Compromised right ventricular contractility in an ovine model of heart transplantation following 24 h donor brain stem death

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Wells, Matthew A
See Hoe, Louise E
Molenaar, Peter
Pedersen, Sanne
Obonyo, Nchafatso G
McDonald, Charles I
Mo, Weilan
Bouquet, Mahè
Hyslop, Kieran
Passmore, Margaret R
Bartnikowski, Nicole
Suen, Jacky Y
Peart, Jason N
McGiffin, David C
Fraser, John F
Dead Heart Project
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BACKGROUND: Heart failure is an inexorably progressive disease with a high mortality, for which heart transplantation (HTx) remains the gold standard treatment. Currently, donor hearts are primarily derived from patients following brain stem death (BSD). BSD causes activation of the sympathetic nervous system, increases endothelin levels, and triggers significant inflammation that together with potential myocardial injury associated with the transplant procedure, may affect contractility of the donor heart. We examined peri-transplant myocardial catecholamine sensitivity and cardiac contractility post-BSD and transplantation in a clinically relevant ovine model. METHODS: Donor sheep underwent BSD (BSD, n = 5) or sham (no BSD) procedures (SHAM, n = 4) and were monitored for 24h prior to heart procurement. Orthotopic HTx was performed on a separate group of donor animals following 24h of BSD (BSD-Tx, n = 6) or SHAM injury (SH-Tx, n = 5). The healthy recipient heart was used as a control (HC, n = 11). A cumulative concentration-effect curve to (-)-noradrenaline (NA) was established using left (LV) and right ventricular (RV) trabeculae to determine β1-adrenoceptor mediated potency (-logEC50 [(-)-noradrenaline] M) and maximal contractility (Emax). RESULTS: Our data showed reduced basal and maximal (-)-noradrenaline induced contractility of the RV (but not LV) following BSD as well as HTx, regardless of whether the donor heart was exposed to BSD or SHAM. The potency of (-)-noradrenaline was lower in left and right ventricles for BSD-Tx and SH-Tx compared to HC. CONCLUSION: These studies show that the combination of BSD and transplantation are likely to impair contractility of the donor heart, particularly for the RV. For the donor heart, this contractile dysfunction appears to be independent of changes to β1-adrenoceptor sensitivity. However, altered β1-adrenoceptor signalling is likely to be involved in post-HTx contractile dysfunction.

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Pharmacological Research
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Pharmacology and pharmaceutical sciences
Brain stem death
Cardiac contractility
Heart transplantation
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Wells, MA; See Hoe, LE; Molenaar, P; Pedersen, S; Obonyo, NG; McDonald, CI; Mo, W; Bouquet, M; Hyslop, K; Passmore, MR; Bartnikowski, N; Suen, JY; Peart, JN; McGiffin, DC; Fraser, JF; Dead Heart Project, , Compromised right ventricular contractility in an ovine model of heart transplantation following 24 h donor brain stem death, Pharmacological Research, 2021, 169, pp. 105631