Selective endothelin-1 receptor type A inhibition in subjects undergoing cardiac surgery with preexisting left ventricular dysfunction: Influence on early postoperative hemodynamics

Abstract

Background and Objective A robust release of endothelin-1-1 (ET) with subsequent ETA 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 highly-selective and potent ET-ARA, sitaxsentan at 1 or 2 mg/kg (IV bolus; n=9, 10 respectively) or vehicle (saline; 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). For example at 24 hrs post-CPB, PVR increased by 40 d.scm-5 in the vehicle group, but directionally decreased by over 40 d·s·cm-5 in the 2 mg/kg ETARA group (p<0.05). Total adverse events were equivalently distributed across the ET-ARA/placebo groups. Conclusions These unique findings demonstrated that infusion of an ET-ARA in high risk cardiac surgery patients was not associated with significant 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.

Endothelin and vasopressin influence splanchnic blood flow distribution during and after cardiopulmonary bypass

“…Our results in the vasopressin group-with normal ET A and ET B expression associated with normal jejunal microcirculation-are compatible with previous findings of a protective effect of ET receptor antagonists in ischemia/ reperfusion injury of the small bowel. 4,22 Additionally, a recent study by Toole and colleagues 23 proved the safety of ET A antagonist treatment in high-risk cardiac surgery patients. In line with this, the administration of ET-1 has been shown to result in reduced microvascular flow of the jejunum and ileum.…”

Surgical pulmonary embolectomy and catheter-based therapies for acute pulmonary embolism: A contemporary systematic review

“…In addition, cardiopulmonary bypass may have adverse effects on pulmonary vascular impedance. 95,96 Finally, postoperative invasive and even noninvasive positivepressure mechanical ventilation also have variable effects on pulmonary vascular impedance. 97,98 These arguments in favor of SE notwithstanding (particularly in critically ill patients such as those with massive PE), the optimal treatment of patients with lesser degrees of PE (ie, submassive or less) is unclear.…”

Endothelin-1 in the Human Myocardium and Circulating Plasma: Evaluation before, during and after Correction of Aortic Stenosis with Aortic Valve Replacement

“…The patients were operated electively and the myocardium was protected with cardioplegia, reducing the peroperative ischemic insult. Thus it seems that AVR in AS patients does not lead to ET-1 augmentation during early reperfusion, contrary to reports from CABG operations where it has been demonstrated that plasma ET-1 levels are elevated after 30 min of reperfusion [32] and continue to rise during the reperfusion phase [8,9,18]. The lack of these findings in our study may be due to the short observational period early in the reperfusion phase (5–20 min), suggesting that ET-1 enters into circulating plasma at a later stage, or that cardiomyocyte and endothelial injury is attenuated during AVR due to a strict cardioprotective regime in the form of timely cardioplegia administration.…”

“…It is documented that ET-1 might affect postoperative outcome negatively in patients undergoing cardiac surgery [8,9,18]. Previous studies have reported that during cardiac surgery, the use of CPB leads to elevated plasma levels of ET-1 [19,20], and that levels remain elevated for 24 h [8,18]. Zhu et al [21] demonstrated that plasma ET-1 peaked after cessation of CPB in patients undergoing valvular surgery and correlated positively with bypass time.…”