Credit：www.freepik.com

Heart failure with preserved ejection fraction (HFpEF) is the predominant form of heart failure among elderly individuals and women, characterized primarily by significant exercise intolerance. Patients with HFpEF frequently experience fatigue during physical activity, impeding their ability to perform routine daily tasks. This condition not only diminishes their quality of life but also exacerbates the healthcare burden.

Study Overview

Lina et al. conducted a cross-sectional study to analyze skeletal muscle mitochondrial function in HFpEF patients compared to age-matched healthy controls, aiming to elucidate the role of mitochondrial dysfunction in the exercise intolerance observed in HFpEF. This study included 72 participants, of whom 50 (69%) were female, with a mean age of 69.6 years. The two groups were matched for age, sex, and body mass index (BMI).

Mitochondrial Function Assessment

High-resolution respirometry was utilized on fresh vastus lateralis muscle fiber bundles to assess the maximum capacity of mitochondrial oxidative phosphorylation and the contributions of complex I and complex II respiration. Exercise performance was evaluated through peak exercise oxygen consumption (peak VO2), a 6-minute walk test, and the Short Physical Performance Battery (SPPB).

Key Findings

Mitochondrial Capacity: The study demonstrated that the maximum mitochondrial capacity in HFpEF patients was significantly lower than in healthy controls, indicating a severe impairment of overall mitochondrial function. Complex I-related respiration, a key component of the mitochondrial electron transport chain, was significantly reduced in HFpEF patients. Similarly, complex II-related respiration was also significantly decreased, indicating further impairment in mitochondrial energy production capacity.

Exercise Performance: HFpEF patients showed significantly lower peak VO2 levels compared to healthy controls, reflecting severely impaired cardiopulmonary function. The 6-minute walk distance was significantly shorter, and SPPB scores were lower, indicating substantial impairment in various aspects of physical performance.

Correlation Analysis: There was a significant positive relationship between maximum mitochondrial capacity and cardiopulmonary endurance, as well as walking ability and SPPB scores. This reinforces the notion that mitochondrial dysfunction is a crucial factor contributing to exercise intolerance in HFpEF patients.

Technological Advancements

The study utilized fresh samples to prevent potential damage or loss of function during freezing, ensuring accurate measurements. High-resolution respirometry technology was employed to precisely assess the capacity of mitochondrial oxidative phosphorylation and the function of respiratory chain complexes. This technology allows for a fine distinction between complex I and complex II-related respiration, which is challenging to achieve with traditional methods.

Implications and Future Directions

This study is the first to directly demonstrate the association between mitochondrial dysfunction and exercise intolerance in HFpEF patients. The findings suggest that mitochondrial function abnormalities could serve as potential therapeutic targets for treating exercise intolerance in HFpEF. Despite significant progress, limitations remain, and future research should focus on expanding sample sizes, controlling for potential confounding factors, integrating multi-omic data, and validating clinical efficacy. These efforts aim to gain a comprehensive understanding of the pathophysiological mechanisms of HFpEF and optimize treatment strategies, ultimately offering more treatment options and improved quality of life for HFpEF patients.

Reference：

Scandalis L, Kitzman DW, Nicklas BJ, et al. Skeletal Muscle Mitochondrial Respiration and Exercise Intolerance in Patients With Heart Failure With Preserved Ejection Fraction. JAMA Cardiol. 2023;8(6):575–584. doi:10.1001/jamacardio.2023.0957