Integrated left ventricular multi-omics landscape of human cardiometabolic HFpEF

Aims Heart failure with preserved ejection fraction (HFpEF), now the leading form of heart failure, is burdened by high morbidity and mortality, owing to gaps in our understanding of its molecular and pathophysiological mechanisms. The obese/cardiometabolic HFpEF phenotype is particularly prevalent and morbid, and obesity is increasingly recognized as a driver of the syndrome, though the underlying mechanisms distinguishing cardiometabolic HFpEF from obesity remain unclear. Comprehensive multi-omics characterization of left ventricular samples from patients with HFpEF and obesity, compared with obese non-failing counterparts, provides an opportunity to deepen our understanding of the pathophysiology of cardiometabolic HFpEF.Methods and results We applied an integrated multi-omics approach to compare left ventricular (LV) endomyocardial biopsies (EMB) from overweight/obese HFpEF patients (n = 19) and non-failing overweight/obese (NFO) individuals (n = 4). Proteomic, metabolomic, and lipidomic data were integrated with clinical parameters, imaging and invasive haemodynamic to investigate the molecular mechanisms and clinical relevance of metabolic dysregulation in HFpEF. HFpEF patients exhibited distinct proteomic signatures marked by extracellular matrix (ECM) remodelling and impaired energy metabolism compared with NFO individuals. Specifically, HFpEF hearts showed diminished glycolysis, altered glucose metabolism, preserved fatty acid oxidation (FAO) and accumulation of succinate, consistent with myocardial energy deprivation. Changes in purine and pyrimidine metabolism further indicated altered nucleotide homeostasis. Integrative analyses revealed strong correlations between metabolic derangements, ECM proteins expression, and clinical indices of cardiac function and disease severity.Conclusion Our findings indicate that metabolic remodelling-particularly dysregulated glycolysis and changes in TCA cycle intermediates -characterize myocardial dysfunction in cardiometabolic HFpEF. Importantly, comprehensive multi-omics analysis of LV EMBs identified HFpEF-specific alterations in cardiac metabolism and remodelling occurring independently from obesity. These insights highlight the interplay between metabolic dysregulation, ECM remodelling, and clinical phenotype in cardiometabolic HFpEF, offering a foundation for targeted metabolic interventions in this syndrome.