Lewsey SC; Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore,
Samuel TJ; Schär M; Sourdon J; Goldenberg JR; Yanek LR; Lai S; Steinberg AM; Bottomley PA; Gerstenblith G; Weiss RG;

Circulation. Heart failure [Circ Heart Fail] 2025 Jun 19, pp. e012512.
Date of Electronic Publication: 2025 Jun 19.

Background: Heart failure with preserved ejection fraction (HFpEF) is a systemic process with contributions from peripheral factors, including skeletal muscle (SM). Age-associated SM loss and impaired energy metabolism occur without heart failure, but the relative importance of changes in SM quantity versus metabolic quality in patients with HFpEF for exercise intolerance (EI) or outcomes has not been studied. We hypothesized that EI and subsequent clinical outcomes across the adult lifespan in patients with HFpEF are related to impaired SM energy metabolism rather than age-associated SM loss.
Methods: Patients with HFpEF (n=64; aged 34-86 years) with left ventricular ejection fraction ≥50% were stratified by age in a prospective study. They underwent 3T magnetic resonance imaging to measure calf muscle quantity and ³¹ P magnetic resonance spectroscopy to measure muscle high-energy phosphate metabolism during plantar flexion exercise.
Results: Older patients with HFpEF exhibited more severe EI, less calf muscle, faster exercise-induced high-energy phosphate decline, and worse SM energetics at fatigue than younger patients. EI correlated closely with muscle metabolic quality, not quantity. Neither magnetic resonance imaging exercise time, 6-minute walk distance, nor peak oxygen uptake at cardiopulmonary exercise testing on cardiopulmonary bicycle exercise testing correlated with calf SM area. In contrast, the 6-minute walk distance and peak oxygen uptake at cardiopulmonary exercise testing were inversely related to rapid exercise-induced high-energy phosphate decline and worse SM energetic profile at fatigue. Rapid exercise-induced high-energy phosphate decline and lower ATP at fatigue were associated with increased cardiovascular death and heart failure hospitalizations in univariate analysis over a median of 39.3 months.
Conclusions: EI in older patients with HFpEF is closely linked to age-associated abnormalities in SM energy metabolism, namely, rapid exercise-induced energetic decline and worse energetic profile at fatigue, and not SM quantity. Abnormal SM energy metabolism is associated with worse outcomes in patients with HFpEF in unadjusted analysis. These findings support SM energy metabolism as a barometer of systemic HFpEF severity and the pursuit of new SM metabolic modulators to reduce disabling EI and possibly adverse outcomes in patients with HFpEF.