Roles of inflammation and apoptosis in experimental brain death-induced right ventricular failure

BACKGROUND: Right ventricular (RV) dysfunction remains the leading cause of early death after cardiac transplantation. Methylprednisolone is used to improve graft quality; however, evidence for that remains empirical. We sought to determine whether methylprednisolone, acting on inflammation and apoptosis, might prevent brain death induced RV dysfunction. METHODS: After randomization to placebo (n = 11) or to methylprednisolone (n = 8; 15 mg/kg), 19 pigs were assigned to a brain-death procedure. The animals underwent hemodynamic evaluation at I and 5 hours after Cushing reflex (i.e., hypertension and bradycardia). The animals euthanized, and myocardial tissue was sampled. This was repeated in a control group (n = 8). RESULTS: At 5 hours after the Cushing reflex, brain death resulted in increased pulmonary artery pressure (27 +/- 2 vs 18 +/- 1 mm Hg) and in a 30% decreased ratio of end-systolic to pulmonary arterial elastances (Ees/Ea). Cardiac output and right atrial pressure did not change. This was prevented by methylprednisolone. Brain death induced RV dysfunction was associated with increased RV expression of heme oxygenase-1, interleukin (IL)-6, IL-10, IL-1 beta, tumor necrosis factor (TNF)-alpha, IL-1 receptor-like (ST)-2, signal transducer and activator of transcription-3, intercellular adhesion molecules-1 and-2, vascular cell adhesion molecule-1, and neutrophil infiltration, whereas EL-33 expression decreased. RV apoptosis was confirmed by terminal deoxynucleotide transferase-mediated deoxy uridine triphosphate nick-end labeling staining. Methylprednisolone pre-treatment prevented RV arterial uncoupling and decreased RV expression of TNF-alpha, IL-1 receptor-like-2, intercellular adhesion molecule-1, vascularcell adhesion molecule-1, and neutrophil infiltration. RV Ees/Ea was inversely correlated to RV TNF-alpha and IL-6 expression. CONCLUSIONS: Brain death induced RV dysfunction is associated with RV activation of inflammation and apoptosis and is partly limited by methylprednisolone. (C) 2016 International Society for Heart and Lung Transplantation. All rights reserved.