Donor brain stem death and cardiac transplantation causes mitochondrial dyscoupling and oxidative stress

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Wells, Matthew
Seehoe, Louise
Zechovic, Olivia
Nchafatso, Obonyo
Bouquet, Mahe
Hyslop, Keiran
Black, Deborah
McDonald, Charles
Pedersen, Sanne
Suen, Jacky
Peart, Jason
McGiffin, David
Fraser, John
Lye, India
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2020
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Melbourne, Australia

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Introduction: Mitochondria are essential for adequate cardiovascular function and are important in the generation of reactive oxygen species (ROS). However, mitochondrial function and ROS post donor brain stem death (BD) and heart transplantation HTx is poorly understood and may contribute to donor heart dysfunction (DHD) and post HTx graft failure (GF). Objectives∖Aims: To examine mitochondrial function and ROS production in hearts both after 24hrs of BSD and post HTx. Methods: Donor sheep underwent BD (BD n=13) or sham instrumentation (SH, n=8) and monitored for 24hrs followed by heart procurement or cold static storage. Orthotopic HTx followed, in 7∖13 BD (BD-Tx) and 4/8 SH donors (SH-Tx). Mitochondrial respirometry was assessed using the Oroboros Oxygraph using carbohydrate (CHO) or fatty acid (FAO) substrates for both ventricles. O2 flux control ratios (FCR) were calculated in LEAK (no ADP) and Complex- I (CI) & II (CII) OXPHOS (with ADP) respiration states. Tissue levels of 3-nitrotyrosine and glutathione:reduced glutathione (GSH:GSSG) ratio were assessed using plate based assays. Results: BD caused a significant increase in LEAK RV proton slip. Both ventricles showed a trend toward higher O2 consumption at CI (known driver of ROS) and a significant decrease in CII respiration for both substrates. Post HTx showed mitochondrial dyscoupling evidenced by a trend toward higher CI O2 consumption, significantly higher RV proton slip, and depressed LV and RV CII respiration. For the LV, GSH:GSSG ratios were significantly lower for BD, BD-Tx and SH-Tx. For the RV, GSH:GSSG ratios were non-significantly depressed post BD both pre and post Tx. Conclusions: We have shown that donor BD and Tx caused significant mitochondrial dyscoupling and higher oxidative stress. Mitochondrial function, particularly CI ROS production may then contribute to DHD and consequently post-HTx GF. Therapeutically targeting mitochondrial ROS could improve patient prognosis.

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Australian Critical Care

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33

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Suppl 1

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Clinical sciences

Nursing

Science & Technology

Life Sciences & Biomedicine

Critical Care Medicine

General & Internal Medicine

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Wells, M; Seehoe, L; Zechovic, O; Nchafatso, O; Bouquet, M; Hyslop, K; Black, D; McDonald, C; Pedersen, S; Suen, J; Peart, J; McGiffin, D; Fraser, J; Lye, I, Donor brain stem death and cardiac transplantation causes mitochondrial dyscoupling and oxidative stress, Australian Critical Care, 2020, 33, pp. S31-S31