Muir_2025_JTCVS.Open_28_262

OBJECTIVE: Coronary artery disease (CAD) remains a leading public health concern in the United States. Dipeptidyl peptidase-4 inhibitors, such as linagliptin, have demonstrated cardioprotective effects in preclinical studies; however, their influence on myocardial metabolic changes remains incompletely characterized. Our study aimed to evaluate the effects of linagliptin, as it influences incretin hormones, on myocardial metabolism and substrate utilization in a clinically relevant model of CAD. METHODS: Eleven-week-old Yorkshire swine underwent placement of an ameroid constrictor to the proximal left circumflex coronary artery to induce chronic myocardial ischemia. After 2 weeks to ensure ameroid closure, swine were divided into a group that received daily oral linagliptin treatment for 5 weeks (n = 8) and a group that received no drug treatment (n = 8) for 5 weeks. After 5 weeks, the swine underwent a terminal harvest procedure and subsequent immunoblotting and proteomic analysis. RESULTS: Linagliptin was associated with reduced fatty acid oxidation on proteomic pathway analysis and decreased expression of carnitine palmitoyltransferase 1 beta (CPT1beta) (P = .0014) and CPT1alpha (P = .02) on immunoblotting. Treatment resulted in strict regulation of glycolysis and increased expression of proteins involved in ketone metabolism and the glycerophosphate shuttle. Additionally, linagliptin enhanced protein expression of several citric acid enzymes and significantly regulated protein expression relating to oxidative stress within the ischemic myocardium. CONCLUSIONS: Linagliptin shifted myocardial metabolism pointing to enhanced ketone utilization, upregulation of the TCA cycle, and reductions in free fatty acid oxidation, glycolysis, and lactate production. These findings suggest a potential cardioprotective role for linagliptin via metabolic manipulation under ischemic conditions, warranting further investigation.