(-)-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.
Year published
2020
Metadata
Show full item recordAbstract
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) ...
View more >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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View more >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.
View less >
Conference Title
Journal of Molecular and Cellular Cardiology
Volume
140
Subject
Cardiorespiratory Medicine and Haematology
Medical Physiology
Science & Technology
Life Sciences & Biomedicine
Cardiac & Cardiovascular Systems
Cell Biology
Cardiology