Obese HFpEF patients exhibit impaired glycolysis and energy deprivation marked by a reduced ATP/ADP ratio, with correlations to worse clinical outcomes (NYHA class, E/e′).
Obese HFpEF is characterized by a distinct myocardial multi-omic signature involving impaired glucose oxidation, energy deprivation, and extracellular matrix remodeling, independent of obesity.
Abstract Background Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart failure and is characterized by high morbidity and mortality. The cardiometabolic, obesity-related HFpEF phenotype is particularly prevalent and severe, yet the myocardial mechanisms that distinguish obese patients with HFpEF from non-failing obese individuals remain unclear. Objective To define obesity-independent molecular features of HFpEF through integrated proteomic, metabolomic, and lipidomic profiling of human left-ventricular (LV) tissue and to relate these to clinical and hemodynamic parameters. Methods LV endomyocardial biopsies were obtained from obese HFpEF patients (n = 19) and overweight/obese non-failing (NFO) controls (n = 4). Clinical, imaging, and invasive hemodynamic data were correlated with multi-omic profiles. Proteins were quantified by data-independent acquisition mass spectrometry, targeted metabolomics covered 73 metabolites, and untargeted lipidomics identified 377 lipid species. Statistical analyses included moderated t-testing (FDR 0.1) and Spearman correlations with clinical indices. Results HFpEF patients were older and showed higher NYHA class (p 0.001), greater NT-proBNP levels (p = 0.009), elevated LV end-diastolic pressure (p 0.001), and more myocardial fibrosis (p 0.001) than NFO, while BMI and diabetes prevalence were comparable. Quantitative proteomics detected 4,879 proteins, of which 72 differed significantly between groups. Gene-ontology enrichment revealed up-regulation of extracellular-matrix (ECM) organization and down-regulation of nucleotide and energy-metabolism pathways in HFpEF. Metabolomic analysis demonstrated accumulation of glucose-6-phosphate and reduced pyruvate concentrations, indicating impaired glycolysis. HFpEF hearts exhibited higher succinate and an increased succinate/fumarate ratio, together with a reduced ATP/ADP ratio, consistent with energy deprivation. Lipidomics showed preserved fatty-acid oxidation but selective depletion of very-long-chain acylcarnitines (AcCa 21:4) and subtle cardiolipin remodeling. Perturbations in purine and pyrimidine pathways included elevated AMP (.Integration with clinical data linked metabolic and proteomic alterations to disease severity: metabolites such as glucose-6-phosphate, acetyl-CoA, and succinate correlated with worse NYHA class, higher E/e′, elevated LV filling pressures, and reduced stroke-volume augmentation during exercise (all p 0.05). Conclusions Obese HFpEF hearts display a distinct, obesity-independent myocardial signature characterized by impaired glucose oxidation, tricarboxylic-acid-cycle imbalance, and ECM remodeling. These findings define two major mechanistic axes—metabolic dysfunction and fibrosis—underlying cardiometabolic HFpEF and provide a translational framework for metabolism- and fibrosis-targeted diagnostic and therapeutic strategies.
Capone et al. (2026) studied this question. Obese HFpEF patients exhibit impaired glycolysis and energy deprivation marked by a reduced ATP/ADP ratio, with correlations to worse clinical outcomes (NYHA class, E/e′).