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  • (-)-Noradrenaline sensitivity, contractility and mitochondrial function in an ovine model of brain stem death and transplantation

    Author(s)
    Wells, Matthew
    Molenaar, Peter
    Hoe, Louise See
    Obonyo, Nchafatso
    James, Lynette
    Bouquet, Mahe
    Bartnikowski, Nicole
    Passmore, Margaret
    Boone, Connie
    Wilde, Karin
    Weilan, Mo
    Hyslop, Kieran
    Peart, Jason
    Fraser, John
    et al.
    Griffith University Author(s)
    Fraser, John F.
    Wells, Matt A.
    Peart, Jason N.
    Year published
    2020
    Metadata
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    Abstract
    Purpose Brain stem death (BD) causes increased levels of catecholamines which may induce β-adrenoceptor desensitisation and mitochondrial dysfunction. Combined, this contributes to donor heart dysfunction (DHD) and post-transplant graft failure. We sought to examine peri-transplant catecholamine sensitivity, cardiac contractility and mitochondrial function post-BD and transplantation (Tx) in a clinically relevant ovine model. Methods Donor sheep underwent BD (BD n = 6) or sham instrumentation (SH, n = 4) and monitored for 24 h followed by heart procurement and cold static storage (CSS). Orthotopic heart transplantation (HTx) ...
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    Purpose Brain stem death (BD) causes increased levels of catecholamines which may induce β-adrenoceptor desensitisation and mitochondrial dysfunction. Combined, this contributes to donor heart dysfunction (DHD) and post-transplant graft failure. We sought to examine peri-transplant catecholamine sensitivity, cardiac contractility and mitochondrial function post-BD and transplantation (Tx) in a clinically relevant ovine model. Methods Donor sheep underwent BD (BD n = 6) or sham instrumentation (SH, n = 4) and monitored for 24 h followed by heart procurement and cold static storage (CSS). Orthotopic heart transplantation (HTx) was performed after CSS with BD (BD-Tx, n = 7) or SH donors (SH-Tx, n = 4). Comparisons were made with the excised healthy recipient heart (HR, n = 9). A cumulative concentration-effect curve to (−)-noradrenaline (NA) was established using left and right ventricular trabeculae to determine β1-adrenoceptor mediated potency and contractility. Phenoxybenzamine (5 μM) and ICI118551 (50 nM) were used to block α- and β2-adrenoceptors, respectively. Mitochondrial respirometry was assessed using the Oroboros Oxygraph in the presence of carbohydrate (CHO) or fatty acid (FAO) substrates. Results BD caused a significant decrease in RV (but not LV) contractility with preserved sensitivity to NA, but an increase in mitochondrial proton slip (in LEAK state). Both ventricles showed a significant decrease in complex-II respiration for CHO and FAO substrates. HTx (SH-Tx and BD-Tx) showed significantly reduced RV contractility and a slight decrease in NA sensitivity. This was in conjunction with mitochondrial dyscoupling evidenced by significantly higher RV proton slip, and depressed LV and RV complex-II respiration for both substrates. Conclusion We have shown that β1-adrenoceptor desensitisation doesn't occur as a result of BD but observed post-Tx, in BD and SH donors. Mitochondrial dysfunction however, plays a significant role in DHD and post-transplant graft failure. These results have significant implications on patient management, highlighting mitochondria as an important contributor to cardiac dysfunction and as a therapeutic target.
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    Conference Title
    Journal of Molecular and Cellular Cardiology
    Volume
    140
    DOI
    https://doi.org/10.1016/j.yjmcc.2019.11.114
    Subject
    Cardiorespiratory Medicine and Haematology
    Medical Physiology
    Science & Technology
    Life Sciences & Biomedicine
    Cardiac & Cardiovascular Systems
    Cell Biology
    Cardiology
    Publication URI
    http://hdl.handle.net/10072/400961
    Collection
    • Conference outputs

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