Preservation of Cardiac Function by Glucagon-Like Peptide-1 (28-36) through Metabolic Modulation and Coronary Vasodilation in a Juvenile Porcine Model of Donation after Circulatory Death
Abstract Body (Do not enter title and authors here): Purpose and Hypothesis: Despite the increasing number of donation after circulatory death (DCD) heart transplants over the last decade, there is no promising cardioprotective agent to improve DCD heart function in this clinical setting. There is some evidence that glucagon-like peptide (GLP)-1 (28-36), a metabolite of the insulinotropic GLP-1(7-36) incretin hormone, provides cytoprotection to the coronary vasculature without activating the GLP-1 receptor. This study aims to explore the potential benefits of GLP-1(28-36) on DCD hearts in juvenile pigs. Methods and Results: DCD heart procurement was performed on twelve Yorkshire juvenile pigs (9-12 kg) with a 15-min warm ischemic period, followed by reperfusion for 2 hours using ex-vivo heart perfusion (unloaded condition) with either GLP-1(28-36) or scrambled GLP-1(28-36) control (SCRAM) (each N=6, 6-nM), before switching to working mode (loaded condition). Between-group differences were analyzed using Wilcoxon rank-sum tests and linear mixed-effects models. Over the reperfusion period, venous lactate levels trended down in the GLP-1(28-36) group, compared to SCRAM (3.0±1.1 vs. 4.4±0.5, mmol/L at 120min, p=0.01; Figure 1A), despite no significant difference seen in plasma cardiac troponin I levels in working mode (GLP-1[28-36] vs. SCRAM, 61±20 vs. 83±18, ng/mL, p=0.08). Coronary vascular resistance was lower in the GLP-1(28-36) group vs. SCRAM (0.48±0.11 vs. 0.93±0.51 mmHg*min/mL/100g at 30min, p<0.01; Figure 1B). During working mode, GLP-1(28-36)-treated hearts showed better diastolic function (dp/dt min: -3357±784 vs. -2372±471 mmHg/sec, p=0.03), with comparable systolic function (p=0.13). Higher levels of cardiac activated endothelial nitric oxide synthase (0.23±0.05 vs. 0.14±0.02, p<0.01) and plasma cyclic guanosine monophosphate (45±22 vs. 23±11, pmol/mL, p=0.03) were observed with GLP-1(28-36) treatment. Conclusion: GLP-1(28-36) preserves diastolic function of DCD hearts during ex-vivo heart perfusion by reducing anaerobic metabolism and maintaining coronary endothelial function.
Kadowaki, Sachiko
( Hospital for Sick Children
, Toronto
, Ontario
, Canada
)
Parker, Marlee
( Hospital for Sick Children
, Toronto
, Ontario
, Canada
)
Kobayashi, Junko
( Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
, Okayama
, Japan
)
Husain, Mansoor
( University of Toronto
, Toronto
, Ontario
, Canada
)
Honjo, Osami
( Hospital for Sick Children
, Toronto
, Ontario
, Canada
)
Siraj, M. Ahsan
( Peter Munk Cardiac Centre
, Toronto
, Ontario
, Canada
)
Deng, Mimi
( Hospital for Sick Children
, Toronto
, Ontario
, Canada
)
Lao, Robert
( Peter Munk Cardiac Centre
, Toronto
, Ontario
, Canada
)
Lamba, Manya
( Hospital for Sick Children
, Toronto
, Ontario
, Canada
)
Li, Jing
( Hospital for Sick Children
, Toronto
, Ontario
, Canada
)
Nagy, Anita
( Hospital for Sick Children
, Toronto
, Ontario
, Canada
)
Mueller, Brigitte
( University Health Network
, Toronto
, Ontario
, Canada
)
Fan, Chun-po
( University Health Network
, Toronto
, Ontario
, Canada
)
Author Disclosures:
Sachiko Kadowaki:DO NOT have relevant financial relationships
| Marlee Parker:No Answer
| Junko Kobayashi:DO NOT have relevant financial relationships
| Mansoor Husain:No Answer
| Osami Honjo:DO NOT have relevant financial relationships
| M. Ahsan Siraj:No Answer
| Mimi Deng:DO NOT have relevant financial relationships
| Robert Lao:DO NOT have relevant financial relationships
| Manya Lamba:No Answer
| Jing Li:No Answer
| Anita Nagy:No Answer
| Brigitte Mueller:DO NOT have relevant financial relationships
| Chun-Po Fan:DO NOT have relevant financial relationships
