Enhanced preservation of the rat heart after prolonged hypothermic ischemia with erythropoietin-supplemented Celsior solution

BACKGROUND: The cardioprotective efficacy of erythropoietin (EPO) has been widely documented in rodent models of acute coronary syndrome. We sought to evaluate its cardioprotective potential as an adjunct to Celsior cardioplegia in a rodent model of prolonged hypothermic global ischemia reperfusion injury. METHODS: Isolated working rat hearts were subjected to 6 or 10 hours of hypothermic ischemic storage in Celsior cardioplegic solution. Celsior was supplemented with EPO over a dose range of 0 to 5 units/ml, as well as with glyceryl trinitrate (0.1 mg/ml) and zoniporide (I mu mol/liter). Myocardial functional recovery was determined after 45 minutes of reperfusion, then left ventricular tissue was prepared for Western blotting. RESULTS: The presence of EPO in Celsior dose-dependently improved recovery of myocardial function after 6 hours ischemic storage time (cardiac output recovery: 52.5 +/- 11.3% vs 2.5 +/- 0.4%; EPO: 5 units/ml vs 0 units/ml; p < 0.05). This functional benefit was associated with decreased lactate dehydrogenase released into coronary effluent and enhanced phosphorylation of STAT3, all of which were completely abrogated by pre-treatment with stattic, a selective inhibitor of STAT3 activation. When the ischemic storage time was extended to 10 hours, additive beneficial effects on myocardial function were seen when EPO was used in combination with the cardioprotective agents glyceryl trinitrate and zoniporide. CONCLUSIONS: EPO has demonstrated cardioprotective efficacy in a rodent model of ischemia reperfusion injury simulating cardiac allograft preservation, which appears to be mediated via activation of the SAFE cytoprotective signaling pathway. (C) 2013 International Society for Heart and Lung Transplantation. All rights reserved.