Skeletal muscle fatty acid oxidation capacity independently associates with cardiorespiratory fitness in patients with heart failure with preserved ejection fraction
A Martinez-Dominguez, M Gutierrez-Garcia, S Oscoz-Ochandorena, M Izquierdo, R Ramirez-VelezAbstract
Background
Skeletal muscle mitochondrial dysfunction and impaired metabolic flexibility have been implicated in exercise intolerance. Whether skeletal muscle fatty acid oxidation (FAO) capacity, an index of mitochondrial oxidative capacity under lipid-supported conditions, independently associates with cardiorespiratory fitness (CRF) in heart failure with preserved ejection fraction (HFpEF) is unclear.
Objectives
This study aimed at determining the association between skeletal muscle FAO capacity and CRF in HFpEF and to compare the relative contributions of FAO, age, and sex.
Methods
This secondary analysis used a subsample of baseline data from 40 adults with HFpEF (66.6±9.6 years). Mitochondrial respiration was determined by high-resolution respirometry in permeabilized fiber bundles from biopsies of the vastus lateralis. FAO capacity was defined as ADP-stimulated respiration with malate (2 mM), octanoyl-carnitine (0.5 mM), and ADP (2.5 mM). Participants underwent a symptom-limited, maximal incremental cardiopulmonary exercise test on a cycle ergometer with breath-by-breath gas exchange analysis to determine cardiorespiratory fitness, quantified as peak oxygen uptake (VO₂peak). Body composition was assessed by dual-energy X-ray absorptiometry. Associations were evaluated using simple and multiple linear regression with age and sex as covariates; unstandardized (B) and standardized (β) coefficients and adjusted R² were reported.
Results
FAO capacity was positively associated with VO₂peak in unadjusted analysis (B=0.460; β=0.566; P<0.001; R²=0.320). In the multivariable model, FAO remained an independent predictor of VO₂peak (B=0.374; β=0.461; P<0.001; adjusted R²=0.59), corresponding to a 0.37 mL·kg⁻¹·min⁻¹ higher VO₂peak per 1 pmol O₂·s⁻¹·mg⁻¹ higher FAO capacity. Male sex was independently associated with higher VO₂peak (B=7.804; β=0.543; P<0.001), whereas age showed a non-significant inverse trend (B=−0.136; β=−0.179; P=0.121).
Conclusions
Skeletal muscle FAO capacity is independently associated with CRF in HFpEF beyond age and sex, supporting skeletal muscle mitochondrial oxidative metabolism as a clinically relevant determinant of functional capacity and a potential therapeutic target. ClinicalTrials.gov: NCT07251361.