Treatment of Brain-Dead Donor Rats with Dimethyloxalylglycine Improves Both Donor and Graft Left-Ventricular Function after Heart Transplantation

Abstract

Introduction: Cardiac transplantation is the most effective treatment of end-stage heart failure. Brain dead (BD) donors are currently the only reliable source for cardiac grafts. However, hemodynamic instability and cardiac dysfunction have been demonstrated in BD donors and this could therefore also affect posttransplant graft function. Hypothesis: Based upon the protective effect of Prolyl-Hydroxylase (PHD)-Hypoxia Inducible Factor (HIF)-1 pathway against ischemia/reperfusion injury (IRI), we tested the hypothesis that treatment of BD donor rats with the non-selective PHD inhibitor dimethyloxalylglycine (DMOG) results in a better graft heart condition in recipients after heterotopic transplantation. Methods: Lewis rats were injected with one shot DMOG (30 mg/kg i.v.) (n = 7) or equal volume of physiological saline (n = 7) and maintained BD for 5h by a subdurally placed and inflated balloon catheter. Controls were sham-operated (n = 11). Then, hearts were explanted, stored in cold preservation solution, heterotopically transplanted and after 1.5h reperfusion left-ventricular (LV) graft function was evaluated in vivo. Myocardial histological and molecular biological analyses were performed. Results: BD was associated with decreased LV function. DMOG treatment of BD animals resulted in better load-independent contractility and end-diastolic stiffness parameters (ESPVR E´max (mmHg/µl): BD+DMOG: 3.7 ± 0.6 vs BD: 3.1 ± 0.5; EDPVR (mmHg/µl): BD+DMOG: 0.13 ± 0.03 vs BD: 0.31 ± 0.06 p < 0.05). Following transplantation, DMOG treatment of BD donors significantly improved the altered LV systolic and diastolic function (at 80µL volume dP/dtmax (mmHg/s): BD+DMOG: 2284 ± 213 vs BD: 1854 ± 124 p < 0.05; dP/dtmin (mmHg/s): BD+DMOG: 1586 ± 183 vs BD: 1154 ± 74, p < 0.05; Tau-W (ms): BD+DMOG: 33 ± 4 vs BD: 43 ± 9 p < 0.05). Significantly lower myocardial inflammatory cell infiltration and necrosis were detected along with, significantly lower DNA-strand breakage in the DMOG treated BD group compared with BD group. Conclusions: Pre-treatment of BD heart donors with DMOG resulted in a significantly better LV graft function after transplantation. These results support the view that preconditioning of BD donors through the activation of HIF-1 pathway has a protective role against myocardial IRI after transplantation.