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Selective Endothelin Receptor type-A Inhibition in Cardiac Surgery Subjects with Pre-Existing LV Dysfunction: Influence on Early Post-Operative Hemodynamics
John M Toole1, *John S. Ikonomidis1, Wilson Y. Szeto2, James L. Zellner3, John Mulcahy1, Rachael L. Deardorff1, Theresa A. Brinsa1, Francis G. Spinale1
1Medical University of South Carolina, Charleston, SC;2University of Pennsylvania, Philadelphia, PA;3University of Tennessee at Chattanooga, Chattanooga, TN
Background and Objective: A robust release of endothelin (ET) with subsequent ET-A subtype receptor (ET-AR) activation occurs in patients following cardiac surgery requiring cardiopulmonary bypass (CPB). Increased ET-AR activation has been identified in patients with poor LV function (reduced ejection fraction; EF). Accordingly, this study tested the hypothesis that a selective ET-AR antagonist (ET-ARA) administered peri-operatively would favorably affect post-CPB hemodynamic profiles in patients with a pre-existing poor LVEF.
Methods and Results: Patients (n=29; 66+2 yrs) with a reduced LVEF (37+2%) were prospectively randomized, in a blinded fashion, at the time of elective coronary revascularization and/or valve replacement requiring CPB, to infusion of the ET-ARA, sitaxsentan at 1 or 2 mg/kg (IV bolus; n=9, 10 respectively) or vehicle (placebo; n=10). Infusion of the ET-ARA/vehicle was performed immediately prior to separation from CPB and again at 12 hrs post-CPB. ET and hemodynamic measurements were performed at baseline, at separation from CPB (Time 0) and at 0.5, 6, 12, 24 hrs post-CPB. Baseline plasma ET (4.0+0.3 fmol/mL) was identical across all 3 groups, but when compared to pre-operative, baseline values obtained from age matched subjects with a normal LVEF (n=37;LVEF>50%), were significantly increased (2.9+0.2 fmol/mL, p<0.05) Baseline systemic (SVR; 1358+83 d.s.cm-5) and pulmonary (PVR; 180+23 d.s.cm-5) vascular resistance were equivalent in all 3 groups. As a function of Time 0, SVR changed in an equivalent fashion in the post-CPB period, but a significant ET-ARA effect was observed for PVR (ANOVA; p<0.05). Moreover, the greatest reduction in PVR was observed in the 2 mg/kg ET-ARA group at the later post-operative time points (Figure 1). Total adverse events were equivalently distributed across the ET-ARA/placebo groups.
Conclusions: This is the first study to utilize an ET-ARA in patients with compromised LV function and elevated pre-operative ET levels in the context of cardiac surgery. The results from this study demonstrated that infusion of an ET-ARA was not associated with hemodynamic compromise. Moreover, ET-ARA favorably affected PVR in the early post-operative period. Thus, the ET-AR serves as a potential pharmacological target for improving outcomes following cardiac surgery in patients with compromised LV function.
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