Abstract 4143581: Dipeptidyl Peptidase 4 Inhibitor Linagliptin Improves Cardiac Function, Fibrosis and Apoptosis in a Swine Model of Chronic Myocardial Ischemia

Introduction: Interest is increasing in using novel diabetic medications, such as GLP-1 receptor agonists, to manage coronary artery disease. Dipeptidyl peptidase-4 (DPP-4) inhibitors enhance GLP-1 activity through the same pathway as GLP-1 agonists; however, DPP-4 inhibitors have not been fully evaluated in the setting of ischemic heart disease. We chose to study the DPP-4 inhibitor linagliptin (LIN) in a swine model of chronic myocardial ischemia (CMI). Goals: Study the effect of DPP-4 inhibitor LIN in a clinically relevant swine model of CMI to gain insight into potential therapies for patients with myocardial ischemia. Methods: Seventeen Yorkshire swine underwent left thoracotomy and ameroid constrictor placement on the left coronary circumflex (LCx) at age 11 weeks. Two weeks later, swine received either vehicle without drug (CON, n=9, F=4, M=5) or LIN 2.5 mg (n=8, F=5, M=3). After 5 weeks of treatment, swine underwent terminal harvest. Results: LIN significantly increased cardiac output, stroke volume, ischemic myocardial perfusion at rest, ischemic myocardial perfusion while pacing at 150 beats per minute, and ejection fraction, while decreasing tau (all p<0.05). Trichrome staining showed a marked reduction in ischemic myocardial interstitial and perivascular fibrosis, accompanied by decreased levels of transforming growth factor beta (all p<0.05). Apoptosis, measured by TUNEL, was significantly reduced, along with decreases in apoptosis-inducing factor, Caspase-9, BAD, and cleaved Caspase-9 (all p<0.05). Additionally, there were significant increases in PI3K, phospho-AKT, AMPK, phospho-AMPK, and ENOS, and a significant reduction in collagen 18 and angiostatin (all p<0.05). There were no significant changes in heart rate, arteriolar density, capillary density, or total oxidative stress. Conclusion: LIN significantly improved myocardial function and perfusion, likely due to reduced fibrosis and apoptosis. The increased perfusion, independent of vascular density, suggests enhanced vascular reactivity. These benefits in a high-fidelity large animal model of CMI warrant further investigation of LIN to fully understand its potential as a therapy for ischemic heart disease.