Metabolic Heterogeneity Across Heart Failure Subtypes Defined by Integrative Multi-Omics Analysis

Heart failure (HF) is a heterogeneous syndrome with diverse etiologies, yet the metabolic determinants specific to its subtype remain unclear. We performed an integrative multi-omics analysis combining metabolomics, genetics, and single-cell transcriptomics to characterize metabolic signatures of distinct HF subtypes. By applying Mendelian randomization of 1,091 circulating metabolites, we identified distinct metabolic patterns: lipid metabolites, particularly sphingolipids, were associated with increased HF risk, while tricarboxylic acid (TCA) cycle intermediates exhibited potential protective effects. Subtype-specific differences included lipid remodeling in coronary heart disease (CHD)-related HF, TCA metabolism in hypertension (HTN)-related HF, and amino acid pathways in overweight-related HF. Integrative analyses highlighted candidate regulators such as UPP1, NEU3, CBS, SHMT1, PLD2, OGDHL, and SULT1A1/2. Single-cell data revealed cardiomyocyte-enriched expression of OGDHL, which was consistently downregulated in experimental HF models. These findings provide insight into metabolic heterogeneity in HF and identify OGDHL as a potential regulator of cardiac metabolic remodeling.