Integrated Myocardial and Plasma Lipidome Across the Human Obesity–Heart Failure Spectrum

Heart failure with preserved ejection fraction (HFpEF) has become the dominant heart failure phenotype, with many patients impacted by marked obesity. Lipid dyshomeostasis is thought to contribute, but human myocardial lipidomic data remain lacking. We performed untargeted lipidomics (>1,000 species) of ventricular samples for non-failing (NF) controls (n=40), HFpEF (n=29), and HFrEF (n=13) patients, integrating results with myocardial transcriptomics, ultrastructure, and plasma lipidomics, across a broad obesity spectrum. Multiple lipid classes increased in HFpEF myocardium including phospholipids, sphingolipids, neutral lipids, and free fatty acids, but acylcarnitines declined. HFrEF had far fewer lipid changes, and cardiolipin and phosphatidylethanolamine depletion. Lipids were minimally altered in NF hearts from obese individuals. Plasma lipidomics identified few inter-group disparities. Heart lipidomics from major animal HFpEF models (high fat diet+L-NAME, ZSF-1 rat, obese-DOCA-salt pig) all differed from human HFpEF. Thus, human HFpEF myocardium has distinctive cardiac lipid accumulation not found with obesity alone or HFrEF, nor mirrored by common preclinical HFpEF models.