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

Matthew A Wells; Louise E See Hoe; Peter Molenaar; Sanne Pedersen; Nchafatso G Obonyo; Charles I McDonald; Weilan Mo; Mahè Bouquet; Kieran Hyslop; Margaret R Passmore; Nicole Bartnikowski; Jacky Y Suen; Jason N Peart; David C McGiffin; John F Fraser; Dead Heart Project

doi:10.1016/j.phrs.2021.105631

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

Pharmacol Res. 2021 Jul:169:105631. doi: 10.1016/j.phrs.2021.105631. Epub 2021 Apr 24.

Authors

Matthew A Wells¹, Louise E See Hoe², Peter Molenaar³, Sanne Pedersen⁴, Nchafatso G Obonyo⁵, Charles I McDonald⁶, Weilan Mo⁷, Mahè Bouquet⁸, Kieran Hyslop⁸, Margaret R Passmore⁸, Nicole Bartnikowski⁹, Jacky Y Suen⁸, Jason N Peart¹⁰, David C McGiffin¹¹, John F Fraser⁸; Dead Heart Project¹²

Affiliations

¹ Critical Care Research Group, The Prince Charles Hospital, Queensland, Australia; School of Medical Sciences, Griffith University, Queensland, Australia.
² Critical Care Research Group, The Prince Charles Hospital, Queensland, Australia; Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Australia. Electronic address: l.seehoe@uq.edu.au.
³ Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Australia; Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Australia.
⁴ Critical Care Research Group, The Prince Charles Hospital, Queensland, Australia.
⁵ Critical Care Research Group, The Prince Charles Hospital, Queensland, Australia; Wellcome Trust Centre for Global Health Research, Imperial College London, United Kingdom; Initiative to Develop African Research Leaders (IDeAL), Kilifi, Kenya.
⁶ The Department of Anaesthesia and Perfusion, The Prince Charles Hospital, Queensland, Australia.
⁷ Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Australia.
⁸ Critical Care Research Group, The Prince Charles Hospital, Queensland, Australia; Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Australia.
⁹ Critical Care Research Group, The Prince Charles Hospital, Queensland, Australia; Faculty of Science and Engineering, School of Mechanical, Medical and Process Engineering, Queensland University of Technology, Australia.
¹⁰ School of Medical Sciences, Griffith University, Queensland, Australia.
¹¹ Critical Care Research Group, The Prince Charles Hospital, Queensland, Australia; Cardiothoracic Surgery and Transplantation, The Alfred Hospital, and Monash University, Melbourne, Australia.
¹² Critical Care Research Group, The Prince Charles Hospital, Queensland, Australia; School of Medical Sciences, Griffith University, Queensland, Australia; Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Australia; Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Australia; Cardiothoracic Surgery and Transplantation, The Alfred Hospital, and Monash University, Melbourne, Australia.

PMID: 33905863
DOI: 10.1016/j.phrs.2021.105631

Abstract

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.

Keywords: Beta-adrenoceptor; Brain stem death; Cardiac contractility; Heart transplantation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain Death / pathology*
Brain Stem / pathology*
Disease Models, Animal
Female
Heart Transplantation / adverse effects*
Myocardial Contraction
Sheep
Ventricular Dysfunction, Right / etiology*
Ventricular Dysfunction, Right / pathology