Excess circulating angiopoietin-2 is a strong predictor of mortality in critically ill medical patients

Abstract

Introduction: The endothelial specific angiopoietin (Ang)-Tie2 ligand-receptor system has been identified as a non-redundant mediator of endothelial activation in experimental sepsis. Binding of circulating Ang-1 to the Tie2 receptor protects the vasculature from inflammation and leakage, whereas binding of Ang-2 antagonises Tie2 signalling and disrupts endothelial barrier function. Here, we examine whether circulating Ang-1 and/or Ang-2 independently predict mortality in a cohort of critically ill medical patients.

Methods: Circulating vascular endothelial growth factor (VEGF), Ang-1 and Ang-2 were prospectively measured in sera from 29 healthy controls and 43 medical ICU patients by immunoradiometric assay (IRMA) and ELISA, respectively. Survival after 30 days was the primary outcome studied.

Results: Median serum Ang-2 concentrations were increasingly higher across the following groups: healthy controls, patients without sepsis, patients with sepsis and patients with septic shock. In contrast, Ang-1 and VEGF concentrations were significantly lower in all patient groups compared with healthy controls. Ang-2 correlated with partial pressure of oxygen in arterial blood (PaO2)/fraction of inspired oxygen (FiO2), tissue hypoxia, Sequential Organ Failure Assessment (SOFA) and Physiology and Chronic Health Evaluation II (APACHE II) score. Multivariate Cox regression analyses confirmed a strong independent prognostic impact of high Ang-2 as a novel marker of 30-day survival.

Conclusions: A marked imbalance of the Ang-Tie system in favour of Ang-2 is present in critically ill medical patients. Our findings highlight the independent prognostic impact of circulating Ang-2 in critical illness. Ang-2 may be used as a readily available powerful predictor of outcome and may open new perspectives to individualise treatment in the ICU.

Figure 1

Box plots of results in healthy controls and study patients. Circulating (a) Angiopoietin (Ang) 1, (b) Ang-2 and (c) vascular endothelial growth factor (VEGF) serum concentrations in healthy controls (n = 29), critically ill patients without infection (no sepsis; n = 14), patients with severe sepsis (n = 12) and septic shock (n = 17). Horizontal bars indicate median values.

Figure 2

Scatter plots showing correlations of results. Correlations of Ang-2 serum concentrations with (a) the Acute Physiology and Chronic Health Evaluation (APACHE) II score and (b) the Sequential Organ Failure Assessment (SOFA) score in 43 critically ill patients (non-septic patients (n = 14); severe sepsis (n = 12) and septic shock (n = 17)).

Figure 3

Kaplan-Meier curves of survival stratified to Angiopoietin (Ang) 2. (less versus greater than median; Log rank test p = 0.009).