Plasma Levels Of Ang-2 Research Articles

Study on the correlation between angiopoietin-2 and prognosis in patients with acute respiratory distress syndrome

To evaluate the predictive value of angiopoietin-2 (Ang-2) for the prognosis in patients with acute respiratory distress syndrome (ARDS). A retrospective study was conducted, and ARDS patients admitted to the department of emergency medicine of Tongde Hospital of Zhejiang Province from December 2020 to September 2022 were enrolled. General information including gender, age, causes of ARDS, disease severity scores, plasma Ang-2 levels before treatment and at 24, 48, and 72 hours after treatment, and record the 60-day prognosis were collected. Differences in clinical data between groups were compared. Multivariate Logistic regression analysis was used to identify the independent risk factors affecting the 60-day prognosis of ARDS patients, and the receiver operator characteristic curve (ROC curve) was plotted to assess the predictive value of these risk factors for patient outcomes. Pearson correlation analysis was used to assess the correlation between Ang-2 and pulmonary vascular permeability index (PVPI) and extravascular lung water index (EVLWI). A total of 132 ARDS patients were included, of which 49 patients died within 60 days and 83 patients survived. In the death group, plasma Ang-2 levels showed a gradually increasing trend, all significantly higher than before treatment (μg/L: 12.75±1.81, 12.74±1.48, 13.45±2.21 vs. 5.98±0.57, all P < 0.05), while the trend in the survival group was not significant. At 24, 48, and 72 hours after treatment, plasma Ang-2 levels in the death group were significantly higher than those in the survival group (μg/L: 12.75±1.81 vs. 7.48±1.22, 12.74±1.48 vs. 7.41±1.19, 13.45±1.41 vs. 6.88±1.41, all P < 0.05). After adjusting for confounding variables, increased plasma Ang-2 level was an independent risk factor for prognosis in ARDS patients within 60 days [odds ratio (OR) = 0.998, 95% confidence interval (95%CI) was 0.997-0.999, P < 0.01]. ROC curve analysis demonstrated that Ang-2 levels had predictive value for prognosis in ARDS patients [area under the ROC curve (AUC) = 0.985, 95%CI was 0.971-1.000, approximate maximum Youden's index 0.867, optimal cut-off value 8.43 μg/L]. Pearson correlation analysis showed that plasma Ang-2 levels were positively correlated with PVPI and EVLWI ( r values were 0.620 and 0.712 respectively, both P < 0.01). Elevated level of Ang-2 is an independent risk factor for increased mortality in patients with ARDS. Higher Ang-2 levels within 72 hours after treatment may indicate poorer prognosis.

Shenfu injection ameliorates endotoxemia-associated endothelial dysfunction and organ injury via inhibiting PI3K/Akt-mediated glycolysis

Ethnopharmacological relevanceMicrocirculatory dysfunction is one of the main characteristics of sepsis. Shenfu Injection (SFI) as a traditional Chinese medicine is widely applied in clinical severe conditions. Recent studies have shown that SFI has the ability to ameliorate sepsis-induced inflammation and to improve microcirculation perfusion. Aim of the studyThis study aims to investigate the underlying mechanism of SFI for ameliorating sepsis-associated endothelial dysfunction and organ injury. Materials and methodsSide-stream dark-field (SDF) imaging was used to monitor the sublingual microcirculation of septic patients treated with or without SFI. Septic mouse model was used to evaluate the effects of SFI in vivo. Metabolomics and transcriptomics were performed on endothelial cells to identify the underlying mechanism for SFI-related protective effect on endothelial cells. ResultsSFI effectively abolished the disturbance and loss of sublingual microcirculation in septic patients. Twenty septic shock patients with or without SFI administration were enrolled and the data showed that SFI significantly improved the levels of total vessel density (TVD), perfused vessel density (PVD), microvascular flow index (MFI), and the proportion of perfused vessels (PPV). The administration of SFI significantly decreased the elevated plasma levels of Angiopoietin-2 (Ang2) and Syndecan-1, which are biomarkers indicative of endothelial damage in sepsis patients. In the mouse septic model in vivo, SFI inhibited the upregulation of endothelial adhesion molecules and Ly6G + neutrophil infiltration while restored the expression of VE-Cadherin in the vasculature of the lung, kidney, and liver tissue. Additionally, SFI reduced the plasma levels of Ang2, Monocyte Chemoattractant Protein-1(MCP1), and Interleukin-6 (IL6), and alleviated liver and kidney injury in septic mice. Moreover, SFI significantly inhibited the inflammatory activation and increased permeability of endothelial cells induced by endotoxins in vitro. By performing metabolomics and transcriptomics, we identified the activation of PI3K/Akt-mediated glycolysis as the underlying mechanism for SFI-related protective effect on endothelial cells. ConclusionsOur findings revealed that SFI may improve microcirculation perfusion and endothelial function in sepsis via inhibiting PI3K/Akt-mediated glycolysis, providing theoretical evidence for the clinical application of SFI.

Angiogenesis-associated pathways play critical roles in neonatal sepsis outcomes

Neonatal sepsis is a major cause of childhood mortality. Limited diagnostic tools and mechanistic insights have hampered our abilities to develop prophylactic or therapeutic interventions. Biomarkers in human neonatal sepsis have been repeatedly identified as associated with dysregulation of angiopoietin signaling and altered arachidonic acid metabolism. We here provide the mechanistic evidence in support of the relevance for these observations. Angiopoetin-1 (Ang-1), which promotes vascular integrity, was decreased in blood plasma of human and murine septic newborns. In preclinical models, administration of Ang-1 provided prophylactic protection from septic death. Arachidonic acid metabolism appears to be functionally connected to Ang-1 via reactive oxygen species (ROS) with a direct role of nitric oxide (NO). Strengthening this intersection via oral administration of arachidonic acid and/or the NO donor L-arginine provided prophylactic as well as therapeutic protection from septic death while also increasing plasma Ang-1 levels among septic newborns. Our data highlight that targeting angiogenesis-associated pathways with interventions that increase Ang-1 activity directly or indirectly through ROS/eNOS provide promising avenues to prevent and/or treat severe neonatal sepsis.

Correlation between angiotensin and acute kidney injury in patients with sepsis.

The aim of the study was to analyze the changes in angiotensin (Ang) levels in patients with sepsis complicated with acute kidney injury (AKI) and evaluate the relationship between Ang and AKI. Prospective research methods were used in this study. A total of 66 sepsis patients admitted to the Intensive care Unit (ICU) of the First Hospital of Hebei Medical University from October 2020 to January 2021 were enrolled. According to the occurrence of AKI, patients were divided into the sepsis-associated AKI (SA-AKI) group and the non-AKI group. The levels of Ang-1 and Ang-2 were compared between the two groups. The relationship between Ang and glomerular filtration rate (GFR) in sepsis patients was studied by correlation analysis. Plasma Ang-1 in the SA-AKI group was significantly higher than that in the non-AKI group (0.39±1.05 ng/ml vs. 0.10±0.24 ng/ml, p=0.039). The Ang-2/Ang-1 in the SA-AKI group was lower than that in the non-AKI group with a significant difference (52.55±191.38 vs. 349.50±327.49, p=0.001). Correlation analysis indicated that Ang-1 was negatively correlated with GFR (r=-0.12, p=0.031), while Ang-2/Ang-1 was positively correlated with GFR (r=0.21, p<0.001). The Ang-2 was positively correlated with GFR (r=0.204, p<0.001) CONCLUSIONS: Plasma Ang-1 and Ang-2 levels are suggestive for assessing the risk of AKI in patients with sepsis.

Peripheral sensory neuropathy is associated with circulating angiopoietins in type 2 diabetes patients in Ghana

ObjectivePeripheral sensory neuropathy (PSN) is a common complication of type 2 diabetes (T2DM) that can lead to frequent ulcerations, lower extremities, and reduced quality of life. Imbalance in the circulating levels of angiogenic growth factors, notably, angiopoietin (Ang)-1, Ang-2 and vascular endothelial growth factor (VEGF) may be among the underlying mechanisms of PSN in T2DM patients. We studied the association between PSN and angiogenic growth factors, Ang-1, Ang-2 and VEGF in T2DM patients in Ghana. MethodsIn a case-control study design, PSN was evaluated in 160 patients with T2DM and 108 nondiabetic controls using vibration perception threshold (VPT) and diabetic neurological examination (DNE). The definition of PSN was abnormal VPT (≥25 mV) or the presence of neuropathic symptoms on examination (DNE score > 3). In addition, fasting venous blood samples were collected to measure circulating levels of Ang-1, Ang-2 and VEGF. ResultsCompared to non-diabetic controls, patients with T2DM had a higher prevalence of PSN using abnormal VPT (20.6 % vs 2.8 %, p < 0.001) or neuropathic symptoms (35.6 % vs 3.7 %, p < 0.001). Compared to nondiabetic controls, patients with T2DM had increased levels of Ang-2 [597 (274 – 1005) vs 838 (473 – 1241) ng/ml, p = 0.018] and VEGF [48.4 (17.4 – 110.1) vs 72.2 (28 – 201.8), p = 0.025] and decreased Ang-1 levels [41.1 (30 – 57.3) vs 36.1 (24.7 – 42.1) ng/ml, p = 0.01]. In regression analyses, an increase in Ang-1 levels was associated with decreased odds, while an increase in Ang-2 levels was associated with increased odds, of abnormal VPT and neuropathic symptoms in T2DM patients. ConclusionIn our study population, PSN was associated with reduced plasma levels of Ang-1 and increased plasma levels of Ang-2 in patients with T2DM. Therefore, an imbalance of angiopoietins may be associated with PSN in T2DM.

#6235 ELEVATED PLASMA ANGIOPOETIN-2 PREDICT THE NEED FOR DIALYSIS INITIATION IN PATIENTS WITH CKD 4 AND 5 WITHIN TWO YEARS

Abstract Background and Aims Volume status, congestion and endothelial activation/injury were found to play a role in GFR decline and CKD progression. This pilot study aimed to determine whether the plasma markers of endothelial injury and activation as well as markers of fluid overload could serve as independent predictors for dialysis initiation in stable patients with CKD 4 and 5 and preserved EF. Method This prospective study was conducted from March 2019 to March 2022 and enrolled consecutive patients with GFR &amp;lt;30ml/min/1.72 m2 and preserved LVEF. Plasma levels of angiopoietin (Ang)-2, Vascular Endothelial Growth Factor-C (VEGF-C), Vascular Cell Adhesion Molecule-1 (VCAM-1), Copeptin (CPP), beta-trace protein (BTP), brain natriuretic peptide (BNP), cardiac troponin I (cTnI) were measured (Quantikine ELISA;R&amp;D Systems Inc, Minneapolis, MN). Clinical markers of congestion were also recorded: lung US (B-lines), bioimpedance (ECV/ICV), echocardiography with global longitudinal strain (GLS), pulse wave velocity (PWV). Study outcome was need to initiate dialysis during 24-months follow-up. Results We analyzed a total of 105 patients with mean eGFR 21,3 ml/min/1.73m. The median age at enrollment was 52 (+/-14.8) years and 65% of the patients were male; 79% were hypertensive and 24% were diabetic. A positive correlation between concentration of Ang-2 and VCAM-1 and BTP was observed. Ang-2 concentration correlated positively with BNP, TnT, sCr, e/e’, ECV/ICV. Over a follow-up period of 24 months, the deterioration of renal function was observed in 47 patients (58%), 31 (38%) presented stable or ameliorated renal function and 24 on maintenance dialysis formed a control group. In Kaplan-Meier analysis significant impact of Ang-2 on renal survival (Figure) was found. Namely, 72% of patients with Ang-2 concentrations below the median (3.15 ng/ml) survived without dialysis for two years, compared to 42% of those with Ang-2 concentrations above the median. Such impact was not observed for GFR, VCAM, CCP, VEGF-C, BTP. Conclusion Endothelial activation, quantified by plasma levels of Ang-2 may play an important role in GFR decline and need for dialysis initiation in patients with CKD 4 and 5.

Platelet‑related parameters as potential biomarkers for the prognosis of sepsis.

Early diagnosis and accurate prognosis are key for reducing the fatality rate and medical expenses associated with sepsis. Platelets are involved in the delayed tissue injury that occurs during sepsis. Therefore, the aim of the present study was to investigate the usefulness of platelets and associated parameters as prognostic markers of sepsis. The present study collected patient samples based on The Third International Consensus Definitions for Sepsis and Septic Shock criteria. Platelet-associated parameters were detected by flow cytometry and their correlation with clinical scores and prognoses was analyzed. Considering the association between endothelial cells and platelet activation, levels of plasma tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and angiopoietin-2 (Ang-2) were analyzed by ELISA. The results showed significant differences in platelet P-selectin expression and phosphatidylserine exposure, mitochondrial membrane potential (Mmp)-Index values and plasma levels of TWEAK and Ang-2 between patients and healthy controls (P<0.05). Except for P-selectin and TWEAK levels, all parameters were correlated with clinical scores (acute physiology and chronic health evaluation II and sequential/sepsis-related organ failure assessment). Additionally, platelet Mmp-Index between admission and the end of therapy was only different in non-survivors (P<0.001) and platelet phosphatidylserine exposure was significantly lower in survivors (P=0.006). Therefore, of the parameters tested, the dynamic monitoring of phosphatidylserine exposure, platelet Mmp-Index values and plasma Ang-2 levels had the most potential for the assessment of disease severity and clinical outcomes.

Reduced Angiopoietin Factor 2 Levels Are Correlated with Better Cardiac Function and Prognosis in Valvular Heart Disease.

There are few circulating biomarkers for valvular heart disease. Angiopoietin (Ang) 1, Ang2, and vascular endothelial growth factor are important inflammation-associated cytokines. The aim of this study was to investigate the clinical significance and association of Ang1, Ang2, and vascular endothelial growth factor in valvular heart disease. This is a retrospective study; a total of 62 individuals (valvular heart disease patients [n=42] and healthy controls [n=20]) were included. Plasma levels of Ang1, Ang2, and vascular endothelial growth factor were detected by enzyme-linked immunosorbent assays. We retrospectively collected the baseline characteristics and short-term outcomes; logistic regression was performed to identify predictor for short-term mortality. Ang2 was significantly decreased in the valvular heart disease group compared with the healthy control group (P=0.023), while no significant difference was observed in the Ang1 and vascular endothelial growth factor levels. The Ang2 level of New York Heart Association (NYHA) I/II patients - but not NYHA III/IV patients - was significantly decreased compared with that of healthy control individuals (NYHA I/II: P=0.017; NYHA III/IV: P=0.485). Univariable logistic regression analysis indicated that Ang2 was a significant independent predictor for short-term mortality (odds ratio 18.75, P=0.033, 95% confidence interval 8.08-102.33). Ang1 was negatively correlated with Ang2 (P=0.032, Pearson's correlation coefficient =-0.317) and was positively correlated with vascular endothelial growth factor (P=0.019, Pearson's correlation coefficient = 0.359). Ang2 might serve as a therapeutic and prognostic target for valvular heart disease.

Glycocalyx heparan sulfate cleavage promotes endothelial cell angiopoietin-2 expression by impairing shear stress-related AMPK/FoxO1 signaling.

Angiopoietin-2 (Ang-2) is a key mediator of vascular disease during sepsis, and elevated plasma levels of Ang-2 are associated with organ injury scores and poor clinical outcomes. We have previously observed that biomarkers of endothelial glycocalyx (EG) damage correlate with plasma Ang-2 levels, suggesting a potential mechanistic linkage between EG injury and Ang-2 expression during states of systemic inflammation. However, the cell signaling mechanisms regulating Ang-2 expression following EG damage are unknown. In the current study, we determined the temporal associations between plasma heparan sulfate (HS) levels as a marker of EG erosion and plasma Ang-2 levels in children with sepsis and in mouse models of sepsis. Second, we evaluated the role of shear stress–mediated 5′-adenosine monophosphate–activated protein kinase (AMPK) signaling in Ang-2 expression following enzymatic HS cleavage from the surface of human primary lung microvascular endothelial cells (HLMVECs). We found that plasma HS levels peaked before plasma Ang-2 levels in children and mice with sepsis. Further, we discovered that impaired AMPK signaling contributed to increased Ang-2 expression following HS cleavage from flow-conditioned HLMVECs, establishing a paradigm by which Ang-2 may be upregulated during sepsis.

Early modulation of Angiopoietin-2 plasma levels predicts benefit from regorafenib in patients with metastatic colorectal cancer

BackgroundNo biomarkers are currently available to predict the efficacy of trifluridine/tipiracil (FTD/TPI) in chemorefractory metastatic colorectal cancer. The multicohort REGOLAND study aims at exploring and validating circulating markers potentially able to predict benefit from regorafenib in this setting. Material and methodsIn the retrospective ‘regorafenib exploratory cohort’, including 105 patients treated with regorafenib, baseline (d1) plasma levels of angiogenesis-related biomarkers and their early modulation after 15 days (d15) of treatment were investigated for correlation with clinical outcome. Based on a pre-specified statistical hypothesis, main retrospective findings were prospectively challenged in the ‘regorafenib validation cohort’, including 100 patients treated with regorafenib. Prospectively validated putative biomarkers were then assessed in the control ‘FTD/TPI cohort’, including 93 patients treated with FTD/TPI. ResultsIn the ‘regorafenib exploratory cohort’, the early (d15) increase of Angiopoietin-2 (Ang-2) was associated with longer progression-free survival (HR:0.57 [95%CI:0.38–0.88], P = 0.004) and a trend towards longer OS (HR:0.74 [95%CI:0.48–1.14], P = 0.165), than the early decrease. Similar results were prospectively confirmed in the ‘regorafenib validation cohort’ (HR for progression-free survival:0.72 [95%CI:0.48–1.08], P = 0.095; HR for OS:0.77 [95%CI:0.51–1.16], P = 0.204). No predictive impact was shown for the early modulation of Ang-2 in the ‘FTD/TPI cohort’. High baseline Ang-2 levels predict poor prognosis in all the investigated cohorts, independently of other clinical prognostic variables. ConclusionsThe early modulation of circulating Ang-2 predicts the efficacy of regorafenib. Baseline Ang-2 plasma levels are an independent prognostic biomarker in chemorefractory metastatic colorectal cancer.

Association of Pre-Transplant Angiopoietin-2 Index with the Risk of Acute Graft-Versus-Host Disease after Hematopoietic Stem Cell Transplantation

Objective:Angiogenic factors (AFs) released under endothelial stress are reflective of tissue healing, while some may also contribute to tissue damage/inflammation. We investigated whether alterations in the pre-transplant levels of AFs were associated with the risk of acute graft-versus-host disease (aGvHD).Materials and Methods:The pre-conditioning plasma levels of angiopoietin-2 (Ang2), endoglin, and follistatin were measured for 37 patients together with inflammatory markers. The index values defined were evaluated to better identify the alterations.Results:The patients had higher pre-conditioning levels of Ang2, endoglin, and follistatin compared to controls. The patients with aGvHD had higher Ang2 index and lower albumin index scores in comparison to those without aGvHD. Multivariate analysis revealed that the pre-transplant Ang2 index was an independent risk factor for aGvHD development.Conclusion:Pre-transplant evaluation of plasma Ang2 levels along with inflammatory status even before conditioning is associated with endothelial vulnerability. The pre-transplant Ang2 index could be a promising candidate to estimate the risk of aGvHD.

Plasma Angiopoietin-2 as a Promising Biomarker for the Prognosis of Acute Pulmonary Embolism.

Endothelial damage is one of the pathogenic conditions of acute pulmonary embolism (APE). The essential role of angiogenin, ribonuclease A family, member 2 (Ang-2) in APE remains unclear. This study aimed to investigate the predictive value of Ang-2 in the clinical outcomes of patients with APE. Plasma Ang-2 levels were measured by an enzyme-linked immunosorbent assay kit using a DuoSet methodology in 118 APE patients and 53 healthy controls. Baseline data relevant to mortality over time were obtained from hospital databases or by patient's follow-up (median follow-up time: 25.0 ± 13.2 months). The main outcome was all-cause mortality. Plasma Ang-2 level was significantly higher in APE patients than in healthy controls (p < 0.001). Patients dying during the first 30 days presented higher baseline levels of Ang-2 than the survivors (p < 0.001). Patients dying during the follow-up also showed higher baseline levels of Ang-2 than the survivors (p < 0.001). The multi-variable logistic regression analysis showed that the N-terminal propeptide of B-type natriuretic peptide (NT-proBNP) [odds ratio (OR): 19.8; 95% CI: 1.5 - 255.8; p = 0.022] and Ang-2 (OR: 9.9; 95% CI: 1.4 - 70.5; p = 0.022) emerged as independent predictors of the 30-day mortality. Furthermore, the multivariable Cox's regression identified plasma Ang-2 [hazards ratio (HR): 1.35; 95% CI: 1.10 - 1.66; p = 0.004] as an independent predictor of long-term mortality in patients with APE. A high circulating level of Ang-2 can be considered as an independent predictor for the poor outcome of APE and may serve as a biomarker for the risk stratification in patients with APE.

Angiopoietin-2 levels correlates with disease activity in children with nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD), a chronic liver disease in children, ranges from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH). We investigated the role of Angiopoietin-2 (Ang-2) as a biomarker for pediatric NAFLD-related liver damage. We assessed the plasma levels of Ang-2 and cytokeratin-18 (CK18) fragments and their association with histologic activity in 76 children with NAFLD and 28 controls. The mean plasma levels of Ang-2 and CK18 were higher in children with NAFLD than in age-matched controls (Ang-2 155.4 ± 72.5 vs 7.5 ± 2.3 ng/mL, p < 0.001; CK18 390.4 ± 145.6 vs 193.9 ± 30.8 IU/L, p < 0.001). Ang-2 was significantly increased (p < 0.0001) in children with NASH (N = 41) while CK18 was significantly increased (p = 0.002) in children with fibrosis (N = 47). Ang-2 levels accurately predicted NASH (AUROC 0.911; 95% CI 0.844-0.979; p < 0.0001), while CK18 predicted both NASH (AUROC 0.827; 95% CI 0.735-0.919; p < 0.0001) and fibrosis (AUROC 0.724; 95% CI 0.611-0.837; p = 0.001). Ang-2 and CK18 in combination were good predictors of NASH with a sensitivity of 71.4% and a specificity of 100%. In conclusion, our data suggested Ang-2 as a suitable biomarker of NASH in the pediatric population. However, our findings need external validation in other cohorts. Several circulating factors have been extensively studied as potential biomarkers for NASH. Angiopoietin-2 circulating levels are increased in children with NAFLD and are associated with NASH. Angiopoietin-2 levels are more efficient than CK18 levels at assessing the most severe form of disease, and the combining of these two biomarkers reached a positive predictive value of 100% for NASH.

Sequential dysregulated plasma levels of angiopoietins (ANG-2 and ratios of ANG-2/ANG-1) are associated with malaria severity and mortality among hospital admitted cases in South Bastar Region of Chhattisgarh, Central India

ABSTRACT Cerebral malaria (CM) is one of the most severe forms of P. falciparum infection, with an associated high case-fatality rate. Angiopoietins (ANG‐1 and ANG‐2) are important biomarkers of endothelial activation and dysfunction. This study was carried out in Maharani Hospital and associated Medical College, Jagdalpur, CG, Central India from 2010 to 2014. Based on the treatment recovery patterns, cases (n = 65) were classified as mild malaria with rapid recovery (MM-RR), n= 14; non-cerebral severe malaria with moderately fast recovery (NCSM‐MFR), n= 9; CM survivors with slow recovery (CMS-SR), n= 36 and deteriorated CM non-survivors (Det‐CMNS), n= 6. Plasma levels (pg/ml) of ANG-1 and ANG-2 were measured by ELISA in all the samples at the time of hospital admission and 48 hours of treatment. Levels were also measured in available samples at the third time point (time of discharge for survivors or 72 hours post-treatment in fatal cases). Data analysis was done by appropriate statistical tests using Stata 11.0 and SPSS 25.0 software. At the time of admission, ANG-2 and ratios of ANG-2/ANG-1 significantly distinguished Det‐CMNS cases from MM-RR and NCSM‐MFR cases with good AUC scores (0.8‐0.9). Further, Det-CMNS cases could also be distinguished from MM-RR, NCSM-MFR, and CMS-SR cases by ANG-2 (AUC scores 0.9) and ratios of ANG‐2/ANG-1 (AUC: 0.8‐0.9) at 48 hours of treatment. Paired analysis of sequential measurement of angiopoietins revealed that compared to admission levels, the ratios of ANG-2/ANG-1 significantly declined 48 hours after treatment in MM-RR (p= 0.041), NCSM-MFR (p= 0.050), and CMS-SR (p= 0.0002) cases but not in cases of Det-CMNS (p= 0.916). In conclusion, plasma levels of ANG-2 and ratios of ANG-2/ANG-1 may serve as good biomarkers to distinguish the malaria severity at the time of hospital admission and recovery patterns upon treatment in Central India

Prognostic role of plasma level of angiopoietin-1, angiopoietin-2, and vascular endothelial growth factor in hepatocellular carcinoma.

BACKGROUNDMost hepatocellular carcinomas (HCCs) are hypervascular, with characteristic features of hepatic arterial supply to the tumor. The factors involved in tumor angiogenesis include angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), and vascular endothelial growth factor (VEGF).AIMTo investigate the profiles of plasma levels of angiogenesis markers in patients with HCC and evaluate their roles in predicting overall survival (OS) and progression-free survival (PFS).METHODSPlasma samples from 240 prospectively enrolled HCC patients in the very early to advanced stages were used to measure the levels of Ang-1, Ang-2, and VEGF. Their associations with clinical characteristics, OS, and PFS were analyzed.RESULTSThe median plasma levels of Ang-1, Ang-2, and VEGF were 3216 pg/mL, 1684 pg/mL, and 26.5 pg/mL, respectively. The plasma level of Ang-2 showed a significant increase from early stage [Barcelona clinic liver cancer (BCLC) A] to intermediate (BCLC B) and advanced stage HCC (BCLC C/D), whereas Ang-1, VEGF, and alpha-fetoprotein (AFP) levels in the plasma did not show any such changes. Multivariable analysis, propensity score-matched analysis, and time-dependent receiver operating curve analysis revealed that Ang-2 levels had the highest predictive power for OS and PFS. Neither Ang-1 nor VEGF was significantly associated with OS or PFS. The neutrophil-to-lymphocyte ratio was an independent factor for OS and PFS. CONCLUSIONThe plasma levels of Ang-2 correlated with liver function, tumor stage, and tumor invasiveness, showing better performance in predicting OS and PFS than AFP, Ang-1, or VEGF.

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 endothelial and epithelial pulmonary injury in mechanically ventilated COVID-19 ICU patients

BackgroundBiomarkers can be used to detect the presence of endothelial and/or alveolar epithelial injuries in case of ARDS. Angiopoietin-2 (Ang-2), soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein-1 (VCAM-1), P-selectin and E-selectin are biomarkers of endothelial injury, whereas the receptor for advanced glycation end-products (RAGE) reflects alveolar epithelial injury. The aims of this study were to evaluate whether the plasma concentration of the above-mentioned biomarkers was different 1) in survivors and non-survivors of COVID-19-related ARDS and 2) in COVID-19-related and classical ARDS.MethodsThis prospective study was performed in two COVID-19-dedicated Intensive Care Units (ICU) and one non-COVID-19 ICU at Ferrara University Hospital. A cohort of 31 mechanically ventilated patients with COVID-19 ARDS and a cohort of 11 patients with classical ARDS were enrolled. Ang-2, ICAM-1, VCAM-1, P-selectin, E-selectin and RAGE were determined with a bead-based multiplex immunoassay at three time points: inclusion in the study (T1), after 7 ± 2 days (T2) and 14 ± 2 days (T3). The primary outcome was to evaluate the plasma trend of the biomarker levels in survivors and non-survivors. The secondary outcome was to evaluate the differences in respiratory mechanics variables and gas exchanges between survivors and non-survivors. Furthermore, we compared the plasma levels of the biomarkers at T1 in patients with COVID-19-related ARDS and classical ARDS.ResultsIn COVID-19-related ARDS, the plasma levels of Ang-2 and ICAM-1 at T1 were statistically higher in non-survivors than survivors, (p = 0.04 and p = 0.03, respectively), whereas those of P-selectin, E-selectin and RAGE did not differ. Ang-2 and ICAM-1 at T1 were predictors of mortality (AUROC 0.650 and 0.717, respectively). At T1, RAGE and P-selectin levels were higher in classical ARDS than in COVID-19-related ARDS. Ang-2, ICAM-1 and E-selectin were lower in classical ARDS than in COVID-19-related ARDS (all p < 0.001).ConclusionsCOVID-19 ARDS is characterized by an early pulmonary endothelial injury, as detected by Ang-2 and ICAM-1. COVID-19 ARDS and classical ARDS exhibited a different expression of biomarkers, suggesting different pathological pathways.Trial registrationNCT04343053, Date of registration: April 13, 2020

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.

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.

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.