Abstract 9706: A Novel High Energy Phosphate Source Resuscitates Poorly Functioning Donor Hearts

Abstract

Introduction: Over 60% of the time donor hearts cannot be utilized for transplant, mostly because of poor left ventricular ejection fraction (EF) of ≤40% due to stress cardiomyopathy (i.e., demand ischemia) with depletion of myocardial adenosine triphosphate (ATP). The bioenergetic cyclocreatine phosphate (CCrP) is an FDA Orphan Designated Drug for heart transplantation . When CCrP is given prophylactically in an isoprenaline (ISO) rat model of demand ischemia, it restored ATP and maintained contractility. Hypothesis: We hypothesized that administering CCrP therapeutically after ISO-induced myocardial dysfunction in rats (simulating rejected donor hearts), will prevent ischemic injury and sustain long-term restoration of EF. Methods: Wistar male rats (180-220 g) were injected SC with ISO (85 and 170 mg/kg/day) for two consecutive days. CCrP (n=6, 0.8 gm/kg/day ip) and saline control (n=4) were administered 1 hour after completing the course of ISO injections and then daily for 2 weeks. A negative control group was injected with saline (n=4). Serum CK-MB and ECG/ST were measured 24 hours after last ISO injection. Evidence of stress cardiomyopathy was assessed after 14 days by ECHO analysis for EF and levels of hs-Troponin I (TnI) and BNP. One-way ANOVA analysis was used. Results: Table I shows two main benefits of therapeutically administered CCrP in this stress cardiomyopathy model: 1) poor heart function was quickly restored in the acute phase (24 hours), as indicated by normal ECG/ST and CK-MB levels; and 2) the restoration of function was sustained over the long term (14 days), as indicated by normal EF% and levels of hs-TnI and BNP. Conclusions: The bioenergetic CCrP is a novel cardioprotective drug that appears to salvage cardiac dysfunction and restore normal EF% in a rat model of stress cardiomyopathy. If this benefit translates into clinical organ donors with poor heart function, CCrP could be used to increase heart utilization for transplantation.