Skeletal Muscle Mitochondrial Respiration and Exercise Intolerance in Patients With Heart Failure With Preserved Ejection Fraction

Abstract

ImportanceThe pathophysiology of exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF) remains incompletely understood. Multiple lines of evidence suggest that abnormal skeletal muscle metabolism is a key contributor, but the mechanisms underlying metabolic dysfunction remain unresolved.ObjectiveTo evaluate the associations of skeletal muscle mitochondrial function using respirometric analysis of biopsied muscle fiber bundles from patients with HFpEF with exercise performance.Design, Setting, and ParticipantsIn this cross-sectional study, muscle fiber bundles prepared from fresh vastus lateralis biopsies were analyzed by high-resolution respirometry to provide detailed analyses of mitochondrial oxidative phosphorylation, including maximal capacity and the individual contributions of complex I–linked and complex II-linked respiration. These bioenergetic data were compared between patients with stable chronic HFpEF older than 60 years and age-matched healthy control (HC) participants and analyzed for intergroup differences and associations with exercise performance. All participants were treated at a university referral center, were clinically stable, and were not undergoing regular exercise or diet programs. Data were collected from March 2016 to December 2017, and data were analyzed from November 2020 to May 2021.Main Outcomes and MeasuresSkeletal muscle mitochondrial function, including maximal capacity and respiration linked to complex I and complex II. Exercise performance was assessed by peak exercise oxygen consumption, 6-minute walk distance, and the Short Physical Performance Battery.ResultsOf 72 included patients, 50 (69%) were women, and the mean (SD) age was 69.6 (6.1) years. Skeletal muscle mitochondrial function measures were all markedly lower in skeletal muscle fibers obtained from patients with HFpEF compared with HCs, even when adjusting for age, sex, and body mass index. Maximal capacity was strongly and significantly correlated with peak exercise oxygen consumption (R = 0.69; P < .001), 6-minute walk distance (R = 0.70; P < .001), and Short Physical Performance Battery score (R = 0.46; P < .001).Conclusions and RelevanceIn this study, patients with HFpEF had marked abnormalities in skeletal muscle mitochondrial function. Severely reduced maximal capacity and complex I–linked and complex II–linked respiration were associated with exercise intolerance and represent promising therapeutic targets.

Skeletal Muscle Mitochondrial Dysfunction and Exercise Intolerance in Heart Failure With Preserved Ejection Fraction

“…Despite these uncertainties, the present study by Scandalis et al represents a major advancement in our understanding of the pathophysiology of HFpEF. It extends our understanding of the mechanisms that underlie peripheral exercise limitations in HFpEF and provides us with potential therapeutic targets for the management of exercise intolerance.…”

“…This study represents a substantial addition to our understanding of the pathophysiology of HFpEF for multiple reasons. First, this is a large study of mitochondrial function in patients with HFpEF and matched controls using gold-standard respirometric analyses of freshly biopsied skeletal muscle.…”

“…The study by Scandalis et al in this issue of JAMA Cardiology represents an important step forward in our understanding of the mechanisms of exercise intolerance in HFpEF. It provides key insights into skeletal-muscle mitochondrial dysfunction by conducting analyses of vastus lateralis skeletal-muscle tissue among patients with HFpEF vs age-matched, healthy, sedentary controls.…”

Mitochondrial Respiration and Exercise Performance in Patients With Heart Failure With Preserved Ejection Fraction

“…To the Editor We read with great interest the insightful study by Scandalis et al showing that patients with heart failure with preserved ejection fraction (HFpEF) have profound reductions in ex vivo skeletal muscle mitochondrial respiration especially with respect to maximal capacity, complex I-linked respiration, and complex II-linked respiration. There is growing interest in the use of sophisticated techniques such as high-resolution respirometry to advance our understanding of how cardiac conditions impact energetics and exercise performance.…”

Mitochondrial Respiration and Exercise Performance in Patients With Heart Failure With Preserved Ejection Fraction

“…To the Editor We read with great interest the excellent article by Scandalis et al on dysfunction of skeletal muscle mitochondria in patients with heart failure with preserved ejection fraction (HFpEF). The authors demonstrate a significant association between maximal mitochondrial respiratory capacity (and contributions of complex I– and complex II–linked respiration) and exercise intolerance, ie, severely reduced peak exercise oxygen consumption (peak VO 2 ) . Although the authors refer to potential confounding associated with partly severe obesity in patients with HFpEF, this aspect and the impact of oxygen delivery factors on individual peak VO 2 need further consideration.…”