Epicardial adipose tissue produces L-3-hydroxybutyrate in advanced heart failure: direct analysis of fat metabolic remodeling

BACKGROUND: Heart failure (HF) progression involves complex metabolic and multi-organ alterations, but the specific adaptations in adipose tissue are not fully understood. AIMS: We aimed to characterize the metabolic remodeling of epicardial (EAT) and subcutaneous (SAT) adipose tissues in HF with reduced ejection fraction (HFrEF), focusing on lipid metabolism, fatty acid oxidation, and ketogenesis. METHODS: Clinical and metabolomic profiling were performed on metabolically stable controls (n = 34), patients with mild HFrEF (n = 45), and severe HFrEF (n = 129). Metabolomics profiling identified over 800 metabolites in EAT and SAT. Clustering and pathway enrichment analyses defined depot-specific metabolic shifts across HF stages, while gene expression analyses provided mechanistic support. RESULTS: Advancing HF was associated with declining cardiac function, systemic congestion, and a metabolic shift toward catabolism. Metabolomics revealed depot-specific adaptations: SAT transitioned smoothly to enhanced lipolysis, whereas EAT demonstrated impaired triacylglycerol replenishment and disrupted final turn of β-oxidation spiral. Both depots increased reliance on acylcarnitine degradation and lipolysis; however, EAT was uniquely characterized by late-stage impairment in mitochondrial and peroxisomal fatty acid oxidation, leading to elevation of 3-hydroxybutyrate and hydroxybutyrylcarnitine tissue levels. Ex vivo analyses of EAT explants showed significantly increased fraction of L-3-hydroxybutyrate enantiomer, produced by EAT, compared to D-3-hydroxybutyrate enantiomer originating from the liver. CONCLUSIONS: HF progression drives major, depot-specific metabolic remodeling in adipose tissue. In advanced HF, EAT shows impaired fatty acid oxidation and enhanced local production of L-3-hydroxybutyrate in the vicinity of myocardium, highlighting the close metabolic cooperation in nutrient supply between EAT and the heart muscle through the coronary circulation.