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 between 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 NYHA 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 (NYHA 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 as compared to healthy and low fatigability HF patients, suggesting SM metabolism is a potentially important target for future HF treatment strategies.

Making the Case for Skeletal Muscle Myopathy and Its Contribution to Exercise Intolerance in Heart Failure With Preserved Ejection Fraction

“…Together with other abnormalities previously reported in skeletal muscle in HFpEF patients, 2, 5–11 these data make a strong case for a ‘skeletal muscle myopathy’ in HFpEF, similar to that described in HFrEF. 2, 12 Importantly, these abnormalities are not merely secondary to deconditioning , since: 1) they develop even when physical activity is forcibly maintained during the development of HFrEF; 12 2) the pattern of abnormalities differs from deconditioning, particularly the fibertype shift which is the exact opposite from deconditioning.…”

“…These abnormalities were significantly worse in HFpEF than in HFrEF. 11 These data provide the strongest proof to date that HFpEF patients have significantly impaired skeletal muscle bioenergetics that contribute to their severe exercise intolerance.…”

“…2 Indeed, it is now known that, as has been previously established in HFrEF, there are multiple skeletal muscle abnormalities in HFpEF that impair oxygen utilization and appear to contribute to reduced peak VO 2 [Table 1]. 2, 5–11 Among these, growing evidence indicates that impaired mitochondrial function may be among the most consequential. As the sole mechanism for utilizing oxygen and fuel substrate to produce energy, mitochondrial health is obviously a critical determinant of peak VO 2 .…”

“…11 Weiss performed serial MRS measurements of PCr during calf extensor exercise to exhaustion and during recovery in HFpEF patients compared to HFrEF patients and healthy controls. Calf extensor exercise was an important feature, since the small mass of exercising muscle excludes reduced CO as a cause of exercise limitation, since even a severely weakened heart would have ample capacity for the work involved.…”

Decreased ATP production and myocardial contractile reserve in metabolic heart disease

“…Our findings suggest that the inability to increase cardiac work due to energetic limitations may be an important cause of exercise intolerance and symptoms in patients with HFpEF. Peripheral factors, some energetic, may contribute to exercise intolerance in HFpEF as well [56]. Thus, while we cannot exclude a role for other factors (e.g., increased myocardial stiffness due to fibrosis or altered properties/function of titin), therapeutic strategies to improve myocardial energetics may be of value in the treatment of HFpEF in the setting of MHD due to obesity, type 2 diabetes and/or metabolic syndrome (Table 2).…”