Selective endothelin-1 receptor type A inhibition in subjects undergoing cardiac surgery with preexisting left ventricular dysfunction: Influence on early postoperative hemodynamics.
OBJECTIVE
A robust release of endothelin-1 with subsequent endothelin-A subtype receptor activation occurs in patients after cardiac surgery requiring cardiopulmonary bypass. Increased endothelin-A subtype receptor activation has been identified in patients with poor left ventricular function (reduced ejection fraction). Accordingly, this study tested the hypothesis that a selective endothelin-A subtype receptor antagonist administered perioperatively would favorably affect post-cardiopulmonary bypass hemodynamic profiles in patients with a preexisting poor left ventricular ejection fraction.


METHODS
Patients (n = 29; 66 +/- 2 years) with a reduced left ventricular ejection fraction (37% +/- 2%) were prospectively randomized in a blinded fashion, at the time of elective coronary revascularization or valve replacement requiring cardiopulmonary bypass, to infusion of the highly selective and potent endothelin-A subtype receptor antagonist sitaxsentan at 1 or 2 mg/kg (intravenous bolus; n = 9, 10 respectively) or vehicle (saline; n = 10). Infusion of the endothelin-A subtype receptor antagonist/vehicle was performed immediately before separation from cardiopulmonary bypass and again at 12 hours after cardiopulmonary bypass. Endothelin and hemodynamic measurements were performed at baseline, at separation from cardiopulmonary bypass (time 0), and at 0.5, 6, 12, and 24 hours after cardiopulmonary bypass.


RESULTS
Baseline plasma endothelin (4.0 +/- 0.3 fmol/mL) was identical across all 3 groups, but when compared with preoperative values, baseline values obtained from age-matched subjects with a normal left ventricular ejection fraction (n = 37; left ventricular ejection fraction > 50%) were significantly increased (2.9 +/- 0.2 fmol/mL, P < .05). Baseline systemic (1358 +/- 83 dynes/sec/cm(-5)) and pulmonary (180 +/- 23 dynes/sec/cm(-5)) vascular resistance were equivalent in all 3 groups. As a function of time 0, systemic vascular resistance changed in an equivalent fashion in the post-cardiopulmonary bypass period, but a significant endothelin-A subtype receptor antagonist effect was observed for pulmonary vascular resistance (analysis of variance; P < .05). For example, at 24 hours post-cardiopulmonary bypass, pulmonary vascular resistance increased by 40 dynes/sec/cm(-5) in the vehicle group but directionally decreased by more than 40 dynes/sec/cm(-5) in the 2 mg/kg endothelin-A subtype receptor antagonist group (P < .05). Total adverse events were equivalently distributed across the endothelin-A subtype receptor antagonist/placebo groups.


CONCLUSIONS
These unique findings demonstrated that infusion of an endothelin-A subtype receptor antagonist in high-risk patients undergoing cardiac surgery was not associated with significant hemodynamic compromise. Moreover, the endothelin-A subtype receptor antagonist favorably affected pulmonary vascular resistance in the early postoperative period. Thus, the endothelin-A subtype receptor serves as a potential pharmacologic target for improving outcomes after cardiac surgery in patients with compromised left ventricular function.
Toole
John M
JM
Medical University of South Carolina, Charleston, SC, USA.
Ikonomidis
John S
JS
Szeto
Wilson Y
WY
Zellner
James L
JL
Mulcahy
John
J
Deardorff
Rachael L
RL
Spinale
Francis G
FG
D000368:Aged; D002315:Cardiopulmonary Bypass; D065130:Endothelin A Receptor Antagonists; D005260:Female; D006439:Hemodynamics; D006801:Humans; D007555:Isoxazoles / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications / Q000517:prevention & control*; D011184:Postoperative Period; D011446:Prospective Studies; D012307:Risk Factors; D016037:Single-Blind Method; D013876:Thiophenes / Q000627:therapeutic use*; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000150:complications*
D065130:Endothelin A Receptor Antagonists; D007555:Isoxazoles; D013876:Thiophenes; C106276:sitaxsentan