Fatigability, Exercise Intolerance, and Abnormal Skeletal Muscle Energetics in Heart Failure

Abstract

Background: Among central and peripheral factors contributing to exercise intolerance (EI) in heart failure (HF), the extent to which skeletal muscle (SM) energy metabolic abnormalities occur and contribute to EI and increased fatigability in HF patients with reduced or preserved ejection fraction (HFrEF and HFpEF, respectively) are not known. An energetic plantar flexion exercise fatigability test and magnetic resonance spectroscopy were used to probe the mechanistic in vivo relationships among SM high-energy phosphate concentrations, mitochondrial function, and EI in HFrEF and HFpEF patients and in healthy controls.

Methods and results: Resting SM high-energy phosphate concentrations and ATP flux rates were normal in HFrEF and HFpEF patients. Fatigue occurred at similar SM energetic levels in all subjects, consistent with a common SM energetic limit. Importantly, HFrEF New York Heart Association class II-III patients with EI and high fatigability exhibited significantly faster rates of exercise-induced high-energy phosphate decline than did HFrEF patients with low fatigability (New York Heart Association class I), despite similar left ventricular ejection fractions. HFpEF patients exhibited severe EI, the most rapid rates of high-energy phosphate depletion during exercise, and impaired maximal oxidative capacity.

Conclusions: Symptomatic fatigue during plantar flexion exercise occurs at a common energetic limit in all subjects. HFrEF and HFpEF patients with EI and increased fatigability manifest early, rapid exercise-induced declines in SM high-energy phosphates and reduced oxidative capacity compared with healthy and low-fatigability HF patients, suggesting that SM metabolism is a potentially important target for future HF treatment strategies.

Keywords: magnetic resonance imaging; magnetic resonance spectroscopy; skeletal muscle.

Figure 1

A.) Mean PFE time, maximum PFE exercise weight, and total PFE work of healthy subjects, HFrEF NYHA class I (HFrEF I), HFrEF NYHA class II–III (HFrEF II–III), and HFpEF patients. All three indices are reduced in HFpEF and HFrEF NYHA class II–III patients as compared to healthy subjects and HFrEF patients with NYHA class I symptoms. B.) Correlations between indices of PFE performance (exercise time, maximum exercise weight, and total work) and more established, functional indices of 6MW and peak VO₂. Comparisons vs healthy subjects,, ** p<0.02, ^§ p<0.005, ^§§§ p<0.001.

Figure 2

A.) Representative MRI of the calf with coil reference (indicated by white arrow). ³¹P spectrum from the calf of the same subject at rest (B) at the time point of fatigue (C). Note the depletion of PCr and accumulation of Pi at fatigue. ³¹P MRS spectra at rest wherein the reduction in the PCr peak during ATP saturation (D, saturation indicated by black arrow), as compared to PCr peak during control saturation (E, saturation indicated by black arrow), is proportional to the ATP synthesis rate through CK. F.) Summary ATP synthesis rates from PCr through CK. G.) Summary ATP synthesis rates from Pi. There are no significant differences among the four groups at baseline resting conditions.

Figure 3

Time course of energetic changes and fatigue symptoms for a healthy subject with low fatigability (A) and for a HF patient with high fatigability (B). In both cases PCr is progressively depleted and Pi accumulates during staged-exercise while ATP is preserved. The rates of PCr decrease and Pi increase are more rapid in the subject with high fatigability. Both subjects reached a similar subjective level of fatigue (Borg scale) and PCr depletion but at different workloads and exercise durations.

Figure 4

Skeletal muscle energetic parameters (PCr, Pi, pH, ADP, ΔG_~ATP) and phosphodiester (PDE) during baseline resting conditions (A–F, left column) and at the point of fatigue (G–K, right column). There are no significant differences in the SM energetic parameters among the four groups at rest or at the point of fatigue (although PDE differed at baseline). Comparisons vs healthy subjects, ^§ p<0.005, ^§§§ p<0.001.

Figure 5

A) Normalized rate of PCr decline during PFE. B) Initial normalized rate of PCr decline during the first 4 minutes of PFE, C) Correlation of maximal PFE time and rate of PCr decline. Significant differences are indicated: * p < 0.05, ^§ p < 0.005. ^§§§ p < 0.001

Figure 6

A) The rate of PCr recovery following PFE is significantly delayed in HFpEF and HFrEF II–III patients as compared to HFrEF class I and healthy subjects. B) Indices of maximal oxidative capacity (Vmax_PCr) are lower in NYHA class II-II HFrEF and HFpEF patients than in the other two groups without EI. Comparisons vs healthy subjects, ^§ p<0.005, ^§§ p<0.002. Comparisons vs HFrEF NYHA class I patients, *** p<0.01.

Figure 7

Anatomical MRI showing fat distribution in the calf of a healthy subject (A) and in the calf of a HFpEF patient (B). C) Muscular fat content in the four groups. Comparisons vs. healthy subjects, ** p<0.02, §§§ p<0.001.

Figure 8

A.) Fatigability construct showing the relationship between fatigue symptoms and activity (adapted from Eldadah). Fatigue and work levels are compared in a healthy subject with low fatigability (blue line) and a subject with high fatigability (red line). Both experience the same level of fatigue symptoms (“fatigue limit”) but at different levels of activity. B.) The fatigability construct is expanded to include energetic contributions (y-axis). If there is no energetic basis for fatigue in HF, then fatigue could occur with residual (less depleted) energy stores in individuals with high fatigability (red line #1) than in those with low fatigability (blue line). However if an energetic component to fatigue in HF is the limiting factor, one would expect subjects with high (red lines #2 and #3) and low (blue line) fatigability to fatigue at the same “energetic limit” albeit at different activity levels. If that is the case, the earlier time to energy depletion in those with high fatigability could be due to either lower resting, baseline energy reserve (red line 3) and/or more rapid decline during exercise (red line 2).