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. Author manuscript; available in PMC: 2011 Mar 1.
Published in final edited form as: J Thorac Cardiovasc Surg. 2010 Jan 13;139(3):646–654. doi: 10.1016/j.jtcvs.2009.11.046

Selective Endothelin-1 Receptor type-A Inhibition in Cardiac Surgery Subjects with Pre-Existing LV Dysfunction: Influence on Early Post-Operative Hemodynamics

John M Toole 1, John S Ikonomidis 1, Wilson Y Szeto 2, James L Zellner 3, John Mulcahy 1, Rachael L Deardorff 1, Francis G Spinale 1
PMCID: PMC2827656  NIHMSID: NIHMS170356  PMID: 20074751

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.

Keywords: Endothelin-1, receptor antagonist, cardiac surgery, systolic dysfunction

Introduction

Cardiopulmonary bypass (CBP) remains a mainstay for the performance of cardiac surgical procedures, including that of coronary artery bypass grafting (CABG) and valve replacement. Following separation from CPB, significant neurohormonal system activation and the release of bioactive molecules invariably occurs and can continue well into the post-operative period. Specifically, increased release of the bioactive molecule endothelin-1 (ET) has been documented in the early post-CPB period and can affect important determinants of post-operative recovery such as systemic, pulmonary and coronary conduit vascular tone.1-8 More complex CABG procedures such as repeat revascularization, concomitant valve repair/replacement, and/or patients with pre-existing co-morbidities such as increased age and left ventricular (LV) systolic dysfunction, have been associated with increased risk for a complex post operative course.9-15 However, the mechanistic relationship between ET receptor signaling and early post-operative hemodynamics, particularly in patients with pre-existing LV dysfunction, has not been examined. Accordingly, the overall goal of this study was to examine early post-operative indices of systemic and pulmonary vascular resistance following administration of an ET receptor in older patients undergoing CABG, valve replacement, or combined procedures requiring CPB, with pre-existing LV dysfunction.

ET mediates a number of biological and physiological responses through 2 primary receptor subtypes; the ET-A and the ET-B receptor.4-8 In past studies, non-selective ET receptor antagonists (those that inhibit ET binding to both the ET-A and ET-B receptor) have been utilized in a number of cardiovascular disease states which included systemic arterial hypertension and in patients with compromised LV function.1,2,16-19 However, outcomes from the use of these non-selective ET receptor antagonists, particularly in patients with reduced LV systolic dysfunction, were equivocal or actually worsened clinical status.16-19 These past results were likely due, at least in part, to the distinctly different receptor transduction pathways inherent to the ET-A and ET-B receptor. Specifically, ET-A receptor activation causes increased activation of certain protein kinase-C isoforms, which in turn mobilizes calcium and ultimately vascular smooth muscle vasoconstriction.4,6 In addition, ET-A receptor activation has been shown to exacerbate myocyte contractile dysfunction following simulated cardioplegic arrest.20 In contradistinction, ET-B receptor activation is coupled to nitric oxide synthesis pathways, which will in turn promote vascular smooth muscle relaxation, particularly in the pulmonary vasculature.5,7 Moreover, the ET-B binds circulating ET within the pulmonary circuit and thereby forms an important clearance pathway for this bioactive peptide.21 Taken together, this would suggest that selective ET-A receptor inhibition in which the ET-B receptor remains unopposed would be of potential hemodynamic benefit. Accordingly, highly selective ET-A receptor antagonists (ET-ARAs) have been developed. One prototypical, highly selective (6500:1, ET-A vs. ET-B) and potent (Ki=0.43nM) ET-ARA is sitaxsentan which has been used in oral formulation in patients with pulmonary arterial hypertension.22,23 In a recently completed dose-ranging study by this laboratory, it was demonstrated that an intravenous formulation of this ET-ARA could be safely administered to patients following CABG and CPB.24,25 However, this past study was performed in patients with minimal comorbidities and normal LV function. Accordingly, the present study was performed with 2 specific aims. First, evaluate the effects of intravenous administration of a selective ET-ARA in older patients with pre-existing LV systolic dysfunction in the post-CPB period with respect to overall safety and hemodynamic stability. Second, examine whether and to what degree ET-ARA administration affected systemic and pulmonary vascular resistance properties in the post-CPB period, in this particular group of patients.

Methods

Patients

After approval by the Human Subjects Review Committee of the Medical University of South Carolina (HR16252), patients undergoing coronary artery bypass (CABG), aortic and/or mitral valve replacement, or combined CABG and valve procedures requiring CPB were initially evaluated for eligibility to this study. The inclusion criteria were greater than 60 years of age and an LV ejection fraction of ≤ 50% documented by a pre-operative echocardiogram, diabetic patients to have a fasting glucose <350 mg/dL or recent hemoglobin A1c [HgbA1c] <9%; and/or if hypertensive, be on a stable medical regimen with no significant changes over the past 30 days. Although the study was conducted at several institutions, a larger proportion of patients were recruited from the Ralph H. Johnson Veterans Affairs Medical Center, and resulted in a larger number of males eligible for enrollment. The exclusion criteria included: emergent revascularization, stroke or thrombo-embolic event within 3 months preceding surgery; a recent (<7 days) myocardial infarction; documented coagulopathy; hepatic dysfunction as defined by aspartate transaminase (AST) or alanine transaminase (ALT) >1.5 times the upper limit of normal. If the patient met these criteria, informed consent was obtained.

Operative Procedure

Standard induction and maintenance of anesthesia was accomplished with a combination of sufentanil, midazolam and isoflurane. Appropriate monitoring lines (radial artery and pulmonary artery catheters) were placed. Prior to CPB, systemic heparinization was accomplished with a heparin dose of 400 units/kg. Additional heparin was administered during CPB to maintain an activated clotting time of > 400 seconds. CPB was maintained at a cardiac index of 2.0 to 2.4 l/min/m2 with a Stockert-Shiley Roller pump using a Sarns membrane oxygenator. The pump prime consisted of 1200 ml of normothermic, lactated Ringers solution, to which 500 ml of hetastarch, 25 meq of sodium bicarbonate and 1000 units of heparin were added; however, retrograde autologous priming was performed whenever possible prior to initiation of CPB. Initial cardioplegic arrest was accomplished with antegrade normothermic administration of a 250 to 500 ml of a solution of D5/0.2 NaCL containing 29 ml of tromethamine (THAM) buffer, 34 ml of adenosine citrate phosphate dextrose and 60 meq of KCL (120 meq/L) in a 4:1 blood:crystalloid mixture. This was followed immediately with retrograde administration of 1000 ml of hypothermic cardioplegic solution. Every 20 minutes cardioplegic arrest was maintained with 250 to 500 ml retrograde administration of the cardioplegic solution with a reduced potassium concentration (60 meq/L) and a 500 mL terminal normothermic cardioplegic shot was given before cross-clamp removal. Patients were not actively cooled while on CPB and were rewarmed to a rectal temperature of 36.5°C prior to separation. At the termination of CPB, heparin was neutralized with protamine in a 1:1 ratio. Nitroglycerin infusion was administered postoperatively for systemic hypertension (defined as a 20% increase over preoperative levels) and ST segment elevation or depression of greater than 1 mm. Epinephrine infusion was administered postoperatively to maintain a cardiac index of greater than 2.0 L/min/m2 when needed. Discharge criteria from the intensive care unit (ICU) included a complete wean from all vasoactive and inotropic infusions, extubation without pulmonary support and no evidence of major organ failure. Discharge criteria from the hospital included stable sinus rhythm, no supplemental oxygen requirement, ambulation, normal bowel and bladder function, and tolerance of oral intake.

Endothelin-1-A Receptor Antagonist (ET-ARA)

The ET-ARA utilized in this study was sitaxsentan sodium (TBC11251Na) which has been described previously.22-26 This study was performed under FDA IND#52,527. It has been demonstrated previously that this ET-ARA quickly reaches a steady-state level (within 30 minutes) following intravenous administration and has a half-life of approximately 6 hours.22,26 Sitaxsentan has been safely utilized in patients with primary pulmonary hypertension.22,23 More recently, we have demonstrated that intravenous sitaxsentan could be safely administered to patients undergoing elective CABG and CPB, with no pre-existing risk factors.24,25 Moreover, these past studies demonstrated that both 1 and 2 mg/kg infusion doses influenced both pulmonary hemodynamics and bioactive signaling. Based upon these past results, the present study tested utilized a 1 and 2 mg/kg ET-ARA infusion protocol which was formulated in sterile saline within 2 hours of systemic infusion. The vehicle for this study was an equal volume of sterile saline.

Study Protocol

Following informed consent, a total of 29 patients were randomized to the following 3 treatment groups utilizing a predetermined randomization coding scheme that was developed prior to the initiation of the study and maintained in a blinded fashion by the study coordinator (JM): (1) Vehicle (saline vehicle bolus), (2) 1 mg/kg of ET-ARA, (3) 2 mg/kg of ET-A antagonist. The vehicle or ET-ARA was infused immediately at separation from CPB as a bolus infusion over 5 minutes, and then again at 12 hours post-CPB. The initial time point of infusion, which corresponded to when the infusion was complete and the patient removed from CPB, was designated as time 0. With this as the reference, the following measurement time points were used: Baseline (following placement of arterial and pulmonary catheters, but prior to the onset of CPB), Time 0 (immediately at cessation of CPB and following placebo/drug infusion), 0.5 hours post-CPB, 6 hours post-CPB, 12 hours post-CPB and 24 hours post-CPB. The hemodynamic measurements obtained/computed at each of these time points were: heart rate, mean arterial pressure, mean pulmonary artery pressure, cardiac output, systemic vascular resistance, and pulmonary vascular resistance. At the designated time points, blood samples were collected to determine plasma ET using radioimmunoassay methods well described by this laboratory.3,24,25 In addition, plasma concentrations of the ET-ARA sitaxsentan, were determined by a pre-calibrated high performance liquid chromatography method described previously.26 In the postoperative period, inotropic and vasodilator requirements were recorded. All adverse events were adjudicated, reviewed and reported to the MUSC Institutional Review Board.

Data Analysis

Hemodynamic parameters and plasma ET-1 levels at each time point were evaluated with a multi-way analysis of variance (ANOVA). If the ANOVA revealed significant differences, pair-wise tests of individual group means were compared by adjusted probabilities (Bonferroni method). Categorical variables such as demographics, and preoperative variables were examined using Chi-Square analysis. The changes in pulmonary and systemic vascular resistance were computed as follows. First, the absolute values at baseline and the designated time points were examined by ANOVA. Second, the change in the main response variables such as systemic and pulmonary vascular resistance was examined as a function from time 0 since this was the index time point for this study with respect to treatment and separation from CPB. Next, pair-wise comparisons in the changes in these parameters were performed using adjusted probabilities. All statistical procedures were performed using STATA statistical software (STATA Intercooled V 8.0. College Station, TX). Results are presented as mean ± standard error of the mean (SEM). Values of p<0.05 were considered to be statistically significant, or as indicated in the results.

Results

Demographic, intra-operative and post-operative descriptive data for the 29 patients enrolled in this study are presented in Table 1. The main pre-operative risk variables of interest; age and LV ejection fraction, were equivalent across the patients randomized to the vehicle, 1 and 2 mg/kg ET-ARA groups. All other pre-operative data were similar across groups with the exception of the number of patients presenting for a re-operation (all a secondary re-vascularization procedure, >1 yr from previous procedure), and diuretic use, in which a higher number of these patients were randomized to the 2 mg/kg group. Baseline plasma ET levels were equivalent across all 3 treatment groups. However, when the composite baseline plasma ET levels were compared to previously obtained pre-operative ET levels in patients undergoing elective CABG, with a normal LV ejection fraction,24 the baseline ET levels obtained in the present study were significantly higher (Figure 1). Aortic cross-clamp time and total CPB times were similar between groups, as were overall time to extubation, intensive care unit stay, and total length of hospital stay (Table 1).

Table 1.

Preoperative Demographics and Perioperative Variables for Patients Randomized to Vehicle or the ET-ARA Sitaxsentan (Vehicle n=10, 1 mg/kg n=9, 2 mg/kg n=10)

ET-ARA
Vehicle 1 mg/kg 2 mg/kg p-value
Preoperative
Age (years) 67 ± 2 62 ± 3 68 ± 3 0.242
LVEF (%) 35 ± 3 38 ± 2 37 ± 3 0.762
Hypertensive (n) 9/10 6/9 8/10 0.273
Diabetic (n) 7/10 4/9 6/10 0.483
Gender (M/F) 9/1 7/2 10/0 0.283
CABG-Only (n) 7/10 8/9 7/10 0.546
Valve Replacement (n) 1/10 0/9 0/10 0.374
CABG-Valve (n) 2/10 1/9 3/10 0.596
Diuretics (n) 3/10 1/9 7/10 0.025
Re-operation(n) 0/10 1/9 4/10 0.051
Plasma ET (fmol/mL) 3.9 ± 0.4 3.7 ± 0.3 4.3 ± 0.7 0.786
Intraoperative
Cross-clamp Time (min) 74 ± 12 88 ± 10 75 ± 4 0.488
CPB Time (min) 103 ± 16 101 ± 9 107 ± 10 0.921
Post-Operative
Intubation Time (hrs) 23 ± 3 24 ± 8 32 ± 13 0.689
ICU Time (days) 6 ± 1 5 ± 1 10 ± 3 0.183
Length of Stay (days) 10 ± 1 11 ± 3 17 ± 4 0.239
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Figure 1.

Figure 1

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Pre-operative (baseline) plasma endothelin-1 (ET) values were determined in patients with a normal LV ejection fraction (LVEF;n=37, defined as >50%) undergoing elective cardiac surgery from a study recently performed using identical high sensitivity immunoassay procedures,24 and were compared to baseline plasma ET values obtained from the present study in patients with a reduced LVEF (n=29, <50%). The distribution of individual values from these 2 patient groups is shown, where the mean baseline ET levels was 2.0±0.2 fmol/mL in the normal LVEF group, and was significantly increased in patients with a reduced LVEF (4.0±0.2 fmol/mL, * p<0.05).

Hemodynamics and ET Levels Post-CPB

Absolute values for heart rate, mean arterial blood pressure, pulmonary artery pressure, systemic and pulmonary vascular resistance, and plasma ET and ET-ARA values at baseline and the designated post-CPB time points are shown in Table 2. Baseline hemodynamics were equivalent in patients randomized to the vehicle, 1 mg/kg or 2 mg/kg ET-ARA groups. Pair-wise comparison results are shown in Table 2, and the results from the ANOVA are summarized for hemodynamic variables in this paragraph. Heart rate increased as a function of post-CPB time (F=10.2, p=0.001), and was higher in the ET-ARA groups at later post-CPB time points. Mean arterial pressure fell at early post-CPB time points, and this was significant time effect (F=6.68, p=0.001). Pulmonary artery pressures tended to increased in the post-CPB periods, and a significant treatment effect on this hemodynamic value was observed (F=5.17, p=0.007). Cardiac output was increased in the early post-operative time points in the ET-ARA groups. Systemic vascular resistance fell in the post-CPB time periods with both a time (F=5.03, p=0.001) and treatment effect (F=4.10, p=0.018), and this parameter fell to the greatest degree in the 2 mg/kg ET-ARA group. Pulmonary vascular resistance changed in a time dependent manner post-CPB (F=2.20, p=0.058). Plasma ET levels increased in the post-CPB period (F=15.45, p=0.001) and higher values were observed in the 2 mg/kg group. Plasma levels for the ET-ARA sitaxsentan immediately following infusion, at the 6 hour time point, immediately following the second infusion at 12 hours, and at the 24 hour time point, are shown in Table 2. At 6 hours following the first infusion of the ET-ARA, a significant reduction in plasma drug concentrations was observed. At 24 hours following the second ET-ARA infusion, drug levels were at minimal detectable levels- consistent with the clearance kinetics of this compound.26 Since a high degree of within-patient variation in systemic and pulmonary vascular resistance occurred at baseline as well as post-CPB time points, these indices were transformed as a function of Time 0 in order to more carefully examine potential treatment effects. There were no significant differences in the relative change in systemic vascular resistance with respect to treatment (ANOVA, F=0.13, p=0.88). However, the relative change in pulmonary vascular resistance was significantly affected by treatment, with the greatest reduction in this parameter in the 2 mg/kg group at the late post-CPB time points (Figure 2).

Table 2.

Hemodynamics at Baseline and Following Cardiopulmonary Bypass in Patients Randomized to Vehicle or to the ET-ARA Sitaxsentan (Vehicle n=10, 1 mg/kg n=9, 2 mg/kg n=10, *p<0.05 vs Baseline, +p<0.05 vs 1 mg/kg ET-ARA)

Post-CPB (hrs)
Baseline 0 6 12 24
Heart Rate (bpm)
 Vehicle 62.6 ± 3.7 77.8 ± 2.9 75.2 ± 3.8 78.5 ± 5.6 78.6 ± 4.1
 1 mg/kg ET-ARA 63.6 ± 2.0 80.1 ± 4.6 85.1 ± 6.4* 88.2 ± 3.2* 91.7 ± 6.6*
 2 mg/kg ET-ARA 62.4 ± 2.8 84.5 ± 5.2* 85.6 ± 5.2* 84.5 ± 5.5* 85.9 ± 4.2*
Arterial Pressure (mmHg)
 Vehicle 82.8 ± 3.9 72.5 ± 3.7 76.1 ± 3.5 72.9 ± 2.8 80.5 ± 4.3
 1 mg/kg ET-ARA 80.7 ± 4.8 69.0 ± 4.6 75.3 ± 3.0 70.2 ± 3.0 80.9 ± 2.3
 2 mg/kg ET-ARA 80.1 ± 3.2 71.9 ± 4.0 73.9 ± 2.8 72.6 ± 1.6 80.1 ± 2.3
Pulmonary Artery Pressure (mmHg)
 Vehicle 20.4 ± 1.4 20.8 ± 2.2 23.8 ± 2.3 24.6 ± 1.4 22.9 ± 1.5
 1 mg/kg ET-ARA 25.7 ± 3.6 19.3 ± 2.4 22.4 ± 1.4 22.1 ± 2.0 24.2 ± 2.3
 2 mg/kg ET-ARA 25.3 ± 4.2 26.0 ± 3.3 28.4 ± 3.2 26.4 ± 1.8 26.6 ± 2.4
Cardiac Output (L/min)
 Vehicle 4.4 ± 0.3 4.8 ± 0.4 5.2 ± 0.4 5.4 ± 0.4 5.3 ± 0.5
 1 mg/kg ET-ARA 4.4 ± 0.6 5.5 ± 0.7 5.9 ± 0.8* 6.8 ± 0.7* 6.9 ± 0.8*
 2 mg/kg ET-ARA 4.3 ± 0.2 5.5 ± 0.4 6.1 ± 0.4* 5.5 ± 0.2 5.6 ± 0.4
Systemic Vascular Resistance (d.s.cm-5)
 Vehicle 1408 ± 119 1155 ± 165 1106 ± 157 962 ± 98 1192 ± 158
 1 mg/kg ET-ARA 1359 ± 210 894 ± 159 1068 ± 193 761 ± 71 898 ± 115
 2 mg/kg ET-ARA 1307 ± 112 960 ± 89* 820.7 ± 67* 897 ± 46* 1015 ± 86
Pulmonary Vascular Resistance (d.s.cm-5)
 Vehicle 153.8 ± 19.9 123.5 ± 20.7 138.7 ± 28.0 146.8 ± 21.6 163.3 ± 26.6
 1 mg/kg ET-ARA 213.0 ± 65.3 125.3 ± 24.8 144.6 ± 15.2 132.7 ± 12.7 125.5 ± 22.3
 2 mg/kg ET-ARA 174.6 ± 28.4 175.8 ± 26.6 132.7 ± 17.6 136.6 ± 17.5 138.7 ± 20.0
Plasma Endothelin-1 (fmol/mL)
 Vehicle 3.9 ± 0.4 5.5 ± 0.8 8.2 ± 1.1* 8.6 ± 1.1* 8.0 ± 1.0*
 1 mg/kg ET-ARA 3.7 ± 0.3 4.7 ± 0.5 7.2 ± 1.3 8.8 ± 1.7* 8.3 ± 1.0*
 2 mg/kg ET-ARA 4.3 ± 0.7 4.1 ± 0.5 7.6 ± 1.2 10.4 ± 1.6* 8.6 ± 1.4*
Sitaxsentan Levels (μg/mL)
 1 mg/kg ET-ARA N/A 7.35 ± 0.83 0.06 ± 0.01 1.88 ± 1.26 0.06 ± 0.01
 2 mg/kg ET-ARA N/A 11.78 ± 1.17+ 2.24 ± 2.13 8.63 ± 3.24+ 0.09 ± 0.01
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Figure 2.

Figure 2

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The changes in pulmonary vascular resistance, computed in absolute units, from Time 0 (Vehicle/ET-ARA infusion and separation from CPB). In the early post-CPB period, a ET-ARA effect was observed for pulmonary vascular resistance (ANOVA, F=4.73, p=0.01). Pairwise comparisons revealed a significantly lower pulmonary vascular resistance at 24 hours post-CPB (*p<0.05 vs vehicle).

Adverse Events

A total of 168 adverse events (AEs) were tabulated in the post-operative period and a categorical distribution of these AEs is presented in Table 3. The total number of AEs were not significantly different between the 3 groups (p=0.09). The AEs were equally distributed across treatment groups with one exception- the hematological/lymphatic category where a higher percent were reported in the 2 mg/kg group. The preponderance of these AEs in the 2 mg/kg group (10), was secondary to low post-operative hematocrit, due to increased perioperative blood loss, that occurred in 5 patients. These AEs were adjudicated not to be study related. With respect to serious adverse events (SAEs), there were a total of 18 reported. These SAEs included 3 patient deaths which occurred in the 1 mg/kg ET-ARA (n=2) and in the 2 mg/kg ET-ARA (n=1) groups, and following adjudication were considered unrelated to ET-ARA treatment. One patient with a significantly low (<30%) preoperative ejection fraction, died on the second post-operative day due to low cardiac output, and respiratory failure. Upon review, this poor post-operative course may have been precipitated by a protamine reaction thereby exacerbating the pre-existing LV dysfunction. The second patient died on post-operative day 3 (within 24 hours of anticipated hospital discharge) following sudden cardiac arrest, during a routine incentive spirometry session. The third patient died 38 days post-operatively in an outlying facility from presumably cardiopulmonary failure. The other SAEs included cardiovascular (thrombo-embolic event, bleeding, n=8), pulmonary/infection (n=6), and gastrointestinal (ischemic bowel, n=1). When the SAEs were considered as a composite, there were no significant differences between treatment groups (Chi-Square 1.59; p=0.452).

Table 3.

Adverse Events in High Risk Patients Following Cardiopulmonary Bypass Randomized to Vehicle or to the ET-ARA Sitaxsentan

Sitaxsentan
Adverse Event Vehicle 1 mg/kg 2 mg/kg Total chi2 pValue
Cardiovascular 12 20 17 49 2 0.368
% 24% 41% 35% 100%
Pulmonary 3 4 8 15 2.8 0.246
% 20% 27% 53% 100%
Neurological 2 0 0 2 0.5 0.779
% 100% 0% 0% 100%
Urinary 2 0 3 5 1.0 0.606
% 40% 0% 60% 100%
Gastrointestinal 9 8 8 25 0.1 0.961
% 36% 32% 32% 100%
Hepatic 0 3 1 4 1.6 0.449
% 0% 75% 25% 100%
Musculoskeletal 1 7 5 13 4.3 0.116
% 8% 54% 38% 100%
Genitourinary/Gynecological 0 0 0 0 n/a n/a
% 0% 0% 0% 0%
Endocrine/Metabolic 1 1 5 7 4.6 0.102
% 14% 14% 71% 100%
Immunological/Allergic 0 1 0 1 2.3 0.316
% 0% 100% 0% 100%
Hematological/Lymphatic 1 4 10 15 8.4 0.015
% 7% 27% 67% 100%
Psychological/Behavioral 3 4 7 14 1.9 0.395
% 21% 29% 50% 100%
HEENT 1 0 0 1 2.0 0.374
% 100% 0% 0% 100%
Infection 3 0 2 5 1.0 0.606
% 60% 0% 40% 100%
Fever 0 3 4 7 1.8 0.417
% 0% 43% 57% 100%
Dermatological 0 3 2 5 1.0 0.606
% 0% 60% 40% 100%
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Discussion

Increased synthesis and release of the peptide endothelin-1 (ET) occurs in a number of cardiovascular disease states and binds to 2 predominant receptor subtypes the ET-A and ET-B receptors. The most studied effects are that of ET binding to the ETA receptor which causes significant vasoconstriction, influences excitation-contraction coupling processes, and modifies sympathetic efferent firing and chronotropy within the myocardium.1-8,20,27-31 In marked contrast, ET binding to the ET-B receptor mediates the release of nitric oxide and can cause relaxation of vascular smooth muscle.1,2,7,16-18,21,32,33 In light of these differential effects, selective ET-A receptor antagonists (ET-ARAs) have been developed and deployed in cardiovascular disease states such as pulmonary hypertension.16,18,22 Past studies have demonstrated that increased ET release occurs in patients following cardiac surgery requiring cardiopulmonary bypass (CPB) and may contribute to a complex post-operative course.3,24,25,34 An initial dose-ranging pilot study in patients undergoing elective CABG requiring CPB, the ET-ARA antagonist sitaxsentan, was well tolerated and caused a dose-dependent decrease in pulmonary vascular resistance in the post-CPB period.25 This initial study was performed in low risk patients with respect to pre-existing risk factors such as left ventricular (LV) function. However, it is in patients with pre-existing risk factors, such as LV systolic dysfunction and complex medical histories (ie hypertension, diabetes, increased age) that present for cardiac surgery and result in a higher incidence of postoperative morbidity and mortality.9-15 Thus, if inhibition of the ET-A receptor is to be considered a viable therapeutic target in cardiac surgery, then an ET-ARA must be evaluated in higher risk cardiac surgery patients. Accordingly, using a blinded and randomized protocol, the present study infused vehicle, 1 mg/kg or 2 mg/kg of the ET-ARA sitaxsentan in patients with pre-existing LV dysfunction at the time of separation from CPB and at 12 hours post-CPB. This initial study demonstrated that the ET-ARA could be utilized in high risk patients and the higher dose of sitaxsentan attenuated the degree of pulmonary vasoconstriction in the post-CPB period. This study adds to the growing body of evidence that inhibition of the ET-A receptor may be a viable therapeutic target in the context of cardiac surgery requiring CPB.

It has been recognized for some time that the synthesis and release of the bioactive molecule ET occurs within all cell types and organ systems, particularly within the cardiovascular system.16-20 While the role of ET in systemic hypertension and heart failure has been the focus of both basic and clinical studies,17-19,28,33 the primary therapeutic target has been that of primary pulmonary hypertension. Specifically, oral formulations of both non-selective and ET-A subtype selective antagonists have been described to be efficacious in pulmonary hypertension16,18,22 However, an oral formulation of an ET-ARA would not be of practical clinical use in an acute care setting, and therefore infusible formulations of selective ET-ARAs would be required. This laboratory has described previously basic and clinical studies using an intravenous formulation of the ET-ARA, sitaxsentan.24,25,35 These past studies demonstrated a significant reduction in pulmonary vascular resistance following post-CPB.25,35 However, these studies were performed in the context of normal LV function, whereas a preponderance of patients may present for cardiac surgery with pre-existing LV myocardial dysfunction and other co-morbidities such as diabetes. Previous work has demonstrated that the density and distribution of myocardial ET-A receptor subtypes may actually be increased in LV dysfunction, and the sensitivity of ET can be actually enhanced with diabetes.33,36,37 The present study was the first to demonstrate that an infusible ET-ARA deployed in patients with significant pre-existing cardiac surgical risk factors, influenced pulmonary vascular resistance in the early post-operative period. However, this study utilized only one highly selective ET-ARA, and therefore whether this is a class effect which can be achieved with other selective ET-ARAs remains to be established.

In the present study, conventional hemodynamic monitoring was performed at pre-specified intervals prior to and following either vehicle or ET-ARA administration. In both the 1 and 2 mg/kg ET-ARA groups, heart rate increased in the post-CPB period. This increased chronotropy with ET-ARA treatment does not appear to have been due to a baro-receptor reflex response, since arterial blood pressure remained unchanged at these post-CPB time points. Rather, it has been reported previously that ET can cause a direct negative effect on chronotropy, and that ET receptor inhibition can cause a positive chronotropic effect, likely due to local sympathetic effects on sino-atrial nodal cells.29-31 There are two important considerations regarding the potential positive chronotropic effect of the ET-ARA which was observed in the present study. First, the increased heart rate can significantly affect cardiac output, and in turn influence the resistance calculations. Indeed, cardiac output was increased to the greatest degree in the ET-ARA groups in the post-operative period. Second, heart rate is an important determinant of myocardial oxygen demand, and therefore the chronotropic effect of ET-ARA infusion may not be a desirable effect in the early post-operative period. A past study by this laboratory demonstrated that exogenous ET caused potent vasoconstriction of vascular conduits used in CABG, and that selective ET-ARAs inhibited this effect.3 Thus, while not directly measured in the present study, infusion of an ET-ARA in the early post-CPB period may have a number of effects on myocardial oxygen demand and blood flow.

In general terms, baseline hemodynamics were similar across the randomized groups, but there was some intrinsic variability in these measurements likely due to patients with varying degrees of cardiopulmonary compromise. Since the true intervention utilized in this study did not occur until vehicle/ET-ARA infusion and separation from CPB, then this time point was utilized as the index event (Time 0). Accordingly, the relative changes in key hemodynamic variables were computed from this index time point. From this analysis, the most significant treatment effect was that observed with respect to pulmonary vascular resistance in the later post-CPB time points. One potential contributory factor for the relative changes in pulmonary vascular resistance that was observed in the ET-ARA groups was an increase in cardiac output. However, the greatest increase in cardiac output was observed in the 1 mg/kg ET-ARA group, whereas the greatest reduction in pulmonary vascular resistance was observed in the in the 2 mg/kg ET-ARA group, which is consistent with the pharmacological effects of ET-ARAs in general, and consistent with our past reports using this infusible ET-ARA.25 In addition, the greatest reduction in systemic vascular resistance was observed in the 2 mg/kg ET-ARA group. However, more sensitive and direct effects on vascular compliance and the potential effects of ET-ARA were not evaluated in the present study. It has been clearly demonstrated that ET receptor inhibition causes a direct vasodilatory effect within the pulmonary vasculature.16-18 Taken together, the mechanisms which underlie the effects of ET-ARA on pulmonary vascular resistance were likely combinatorial and included increased cardiac output as well as direct effects on pulmonary vascular tone.

The current study predicated the 2 doses of the ET-ARA on the results of past dose-ranging subjects in patients undergoing elective CABG with normal LV ejection fraction.25 Furthermore, the rationale for the timing of the ET-ARA infusions was based upon previous observations regarding the temporal dynamics of ET release in the post-CPB period as well as the pharmacokinetics of ET-ARA itself.24-26,34 Specifically, the release of ET following CPB appears to occur in a bi-phasic manner where an initial surge occurs immediately following separation from CPB, and a second peak occurs at approximately 12 hours following CPB.24, 34 Thus, the present study was designed in order to target both of these phases of ET release through bolus infusions of the ET-ARA immediately following CPB as well as 12 hours post-CPB. Consistent with the pharmacokinetics of sitaxsentan, plasma levels of this ET-ARA were detectable at 6 hours post bolus infusion of the 2 mg/kg dose, but were nominal by 12 hours post bolus infusion.26 In light of this, the direct pharmacological effects of the ET-ARA which were observed in the present study would not likely persist beyond 12 hours post dosing. Thus, the fact that steady-state hemodynamics and pulmonary vascular resistance did not abruptly increase at the 24 hour post-CPB time point suggest that a significant autoregulatory, or pharmacological “rebound effect” may not be operative with this dosing regimen. However, there are several issues which warrant consideration with respect to the pharmacological utilization of this ET-ARA in the context of cardiac surgery. First, longer monitoring periods will be necessary to fully examine the hemodynamic effects of the ET-ARA infusion protocol used in the present study. Second, whether the effects of this infusible ET-ARA causes dose-dependent effects on pulmonary vascular resistance, and whether 2 mg/kg of the ET-ARA is a maximally effective dose in a high risk cardiac surgical population will require a larger prospective study.

The present study examined plasma ET levels in patients with pre-existing LV dysfunction preoperatively as well as following CPB. The first important observation from these set of measurements was that preoperative, steady-state plasma ET levels were higher in patients with pre-existing LV systolic dysfunction when compared to preoperative ET levels measured under identical conditions in an age matched cohort of patients with normal LV systolic function.24,25 It has been reported previously in patients with significant heart failure that plasma ET levels were increased.17-19,33 Thus, the increased plasma ET levels are likely reflective of the pathophysiological consequences of LV dysfunction. While remaining speculative, the present study provides evidence to suggest that preoperative measurements of plasma ET may serve as a biomarker for patients that may be at increased risk for ET mediated events, such as increased pulmonary vascular resistance, in the post-CPB period. A larger, prospective study will be necessary to directly address this issue. Consistent with past reports,24,25,34,35 plasma ET levels increased significantly in the post-CPB period, and is likely due increased synthesis and spillover from interstitial compartments such as the myocardium.33,34 In the ET-ARA groups, plasma ET levels were increased to the greatest degree in the post-CPB period. The reasons for the increased circulating levels of ET with infusion of the ET-ARA are likely to be 2-fold. First, inhibition of the ET-A receptor likely interrupts a receptor-transduction feedback pathway and thereby may induce increased synthesis and release of ET. Second, occupancy of the ET-A receptor with the antagonist will displace bound ET and therefore cause a reflective increase in plasma levels. Since the highest levels of ET occurred at the 12 hour-post CPB period, where a second infusion of the ET-ARA was delivered, then this would lend support for the displacement of bound ET to cognate ET-A receptors. While the increased plasma levels of ET in the late post-CPB period in the ET-ARA groups is likely a summation of these factors, the increased plasma ET is evidence for a pharmacological effect of the ET-ARA.

Since sitaxsentan is a potent and selective ET-ARA, then the increased levels of ET would potentially cause heightened binding and activation of the ET-B receptor. The increased activation of the ET-B receptor, in turn would cause increased nitric oxide release and vascular smooth muscle relaxation, particularly in the pulmonary vasculature. Thus, a potential indirect pathway by which ET-ARA infusion facilitated a reduction in pulmonary vascular resistance in the post-CPB period was through increased and unopposed activation of the pulmonary ET-B receptor. The selective reduction in pulmonary vascular resistance may hold particular relevance in patients with pre-existing right ventricular (RV) failure, or those that develop RV failure perioperatively. Specifically, a relative reduction in RV afterload would be potentially beneficial in the early post-operative period, particularly since RV failure is not an uncommon occurrence in the context of cardiac surgery.36,37 However, this issue was not directly addressed in the present study.

The present study was the first to utilize a selective ET-ARA in patients undergoing cardiac surgery with significant pre-operative risk factors. Due to the advanced age and poor LV systolic performance of these patients, it was not surprising that there were a number of adverse events encountered during the course of the study. One of the first major limitations of this study was the small sample size, which in turn can result in a disproportionate number of patients with greater pre-operative risk profiles randomized to one treatment group. Indeed, a significantly greater number of patients randomized to the 2 mg/kg ET-ARA group presented for re-operation and increased diuretic dependency. All five reoperations randomized to an ET-ARA group, four of these to the 2 mg/kg group. The increased incidence of low hematocrit/hemoglobin in the early post-operative period in the 2 mg/kg ET-ARA group may have been due, in part to the increased perioperative bleeding which can occur in reoperation. Speculatively, diuretic dependence may be an indicator of more advanced heart failure. It is notable that, despite a higher preoperative risk profile in the 2 mg/kg ET-ARA group, the total number of adverse events and serious adverse events were not significantly increased. With respect to the 3 deaths encountered in this study, these patients carried a significant preoperative risk and were adjudicated not be associated with ET-ARA treatment. Furthermore, the statistical analysis suggests that these deaths which occurred in the ET-ARA groups were strictly due to chance. Nevertheless, these outcomes coupled with the limited sample size of this initial feasibility study warrant a note of caution which can only be further addressed by a larger prospective study. What can be concluded from this study is that in patients with preexisting LV systolic dysfunction, increased ET-A receptor activation likely contributes to changes in hemodynamic profiles following cardiac surgery requiring CPB, and therefore constitutes a viable therapeutic target.

Acknowledgments

The authors would like to acknowledge Theresa A. Brinsa for her assistance with data analysis. This study was supported by an unrestricted research grant from Encysive Pharmaceuticals, which was acquired by Pfizer Inc. in June 2008, NIH grant HL87134 and a Merit Award from the Veterans' Affairs Health Administration.

Footnotes

Presented at the 35th Annual Meeting of the Western Thoracic Surgical Association, June 27, 2009.

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