Integrated left ventricular multi-omics landscape of human cardiometabolic HFpEF

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF), 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, will help to solve this issue. 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 hemodynamics to investigate the molecular mechanisms and clinical relevance of metabolic dysregulation in HFpEF.HFpEF patients exhibited distinct proteomic signatures marked by extracellular matrix (ECM) remodeling 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. CONCLUSIONS: Our findings indicate that metabolic remodeling - particularly dysregulated glycolysis and TCA cycle intermediates changes - contributes to myocardial dysfunction in cardiometabolic HFpEF. Importantly, comprehensive multi-omics analysis of LV EMBs identified HFpEF-specific alterations in cardiac metabolism and remodeling occurring independently from obesity. These insights highlight the interplay between metabolic dysregulation, ECM remodeling, and clinical phenotype in cardiometabolic HFpEF, offering a foundation for targeted metabolic interventions in this syndrome.