The Pleiotropic Effects of Oxygen-Derived Free-Radical Scavengers on the Graft During Normothermic Ex Situ Heart Perfusion

Abstract

<h3>Purpose</h3> The management of oxidative stress is pivotal during ESHP. The lack of sufficient antioxidant systems allow the accumulation of reactive oxygen species (ROS) which can negatively affect myocardial function. We aim to evaluate the use of oxygen-derived free-radical (OFR) scavengers on cardiac functional preservation during ESHP. <h3>Methods</h3> Using a porcine heart perfusion model, we compared the effect of different OFR scavengers. Hearts from juvenile Yorkshire pigs were perfused in working mode for 6 hours either in the control group (n=6) or adding polyethylene glycol (PEG)-catalase (10,000U/L, n=6) and PEG-superoxide dismutase (SOD) (550U/L, n=6) at the initiation of perfusion. Another group (n=6) of freshly procured heart were obtained as tissue control. Contractile function, myocardial injury and endothelial integrity were evaluated. The oxidative modification and antioxidant activity were determined in the myocardium and coronary vasculature. <h3>Results</h3> Cardiac function was better preserved in the catalase group (p<0.05, Figure A). Catalase and SOD both decreased perfusate cTnI, indicating less myocardial injury. The catalase group had lower perfusate vWF than the other two groups, suggesting less endothelial injury (p<0.05, Figure B). Compared to SOD, catalase reduced ROS production and oxidatively modified protein, indicated by protein carbonyl content in the myocardium and nitrotyrosine in the coronary vasculature (p<0.05, Figure C). The catalase and glutathione peroxidase activity decreased in all groups. However, adding catalase partially restored enzyme activity (Figure D). <h3>Conclusion</h3> The antioxidant enzyme activity decreased during <i>ex situ</i> heart perfusion. Catalase better preserved cardiac function and coronary endothelium than SOD, likely resulting from distinct oxidative stress states in the graft. Catalase and SOD have opposing effects on hydrogen peroxide detoxification, which may explain the differences observed in this study.