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Objective: Higher circulating Angiopoietin-2 (Ang-2) levels predict cardiovascular events and mortality in clinical samples and in the general population. To better understand the underlying mechanisms, we investigated the association of circulating Ang-2 and sTie-2 (the soluble form of the Ang-2 receptor) levels with various measures of subclinical cardiovascular disease., Methods: Cross-sectional data of 3204 participants (1654 women) aged 25-88 years from the population-based Study of Health in Pomerania were analysed. LV mass (LVM) and fractional shortening were determined echocardiographically as indices of cardiac structure and function, respectively. Intima media thickness (IMT) of the common carotid artery, the number of carotid plaques and flow-mediated dilation (FMD) were used to characterise large and medium-sized arterial structure and function., Results: Multivariable-adjusted linear and negative binomial regression models revealed an inverse association of circulating Ang-2 levels (independent variable) with fractional shortening (ß=-0.51 per 1 SD increment; 95% CI -0.86 to -0.16, p=0.005) and a positive association with number of carotid plaques (rate ratio=1.04 95% CI 1.01 to 1.07, p=0.019). No associations of Ang-2 or sTie-2 with LVM, IMT and FMD were found., Conclusions: Circulating Ang-2 levels were associated with select subclinical cardiovascular disease traits, consistent with the notion that the Ang-2-pathway plays a role in mediating cardiovascular morbidity., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Aims: To assess the association of circulating concentrations of angiopoietin-2 (Ang-2) and its soluble receptor Tie-2 (sTie-2) with all-cause, cardiovascular, and cancer mortality in a population-based sample., Methods and Results: Angiopoietin-2 and sTie-2 were measured in 3220 participants (1665 women; mean age 54.4 years) in the Study of Health in Pomerania (SHIP). Multivariable adjusted hazard ratios (HRs) for mortality were estimated using Cox proportional hazard models. During a median follow-up of 6.2 years, 217 participants died. Ang-2 levels were positively associated with all-cause mortality [HR 1.29; 95% confidence interval (CI) 1.19-1.39 per 1 SD increment; P < 0.001] and cardiovascular mortality (HR 1.32; 95% CI 1.18-1.49; P < 0.001), but not with cancer mortality (HR 1.08; 95% CI 0.89-1.32; P = 0.416). Levels of sTie-2 were not significantly related to all-cause mortality (HR 1.12; 95% CI 0.98-1.27; P = 0.102). Adding Ang-2 to a prediction model for all-cause mortality with standard risk factors slightly improved discrimination (Δ Harrell's C, 0.008; P < 0.001) but not risk reclassification (continuous net reclassification improvement, -0.015; P = 0.571)., Conclusion: In our community-based sample, higher serum Ang-2 concentrations were associated with greater risk for all-cause and cardiovascular mortality, suggesting that subtle increases in Ang-2 levels might reflect processes such as vascular remodelling that are associated with higher mortality risk. Adding Ang-2 to a mortality prediction model only modestly improved discrimination.

In critically ill patients, the massive release of angiopoietin-2 (Ang-2) from Weibel-Palade bodies interferes with protective angiopoietin-1 (Ang-1)/Tie2 signalling in endothelial cells, thus leading to vascular inflammation and subsequent organ-dysfunction. We hypothesised that plasma exchange (PE) is efficient for lowering excess Ang-2 levels in critically ill patients with thrombocytic microangiopathy (TMA) or anti-glomerular basement membrane (anti-GBM) disease. Plasma Ang-1 and Ang-2 were measured by immuno-luminometric assays in patients with TMA (n=9) or anti-GBM disease (n=4) before and after up to four PE sessions. Twenty apparently healthy volunteers served as controls. Median (IQR) plasma levels of Ang-2 were markedly increased in patients with TMA (7.3 (2.4-21.1) ng/ml) and anti-GBM disease (5.8 (3.4-7.0) ng/ml) compared to healthy controls (1.0 (0.9-1.4) ng/ml, p <0.001). Moreover, Ang-1 plasma levels were decreased in both, TMA (1.02 (0.62-1.62) ng/ml) and anti-GBM disease patients (0.74 (0.59-3.62) ng/ml) compared to healthy controls (2.5 (1.93-3.47) ng/ml, p <0.005). During a total of 32 treatments, PE effectively lowered elevated mean (SD) Ang-2 plasma levels by 36.7 ± 19.6% per treatment (p <0.0001), whereas low Ang-1 plasma levels remained unchanged (0.3 ± 58.5%; p=0.147). Ang-2 levels declined to almost normal values during ≤4 PE treatments (Friedman´s test p<0.0001). PE is an effective method to remove excess circulating Ang-2. It remains to be elucidated if the removal of Ang-2 is crucial to ameliorate endothelial damage in critically ill patients with severely altered endothelial integrity.

Objectives: Patients with severe acute pancreatitis (AP) typically develop vascular leak syndrome, resulting in hemoconcentration, hypotension, pulmonary edema, and renal insufficiency. Angiopoietin-1 (Ang-1) and 2 (Ang-2) are autocrine peptides that reduce or increase endothelial permeability, respectively. The aim of this study was to determine whether Ang-1 and/or Ang-2 levels are predictive biomarkers of persistent organ failure (>48 h) and prolonged hospital course., Methods: Banked serum from 28 patients enrolled in the Severity of Acute Pancreatitis Study at the University of Pittsburgh Medical Center (UPMC) and 58 controls was analyzed for Ang-1 and Ang-2 levels. Separately, serum from 123 patients and 103 controls at Greifswald University (GU), Germany was analyzed for Ang-2 levels. Angiopoietin levels were measured by enzyme-linked immunosorbent assay., Results: In all, 6 out of 28 UPMC patients (21%) and 14 out of 123 GU patients (13%) developed persistent organ failure and were classified as severe AP. Ang-2 was significantly higher on admission in patients who developed persistent organ failure compared with those who did not in UPMC (3,698 pg/ml vs. 1,001 pg/ml; P=0.001) and GU (4,945 pg/ml vs. 2,631 pg/ml; P=0.0004) cohorts. After data scaling, admission Ang-2 levels showed a receiver-operator curve of 0.81, sensitivity 90%, and specificity 67% in predicting persistent organ failure. In addition, Ang-2 levels remained significantly higher in severe AP compared with mild AP patients until day 7 (days 2-4: P<0.005; day 7: P<0.02). Ang-1 levels were not significantly different between mild and severe AP patients on admission., Conclusions: Elevated serum Ang-2 levels on admission are associated with and may be a useful biomarker of predicting persistent organ failure and ongoing endothelial cell activation in AP.

Purpose: Endothelial activation has emerged as an early event in the pathogenesis of microcirculatory dysfunction, capillary leakage and multi-organ dysfunction syndrome (MODS). Angiopoietin-2 (Ang-2), a circulating antagonistic ligand of the endothelial-specific Tie2 receptor, has been identified as a non-redundant gatekeeper of endothelial activation. On the basis of our previous report demonstrating release of Ang-2 in endotoxemia and sepsis, we aimed to study the utility of Ang-2 to serve as an outcome-specific biomarker in patients requiring renal replacement therapy (RRT) in the intensive care unit (ICU)., Methods: We measured circulating Ang-2 by ELISA in 117 critically ill patients with AKI at inception of RRT in the ICU. Mortality, length of stay and renal recovery were prospectively assessed during a study period of 28 days after the inception of RRT., Results: Circulating Ang-2 levels were significantly higher in AKI patients with RIFLE category-Injury or -Failure, compared to patients with RIFLE category-Risk. Elevated levels of circulating Ang-2 correlated with impaired oxygenation, low mean arterial pressure, vasopressor dose and the sequential organ failure assessment (SOFA) score. Ang-2 concentrations were significantly higher in non-survivors than in survivors at day 0 and day 14 after initiation of RRT. Multivariate Cox regression and decision tree analyses confirmed a strong independent prognostic impact of elevated Ang-2 as a predictor of 28-day survival., Conclusions: The results from this study indicate that circulating Ang-2 is as a strong and independent predictor of mortality in ICU patients with dialysis-dependent AKI.

Background: Accelerated atherosclerosis in patients with chronic kidney disease (CKD) is still incompletely understood. Angiopoietin 1 (Ang-1) and Ang-2 are 55-kDa antagonistic nonredundant gatekeepers of endothelial activation and thus are potential important factors in accelerated atherosclerosis. We aimed to study: (1) angiopoietin levels in patients treated by means of dialysis and kidney transplantation, (2) the association of altered angiopoietin levels with atherosclerosis, and (3) changes in altered levels after renal transplantation., Study Design: Cross-sectional and longitudinal observational study., Setting & Participants: 117 patients with CKD (61 hemodialysis [HD] patients, 24 peritoneal dialysis [PD] patients, and 32 renal transplant recipients) and 22 healthy controls., Predictor: Treatment by means of HD or PD or renal transplantation versus healthy controls., Outcome: Serum Ang-1 and Ang-2 levels and ratio and changes in levels before and 3 months after transplantation. Correlations of angiopoietin levels with the presence and severity of coronary heart disease and peripheral arterial disease., Measurements: Ang-1 and Ang-2 were measured in sera by using an immunoradiometric sandwich assay and enzyme-linked immunosorbent assay, respectively. Coronary heart disease was scored by using coronary angiography, and peripheral arterial disease, by using ultrasonography., Results: Ang-1 level was decreased in HD patients compared with controls (29.1 +/- 12 versus 45.3 +/- 11.5 ng/mL; P < 0.001). In contrast, Ang-2 level was increased (HD, 8.7 +/- 0.64; PD, 6.48 +/- 8.1 ng/mL versus controls, 0.88 +/- 0.43 ng/mL; P < 0.001). Ang levels in renal transplant recipients were not different from healthy controls. Longitudinally, individual Ang-2 levels decreased after kidney transplantation (P = 0.01). In addition, in patients with CKD, Ang-2 level correlated significantly with scores of coronary heart disease (r = 0.486; P < 0.001) and peripheral arterial disease (r = 0.648; P < 0.001)., Limitations: Cross-sectional study design., Conclusions: Circulating Ang-2 level was increased in patients treated with dialysis, although the mechanism is unknown. Kidney transplantation normalized circulating Ang-2 levels after 3 months. In addition, Ang-2 might be a mediator (and thus a marker) that accounts for accelerated atherosclerosis in dialysis patients.

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.