Tacrolimus for Prevention of Right and Left Ventriculo-Arterial Coupling Changes in Experimental Brain Death.

Right ventricular (RV) dysfunction remains the leading cause of early mortality after cardiac transplantation. Tacrolimus (FK506) is an immune suppressor that could preserve heart function via its anti-inflammation effect in animal models. We sought to determine whether Tacrolimus might prevent brain death-induced RV dysfunction, and biological changes in myocarditis caused by BD acting on inflammation and apoptosis. After randomisation to placebo (n=9) or to Tacrolimus (n=8; 0.05 mg.kg−1.day−1), seventeen pigs were assigned to a brain death procedure. One, three, five and seven hours after Cushing reflex, the animals underwent hemodynamic evaluation. After euthanasia of the animals, myocardial tissue was sampled. This was repeated in a control group (n=7). Seven hours after Cushing reflex, brain death had resulted in increased pulmonary artery pressure (29±2 versus 19±1 mmHg) and in a 33%-decreased RV ratio of end-systolic to pulmonary arterial elastances (Ees/Ea), while left ventriculo (LV)-arterial coupling did not change. This was prevented by Tacrolimus. Brain death-induced RV dysfunction was associated with increased RV expression of interleukin(IL)-6/IL-10, IL-1β, receptors for IL-1 and IL-6, β-3 adrenergic receptor, Toll-like receptor (TLR)-4 and neutrophil infiltration, while β-1 adrenergic receptor, TLR-2 and NLR family pyrin-domain-containing-3 expressions decreased. RV but not LV apoptosis was confirmed by TUNEL staining. Tacrolimus pre-treatment prevented RV-arterial uncoupling and changes in RV expression of IL-1 R, IL-6 R, RV apoptosis, as well as in neutrophil infiltration. Brain death-induced isolated RV dysfunction is associated with RV activation of inflammation and apoptosis, partly limited by Tacrolimus. [ABSTRACT FROM AUTHOR]