Effects of Hope (Hypothermic Oxygenated Perfusion) on Preservation of Vascular and Contractile Function in Cardiac Grafts in a Rat Model of Donation after Circulatory Death (DCD)

Abstract

Purpose Although heart donation after circulatory death (DCD) is a promising option to increase graft availability, hearts undergo warm, global ischemia prior to procurement, which is a concern for graft quality. In clinical DCD, hearts are commonly procured and subjected to cold, static storage (CSS) prior to ex-situ normothermic machine perfusion for transport and graft evaluation. Cold ischemia induced by CSS and reoxygenation at normothermic temperatures, however, may aggravate graft injury, especially in endothelial cells. We hypothesized that replacing CSS with hypothermic, oxygenated perfusion (HOPE) provides cardioprotection by preserving the vasculature through the production of nitric oxide. Methods Following anaesthesia, diaphragm transection and circulatory arrest in male Wistar rats to simulate DCD conditions, hearts underwent 21 min of warm, in-situ ischemia. Hearts were then subjected to either 30 min of CSS, HOPE, or HOPE with the presence of L-NAME (nitric oxide synthase inhibitor). Afterwards, hearts were reperfused ex-situ for 60 min under oxygenated, normothermic conditions. Results Compared to CSS, HOPE hearts demonstrated higher cardiac function (determined by cardiac output, left ventricular work, as well as contraction and relaxation rates) after 60 min of reperfusion. Furthermore, preliminary results indicate a higher coronary vascular resistance at the end of the hypothermic perfusion period in hearts with L-NAME compared to HOPE alone. Early reperfusion coronary flow, an indicator of vascular function, tended to be higher in hearts subjected to HOPE compared to hearts treated with L-NAME or to the current clinical scenario (CSS). Conclusion Preservation of vascular and contractile function with HOPE appears superior to the current clinical protocol (CSS). The increase in coronary flow during early reperfusion in HOPE hearts was abolished with the addition of L-NAME, indicating that the beneficial vascular effects of HOPE could be mediated by the production of nitric oxide. Consequently, we believe that HOPE holds great potential for preservation of cardiac grafts obtained with DCD.