Elevated Angiopoietin-2 Levels Research Articles

Angiopoietin-2 and D-dimer add prognostic information to clinical risk in pulmonary arterial hypertension

Thrombosis and endothelial injury are pathologic hallmarks of pulmonary arterial hypertension (PAH). We aimed to evaluate whether markers of endothelial dysfunction and coagulation in the blood would provide insight into disease activity, treatment response, and outcomes in PAH. MethodsWe prospectively collected baseline and 3-month follow-up blood samples from treatment-naïve PAH patients (n=22) and those who had a clinical indication to intensify therapy (n=19). In addition, we recruited 12 healthy people and clinically stable PAH patients (n=45) as controls who had two blood samples collected twice within 14 days. We generated platelet-free plasma and measured D-dimer, angiopoietin-2, thrombin time, soluble P-selectin, von Willebrand factor, and vascular endothelial growth factor. We assessed treatment response with Reveal Lite 2 scores (all patients had NT-pro-BNP, 6-minute-walk, and functional class assessment at both visits) and followed clinical outcomes for 3 years. ResultsAngiopoietin-2 levels were elevated and fell with response to effective therapy (drop in Reveal Lite 2 score). At follow-up, persistently elevated angiopoietin-2 levels predicted clinical events and even identified low-risk participants who subsequently had events. D-dimer levels were also elevated in PAH patients but didn’t change in response to therapy. Several other abnormalities in endothelial and platelet activation were identified (including elevated soluble P-selectin, elevated von Willebrand factor, and elevated vascular endothelial growth factor) but these did not change with treatment or predict outcome. ConclusionsAngiopoietin-2 and D-dimer are elevated in PAH patients and may add prognostic information to routine clinical assessment.

Impact of the elevated angiopoietin-2 levels during Impella support on the short-term prognosis.

Elevated serum angiopoietin-2 levels in patients with acute myocardial infarction-related cardiogenic shock with and without intra-aortic balloon pump as well as acute decompensated heart failure are associated with short-term mortality. However, its prognostic impact in patients with cardiogenic shock supported by Impella-incorporated mechanical circulatory support (MCS) remains unknown. Patients who received temporary MCS (Impella alone or Impella and veno-arterial extracorporeal membrane oxygenation) in our institute between August 2018 and January 2022 were included in this prospective study. The serum levels of angiopoietin-2 were measured just before and following the initiation of temporary MCS therapy. Association between the levels of serum angiopoietin-2 and 30-day mortality was investigated. A total of 38 patients (median 72years old, 63% men) were included. The median levels of serum angiopoetin-2 tended to decrease from baseline to 4days following the initiation of temporary MCS from 5.2 (3.3, 10.5)ng/mL to 4.8 (2.7, 6.8)ng/mL (p = 0.132). A higher angiopoietin-2 (> 6.8ng/mL) following the initiation of temporary MCS was associated with higher 30-day mortality (89.7% versus 44.4%, p = 0.0048) with an odds ratio 18.946 (95% confidence interval 1.624-218.695, p = 0.018) adjusted for potential confounders. A higher serum angiopoietin-2 level following the initiation of Impella-incorporated temporary MCS, instead of baseline angiopoetin-2 level, was associated with higher short-term mortality.

Elevated Angiopoietin-2 Levels Correlated with Sepsis Diagnosis in Patients with Stage 5 Chronic Kidney Disease

Introduction: Infection is the second most common cause of death among patients with stage 5 chronic kidney disease undergoing hemodialysis (CKD5D). Sepsis, defined as life-threatening organ dysfunction due to dysregulated host response to infection, accounts for more than three-quarters of all such cases. Sepsis has implications in worsening morbidity and mortality rates for CKD5D patients. Even after sepsis resolution, there are residual pathological and biochemical irregularities caused by infection which result in a diminished quality of life for survivors.Circulating angiopoietin-2 (Ang-2) levels has been reported to be upregulated in a variety of inflammatory conditions, including sepsis and CKD5D. Ang-2 is an angiogenic growth factor implicated in endothelial dysfunction and inflammatory processes. We hypothesize that elevated Ang-2 levels in CKD5D patients will be further amplified in those with a previous history of sepsis. Measuring Ang-2 levels in these conditions may lead to a broader understanding of the pathogenesis of sepsis and its long-term consequences in the CKD5D patient population.Methods: Plasma Ang-2 levels in CKD5D patients (n=97) and normal controls (n=50; George King Bio-Medical, Inc., Overland Park, KS) were measured using the Ang-2 sandwich ELISA (R&D Systems, Minneapolis, MN, USA) method. Of the 38 CKD5D patients who had a past medical history of sepsis, 6 had ongoing sepsis upon the blood draw date, 16 were diagnosed <1 year prior, and 26 were diagnosed <2 years prior. GraphPad Prism v7 was used to perform Mann-Whitney t-tests and Kruskal-Wallis non-parametric ANOVA to compare CKD5D patients with sepsis diagnosis to non-sepsis CKD5D patients.Results: Mean Ang-2 levels were markedly higher in CKD5D patients with a previous sepsis diagnosis at all time intervals (11.55 ± 3.29 ng/mL CKD5D (+)sepsis ongoing, 12.67 ± 2.34 ng/mL CKD5D (+)sepsis <1 year, 11.80 ± 1.51 ng/mL CKD5D (+)sepsis <2 years, 12.14 ± 1.22 ng/mL CKD5D (+)sepsis history) than in CKD5D patients with no sepsis history (9.38 ± 0.74 ng/mL). Mann-Whitney t-tests showed statistical significance when comparing CKD5D patients with no sepsis history to those diagnosed <2 years prior to the blood draw date (p=0.0432), as well as to those with a sepsis diagnosis at any time in their medical history (p=0.0138). In comparison to controls, ANOVA reported significantly elevated Ang-2 levels in CKD5D patients (-)sepsis (p<0.0001), CKD5D (+)sepsis ongoing (p=0.0014), CKD5D (+)sepsis <1 year (p<0.0001), CKD5D (+)sepsis <2 years (p<0.0001), and CKD5D (+)sepsis history (p<0.0001).Conclusion: Circulating Ang-2 levels are upregulated during sepsis and has been correlated to the severity of this disease, as well as mortality. Additionally, Ang-2 levels are raised in CKD5D. This study found a general trend demonstrating Ang-2 levels to be continually elevated in CKD5D patients following a past history of sepsis. Understanding the upregulation of Ang-2 in CKD5D may provide insight into the pathophysiology of sepsis within the CKD5D population, and may be of prognostic value in the management of these patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Markers of angiogenesis and macrophage products for predicting disease course and monitoring vascular inflammation in giant cell arteritis.

ObjectiveGCA, a systemic vasculitis, is characterized by an IL-6-dependent acute-phase response. This response is typically suppressed by treatment rendering CRP/ESR unreliable for monitoring vascular inflammation. Also, there are no accurate biomarkers predicting a non-favourable disease course. Here we investigated macrophage products and markers of angiogenesis as biomarkers for prognosis and monitoring of vascular inflammation.MethodsForty-one newly diagnosed, glucocorticoid-naive GCA patients were prospectively followed for relapses and glucocorticoid requirement for a median of 30 months (range 0–71). Serum markers at baseline and during follow-up were compared with 33 age-matched healthy controls and 13 infection controls. Concentrations of IL-6, serum amyloid A, soluble CD163, calprotectin, YKL-40, VEGF, angiopoietin-1 and -2 and sTie2 were determined by ELISA/Luminex assay.ResultsSerum concentrations of all markers, but not angiopoietin-1, were elevated in GCA patients at baseline when compared with healthy controls. High VEGF (P = 0.0025) and angiopoietin-1 (P = 0.0174) and low YKL-40 (P = 0.0369) levels at baseline were predictive of a short time to glucocorticoid-free remission. Elevated angiopoietin-2 levels were associated with an imminent relapse during treatment (P < 0.05). IL-6 correlated strongly with acute-phase markers and soluble CD163 but not with markers of angiogenesis, YKL-40 or calprotectin. Glucocorticoid treatment down-modulated all markers except for calprotectin and YKL-40. Tissue expression of markers in temporal arteries was confirmed.ConclusionMarkers of angiogenesis at baseline and during treatment predict GCA disease course, suggesting utility in patient stratification for glucocorticoid-sparing therapy. Calprotectin and YKL-40 are candidate markers for monitoring vessel wall inflammation.

Evaluation of Serum Angiopoietin-2 in Children and Adolescents with Sickle Cell Disease

Background: A pro-angiogenic state has been found in adults with sickle cell disease (SCD), mainly because of elevated angiopoietin-2 levels. Aim of the work was to determine the level of Angiopoietin-2 in children and adolecents with SCD and assess its relation to markers of hemolysis and iron overload. Methods: Forty SCD patients in steady state were studied focusing on hydroxyurea therapy, hematological profile and serum ferritin. Patients were compared to 40 healthy controls. Results: Angiopoietin-2 levels were significantly higher in SCD patients compared with healthy controls (8506.3 ± 3789.5 pg/mL versus 2791.7 ± 1263.6 pg/mL; p<0.001). Angiopoietin-2 levels were significantly higher in SCD patients with cardiopulmonary complications. Significant positive correlations were found between serum angiopoietin-2 levels and age as well as HbS. Conclusions: Elevated angiopietin-2 levels in SCD highlights the role of angiogenesis in the pathophysiology of SCD. Angiopoietin-2 may be considered a promising risk marker for screening of SCD patients at risk of cardiopulmonary complications.

Abstract 15880: Angiopoietin 2, a Pro-inflammatory Protein, is Associated With Major Adverse Cardiovascular Events in Patients With Peripheral Arterial Disease

Introduction: Angiopoietin 2 (ANG2) is a pro-inflammatory protein which is elevated in several inflammatory conditions and associated with increased morbidity and mortality. Hypothesis: ANG2 is associated with the composite of death, non-fatal myocardial infarction and non-fatal stroke (MACE) in patients with peripheral arterial disease (PAD). Methods: We measured serum ANG2 levels at baseline in 363 consecutive PAD patients with using multiplex bead array technology. Follow-up was five years. In Cox regression, confounding was evaluated by examining the relative change in coefficients (delta-beta) for ANG2 after the omission of the respective potential confounder from the fully adjusted model. Significant Confounding was defined as a delta-beta &gt; 10%. Results: Using receiver operating characteristics, ANG2 exhibited an area under the curve of 0.6 (95%CI: 0.522 - 0.678) for the proper discrimination between MACE and non-events. A cut-off of 3.74 ng/ml resulted in the highest possible combination of specifity (57.5%) and sensitivity (63.3%) leading to an unadjusted hazard ratio (HR) of 2.17 (95%CI: 1.28 - 3.67) in Cox regression (p=0.004). Adjusting for age, sex, diabetes, systolic blood pressure, smoking status and renal function lead to a HR of 1.89 (95%CI: 1.11 - 3.24) for ANG2 &gt;3.74 ng/ml (p=0.020). The additional adjustment for c-reactive protein (CRP) resulted in a no more significant HR of 1.68 (95%CI: 0.97 - 2.92)for high ANG2 (p=0.067). Diabetes and CRP, both significant predictors of MACE in our cohort, proved to be significant confounders with concomitant delta-betas of 19.7% and 22.9%, respectively. Conclusions: We are the first to demonstrate that elevated ANG2 levels are interrelated with MACE in patients with PAD. Inflammation and glucose hemostasis seem to influence this association.

Circulating Angiopoietin-2 Is a Marker for Early Cardiovascular Disease in Children on Chronic Dialysis

Cardiovascular disease (CVD) is increasingly recognised as a complication of childhood chronic kidney disease (CKD) even in the absence of diabetes and hypertension. We hypothesized that an alteration in angiopoietin-1 and -2, growth factors which regulate endothelial and vascular function could be involved. We report that the endothelial survival factor, angiopoietin-1 is low in children with pre-dialysis CKD whereas the pro-inflammatory angiopoietin-2 is elevated in children on dialysis. In dialysis patients, angiopoietin-2 positively correlated with time on dialysis, systolic blood pressure, and carotid artery intima media thickness. Elevated angiopoietin-2 levels in dialysis versus pre-dialysis CKD patients were also associated with an anti-angiogenic (high soluble VEGFR-1 and low VEGF-A) and pro-inflammatory (high urate, E-selectin, P-selectin and VCAM-1) milieu. Ang-2 was immunodetected in arterial biopsy samples whilst the expression of VEGF-A was significantly downregulated in dialysis patients. Serum urate correlated with angiopoietin-2 levels in dialysis patients and addition of uric acid was able to induce rapid release of angiopoietin-2 from cultured endothelial cells. Thus, angiopoietin-2 is a marker for cardiovascular disease in children on chronic dialysis and may act as an anti-angiogenic and pro-inflammatory effector in this context. The possibility that the release of angiopoietin-2 from endothelia is mediated by urate should be explored further.

Focusing on the Flood

Focusing on the Flood

Promoter variant of angiopoietin-2 and plasma angiopoietin-2 are associated with risk of stroke recurrence in lacunar infarct patients

Angiopoietin-2 has been reported to regulate the inflammation process, which is associated with recurrence of stroke. The purpose of this study was to test the hypothesis that plasma levels of angiopoietin-2 and variants of angiopoietin-2 will confer risk of stroke recurrence. The association of plasma angiopoietin-2 (determined by using ELISA) and the variants in angiopoietin-2 promoter with stroke recurrence was tested in 1735 patients with stroke of three subtypes, lacunar infarct (n=475), atherothrombotic (n=794) and hemorrhage (n=466), for a period of following-up 4.5years (mean), the association was evaluated by using Kaplan–Meier analysis and the Cox regression models. We found that angiopoietin-2 levels were associated with risk of stroke recurrence in lacunar infarct patients. Taking the lowest quartile as reference, the adjusted hazard ratio (HR) and 95% confidence intervals (CI) for stroke recurrence was 1.48 (0.74–2.95) for the second quartile, 2.56 (1.35–4.86) for the third and 2.15 (1.11–4.17) for the fourth. Allele T of rs3739391 in angiopoietin-2 promoter was associated with elevated angiopoietin-2 levels and increased risk of stroke recurrence in patients with lacunar infarct with HR 1.67 (1.06–2.63) relative to the allele C, but neither in those with atherothrombotic nor in those with hemorrhagic stroke. Our results indicate that both angiopoietin-2 and allele T of rs3739391 might be the risk marker for stroke recurrence in the patients with lacunar infarction. These findings may help to improve future prevention or therapy strategies for stroke. Even some conventional risk factors have been identified responsible for stroke recurrence, but these factors could not fully explain all the recurrent stroke events. Our study opens a new page for the first time that angiopoietin/tie2 pathway has a potential role in lacunar stroke recurrence. Since several strategies are available for blocking or neutralizing plasma angiopoietin-2, especially eicosapentaenoic acid rich in sea food. Our finding obviously has its clinical implication if it was proved by large, prospective clinical studies.

Abstract 5499: Promoter Variant of Angiopoietin-2 and Plasma Angiopoietin-2 Are Associated With Risk of Stroke Recurrence in Patient With Lacunar Infarction

Background- Risk factors for stroke recurrence are still not fully defined. Angiopoietin-2 is a very important mediator in the vessel development and repair. We hypothesized that altered expression of angiopoietin-2 will confer risk of stroke recurrence. Methods - The association of plasma angiopoietin-2 (determined by using ELISA) and the variants in angiopoietin-2 promoter with stroke recurrence was tested in 1735 patients with stroke of three subtypes, lacunar infarct (n=475), atherothrombotic (n=794) and hemorrhage (n=466), for a period of following-up 4.5 years (mean), the association was evaluated by using Kaplan-Meier analysis and the Cox regression models. Results -We found that angiopoietin-2 levels were associated with risk of stroke recurrence in lacunar infarct patients. Taking the lowest quartile as reference, the adjusted hazard ratio (HR) and 95% confidence intervals (CI) for stroke recurrence was 1.47 (0.75–2.88) for the second quartile, 2.44 (1.31–4.56) for the third and 2.00 (1.05–3.85) for the fourth. Allele T of rs3739391 in angiopoietin-2 promoter was associated with elevated angiopoietin-2 levels and increased risk of stroke recurrence in patients with lacunar infarct with HR 1.72 (1.09–2.72) relative to the allele C, but neither in those with atherothrombotic nor in those with hemorrhagic stroke. Conclusion- Our results indicate that both angiopoietin-2 and allele T of rs3739391 might be the risk marker for stroke recurrence in the patients with lacunar infarction. These findings may help to improve future prevention or therapy strategies for stroke.

ANGIOPOIETIN-2, A REGULATOR OF VASCULAR PERMEABILITY IN INFLAMMATION IS ELEVATED IN SEVERE ACUTE PANCREATITIS AND IS ASSOCIATED WITH SYSTEMIC ORGAN FAILURE

Background: A major complication of severe acute pancreatitis is the vascular leak syndrome, which can result in intravascular volume depletion and adult respiratory distress syndrome. Angiopoietin-2 is an endothelial cell autocrine peptide, released by local injury and leading to destabilization of endothelial cells with increased vascular permeability. Aim: To assess serum levels of Angiopoietin-2 in patients with AP and their role as predictor of disease severity. Methods: A cohort of 185 patients with acute pancreatitis was prospectively enrolled between June 2003 and September 2007. Demographic information, clinical features, DNA and daily serum samples were collected. Patients were classified into mild (79%) and severe acute pancreatitis (21%) based on the presence of organ failure. Angiopoietin-2 levels were measured in previously frozen serum samples from patients on days 2-7 from onset of pain and controls. Angiopoietin-2 levels were compared with clinical outcomes using Naïve Bayes and logistic ridge regression to generate statistical models predicting disease severity. Results: Angiopoietin-2 levels were measured in 93 patient serum samples on Days 2-7 and 58 controls. Angiopoietin-2 levels were significantly higher in patients with severe acute pancreatitis compared to mild acute pancreatitis and control subjects on all days. Using logistic ridge regression the highest accuracy was on day 2 (84%) with an area under the curve of 0.76 as a predictive statistical model for disease severity. Conclusions: In AP significantly elevated angiopoietin-2 levels are strongly associated with organ failure and disease severity. Angiopoietin-2 levels early in the course of the disease appear to accurately predict a severe course.