Sex differences in cardiac graft recovery and pathophysiologic changes in a rat model of donation after circulatory death

Biological sex affects cardiac tolerance to ischemia and reperfusion, but little is known about sex differences in heart transplantation with donation after circulatory death (DCD). Using a rat model, we characterized differences between sexes both in the donor, during simulated DCD, and in the procured heart, to evaluate recovery upon reperfusion. Adult male, female and ovariectomized Wistar rats underwent simulated DCD with 22 min of warm, in-situ ischemia. Hearts were then explanted and maintained in cold static storage for 30 min. Isolated hearts then underwent normothermic, oxygenated reperfusion for 60 min with left ventricular loading. In-situ characteristics, as well as ventricular function, coronary flows and metabolic post-ischemic recovery were assessed. Post-ischemic ventricular recovery was significantly higher in female compared to male and ovariectomized hearts. Furthermore, several in-situ circulating factors, including free fatty acids and potassium, were significantly lower in females compared with males. Greater post-ischemic ventricular function in female vs. male and ovariectomized hearts following DCD indicates that sex affects tolerance to DCD conditions and that female sex hormones contribute to cardioprotection. Greater understanding of sex-specific tolerance to DCD conditions may serve as a basis to better define precise mechanisms of cardiac injury and thereby contribute to optimizing clinical protocols.