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American Heart Association

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Final ID: 4143581

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

Abstract Body (Do not enter title and authors here): 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.
  • Harris, Dwight  ( Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University , Providence , Rhode Island , United States )
  • Stone, Christopher  ( Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University , Providence , Rhode Island , United States )
  • Broadwin, Mark  ( Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University , Providence , Rhode Island , United States )
  • Kanuparthy, Meghamsh  ( Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University , Providence , Rhode Island , United States )
  • Sabe, Sharif  ( Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University , Providence , Rhode Island , United States )
  • Nho, Ju-woo  ( Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University , Providence , Rhode Island , United States )
  • Hamze, Jad  ( Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University , Providence , Rhode Island , United States )
  • Abid, Ruhul  ( Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University , Providence , Rhode Island , United States )
  • Sellke, Frank  ( Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University , Providence , Rhode Island , United States )
  • Author Disclosures:
    Dwight Harris: DO NOT have relevant financial relationships | Christopher Stone: DO NOT have relevant financial relationships | Mark Broadwin: DO NOT have relevant financial relationships | Meghamsh Kanuparthy: DO NOT have relevant financial relationships | Sharif Sabe: DO NOT have relevant financial relationships | Ju-Woo Nho: DO NOT have relevant financial relationships | Jad Hamze: DO have relevant financial relationships ; Researcher:Brown University:Active (exists now) ; Researcher:Brown University:Past (completed) | Ruhul Abid: DO have relevant financial relationships ; Consultant:XM Therapeutics:Active (exists now) ; Executive Role:Health and Education for All (non-profit, 501c3):Active (exists now) ; Consultant:Alamgir Research Inc:Past (completed) | Frank Sellke: DO have relevant financial relationships ; Ownership Interest:Xm therapeutics:Active (exists now)
Meeting Info:

Scientific Sessions 2024

2024

Chicago, Illinois

Session Info:

Melvin L. Marcus Early Career Investigator Award in Cardiovascular Sciences Competition

Saturday, 11/16/2024 , 03:15PM - 04:30PM

Abstract Oral Session

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