Key result
Human HFpEF myocardium exhibits distinct and broad multi-class lipid accumulation (favoring accumulation over depletion by a 60:1 ratio) that is independent of obesity alone, not found in HFrEF, and not mirrored by common preclinical animal models.
Why the study?
Human myocardial lipidomic data across the obesity-heart failure spectrum, particularly in HFpEF, remain lacking despite lipid dyshomeostasis being implicated in HFpEF pathophysiology.
Does the human myocardial and plasma lipidome differ significantly between HFpEF, HFrEF, and non-failing controls, and do animal models recapitulate these changes?
Observational (n=82)
Yes
Does the human myocardial and plasma lipidome differ significantly between HFpEF, HFrEF, and non-failing controls, and do animal models recapitulate these changes?
Human HFpEF is characterized by profound and unique myocardial lipid accumulation that differs distinctly from HFrEF, is not driven purely by obesity, and is not accurately captured by standard preclinical animal models.
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.
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Kass et al. (2026) conducted an observational in Heart Failure with Preserved Ejection Fraction (HFpEF) (n=82). Heart failure with preserved ejection fraction (HFpEF) vs. Non-failing controls and HFrEF was evaluated on Myocardial lipid species abundance across lipid classes. Human HFpEF myocardium exhibits distinct and broad multi-class lipid accumulation (favoring accumulation over depletion by a 60:1 ratio) that is independent of obesity alone, not found in HFrEF, and not mirrored by common preclinical animal models.
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