Myopenia in HFpEF: Impaired Muscle Quality Beyond the Heart

Abstract

Heart failure with preserved ejection fraction (HFpEF) is increasingly understood as a systemic disorder of impaired energetics and metabolic inflammation rather than an isolated disease of cardiac structure or haemodynamics. Although cardiac abnormalities define the diagnosis, they do not explain the severity of exercise intolerance, fatigue and loss of physical function that dominate the clinical phenotype. Converging physiological, metabolic and clinical evidence identifies extracardiac mechanisms, particularly skeletal muscle dysfunction, as key determinants of disability in HFpEF. Recent studies have reported an association between expansion of epicardial adipose tissue (EAT) and skeletal muscle fatigability in HFpEF, independent of generalized obesity or body mass index. Strikingly, muscle endurance is disproportionately impaired relative to muscle mass or maximal strength, revealing a qualitative defect in muscle performance rather than classical sarcopenia. This dissociation, illustrated by preserved force generation alongside accelerated fatigue, implicates impaired mitochondrial oxidative capacity and reduced fatigue resistance as central contributors to functional limitation. In this review, we synthesize emerging evidence on skeletal muscle bioenergetics, mitochondrial dysfunction and adipose–muscle crosstalk to propose a myopenic phenotype as a unifying framework for HFpEF-related disability. Myopenia, defined as clinically meaningful muscle dysfunction driven primarily by impaired muscle quality rather than overt muscle wasting, captures a pattern of wasting biology without obligatory loss of muscle mass. Within this framework, EAT is conceptualized as a metabolically active visceral fat depot that may amplify systemic inflammation and disrupt skeletal muscle oxidative metabolism through an integrated adipo-muscular axis. By shifting emphasis from cardiac mechanics and muscle quantity towards muscle endurance, metabolic efficiency and inter-organ energetic signalling, this framework aligns HFpEF with systems-level paradigms underlying cachexia, metabolic ageing and chronic organ failure. Framing HFpEF as a clinically relevant myopenic state supports muscle-centric outcome measures and integrated therapeutic strategies aimed at correcting multisystem energetic failure and preventing loss of physical function.