• Natalia Méndez-Carmona, Rahel K Wyss, Maria Arnold, Anna Joachimbauer, Adrian Segiser, Georg M Fiedler, Thierry P Carrel, Hendrik T Tevaearai Stahel, and Sarah L Longnus.
• Department of Cardiovascular Surgery, Inselspital, Bern University Hospital, Bern, Switzerland; Department for BioMedical Research, University of Bern, Bern, Switzerland.
• J. Heart Lung Transplant. 2019 Jul 1; 38 (7): 767-777.

BackgroundDonation 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.MethodsIsolated, 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.ResultsCompared 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).ConclusionsThe 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.Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

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