V̇o2 kinetics associated with moderate-intensity exercise in heart failure: impact of intrathecal fentanyl inhibition of group III/IV locomotor muscle afferents

Abstract

Heart failure (HF) patients demonstrate impaired pulmonary, circulatory, and nervous system responses to exercise. While HF demonstrates prolonged [time constant (τ)] pulmonary O₂ uptake (V̇o₂) on-kinetics, contributing to exercise intolerance, it is unknown whether abnormal V̇o₂ kinetics couple with ventilatory and circulatory dysfunction secondary to impaired group III/IV afferents in HF. Because lower lumbar intrathecal fentanyl inhibits locomotor muscle afferents, resulting in improved exercise ventilation and hemodynamics, we tested these hypotheses: HF will demonstrate 1) rapid V̇o₂ on-kinetics and 2) attenuated steady-state V̇o₂ amplitude and O₂ deficit (O₂def) during exercise with fentanyl versus placebo. On separate visits (randomized), breath-by-breath V̇o₂ was measured in HF (ejection fraction: 27 ± 6%, New York Heart Association class I-III) and age- and sex-matched controls (both n = 9, ages: 60 ± 6 vs. 63 ± 8 yr, P = 0.37) during cycling transitions at 65% peak workload (78 ± 24 vs. 115 ± 39 W, P < 0.01) with intrathecal fentanyl or placebo. Regardless of group or condition, optimal phase II (primary component) curve fits reflected a phase I period equal to 35 s (limb-to-lung timing) via single-exponential functions. Condition did not affect steady-state V̇o₂, the phase II τ of V̇o₂, or O₂def within controls (P > 0.05). Without differences in steady-state V̇o₂, reduced O₂def in fentanyl versus placebo within HF (13 ± 4 vs. 22 ± 15 ml/W, P = 0.04) was accounted for by a rapid phase II τ of V̇o₂ in fentanyl versus placebo within HF (45 ± 11 vs. 57 ± 14 s, P = 0.04), respectively. In an integrative manner, these data demonstrate important effects of abnormal locomotor muscle afferents coupled to pulmonary and circulatory dysfunction in determining impaired exercise V̇o₂ in HF. Effects of abnormal muscle afferents on impaired exercise V̇o₂ and hence exercise intolerance may not be discernable by independently assessing steady-state V̇o₂ in HF.NEW & NOTEWORTHY Inhibition of locomotor muscle afferents results in rapid primary-component O₂ uptake (V̇o₂) on-kinetics accounting for the decreased O₂ deficit in heart failure (HF). This study revealed that abnormal musculoskeletal-neural afferents couple with pulmonary and circulatory dysfunction to provoke impaired exercise V̇o₂ in HF. Steady-state V̇o₂ cannot properly phenotype abnormal muscle afferent contributions to impaired exercise V̇o₂ in HF.

Keywords: exercise transition; group III-Aδ and IV-C muscle afferents; muscle oxygen uptake kinetics; on-transient oxygen uptake kinetics; oxygen deficit; square-wave exercise.

Fig. 1.

Ideal schematic models illustrating modest-to-moderate intensity (A; <θ_L) compared with high-to-heavy (B; >θ_L) exercise intensity pulmonary O₂ uptake (V̇o₂) on-kinetics. Y_t is V̇o₂ at any time (t); Y_B is resting V̇O₂; A₁ is the amplitude of the steady-state increase in V̇o₂ above rest in phase II (fast primary component); A₂ (when present) is the amplitude of V̇o₂ above phase II (phase III, slow component); TD₁ and TD₂ (when present) are independent unconstrained time delays (phase II and III, respectively); and τ₁ and τ₂ are the time constants for phase II and phase III components, respectively. Phase I (cardiodynamic, limb-to-lung transit time) in these ideal theoretical models was constrained to the first 20 s at the onset of exercise. Compared with A, B shows that oxygen deficit (O₂def) can be increased by the presence of a slow phase III component.

Fig. 2.

Ensemble-averaged on-transient pulmonary V̇o₂ kinetics in 10-s binned periods in representative participants of each group for placebo (PLB) or fentanyl (FNT). A and B: models represent single-exponential functions in heart failure (HF) and healthy control (CTL), respectively. The illustrated time constant (τ) in A and B for both experimental arms reflect an optimal cardiodynamic (phase I) period of 35 s representative of group means (see Tables 2 and 3 for further detail). The percent change noted in both A and B is that of each group (means ± SD) from PLB to FNT. The shaded area in A conceptualizes the influence that a prolonged τ in the absence of differences in steady-state V̇o₂ has on increasing O₂def. The sampling period accounted for >98% (i.e., τ × 4) of the response in A and B. C and D: residual plots of single-exponential function curve fits from A and B in HF and CTL, respectively. Residual plots illustrate single exponential functions fit from time = 0 or from an optimal phase I period extending from 0 to 35 s.

Fig. 3.

O₂def for transitions of exercise instituted from rest beginning at time 0 using a single-exponential function (accounting for an unconstrained time delay, see Eq. 3). Data are expressed as means ± SD. A: absolute O₂def. B: O₂def indexed to relative fixed workloads (in W).