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

Abstract

<h3>Purpose</h3> 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. <h3>Methods</h3> 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). <h3>Results</h3> 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. <h3>Conclusion</h3> Brain death-induced isolated RV dysfunction is associated with RV activation of inflammation and apoptosis, partly limited by Tacrolimus.