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. 2023 Jun 1;8(6):575-584.
doi: 10.1001/jamacardio.2023.0957.

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

Lina Scandalis  1 , Dalane W Kitzman  2 , Barbara J Nicklas  3 , Mary Lyles  3 , Peter Brubaker  4 , M Benjamin Nelson  2 , Michelle Gordon  3 , John Stone  3 , Jaclyn Bergstrom  1 , P Darrell Neufer  5 , Erich Gnaiger  6 , Anthony J A Molina  1
Affiliations

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

Lina Scandalis et al. JAMA Cardiol. .

Abstract

Importance: The 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.

Objective: To 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 participants: In 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 measures: Skeletal 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.

Results: Of 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 relevance: In 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Kitzman has received grants from the National Institutes of Health during the conduct of the study; grants from Novartis, Rivus, NovoNordisk, AstraZeneca, Pfizer, and Bayer; and personal fees from Bayer, Merck, Medtronic, Relypsa, Corvia Medical, Rivus, NovoNordisk, AstraZeneca, Pfizer, Novartis, and Boehringer Ingelheim outside the submitted work; and owns stock in Gilead Sciences. Dr Nicklas has received grants from the National Institutes of Health during the conduct of the study. Dr Gnaiger is founder and CEO of Oroboros Instruments outside the submitted work. Dr Molina has received grants from the National Institutes of Health during the conduct of the study as well as personal fees from Stealth Bioscience and the Gerontological Society of America/Nestle Health Science outside the submitted work and serves as a key opinion leader of Oroboros Instruments. No other disclosures were reported.

Figures

Figure.
Figure.. Associations of Maximal Capacity With Exercise Capacity and Physical Ability
The blue line indicates the simple linear regression line. HC indicates healthy control; HFpEF, heart failure with preserved ejection fraction; peak VO2, peak exercise oxygen consumption; SPPB, Short Physical Performance Battery.
See this image and copyright information in PMC

Comment in

References

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