Abstract 3717: Selective Interruption of the Endothelin Subtype-A Receptor in Patients Early Following Cardioplegic Arrest and Cardiopulmonary Bypass Modifies a Specific Portfolio of Cytokines
Background: A robust release of endothelin (ET) with subsequent ET-A subtype receptor (ET-AR) activation occurs in patients following cardioplegic arrest and cardiopulmonary bypass (CPB) and has been associated with changes in cardiovascular performance and indices of post-CPB recovery. However, the mechanisms by which ET-AR caused adverse effects post-CPB remain poorly understood. This study tested the hypothesis that administration of a selective ET-AR antagonist (ET-ARA) would alter pro-inflammatory cytokine release and activation in patients in the post-CPB period.
Methods/Results: Patients (age 62±1 yrs) were randomized to receive vehicle (n=9) or ET-ARA (sitaxsentan, 2 mg/kg IV- bolus infusion; n=8) at separation from CPB (Time 0). Pulmonary vascular resistance index (PVRI), and plasma levels of tumor necrosis factor alpha (TNF), the interleukins (IL) − 4, −6, 10, and interferon gamma (INF) were measured at baseline (BASE) and at Time 0, 0.5, 6 and 24 hours post-CPB using a calibrated, high sensitivity enzyme-linked flow cytometric system. PVRI was reduced by −28.6±16% from baseline (249±22 dyn.s/cm5/m2) in the 2 mg/kg ET-ARA group at 30 min post-CPB and remained reduced up to 6 hrs post-CPB (p<0.05). TNF increased from baseline (70±30 pg/mL) in the vehicle group (130±62 pg/mL) at 24 hours post-CPB (p<0.05), but was reduced in the ET-ARA group (39±23 pg/mL, p<0.05). By 24 hours post-CPB, IL-4 increased from non-detectable values in the vehicle group (135±62 pg/mL,p<0.05), and was reduced in the ET-ARA group (67±33 pg/mL, p<0.05). IL-6 and IL-10 levels followed a similar pattern. In contrast, IFN was non-detectable at time 0 and rose to a similar degree in the vehicle and ET-ARA groups (370±153, 267±109 pg/mL, both p<0.05).
Conclusions: The unique findings from this study were:
increased ET-AR activation contributes to hemodynamic and cytokine release in patients post-CPB;
the ET-AR is an upstream component of a signaling cascade that contributes to selective cytokine activation such as TNF and the ILs.
Thus, selective inhibition of the ET receptor system modifies several biological processes relevant to the post cardiac surgery setting and thereby constitutes a relevant therapeutic target.