, impairments in pulmonary diffusion and ventilatory reserve, and abnormalities in skeletal muscle composition, oxygen (O 2 ) uptake, and peripheral O 2 transport 2–11 . The interplay between these multistep impairments in O 2 transport synergize in a complex way to impair aerobic capacity, suggesting that efficacious treatments should optimally target multiple steps 7 .…”