AbstractsMedical & Health Science

Primary graft failure (PGF) is the leading cause of early mortality following heart transplantation. It occurs as a consequence of the effects of donor brain death, ischaemia-reperfusion injury, and recipient factors. Research in the area of myocardial preservation is aimed at reducing the incidence of this feared complication. This thesis presents a clinical study aimed at defining the incidence of, and risk factors for, PGF requiring mechanical circulatory support (MCS). This is followed by a series of experimental studies using a small (rat) and large (pig) animal model to evaluate a novel cardiac allograft preservation strategy: the proprietary heart preservation solution Celsior modified by the addition of erythropoietin (EPO), glyceryl trinitrate (GTN) and zoniporide. A retrospective analysis of 102 consecutive isolated orthotopic heart transplants performed at St Vincent’s Hospital, Sydney, identified 36 patients who required MCS within 24 hours of reperfusion. Risk factors were ischaemic time greater than 300 minutes and donor heart dysfunction. Although perioperative mortality was increased in patients requiring extracorporeal membrane oxygenation, mid-term survival was not influenced by the need for postoperative MCS. Isolated working rat hearts were arrested with Celsior and subjected to prolonged hypothermic storage. The presence of EPO in Celsior dose-dependently improved post-ischaemic recovery of contractile performance after 6 hours storage. This effect was mediated by phosphorylation of the survival kinase STAT3 and dependent on intact Akt signalling. EPO, GTN or zoniporide were insufficient to rescue the rat heart from severe reperfusion injury when the storage time was extended to 10 hours. Use of EPO or zoniporide in combination with GTN resulted in modest recovery of function, however excellent recovery was seen when all three agents were used in combination. These results were then translated into an orthotopic porcine heart transplant model. Hearts preserved with triple-supplemented Celsior were more likely to wean from cardiopulmonary bypass, and with superior contractility and haemodynamics, than control hearts or hearts preserved with double-supplemented Celsior. This thesis presents a novel allograft preservation strategy, which shows promise for application in human heart transplantation. If successfully translated into clinical practice this has the potential to improve early post-transplant outcomes.