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

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; t...

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Bibliographic Details
Published in:American journal of transplantation 2019-02, Vol.19 (2), p.331-344
Main 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.
Format: Article
Language:English
Subjects:
Animals
ATP
basic (laboratory) research/science
Cytochrome c
Death
donors and donation: donation after circulatory death (DCD)
Electron transport chain
Heart transplantation
Heart Transplantation - methods
heart transplantation/cardiology
Heart transplants
Hypothermia
Hypoxia
Ischemia
ischemia reperfusion injury (IRI)
Life Sciences
Male
metabolism/metabolite
Mitochondria
Mitochondria - metabolism
Mitochondria - pathology
NADH-ubiquinone oxidoreductase
Organ Preservation - methods
Oxygen consumption
Phosphocreatine
Rats
Rats, Wistar
Recovery of function
Reperfusion
Reperfusion Injury - prevention & control
Therapeutic applications
Tissue and Organ Procurement - standards
Tissue Donors
Warm Ischemia
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Summary: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. 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.
ISSN:1600-6135
1600-6143
DOI:10.1111/ajt.15024