Reducing mitochondrial dysfunction through combination therapy to limit ischemia-reperfusion injury in male DCD rats

Introduction: Two predominant pathways contribute to ischemia reperfusion injury (IRI) following donation after circulatory death (DCD): mitochondrial permeability transition pore (MPTP) opening and Calpain-1 (CPN1) activation. Each pathway has established inhibitors; Cyclosporine A (CyA) and MDL-28170 (MDL), respectively, which are effective in modulating IRI in a DCD heart with 25 min of warm ischemia time (WIT). We studied the effect of co-administering CyA and MDL during reperfusion on infarct size and graft function in DCD rat hearts with extended WIT of 35 min. Methods: Male rats were exposed to 35 min of warm ischemia followed by 90 min of reperfusion. During reperfusion, hearts were given either 0.5 mM of CyA, 10 mM of MDL, or mixed CyA and MDL. Cardiac function and coronary flow rates were monitored throughout reperfusion and infarct size at the end of reperfusion. Results: Infarct size in hearts treated with mixed CyA + MDL (31.59 ± 7.1%) was less than that of MDL-treated hearts (33.26 ± 4.3%) but larger than CyA-treated hearts (25.49 ± 5.9%). Graft function and coronary flow rates were variable amongst groups. CyA-treated hearts had more profound infarct size reduction when compared to MDL, and no additional synergistic effect was seen with combination treatment. Discussion: Our results indicate that MPTP opening contributes significantly to the development of IRI in DCD hearts.