Ang-2 Levels Research Articles

Sex-specific microRNAs in women with diabetes and left ventricular diastolic dysfunction or HFpEF associate with microvascular injury

Left ventricular diastolic dysfunction (LVDD) and heart failure with preserved ejection fraction (HFpEF) are microcirculation defects following diabetes mellitus (DM). Unrecognized HFpEF is more prevalent in women with diabetes compared to men with diabetes and therefore sex-specific diagnostic strategies are needed. Previously, we demonstrated altered plasma miRs in DM patients with microvascular injury [defined by elevated plasma Angiopoietin-2 (Ang-2) levels]. This study hypothesized the presence of sex-differences in plasma miRs and Ang-2 in diabetic (female) patients with LVDD or HFpEF. After a pilot study, we assessed 16 plasma miRs in patients with LVDD (n = 122), controls (n = 244) and female diabetic patients (n = 10). Subsequently, among these miRs we selected and measured plasma miR-34a, -224 and -452 in diabetic HFpEF patients (n = 53) and controls (n = 52). In LVDD patients, miR-34a associated with Ang-2 levels (R2 0.04, R = 0.21, p = 0.001, 95% CI 0.103–0.312), with plasma levels being diminished in patients with DM, while women with an eGFR < 60 ml/min and LVDD had lower levels of miR-34a, -224 and -452 compared to women without an eGFR < 60 ml/min without LVDD. In diabetic HFpEF women (n = 28), plasma Ang-2 levels and the X-chromosome located miR-224/452 cluster increased compared to men. We conclude that plasma miR-34a, -224 and -452 display an association with the microvascular injury marker Ang-2 and are particularly targeted to women with LVDD or HFpEF.

Novel biomarkers of bronchopulmonary dysplasia and bronchopulmonary dysplasia-associated pulmonary hypertension.

ObjectiveTo quantify and compare levels of potential biomarkers in neonates with i) Bronchopulmonary dysplasia (BPD); ii) BPD-associated pulmonary hypertension (BPD-PH); iii) PH without BPD; and iv) neonates without lung disease at ~36 weeks postmenstrual age.Study DesignMultiple potential biomarkers were measured in plasma samples of 90 patients using a multi-spot enzyme-linked immunosorbent assay. Statistical tests done included one-way ANOVA to compare levels of biomarkers between different groups.ResultsHigher levels of ICAM-1 were present in infants with BPD and correlated with its severity. Infants with BPD have significantly higher levels of ANG-2 and lower levels of ANG-1. Infants with PH have higher levels of: IL-6, IL-8, IL-10, and TNF-α. Infants with BPD-PH, have significantly lower levels of MCP-1 and higher levels of IL-1β than in infants with PH without BPD.ConclusionICAM-1 may be used as a specific biomarker for diagnosis of BPD and its severity.

Shared changes in angiogenic factors across gastrointestinal vascular conditions: A pilot study.

BACKGROUNDNeovascularisation is common to a variety of gastrointestinal (GI) disorders with differing aetiologies and presentations; usually affecting adults above 60 years. Shared angiogenic factors modulated by disease specific elements could be a common denominator and represent novel diagnostic and therapeutic targets. As yet, assessment of angiogenic factors across several GI vascular disorders associated with recurrent bleeding and anaemia has not been reported.AIMTo assess serum levels of angiogenic factors in several intestinal vascular disorders.METHODSA case control study was performed in Tallaght University Hospital in patients with endoscopically proven small bowel angiodysplasia (SBA), portal hypertensive gastropathy (PHG), gastric antral vascular ectasia (GAVE) and non-bleeding, non-anaemic controls. Using enzyme-linked immunosorbent assay, concentrations of Angiopoietin 1 (Ang-1), Ang-2 and vascular endothelial growth factor (VEGF) were measured from 2 serum tubes of blood following informed consent. The relative expression of Ang-1 and Ang-2 and Ang-1/2 ratio was calculated and compared between groups. Statistical analysis was applied using a t-test, and a P value of < 0.05 was considered significant.RESULTSTo date 44 samples were tested: 10 SBA, 11 PHG, 8 GAVE and 15 controls. Mean age 60 (range 20-85) years and 20 (45%) were males. Controls were significantly younger (49 years vs 66 years, P = 0.0005). There was no difference in VEGF levels between the groups (P = 0.6). SBA, PHG and GAVE Ang-1 levels were similar and were significantly lower than controls, (P = 0.0002, 95%CI: 241 to 701). Ang-2 levels were statistically higher in PHG and GAVE groups compared to controls (P = 0.01, 95%CI: 77.8 to 668) and as a result, also had a lower Ang-1/2 ratios compared to controls. While SBA Ang-2 levels were higher than controls, this did not reach statistical significance. Neither age nor haemoglobin level, which was similar between disease groups, could explain the difference. In addition, the median Ang-1/Ang-2 ratio for all patients was found to be significantly lower compared to controls, 8 vs 28 respectively, P = 0.001, 95%CI: -27.55 to -7.12.CONCLUSIONOur novel pilot study suggests common alterations in Ang-1 and Ang-2 levels across several GI vascular disorders. Differences in Ang-1/Ang-2 ratios among vascular disorders compared to controls suggest disease-specific modulation.

Significance of Serum Angiopoietin-2 in Patients with Hemorrhage in Adult-Onset Moyamoya Disease.

Background Moyamoya disease (MMD) is a progressive occlusive cerebrovascular disease that is characterized by abnormal angiogenesis at the base of the brain. This pathological abnormal angiogenesis is susceptible to disturbances, including spontaneous hemorrhage and vasogenic edema. However, the underlying mechanisms of pathological angiogenesis and occurrence of hemorrhage are unclear. Angiopoietins play a fundamental role in the pathophysiology of central nervous system disorders in angiogenesis. This study was aimed at examining whether angiopoietins are associated with formation of abnormal collateral vessels and the occurrence of hemorrhage in adult-onset moyamoya disease (HMMD). Methods A total of 27 consecutive adult patients with HMMD were enrolled from June 2011 to May 2017. Serum levels of angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) were examined by enzyme-linked immunosorbent assay. Patients with HMMD were compared with those with spontaneous hemorrhage (controls) and nonhemorrhagic-onset MMD (NHMMD). Results Serum Ang-2 levels were significantly higher in patients with adult HMMD than in those with spontaneous hemorrhage and NHMMD. The ROC curve identified that a baseline serum Ang-2 level > 1230 ng/ml may be associated with adult HMMD with 88.39% sensitivity and 70.37% specificity (area under the curve (AUC), 0.89; 95% CI, 0.808-0.973; P < 0.001). Moreover, serum Ang-2 levels were significantly elevated in stages II, III, and IV. In subgroup analysis of a high and low degree of moyamoya vessels, serum Ang-2 levels were significantly higher in the high moyamoya vessel group than in the low moyamoya vessel group. Serum Ang-2 levels were also significantly higher in the low moyamoya vessel group compared with the control group. Serum Ang-1 levels were not significantly different among the groups. Conclusion Increased serum Ang-2 levels may contribute to pathological abnormal angiogenesis and/or to the instability of vascular structure and function, thus causing brain hemorrhage in adult HMMD.

Relationship between 3D Power Doppler Ultrasound and Serum MMP-2 and Ang-2 Levels in Pregnant Women with Preeclampsia.

To explore the relationship between 3D power Doppler ultrasound (3D-PDU) and serum MMP-2 and Ang-2 levels in pregnant women with preeclampsia (PE). Comparative analytical study. The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, China, from October 2017 to January 2020. One hundred and thirty-four pregnant women with PE were selected as the research subjects, with 67 cases in mild group and 67 cases in severe group. Sixty-seven healthy primigravidas were selected as normal control group. Serum MMP-2 and Ang-2 were detected. All subjects underwent prenatal 3D-PDU examination, and VI, FI and VFI were measured. Compared to normal control group, serum MMP-2 and Ang-2 levels of mild group and severe group decreased successively (all p <0.001); VI, FI, and VFI of mild group and severe group decreased successively (both p <0.001). Pearson correlation analysis showed that serum MMP-2 in pregnant women with PE was positively correlated with VI, FI, VFI (r = 0.940, p <0.001, r = 0.938, p <0.001, and r = 0.921, p <0.001, respectively); and serum Ang-2 was positively correlated with VI, FI, VFI (r = 0.958, p <0.001; r = 0.960; p <0.001; r = 0.945, p <0.001, respectively). 3D-PDU has a certain application value in the diagnosis of pregnant women with PE, variation tendency of VI, FI and VFI detected by 3D-PDU is closely associated with serum MMP-2 and Ang-2 levels. Key Words: Preeclampsia, Pregnant women, MMP-2, Ang-2, 3D power Doppler ultrasound (3D-PDU).

SAT481 - Early changes in circulating FGF19 and ANG-2 levels as a possible predictive biomarker for lenvatinib therapy in hepatocellular carcinoma

SAT481 - Early changes in circulating FGF19 and ANG-2 levels as a possible predictive biomarker for lenvatinib therapy in hepatocellular carcinoma

Significance of high mobility group box 1, von Willebrand factor and other cytokines in the evaluation of severity and prognosis of sepsis patients

To explore the value of high mobility group box 1 (HMGB1), von Willebrand factor (vWF) and other cytokines in predicting the severity and prognosis of sepsis patients. Patients with sepsis and septic shock who ≥ 18 years old and met the Sepsis-3 diagnostic criteria admitted to the department of critical care medicine of Binzhou Medical University Hospital from January to June 2019 were taken as the research objects. The healthy individuals for regular health examination in the same period were taken as the control. The basic information, acute physiology and chronic health evaluation II (APACHE II) and sequential organ failure assessment (SOFA) scores were recorded. The venous blood was taken within 24 hours after the patients were diagnosed. The levels of HMGB1, vWF, tumour necrosis factor-α (TNF-α), interleukin-10 (IL-10), soluble thrombomodulin (sTM), vascular endothelial growth factor receptor 2 (VEGFR-2), angiopoetin-2 (Ang-2) and other cytokines in serum were determined by enzyme linked immunosorbent assay (ELISA). Differences among patients with sepsis, septic shock, healthy physical examinees, and patients who died in 28-day and those who survived, were compared. Spearman rank correlation method was used to analyze the correlation among each cytokine and APACHE II, SOFA scores. The receiver operating characteristic (ROC) curve was drawn to evaluate the predictive value of cytokines on the prognosis of patients with sepsis/septic shock. Logistic regression was used to analyze the risk factors of 28-day death. Eleven patients with sepsis, 25 patients with septic shock and 30 healthy individuals were enrolled. Among the patients with sepsis/septic shock, 15 died in 28-day and 21 survived. The serum levels of TNF-α, IL-10, HMGB1, vWF, sTM and VEGFR-2 in patients with sepsis were significantly higher than those in the healthy control group. The levels of TNF-α, IL-10, HMGB1, vWF, sTM in septic shock group were higher than those in the sepsis group, while the Ang-2 level decreased significantly. The serum levels of TNF-α, IL-10, HMGB1, vWF and sTM in the death group were higher than those in the survival group, while Ang-2 was lower than the survival group. Spearman correlation analysis showed that HMGB1, TNF-α, sTM, IL-10, vWF were positively correlated with APACHE II score when patients with sepsis/septic shock were enrolled (r values were 0.652, 0.666, 0.445, 0.430 and 0.355, respectively, all P < 0.05), and HMGB1, TNF-α also positively correlated with SOFA score (r values were 0.433, 0.479, both P < 0.05). Ang-2 was negatively correlated with APACHE II and SOFA scores (r values were -0.519, -0.440, both P < 0.05). ROC curve analysis showed that the predictive value of HMGB1, vWF, IL-10, sTM for 28-day death in patients with sepsis/septic shock were higher than the APACHE II score [the area under ROC curve (AUC) and 95% confidence interval (95%CI): 0.946 (0.870-1.000), 0.902 (0.790-1.000), 0.877 (0.745-1.000), 0.868 (0.734-1.000) vs. 0.846 (0.700-0.991)]. Logistic regression analysis showed that APACHE II score, vWF, sTM, and IL-10 were independent risk factors for 28-day death in patients with sepsis/septic shock (β values were 4.731, 0.407, -7.058, -0.887, all P < 0.05). HMGB1, vWF, IL-10, sTM and other cytokines all can be used to evaluate the severity and prognosis of sepsis patients.

Dysregulation of angiopoietin-Tie-2 axis in ugandan children hospitalized with pneumonia

ObjectivePneumonia is the leading cause of death in children under 5, with the highest burden in resource-limited countries. Endothelial activation occurs in pneumonia and can be assessed using quantitative levels of biomarkers angiopoietin (Ang)-1 and Ang-2. We examined admission levels of Ang-1 and Ang-2 in pediatric pneumonia and their association with disease severity and outcome. MethodsProspective cohort study of children with hypoxemic pneumonia admitted to two hospitals in Uganda. Clinical, radiographic, and microbiologic characteristics were measured at admission. Disease severity was assessed using the Respiratory Index of Severity in Children (RISC). Plasma levels of Ang-1 and Ang-2 were quantified by enzyme-linked immunosorbent assay. Vital signs, oxygen supplementation, and mortality were assessed prospectively. ResultsWe included 65 patients (43% female) with median age 19 months (IQR 8–24). Admission Ang-2/Ang-1 ratio directly correlated with RISC (ρ = 0.32, p = 0.008) and lactate level (ρ = 0.48, p < 0.001). Ang-2/Ang-1 ratio was higher in pneumococcal pneumonia than viral RTI (0.19 [IQR: 0.076–0.54] vs. 0.078 [IQR: 0.027–0.11]; p = 0.03). Elevated Ang-2/Ang-1 ratio (>0.084) was associated with prolonged tachypnea (HR 0.50 (95%CI 0.29–0.87), p = 0.02), fever (HR 0.56 (95%CI 0.33 to 0.96), p = 0.02), longer duration of oxygen therapy (HR 0.59 (95%CI 0.35–0.99), p = 0.04), and hospital stay (HR 0.43 (95%CI 0.25–0.74), p = 0.001). The Ang-2/Ang-1 ratio at admission was higher in fatal cases relative to survivors (0.36 [IQR: 0.17–0.58] vs. 0.077 [IQR: 0.025–0.19]; p = 0.05) ConclusionEndothelial activation in hypoxemic pediatric pneumonia, reflected by high plasma Ang-2/Ang-1 ratio, is associated with disease severity, prolonged recovery time, and mortality.

The tumour microenvironment of the upper and lower gastrointestinal tract differentially influences dendritic cell maturation

BackgroundOnly 10–30% of oesophageal and rectal adenocarcinoma patients treated with neoadjuvant chemoradiotherapy have a complete pathological response. Inflammatory and angiogenic mediators in the tumour microenvironment (TME) may enable evasion of anti-tumour immune responses.MethodsThe TME influence on infiltrating dendritic cells (DCs) was modelled by treating immature monocyte-derived DCs with Tumour Conditioned Media (TCM) from distinct gastrointestinal sites, prior to LPS-induced maturation.ResultsCell line conditioned media from gastrointestinal cell lines inhibited LPS-induced DC markers and TNF-α secretion. TCM generated from human tumour biopsies from oesophageal, rectal and colonic adenocarcinoma induced different effects on LPS-induced DC markers - CD54, CD80, HLA-DR, CD86 and CD83 were enhanced by oesophageal cancer; CD80, CD86 and CD83 were enhanced by rectal cancer, whereas CD54, HLA-DR, CD86, CD83 and PD-L1 were inhibited by colonic cancer. Notably, TCM from all GI cancer types inhibited TNF-α secretion. Additionally, TCM from irradiated biopsies inhibited DC markers. Profiling the TCM showed that IL-2 levels positively correlated with maturation marker CD54, while Ang-2 and bFGF levels negatively correlated with CD54.ConclusionThis study identifies that there are differences in DC maturational capacity induced by the TME of distinct gastrointestinal cancers. This could potentially have implications for anti-tumour immunity and response to radiotherapy.

Higher serum angiopoietin 2 levels are independently associated with coronary microvascular dysfunction in patients with angina in the absence of obstructive coronary artery disease.

BackgroundAngiopoietin-2 (Ang-2) is a type of endothelial growth factor involved in angiogenesis and vascular remodeling. Circulating Ang-2 levels are elevated in patients with obstructive coronary artery disease (CAD). This study aimed to evaluate the association between serum Ang-2 levels and coronary microvascular dysfunction in patients without obstructive CAD.MethodsA total of 125 patients with angina in the absence of obstructive CAD were included in this cross-sectional study. Coronary flow reserve (CFR) was measured in the distal left anterior descending coronary artery by trans-thoracic Doppler echocardiography. The patients were divided into the following two sub-groups according to CFR: the impaired CFR group with CFR values <2.5 and the preserved CFR group with CFR values ≥2.5. Serum Ang-2 levels were determined using enzyme-linked immunosorbent assay. Independent predictors for impaired CFR were identified by binary logistic regression analysis. The receiver-operating characteristic curve was determined to evaluate the ability of serum Ang-2 in predicting impaired CFR.ResultsWe found that age, percentage of female sex, N-terminal pro-B-type natriuretic peptide levels, Ang-2 levels (763.3 ± 264.9 vs. 579.7 ± 169.3 pg/mL, P < 0.001), and the left atrial volume index were significantly higher in patients with impaired CFR than in patients with preserved CFR. Serum Ang-2 levels were negatively correlated with CFR (r = −0.386, P < 0.001). Binary logistic regression analysis showed that Ang-2 (odds ratio: 1.004, 95% confidence interval [CI]: 1.001–1.006, P = 0.003) and age (odds ratio: 1.088, 95% CI: 1.023–1.156, P = 0.007) were independently associated with impaired CFR. Furthermore, Ang-2 was a significant predictor of impaired CFR on the receiver-operating characteristic curve (P < 0.001). The area under the curve was 0.712 (95% CI: 0.612–0.813).ConclusionsHigh serum Ang-2 levels are independently associated with impaired CFR in patients with angina in the absence of obstructive CAD.

Quantification of angiogenic factors and their clinicopathological associations in breast cancer.

Breast cancer (BC) is one of the top three common cancers in women, responsible for nearly one-third of all new cancer diagnoses. Angiogenesis plays a crucial role in BC progression. In this study, we aimed to measure the serum concentrations of eight angiogenic factors in BC patients and healthy controls and to assess their correlation with clinicopathological variables. In a case-control study, 62 pathologically confirmed BC patients as well as 54 age-matched controls were recruited. A bead-based immunoassay was used to measure serum levels of VEGF-A, ANG-2, PDGF-AA, PDGF-BB, EGF, TGF-α, HGF, and bFGF. We observed a significant elevation in serum levels of VEGF-A, EGF, and PDGF-AA in BC patients compared with the controls (P < 0.05). Patients with grade III had higher ANG-2 levels compared with those with grades I (P = 0.007) and II of the disease (P = 0.003). In addition, estrogen-positive and progesterone-positive BC patients had higher levels of TGF-α (P < 0.05). The significant elevation of VEGF-A, EGF, and PDGF-AA serum levels in BC patients suggests these cytokines might have diagnostic value as potential biomarkers in BC. Further large-scale studies are needed to generalize these results to all BC patients.

Angiopoietin-2 regulated by progesterone induces uterine vascular remodeling during pregnancy.

During pregnancy, the uterus undergoes intense neovascularization and vascular remodeling to supply oxygen and nutrients to the embryo. During this period, progesterone secreted from the ovary has effects on vascular remodeling in the endometrium and interacts with angiogenic factors. However, the exact mechanism of uterine vascular remodeling during pregnancy is poorly understood. Therefore, the aim of the present study was to investigate the association between angiopoietin-2 (Ang-2), one of the angiopoietins, and intrauterine vessel remodeling during pregnancy, and to determine the effect of progesterone on Ang-2 levels. Changes in Ang-2 expression were observed according to quantitative modification of progesterone using pregnant mice and human uterine microvascular endothelial cells. As a result, Ang-2 was observed mainly in the mesometrial region (MR) of the uterus during the period between implantation and placentation. Furthermore, a substantial amount of Ang-2 also appeared in endothelial cells, particularly of the venous sinus region (VSR). Interestingly, Ang-2 expression was increased by progesterone, whereas estrogen had limited effects. To confirm the association between Ang-2 and progesterone, the function of the progesterone receptor (PR) was inhibited using RU486, a blocker of PR. Ang-2 expression and vascular remodeling of the VSR in the uterus were decreased when the functions of progesterone were inhibited. Overall, the regulation of Ang-2 by progesterone/PR was associated with vascular remodeling in the VSR during pregnancy. The present study proposed a solution to prevent pregnancy failure due to a lack of vascularity in the uterus in advance.

Effect of cryoprecipitate on neoangiogenesis in patients with purulent pyelonephritis

The aim of the study is to investigate the effectiveness of conservative therapy with the inclusion of cryoprecipitate in its composition and its effect on the angiogenesis of renal blood vessels in patients with purulent pyelonephritis.&#x0D; Materials and methods. The study included 30 patients aged from 20 to 45 years (6 men, 24 women) with acute purulent pyelonephritis. All patients were assessed for markers of angiogenesis in blood plasma: vascular endothelial growth factor (VEGF-A), angiopoietin 1 (Ang1) and angiopoietin 2 (Ang2). The patients were divided into two groups. Patients of group 1 (n = 15) received conservative therapy with the inclusion of cryoprecipitate, patients of group 2 (n = 15) received surgical treatment. The control group consisted of 10 healthy donors aged 2035 years, whose blood angiogenesis markers were determined to obtain reference values.&#x0D; Results. In the course of preliminary studies, the blood content of angiogenesis markers was determined in 10 healthy donors. The level of VEGF-A in patients of both groups and the level of Ang1 in patients of group 1 at admission to the hospital significantly exceeded the corresponding values in the control group. In group 2 patients, the level of VEGF-A and Ang1 remained elevated during treatment, which indirectly indicated an ongoing inflammatory process. The level of Ang2 in patients of both groups did not change significantly. Conservative treatment of group 1 patients showed high efficiency, which was confirmed by positive dynamics of clinical and laboratory indicators, as well as data from instrumental examination.&#x0D; Conclusions. The results obtained indicate the effectiveness of conservative therapy with the administration of cryoprecipitate in patients with purulent pyelonephritis, and the effectiveness of such treatment is comparable to the effectiveness of surgical treatment . The use of cryoprecipitate has an endothelioprotective and anti-inflammatory effect on blood vessels, stabilizes the processes of angiogenesis, which contributes to limiting the inflammatory process and its regression.

Digoxin Treatment Reverses Angiogenic Switch during HeartMate 3 Support and is Associated with Decrease Risk for Gastrointestinal Bleeding

Gastrointestinal bleeding (GIB) in LVAD patients is most commonly caused by gastrointestinal angiodysplasia (GIAD). Non-pulsatile blood flow in LVAD patients can cause splanchnic submucosal hypoperfusion and hypoxia leading to activation of a HIF1-α /Angiopoietins (Ang) signaling cascade, that can trigger pathological angiogenesis. We have recently shown that the use of digoxin, a potent inhibitor of HIF1-α, is associated with a significant reduction in GIAD related GIB in HeartMate (HM) II and HeartWare HVAD patients. However, HM3 support is associated with less GIB then previous generation pumps. We now hypothesize that dysregulation of Ang-1 and Ang-2 levels in patients with HM3 can be restored by digoxin treatment and may contribute to decreased incidence of GIB. We have collected blood samples from 7 patients supported with HM3 before and after two weeks of digoxin therapy (0.125 mg daily). Ang-1 and Ang-2 levels were measured in patients' serum by ELISA. In single-center retrospective study, charts of all patients implanted with HM3 between June 2015 and October 2019 were reviewed with emphasis on the occurrence of GIB and digoxin therapy. Pearson's chi-squared test was used to assess the frequency of overall GIB and their association with digoxin therapy. Digoxin treatment in HM3 patients increased Ang-1 (11.5 to 30.7 ng/ml, p=0.02), and decreased Ang-2 levels (14.9 to 9.4 ng/ml, p=0.04), reversing angiogenic switch. Seven of 72 patients (10%) supported by HM3 during median observation time (236, IQR76-620) days experienced a GIB. We identified 38 patients treated and 34 not treated with digoxin (age 52.38 vs. 52.65, p=0.97). The frequency of GIB was significantly lower in the patients receiving compared to the ones not receiving digoxin (3% vs. 17% p=0.03; Fig.1), respectively. Digoxin, an inhibitor of HIF1-α signaling cascade, may contribute to a lower risk of GIB in HM3 patients by restoring angiogenic equilibrium.

Dysregulation of the Angiopoietin-2/Tie-2 Axis is Associated with Reduced Pulsatility and Increased Arteriovenous Malformation Related Gastrointestinal Bleeding Following Left Ventricular Assist Device Implantation

Recent studies have suggested arteriovenous malformation related gastrointestinal bleeding (AVM-GIB) after left ventricular assist device (LVAD) implantation is associated with reduced arterial pulsatility and right heart failure. Angiopoietin-2 (Ang-2) is elevated among patients on LVAD support, and in concert with abnormal expression of vascular endothelial growth factor (VEGF), binding of Ang-2 to the Tie-2 receptor contributes to abnormal angiogenesis and post-LVAD GIB. The purpose of this study was to evaluate the association between Ang-2, Tie-2, and VEGF with AVM-GIB and its clinical associates. We evaluated 65 patients who underwent LVAD implantation at Loyola University Medical Center. Blood samples were obtained at a median follow up of 13 (interquartile range 1.7-31.5) months following LVAD implantation. A total of 19 (29%) patients developed AVM-GIB. Patients with AVM-GIB were older at the time of LVAD implantation (63±10 vs. 53±15 years; p=0.048), but the groups were otherwise balanced in baseline characteristics. Patients with AVM-GIB had increased levels of Ang-2 (8169±4.471 vs. 6560±397 pg/mL; p=0.02) and Tie-2 (20.0±3.3 vs. 17.3±4.0 ng/mL; p=0.07) without a difference in VEGF (200.5±183.3 vs. 216.6±220 pg/mL; p=0.7). Patients whose aortic valve opened less than 80% of cardiac cycles had significantly higher levels of Ang-2 (7948±4226 vs 5566±3691 pg/mL; p=0.02) and Tie-2 (19.6±4.5 vs. 16.3±3.2 ng/mL; p=0.001). There was no association between the evaluated biomarkers and other demographic or clinical characteristics including invasive and noninvasive hemodynamics. Our study suggests that dysregulation of the Ang-2/Tie-2 axis among LVAD patients is associated with AVM-GIB. Further, we find that reduced pulsatility is associated with elevations of Ang-2 and Tie-2, providing a possible mechanism for the link between reduced pulsatility and GIB. Whether hemodynamic optimization with ramp studies could reduce Ang-2 and AVM-GIB is a subject of our ongoing research.

High Levels of Serum Angiopoietin 2 and Angiopoietin 2/1 Ratio at the Critical Stage of Dengue Hemorrhagic Fever in Patients and Association with Clinical and Biochemical Parameters.

Longitudinal changes of serum angiopoietin 1 (Ang-1) and angiopoietin 2 (Ang-2) associated with endothelial stability in dengue patients with different disease stages were studied. Serum Ang-1 and Ang-2 levels were measured in confirmed dengue fever (DF) patients on admission (DFA, n = 40) and discharge (DFD, n = 20); in dengue hemorrhagic fever (DHF) patients on admission (DHFA, n = 40), at critical stage (DHFC, n = 36), and on discharge (DHFD, n = 20); and in healthy controls (HC, n = 25). DHFC had the highest serum Ang-2 and lowest Ang-1 levels compared to DFA, DHFA, and HC (P < 0.050). The ratio of serum Ang-2/Ang-1 in DHFC was the highest among all study categories tested (P < 0.001). Significant positive correlations were observed between serum Ang-1 and platelet count in DHFA (Pearson r = 0.653, P < 0.001) and between Ang-1 and pulse pressure in DHFC (r = 0.636, P = 0.001). Using a cutoff value of 1.01 for the Ang-2/Ang-1 ratio for DHFC, a sensitivity of 83.2% and a specificity of 81.2% discerning DF from DHF were obtained. Therefore, serum Ang-2/Ang-1 could be used as a biomarker for endothelial dysfunction in severe dengue at the critical stage.

Angiopoietin-2 Is an Early Predictor for Acute Gastrointestinal Injury and Intestinal Barrier Dysfunction in Patients with Acute Pancreatitis.

Angiopoietin-2 (Ang-2) is a new predictor for acute pancreatitis (AP). To assess the predictive value of Ang-2 in determining the progress of AP and the subsequent acute gastrointestinal injury (AGI). This was a prospective study that enrolled 170 patients with AP and 100 healthy controls. Blood samples were collected within 24h of the onset of AP. The majority (108) of the patients were categorized as having MAP with the rest (62) classified as suffering from SAP. Considering AGI grading, there were 118 grade 1 and 12 grade 4 patients; in grades 2 and 3, there were 20 patients each. AP was accompanied by MODS and pancreatic necrosis in 46 and 24 cases, respectively. Eighty patients were admitted to the ICU, while mortality was reported among 7.1% patients. The plasma Ang-2 levels were higher among patients with AP than in controls. A similar trend prevailed, in patients with SAP compared to those with MAP. Ang-2 was significantly increased from AGI grade 1 through to grade 4, showing a desirable positive predictive accuracy. Moreover, Ang-2 also showed strong correlations with intestinal permeability as evaluated by d-lactate (DLA), diamine oxidase (DAO), and intestinal fatty acid binding proteins (I-FABPs). Tools (Ranson and APACHE II scores, CRP), which are used more conventionally, could not effectively distinguish the various grades of AGI. Furthermore, Ang-2 predicted poor prognosis and adverse outcomes, including mortality, among patients with AP. This study showed Ang-2 to be an accurate early predictor for SAP, AGI, and intestinal barrier dysfunction, outperforming conventional biomarkers. Ang-2 levels also predicted the adverse outcomes and mortality due to AP.

Association between serum angiopoietin-2 concentrations and periprocedural myocardial injury in patients undergoing elective percutaneous coronary intervention.

Angiopoietin-2 (Ang-2) is a proangiogenic factor that mediates inflammation and atherosclerosis. We evaluated the predictive value of circulating Ang-2 levels for periprocedural myocardial injury (PMI) in 145 patients undergoing elective percutaneous coronary intervention (PCI), and investigated whether post-PCI Ang-2 levels are influenced by PMI. PMI was defined as a post-procedural troponin elevation above the 5×99th percentile upper reference limit. Blood samples for Ang-2 analysis were collected at admission and on postoperative days 1 and 3. PMI occurred in 40 patients (28%). At baseline, there was no difference in Ang-2 levels between PMI and non-PMI patients (P=0.554). However, a significant interaction effect between PMI occurrence and time on Ang-2 levels was observed (interaction P=0.036). Although serum Ang-2 levels in non-PMI patients gradually decreased, Ang-2 levels in PMI patients did not change between different time-points. Multiple logistic regression analysis revealed that age, total stent length, and serum levels of N-terminal pro-brain natriuretic peptide were independent PMI predictors. These findings indicate that pre-procedural Ang-2 levels do not impact PMI occurrence after elective PCI. However, changes in Ang-2 levels after the procedure are closely related to PMI.

Angiopoietin-2 as a Prognostic Factor in Patients with Incurable Stage IV Colorectal Cancer.

Angiopoietin (Ang), a ligand of the endothelium-specific receptor Tie-2 system, is associated with tumor growth and progression that depend on angiogenesis. The present study aimed to investigate the predictive potential of angiopoietin factors in incurable stage IV colorectal cancer (CRC) patients who have undergone primary tumor resection. The study included 40 consecutive patients with incurable stage IV CRC who underwent primary tumor resection at our hospital between 2011 and 2015. Patients were divided into subgroups of low and high Ang-1, Ang-2, and Tie-2. Patient age and sex, tumor location, TNM stages, vascular invasion, chemotherapy, and overall survival were assessed. The cut-off values of Ang-1, Ang-2, and Tie-2 were 0.4, 1.8, and 15.0ng/mL, respectively. Overall survival was significantly longer in the low Ang-2 group than in the high Ang-2 group. High Ang-2 levels were associated with age, N stage, and chemotherapy. Immunofluorescent staining of Ang-2 revealed that endothelial cells and cancer cells expressed Ang-2 in each case. Our findings suggest that the serum Ang-2 level is associated with disease progression and is an important predictor of mortality in incurable stage IV CRC patients. Thus, it may be a useful prognostic biomarker in these patients.

Serum VEGF and Ang-2 Levels in Infants Before and After Laser Treatment for Retinopathy of Prematurity

Objectives To investigate VEGF and Ang-2 level changes in the systemic circulation after laser photocoagulation in premature infants with ROP. Methods: Eleven infants (4 girls and 7 boys) had serum levels determined for VEGF and Ang-2, collected 1 day prior to and 7 days after ROP laser therapy. Serum levels of VEGF and Ang-2 were quantified by enzyme-linked immunosorbent assay (ELISA). Results: Serum VEGF levels were significantly lower at 7 days after laser therapy compared to that at 1 day prior to laser therapy (p = 0.045). Serum Ang-2 levels increased significantly at 7 days after laser therapy compared with that at 1 day prior to laser therapy (p = 0.046). Conclusions: Serum VEGF levels in patients with ROP were suppressed and Ang-2 levels elevated significantly after laser therapy. The results suggest that changes in VEGF and Ang-2 serum levels may reflect regression and treatment of ROP.