Abstract
Donation after circulatory death (DCD) could improve donor heart availability; however, warm ischemia-reperfusion injury raises concerns about graft quality. Mechanical postconditioning (MPC) may limit injury, but mechanisms remain incompletely characterized. Therefore, we investigated the roles of glucose metabolism and key signaling molecules in MPC using an isolated rat heart model of DCD. Hearts underwent 20 min perfusion, 30 min global ischemia, and 60 minu reperfusion with or without MPC (two cycles: 30 s reperfusion—30 s ischemia). Despite identical perfusion conditions, MPC either significantly decreased (low recovery = LoR; 32 ± 5%; p < 0.05), or increased (high recovery = HiR; 59 ± 7%; p < 0.05) the recovery of left ventricular work compared with no MPC (47 ± 9%). Glucose uptake and glycolysis were increased in HiR vs. LoR hearts (p < 0.05), but glucose oxidation was unchanged. Furthermore, in HiR vs. LoR hearts, phosphorylation of raptor, a downstream target of AMPK, increased (p < 0.05), cytochrome c release (p < 0.05) decreased, and TNFα content tended to decrease. Increased glucose uptake and glycolysis, lower mitochondrial damage, and a trend towards decreased pro-inflammatory cytokines occurred specifically in HiR vs. LoR MPC hearts, which may result from greater AMPK activation. Thus, we identify endogenous cellular mechanisms that occur specifically with cardioprotective MPC, which could be elicited in the development of effective reperfusion strategies for DCD cardiac grafts.
Highlights
For patients with end-stage heart failure, a heart transplantation is the gold-standard treatment [1]
Using an isolated rat heart model of Donation after circulatory death (DCD), we demonstrate that Mechanical postconditioning (MPC) can have deleterious—as well as protective—effects on post-ischemic cardiac recovery, and is not a safe strategy to use with DCD cardiac grafts
The existence of two subgroups in our study provides the unique opportunity to directly compare high- vs. low-recovery hearts that were all subjected to MPC, and may aid in pinpointing critical MPC-induced protective mechanisms, while eliminating MPC-associated changes that do not contribute to cardioprotection
Summary
For patients with end-stage heart failure, a heart transplantation is the gold-standard treatment [1]. In DCD, reperfusion is a clinically scheduled, timely intervention and co-morbidities and co-medications are limited through donor selection Approaches such as MPC may provide more consistent protection in this context. The cardioprotective efficacy of MPC varies according to the experimental model and specific conditions (i.e., energy substrate availability [12], age [13], in vivo vs ex vivo [14], Langendorff vs working mode [15], ischemic temperature [15] or postconditioning algorithm [16]) This variability highlights our incomplete understanding of the precise mechanisms responsible for the cardioprotective effects of MPC. Sci. 2020, 21, 964 cardioprotection in an isolated, working rat heart model of DCD that includes clinically relevant circulating levels of free fatty acids prior to warm ischemia
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