Cardioprotective reperfusion strategies differentially affect mitochondria: Studies in an isolated rat heart model of donation after circulatory death (DCD). Issue 2 (27th August 2018)

• Record Type: Journal Article
• Authors: Sanz, Maria N.; Farine, Emilie; Niederberger, Petra; Méndez‐Carmona, Natalia; Wyss, Rahel K.; Arnold, Maria; Gulac, Patrik; Fiedler, Georg M.; Gressette, Mélanie; Garnier, Anne; Carrel, Thierry P.; Tevaearai Stahel, Hendrik T.; Longnus, Sarah L.
• Is Part Of: American journal of transplantation. Volume 19:Issue 2(2019)
• Page Start: 331
• Page End: 344
• Publication Date: 2018-08-27
• Subjects: basic (laboratory) research/science -- donors and donation: donation after circulatory death (DCD) -- heart transplantation/cardiology -- ischemia reperfusion injury (IRI) -- metabolism/metabolite; Transplantation of organs, tissues, etc -- Periodicals; 617.95
• DOI: 10.1111/ajt.15024
• Languages: English
• ISSNs: 1600-6135

Abstract

Abstract : 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 preischemic 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 3 reperfusion strategies—mild hypothermia, mechanical postconditioning, 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 3 strategies improve oxygen‐consumption–cardiac‐work coupling and increase tissue adenosine triphosphate content, in parallel with increased functional recovery. These reperfusion strategies, however, differentially affect mitochondria; mild hypothermia also increases phosphocreatine content, while mechanical postconditioning stimulates mitochondrial complex I activity and reduces cytochrome c release (marker of mitochondrial damage), whereas hypoxia upregulates the expression of peroxisome proliferator‐activated receptor‐gamma coactivator (regulator of mitochondrial biogenesis). Characterization of the role of mitochondria in cardioprotective reperfusion strategies should aid in the identification of new, mitochondrial‐based therapeutic targets and the development of effective reperfusion strategies that could ultimately facilitate DCD heart transplantation. Abstract : In an isolated rat heart model of DCD, cardioprotective reperfusion strategies, mild hypothermia, mechanical postconditioning, and brief hypoxia all improve recovery of contractile function and ATP content, but affect different aspects of mitochondrial function and integrity following warm, global ischemia and reperfusion.