Purpose Brain stem death (BD) causes increased levels of catecholamines which may induce β-adrenoceptor desensitisation and mitochondrial dysfunction. Combined, this contributes to donor heart dysfunction (DHD) and post-transplant graft failure. We sought to examine peri-transplant catecholamine sensitivity, cardiac contractility and mitochondrial function post-BD and transplantation (Tx) in a clinically relevant ovine model.

Methods Donor sheep underwent BD (BD n = 6) or sham instrumentation (SH, n = 4) and monitored for 24 h followed by heart procurement and cold static storage (CSS). Orthotopic heart transplantation (HTx) was performed after CSS with BD (BD-Tx, n = 7) or SH donors (SH-Tx, n = 4). Comparisons were made with the excised healthy recipient heart (HR, n = 9). A cumulative concentration-effect curve to (−)-noradrenaline (NA) was established using left and right ventricular trabeculae to determine β1-adrenoceptor mediated potency and contractility. Phenoxybenzamine (5 μM) and ICI118551 (50 nM) were used to block α- and β2-adrenoceptors, respectively. Mitochondrial respirometry was assessed using the Oroboros Oxygraph in the presence of carbohydrate (CHO) or fatty acid (FAO) substrates.

Results BD caused a significant decrease in RV (but not LV) contractility with preserved sensitivity to NA, but an increase in mitochondrial proton slip (in LEAK state). Both ventricles showed a significant decrease in complex-II respiration for CHO and FAO substrates. HTx (SH-Tx and BD-Tx) showed significantly reduced RV contractility and a slight decrease in NA sensitivity. This was in conjunction with mitochondrial dyscoupling evidenced by significantly higher RV proton slip, and depressed LV and RV complex-II respiration for both substrates.

Conclusion We have shown that β1-adrenoceptor desensitisation doesn't occur as a result of BD but observed post-Tx, in BD and SH donors. Mitochondrial dysfunction however, plays a significant role in DHD and post-transplant graft failure. These results have significant implications on patient management, highlighting mitochondria as an important contributor to cardiac dysfunction and as a therapeutic target.