Increased Circulating Endothelin 1 Is Associated With Postoperative Hypoxemia in Infants With Single-Ventricle Heart Disease Undergoing Superior Cavopulmonary Anastomosis

Abstract

Background Inadequate pulmonary vascular growth results in morbidity for many children with single-ventricle heart disease (SVHD). Endothelin 1 (ET1) is a potent vasoconstrictor and stimulator of pulmonary artery smooth muscle proliferation. Circulating ET1 levels and their association with outcomes have not been studied during early SVHD palliation. We aimed to define circulating levels of ET1 in patients with SVHD undergoing stage 2 palliation and evaluate their relationship to postoperative hypoxemia. We hypothesized that patients with SVHD with higher ET1 concentration would have a greater post-stage 2 hypoxemia. Methods and Results Prospective cohort study of 55 subjects with SVHD undergoing stage 2 palliation and 50 controls. Samples for ET1 analysis were collected at preoperation (systemic and pulmonary vein) and 2, 24, and 48 hours postoperation for cases and a single time point for controls. The primary outcome was percentage of first 48 postoperative hours with clinically significant hypoxemia (saturation, <70%). ET1 concentration was lower in preoperative cases than controls (2.2 versus 2.7 pg/mL; P=0.0015) and in the pulmonary vein than systemic vein (1.7 versus 2.2 pg/mL; P<0.001). ET1 level increased by 2 hours postoperation and trended back to baseline by 48 hours. Higher preoperative pulmonary vein ET1 and 2 hours postoperative ET1 were associated with larger hypoxemia burden (10.6% versus 2.7% [P=0.0081]; and 7.6% versus 3.2% [P=0.01], respectively). Multivariable testing demonstrated ET1 concentration and cardiopulmonary bypass time were associated with hypoxemia, whereas catheterization measurements and clinical variables were not. Conclusions Infants with SVHD with higher perioperative ET1 concentration experience more post-stage 2 hypoxemia. ET1 activity may be a modifiable risk factor of pulmonary vascular inadequacy for stage 2 palliation.

Keywords: Glenn operation; biomarkers; endothelin 1; hypoxemia; single‐ventricle palliation.

Figure 1. Endothelin 1 (ET1) distribution.

Violin plots depicting ET1 concentration. The upper and lower borders of the box represent the upper and lower quartiles. The middle horizontal line represents the median. The upper and lower whiskers represent the maximum and minimum values of nonoutliers. Extra dots represent outliers. Wider distribution represents a greater proportion of values at that concentration. A, Interstage infants with single‐ventricle heart disease (SVHD) have lower circulating ET1 concentration than similar aged healthy controls. *P<0.05. B, Interstage infants with SVHD demonstrate net pulmonary clearance of ET1 with lower concentration in the pulmonary vein than in the systemic vein sample. *P<0.05. C, ET1 concentrations increase immediately after stage 2 palliation and then trend down to baseline by 48 hours postoperatively (Post‐op). *P<0.05 compared to preoperatively (Pre‐op), **P<0.05 compared to 2 hours, ***P<0.05 compared to 24 hours. All P values reflect results of Wilcoxon test. All ET1 levels reported in pg/mL.