Abstract
Introduction: Small animal models have shown increased cardiac function and decreased infarct size with DPP-4 inhibition, but many human studies have shown increased heart failure readmission or no benefits. We seek to bridge the gap from small animal models to humans by studying DPP-4 inhibitor sitagliptin in a swine model of chronic myocardial ischemia using proteomic analysis. Methods: Thirteen Yorkshire swine underwent placement of an ameroid constrictor on the left coronary circumflex artery to model chronic myocardial ischemia. Two weeks post-op, swine received either sitagliptin 100 mg daily (SIT, n=5) or no drug (CON, n=8). After five weeks of treatment, swine underwent functional measurements and tissue harvest. Myocardial tissue was sent for proteomic analysis or analyzed with immunoblot. Results: In the SIT group compared to CON, there was a strong trend towards decreased cardiac index (p=0.06), with decreased end-systolic and diastolic volumes (all p<0.05, Figure 1). Proteomics analysis identified 1,003 proteins in the non-ischemic and 728 proteins in the ischemic myocardium. The non-ischemic and ischemic myocardium had 396 and 166 significantly decreased proteins, respectively, in the SIT group compared to CON (all p<0.01). This included proteins involved in the citric acid cycle (TCA), fatty acid oxidation (FAO), and oxidative phosphorylation (OXPHOS). Immunoblotting confirmed SIT was associated with decreased expression of several metabolic proteins including FAS, CPT1α, IDH1, and mitochondrial complexes I and II (all p<0.05). Conclusions: In a swine model of chronic myocardial ischemia, sitagliptin treatment resulted in a trend towards decreased cardiac index and decreased expression of proteins involved in OXPHOS, FAO, and the TCA in both ischemic and non-ischemic myocardium. These metabolic and functional changes may provide some mechanistic evidence for the increased heart failure readmission in clinical studies.
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