Characterization of Endothelial Function Following Various Ischemic Durations in an Isolated Rat Heart Model of Donation After Circulatory Death

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BackgroundIn addition to conventional donation after brain death, donation after circulatory death (DCD) could significantly improve the number of cardiac grafts for transplantation. However, DCD hearts undergo a period of warm ischemia followed by reperfusion (I/R), which leads to injury that raises concern for graft function.Endothelial damage is a key factor in cardiac I/R injury. Thus, in order to improve the timing and choice of therapeutic targets for cardioprotection in DCD heart transplantation, we characterized hemodynamic and endothelial function following various ischemic durations in an isolated rat heart model of DCD.MethodsIsolated, working rat hearts were perfused aerobically for a period of 20 min with modified Krebs-Henseleit buffer, then underwent various periods (0, 21, 24, 27, 30 and 33 min) of warm global ischemia (I), followed by reperfusion of 30 or 60 min. Hemodynamic recovery was monitored, coronary flow was measured as an indicator of vascular function, and endothelial function was assessed by comparing vasodilatory responses between endothelium-dependent (bradykinin; 10-9 and 10-8 M) and endothelium-independent (sodium nitroprusside; 3x10-5 M) vasodilators.ResultsAt 60 min reperfusion, recovery of left ventricular work (heart rate–developed pressure product), was significantly lower compared with non-ischemic controls (100 ± 11%), after 27’ I (76 ± 12%), 30’ I (69 ± 16%) or 33’ I (29 ± 20%; p<0.05 for all), but was unchanged after 21’ I (91 ± 5%) or 24’ I (86 ± 13%; n=6-8/group). At 20 min reperfusion, coronary flow (in mL/min) was not different after 21’ I (24 ± 3) or 24’ I (19 ± 3) compared to non-ischemic controls (25 ± 4), but was significantly decreased after 27’ I (19 ± 3), 30’ I (17 ± 6), and 33’I (13 ± 2; p<0.05 for all). After 30 min reperfusion, endothelial function was impaired after >24’ I, while smooth muscle function was impaired only after >27’ I (n=6/group).ConclusionEndothelial dysfunction occurs with periods of ischemia shorter than those required to induced hemodynamic and smooth muscle dysfunction. Thus, a window of opportunity exists for the application of endothelial-based therapies aimed at optimizing both endothelial and myocardial recovery, ultimately to improve DCD graft quality and facilitate heart transplantation.

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