The interplay of diet and disease: High-fat feeding in chronic myocardial ischemia–A translational swine proteomics study

BACKGROUND: The effect of a high-fat diet on ischemic heart disease remains debated, with some studies suggesting paradoxical benefits. We investigated the direct myocardial effects of a high-fat diet in chronic ischemia using a clinically relevant swine model with integrated functional and proteomic assessment. METHODS: Twenty juvenile Yorkshire swine were randomized to a normal diet (n = 9) or high-fat diet (n = 11) for 5 weeks before placement of an ameroid constrictor on the left circumflex artery. The swine were then maintained on the assigned diet for 7 additional weeks. Terminal studies included pressure-volume hemodynamics, microsphere-derived myocardial perfusion, and proteomic profiling of ischemic and non-ischemic myocardium. RESULTS: High-fat diet swine developed a swine-specific, metabolic syndrome-like lipid phenotype: markedly elevated total cholesterol and low-density lipoprotein, increased high-density lipoprotein, and low/variable triglycerides, despite similar body mass index. Compared with the normal diet swine, the high-fat diet animals demonstrated higher ejection fraction (P = .03), preload recruitable stroke work (P = .02), and lower tau (P = .001), reflecting improved systolic and diastolic performance. Perfusion to ischemic myocardium was greater at rest (P = .004) and pacing (P = .0048). Proteomics (2,782 proteins) revealed upregulation of fatty acid metabolism and mitochondrial transport with downregulation of cytoskeletal pathways, indicating metabolic remodeling toward lipid utilization. CONCLUSIONS: A high-fat diet enhances function and perfusion in ischemic swine hearts through metabolic rewiring, supporting the short-term adaptive phase of the obesity paradox while underscoring the need to define long-term consequences.