Endothelin receptor subtype A blockade selectively reduces pulmonary pressure after cardiopulmonary bypass

Joffs, Cassandra; Walker, C.Allyson; Hendrick, Jennifer W.; Fary, David J.; Almany, Daniel K.; Davis, Jennifer Nerissa; Goldberg, Aron T.; Crawford, Fred A.; Spinale, Francis G.

doi:10.1067/mtc.2001.114938

Cited by 16 publications

(23 citation statements)

References 37 publications

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“…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.…”

Section: Discussionsupporting

confidence: 89%

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Discussionmentioning

confidence: 99%

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

O’Toole

Ikonomidis

Szeto

et al. 2010

The Journal of Thoracic and Cardiovascular Surgery

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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.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

O’Toole

Ikonomidis

Szeto

et al. 2010

The Journal of Thoracic and Cardiovascular Surgery

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“…While mechanistic links remain to be established, ET release and cytokine activation have been associated with a protracted post operative course following CPB [6–9]. Past studies have demonstrated that ET has diverse biological effects on myocyte contractility and upon the vasculature [10–12]. The cardiovascular effects of ET are mediated through two unique receptor subtypes: ET-A receptor (ET-AR) and ET-B receptor (ET-BR).…”

Section: Introductionmentioning

confidence: 99%

“…The cardiovascular effects of ET are mediated through two unique receptor subtypes: ET-A receptor (ET-AR) and ET-B receptor (ET-BR). ET-AR mediates local and systemic vasoconstriction and has negative inotropic effects [10–12]. In contradistinction, ET-BR mediates the release of vasodilatory factors, such as nitric oxide, as well as facilitates ET clearance [13, 14].…”

Section: Introductionmentioning

confidence: 99%

Endothelin-A Receptor Inhibition After Cardiopulmonary Bypass: Cytokines and Receptor Activation

Ford

Mains

Hilton

et al. 2008

The Annals of Thoracic Surgery

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Right ventricular function declines after cardiac surgery in adult patients with congenital heart disease

Schuuring

Bolmers

Mulder

et al. 2011

Int J Cardiovasc Imaging

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Right ventricular function (RVF) is often selectively declined after coronary artery bypass graft surgery. In adult patients with congenital heart disease (CHD) the incidence and persistence of declined RVF after cardiac surgery is unknown. The current study aimed to describe RVF after cardiac surgery in these patients. Adult CHD patients operated between January 2008 and December 2009 in the Academic Medical Centre in Amsterdam were studied. Clinical characteristics, laboratory tests, surgical data and intensive care unit outcome were obtained from medical records. RVF was measured by trans-thoracic echocardiography (TTE) and expressed by tricuspid annular plane systolic excursion (TAPSE), tissue Doppler imaging (RV S’) and myocardial performance index (MPI) pre-operatively and direct, at intermediate and late follow up. Of a total of 185 operated, 86 patients (mean age 39 ± 13 years, 54% male) had echo data available. There was a significant fall in RVF after cardiac surgery. TAPSE and RV S’ were significantly higher and MPI was significantly lower pre-operatively compared to direct post-operative values (TAPSE 22 ± 5 versus 13 ± 3 mm (P < 0.01), RV S’ 11 ± 4 versus 8 ± 2 cm/s (P < 0.01) and MPI 0.36 ± 0.14 vs 0.62 ± 0.25; P < 0.01). There were no significant differences in left ventricular function pre-operatively compared to post-operative values. Right-sided surgery was performed in 33, left-sided surgery in 37 and both sided surgery in 16 patients. Decline in RVF was equal for those groups. Patients with severe decline in RVF, were patients who underwent tricuspid valve surgery. Decline in RVF was associated with post-operative myocardial creatine kinase level and maximal troponin T level. There was no association between decline in RVF and clinical outcome on the intensive care unit. 18 months post-operatively, most RVF parameters had recovered to pre-operative values, but TAPSE which remained still lower (P < 0.01). CHD patients have a decline in RVF directly after cardiac surgery, regardless the side of surgery. Although a gradual improvement was observed, complete recovery was not seen 18 months post-operatively.

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Endothelin receptor subtype A blockade selectively reduces pulmonary pressure after cardiopulmonary bypass

Cited by 16 publications

References 37 publications

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

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

Endothelin-A Receptor Inhibition After Cardiopulmonary Bypass: Cytokines and Receptor Activation

Right ventricular function declines after cardiac surgery in adult patients with congenital heart disease

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