Cardioprotective reperfusion strategies differentially affect mitochondria:studies in an isolated rat heart model of donation after circulatory death (DCD).

Sanz-Garcia, Maria Nieves; Farine, Emilie; Niederberger, Petra; Méndez Carmona, Natalia; Wyss, Rahel Kathrin; Arnold, Maria Regula; Gulac, Patrik; Fiedler, Georg M; Gressette, Mélanie; Garnier, Anne; Carrel, Thierry; Tevaearai Stahel, Hendrik T; Henning Longnus, Sarah (2019). Cardioprotective reperfusion strategies differentially affect mitochondria:studies in an isolated rat heart model of donation after circulatory death (DCD). American journal of transplantation, 19(2), pp. 331-344. Wiley-Blackwell 10.1111/ajt.15024

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Donation after circulatory death (DCD) holds great promise for improving cardiac graft availability, however concerns persist regarding injury following warm ischemia, after donor circulatory arrest, and subsequent reperfusion. Application of pre-ischemic treatments is limited for ethical reasons, thus cardioprotective strategies applied at graft procurement (reperfusion) are of particular importance in optimizing graft quality. Given the key role of mitochondria in cardiac ischemia-reperfusion injury, we hypothesize that three reperfusion strategies: mild hypothermia, mechanical post-conditioning and hypoxia, when briefly applied at reperfusion onset, provoke mitochondrial changes that may underlie their cardioprotective effects. Using an isolated, working rat heart model of DCD, we demonstrate that all three strategies improve oxygen-consumption-cardiac-work coupling and increase tissue ATP content, in parallel with increased functional recovery. These reperfusion strategies, however, differentially affect mitochondria; mild hypothermia also increases phosphocreatine content, while mechanical post-conditioning stimulates mitochondrial complex I activity and reduces cytochrome c release (marker of mitochondrial damage), whereas hypoxia up-regulates the expression of Pgc-1α (regulator of mitochondrial biogenesis). Characterisation of the role of mitochondria in cardioprotective reperfusion strategies should aid in the identification of new, mitochochondrial-based therapeutic targets and the development of effective reperfusion strategies that could ultimately facilitate DCD heart transplantation. This article is protected by copyright. All rights reserved.

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