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Updated: Jan 26, 2026

Pre-clinical Model of Cardiac Donation after Circulatory Death
Published on: August 2, 2019
Differential effects of ischemia/reperfusion on endothelial function and contractility in donation after circulatory
Natalia Méndez-Carmona1, Rahel K Wyss1, Maria Arnold1
1Department of Cardiovascular Surgery, Inselspital, Bern University Hospital, Bern, Switzerland; Department for BioMedical Research, University of Bern, Bern, Switzerland.
Insights
Donation after circulatory death (DCD) heart ischemia impairs endothelial function earlier than cardiac function. Improving endothelial nitric oxide synthase (eNOS) coupling may enhance DCD heart recovery for transplantation.
Area of Science:
- Cardiovascular Research
- Transplantation Immunology
- Organ Preservation
Background:
- Donation after circulatory death (DCD) offers potential for increased cardiac graft availability.
- DCD hearts face challenges from warm ischemia/reperfusion (I/R) injury.
- Endothelial damage is a critical component of cardiac I/R injury.
Purpose of the Study:
- Investigate the tolerance of cardiac and endothelial function to varying warm ischemia durations.
- Inform optimal timing and selection of cardioprotective therapies for DCD hearts.
- Determine the threshold for warm ischemia-induced endothelial dysfunction.
Main Methods:
- Isolated, working rat hearts subjected to 20 minutes aerobic perfusion.
- Varied durations of warm global ischemia followed by 30 or 60 minutes reperfusion.
- Assessed cardiac function (left ventricular work) and endothelial function (vasodilation).
Main Results:
- Cardiac function recovery reduced with ≥27 minutes ischemia.
- Cell death and edema increased with ≥27 minutes ischemia.
- Endothelial dysfunction observed with ≥24 minutes ischemia; eNOS uncoupling indicated by increased superoxide and peroxynitrite.
Conclusions:
- Endothelial dysfunction occurs earlier than cardiac functional decline following ischemia.
- Increased eNOS uncoupling may drive early endothelial dysfunction.
- Enhancing eNOS coupling could improve DCD heart recovery and transplantation outcomes.
Background:
Donation after circulatory death (DCD) could significantly improve cardiac graft availability. However, DCD hearts undergo potentially deleterious warm ischemia/reperfusion (I/R). As endothelial damage is a key factor in cardiac I/R injury, we aimed to investigate the tolerance of cardiac and endothelial function after various durations of warm ischemia to improve the timing and choice of cardioprotective therapies.
Methods:
Isolated, working rat hearts were perfused for 20 minutes aerobically, then underwent various periods of warm global ischemia and either 30 or 60 minutes of reperfusion.
Results:
Compared with non-ischemic hearts, recovery of left ventricular work (heart rate-developed pressure product) was significantly reduced at 60 minutes of reperfusion with ≥27 minutes of ischemia (p <0.05 for all), but was unchanged after 21 or 24 minutes of ischemia. Markers of cell death and edema significantly increased with ≥27-minute ischemia compared with non-ischemic hearts (p <0.05 for all). Endothelial-dependent vasodilation was significantly impaired compared with non-ischemic hearts with ≥24 minutes of ischemia, whereas endothelial-independent vasodilation was impaired with ≥27 minutes of ischemia (p <0.05 for all). Furthermore, with ≥24 minutes of ischemia, superoxide production by nitric oxide synthase and peroxynitrite levels were significantly increased compared with non-ischemic hearts, suggesting endothelial nitric oxide synthase (eNOS) uncoupling (p <0.05 for both).
Conclusions:
The first signs of endothelial dysfunction after cardiac ischemia occur with less ischemia than cardiac functional alterations, and may result from increased eNOS uncoupling. Strategies aimed at improving eNOS coupling may thus help to optimize both endothelial and myocardial recovery, ultimately facilitating DCD heart transplantation.
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