Levels of Angiopoietin 2 Are Predictive for Mortality in Patients Infected With Yellow Fever Virus.

In 2018 there was a large yellow fever outbreak in São Paulo, Brazil, with a high fatality rate. Yellow fever virus can cause, among other symptoms, hemorrhage and disseminated intravascular coagulation, indicating a role for endothelial cells in disease pathogenesis. Here, we conducted a case-control study and measured markers related to endothelial damage in plasma and its association with mortality. We found that angiopoietin 2 is strongly associated with a fatal outcome and could serve as a predictive marker for mortality. This could be used to monitor severe cases and provide care to improve disease outcome.

Loss of TGFß-Mediated Repression of Angiopoietin-2 in Pericytes Underlies Germinal Matrix Hemorrhage Pathogenesis.

BACKGROUND: TGF (transforming growth factor)-ß pathway is central to blood-brain barrier development as it regulates cross talk between pericytes and endothelial cells. Murine embryos lacking TGFß receptor Alk5 (activin receptor-like kinase 5) in brain pericytes (mutants) display endothelial cell hyperproliferation, abnormal vessel morphology, and gross germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH), leading to perinatal lethality. Mechanisms underlying how ALK5 signaling in pericytes noncell autonomously regulates endothelial cell behavior remain elusive. METHODS: Transcriptomic analysis of human brain pericytes with ALK5 silencing identified differential gene expression. Brain vascular cells isolated from mutant embryonic mice with GMH-IVH and preterm human IVH brain samples were utilized for target validation. Finally, pharmacological and genetic inhibition was used to study the therapeutic effects on GMH-IVH pathology. RESULTS: Herein, we establish that the TGFß/ALK5 pathway robustly represses ANGPT2 (angiopoietin-2) in pericytes via epigenetic remodeling. TGFß-driven SMAD (suppressor of mothers against decapentaplegic) 3/4 associates with TGIF1 (TGFß-induced factor homeobox 1) and HDAC (histone deacetylase) 5 to form a corepressor complex at the Angpt2 promoter, resulting in promoter deacetylation and gene repression. Moreover, murine and human germinal matrix vessels display increased ANGPT2 expression during GMH-IVH. Isolation of vascular cells from murine germinal matrix identifies pericytes as a cellular source of excessive ANGPT2. In addition, mutant endothelial cells exhibit higher phosphorylated TIE2 (tyrosine protein kinase receptor). Pharmacological or genetic inhibition of ANGPT2 in mutants improves germinal matrix vessel morphology and attenuates GMH pathogenesis. Importantly, genetic ablation of Angpt2 in mutant pericytes prevents perinatal lethality, prolonging survival. CONCLUSIONS: This study demonstrates that TGFß-mediated ANGPT2 repression in pericytes is critical for maintaining blood-brain barrier integrity and identifies pericyte-derived ANGPT2 as an important pathological target for GMH-IVH.

Angiopoietins as Predictor Indexes in COVID-19 Patients in Delta and Omicron Waves.

This study aimed to explore the correlation between Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2) concentrations and the Angiopoietin-2/Angiopoietin-1 ratio (Ang-2/Ang-1) with clinical outcomes, potentially serving as disease severity and survival biomarkers. A study at AHEPA University Hospital involved 90 Coronavirus Disease 2019 (COVID-19) adult patients, 30 hospitalized intensive care units (ICU), 30 inward units (non-ICU), and 30 asymptomatic non-hospitalized individuals as controls. Estimated endothelial dysfunction markers related to angiogenesis were measured. There was a statistically significant difference only between outpatient and hospitalized patients (non-ICU-ICU groups) for the Ang-1 and Ang-2 indices. The Ang-2/Ang-1 ratio has differed significantly among the individual patient groups. An ROC analysis was conducted to find an optimal threshold for distinguishing between (outpatients-non-ICU) and (non-ICU-ICU) groups. It was based on Youden's index of 0.1122 and 0.3825, respectively. The Ang-1, Ang-2 levels, and Ang-2/Ang-1 ratio were analyzed as severity indicators in COVID-19 patients. The Ang-2/Ang-1 ratio demonstrated better prognostic and diagnostic utility than individual biomarker levels. Monitoring the Ang-2/Ang-1 ratio can identify COVID-19 patients at risk and assist clinicians in tailoring treatment strategies to improve outcomes.

Faricimab Treat-and-Extend for Diabetic Macular Edema: Two-Year Results from the Randomized Phase 3 YOSEMITE and RHINE Trials.

PURPOSE: To evaluate the 2-year efficacy, durability, and safety of dual angiopoietin-2 and vascular endothelial growth factor (VEGF) A pathway inhibition with intravitreal faricimab according to a personalized treat-and-extend (T&E)-based regimen with up to every-16-week dosing in the YOSEMITE and RHINE (ClinicalTrials.gov identifiers, NCT03622580 and NCT03622593, respectively) phase 3 trials of diabetic macular edema (DME). DESIGN: Randomized, double-masked, noninferiority phase 3 trials. PARTICIPANTS: Adults with visual acuity loss (best-corrected visual acuity [BCVA] of 25-73 letters) due to center-involving DME. METHODS: Patients were randomized 1:1:1 to faricimab 6.0 mg every 8 weeks, faricimab 6.0 mg T&E (previously referred to as personalized treatment interval), or aflibercept 2.0 mg every 8 weeks. The T&E up to every-16-week dosing regimen was based on central subfield thickness (CST) and BCVA change. MAIN OUTCOME MEASURES: Included changes from baseline in BCVA and CST, number of injections, durability, absence of fluid, and safety through week 100. RESULTS: In YOSEMITE and RHINE (n = 940 and 951, respectively), noninferior year 1 visual acuity gains were maintained through year 2; mean BCVA change from baseline at 2 years (weeks 92, 96, and 100 average) with faricimab every 8 weeks (YOSEMITE and RHINE, +10.7 letters and +10.9 letters, respectively) or T&E (+10.7 letters and +10.1 letters, respectively) were comparable with aflibercept every 8 weeks (+11.4 letters and +9.4 letters, respectively). The median number of study drug injections was lower with faricimab T&E (YOSEMITE and RHINE, 10 and 11 injections, respectively) versus faricimab every 8 weeks (15 injections) and aflibercept every 8 weeks (14 injections) across both trials during the entire study. In the faricimab T&E arms, durability was improved further during year 2, with > 60% of patients receiving every-16-week dosing and approximately 80% receiving every-12-week or longer dosing at week 96. Almost 80% of patients who achieved every-16-week dosing at week 52 maintained every-16-week dosing without an interval reduction through week 96. Mean CST reductions were greater (YOSEMITE/RHINE weeks 92/96/100 average: faricimab every 8 weeks -216.0/-202.6 µm, faricimab T&E -204.5/-197.1 µm, aflibercept every 8 weeks -196.3/-185.6 µm), and more patients achieved absence of DME (CST < 325 µm; YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 87%-92%/88%-93%, faricimab T&E 78%-86%/85%-88%, aflibercept every 8 weeks 77%-81%/80%-84%) and absence of intraretinal fluid (YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 59%-63%/56%-62%, faricimab T&E 43%-48%/45%-52%, aflibercept every 8 weeks 33%-38%/39%-45%) with faricimab every 8 weeks or T&E versus aflibercept every 8 weeks through year 2. Overall, faricimab was well tolerated, with a safety profile comparable with that of aflibercept. CONCLUSIONS: Clinically meaningful visual acuity gains from baseline, anatomic improvements, and extended durability with intravitreal faricimab up to every 16 weeks were maintained through year 2. Faricimab given as a personalized T&E-based dosing regimen supports the role of dual angiopoietin-2 and VEGF-A inhibition to promote vascular stability and to provide durable efficacy for patients with DME. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Efficacy and Safety of Faricimab for Macular Edema due to Retinal Vein Occlusion: 24-Week Results from the BALATON and COMINO Trials.

PURPOSE: To evaluate the 24-week efficacy and safety of the dual angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF)-A inhibitor faricimab versus aflibercept in patients with vein occlusion. DESIGN: Phase 3, global, randomized, double-masked, active comparator-controlled trials: BALATON/COMINO (ClincalTrials.gov identifiers: NCT04740905/NCT04740931; sites: 149/192). PARTICIPANTS: Patients with treatment-naïve foveal center-involved macular edema resulting from branch (BALATON) or central or hemiretinal (COMINO) RVO. METHODS: Patients were randomized 1:1 to faricimab 6.0 mg or aflibercept 2.0 mg every 4 weeks for 24 weeks. MAIN OUTCOME MEASURES: Primary end point: change in best-corrected visual acuity (BCVA) from baseline to week 24. Efficacy analyses included patients in the intention-to-treat population. Safety analyses included patients who received ≥ 1 doses of study drug. RESULTS: Enrollment: BALATON, n = 553; COMINO, n = 729. The BCVA gains from the baseline to week 24 with faricimab were noninferior versus aflibercept in BALATON (adjusted mean change, +16.9 letters [95.03% confidence interval (CI), 15.7-18.1 letters] vs. +17.5 letters [95.03% CI, 16.3-18.6 letters]) and COMINO (+16.9 letters [95.03% CI, 15.4-18.3 letters] vs. +17.3 letters [95.03% CI, 15.9-18.8 letters]). Adjusted mean central subfield thickness reductions from the baseline were comparable for faricimab and aflibercept at week 24 in BALATON (-311.4 µm [95.03% CI, -316.4 to -306.4 µm] and -304.4 µm [95.03% CI, -309.3 to -299.4 µm]) and COMINO (-461.6 µm [95.03% CI, -471.4 to -451.9 µm] and -448.8 µm [95.03% CI, -458.6 to -439.0 µm]). A greater proportion of patients in the faricimab versus aflibercept arm achieved absence of fluorescein angiography-based macular leakage at week 24 in BALATON (33.6% vs. 21.0%; nominal P = 0.0023) and COMINO (44.4% vs. 30.0%; nominal P = 0.0002). Faricimab was well tolerated, with an acceptable safety profile comparable with aflibercept. The incidence of ocular adverse events was similar between patients receiving faricimab (16.3% [n = 45] and 23.0% [n = 84] in BALATON and COMINO, respectively) and aflibercept (20.4% [n = 56] and 27.7% [n = 100], respectively). CONCLUSIONS: These findings demonstrate the efficacy and safety of faricimab, a dual Ang-2/VEGF-A inhibitor, in patients with macular edema secondary to retinal vein occlusion. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

TENAYA and LUCERNE: Two-Year Results from the Phase 3 Neovascular Age-Related Macular Degeneration Trials of Faricimab with Treat-and-Extend Dosing in Year 2.

PURPOSE: To evaluate 2-year efficacy, durability, and safety of the bispecific antibody faricimab, which inhibits both angiopoietin-2 and VEGF-A. DESIGN: TENAYA (ClinicalTrials.gov identifier, NCT03823287) and LUCERNE (ClinicalTrials.gov identifier, NCT03823300) were identically designed, randomized, double-masked, active comparator-controlled phase 3 noninferiority trials. PARTICIPANTS: Treatment-naive patients with neovascular age-related macular degeneration (nAMD) 50 years of age or older. METHODS: Patients were randomized (1:1) to intravitreal faricimab 6.0 mg up to every 16 weeks (Q16W) or aflibercept 2.0 mg every 8 weeks (Q8W). Faricimab fixed dosing based on protocol-defined disease activity at weeks 20 and 24 up to week 60, followed up to week 108 by a treat-and-extend personalized treatment interval regimen. MAIN OUTCOME MEASURES: Efficacy analyses included change in best-corrected visual acuity (BCVA) from baseline at 2 years (averaged over weeks 104, 108, and 112) and proportion of patients receiving Q16W, every 12 weeks (Q12W), and Q8W dosing at week 112 in the intention-to-treat population. Safety analyses included ocular adverse events (AEs) in the study eye through study end at week 112. RESULTS: Of 1326 patients treated across TENAYA/LUCERNE, 1113 (83.9%) completed treatment (n = 555 faricimab; n = 558 aflibercept). The BCVA change from baseline at 2 years was comparable between faricimab and aflibercept groups in TENAYA (adjusted mean change, +3.7 letters [95% confidence interval (CI), +2.1 to +5.4] and +3.3 letters [95% CI, +1.7 to +4.9], respectively; mean difference, +0.4 letters [95% CI, -1.9 to +2.8]) and LUCERNE (adjusted mean change, +5.0 letters [95% CI, +3.4 to +6.6] and +5.2 letters [95% CI, +3.6 to +6.8], respectively; mean difference, -0.2 letters [95% CI, -2.4 to +2.1]). At week 112 in TENAYA and LUCERNE, 59.0% and 66.9%, respectively, achieved Q16W faricimab dosing, increasing from year 1, and 74.1% and 81.2%, achieved Q12W or longer dosing. Ocular AEs in the study eye were comparable between faricimab and aflibercept groups in TENAYA (55.0% and 56.5% of patients, respectively) and LUCERNE (52.9% and 47.5% of patients, respectively) through week 112. CONCLUSIONS: Treat-and-extend faricimab treatment based on nAMD disease activity maintained vision gains through year 2, with most patients achieving extended dosing intervals. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Experimentally Induced Peripheral Venous Congestion Exacerbates Inflammation, Oxidative Stress, and Neurohormonal and Endothelial Cell Activation in Patients With Systolic Heart Failure.

BACKGROUND: Venous congestion (VC) is a hallmark of symptomatic heart failure (HF) requiring hospitalization; however, its role in the pathogenesis of HF progression remains unclear. We investigated whether peripheral VC exacerbates inflammation, oxidative stress and neurohormonal and endothelial cell (EC) activation in patients with HF with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Two matched groups of patients with HFrEF and with no peripheral VC vs without recent HF hospitalization were studied. We modeled peripheral VC by inflating a cuff around the dominant arm, targeting ∼ 30 mmHg increase in venous pressure (venous stress test [VST]). Blood and ECs were sampled before and after 90 minutes of VST. We studied 44 patients (age 53 ± 12 years, 32% female). Circulating endothelin-1, tumor necrosis factor-α, interleukin-6, isoprostane, angiotensin II (ang-2), angiopoietin-2, vascular cell adhesion molecule-1, and CD146 significantly increased after the VST. Enhanced endothelin-1 and angiopoietin-2 responses to the VST were present in patients with vs without recent hospitalization and were prospectively associated with incident HF-related events; 6698 messenger ribonucleic acid (mRNA probe sets were differentially expressed in ECs after VST. CONCLUSIONS: Experimental VC exacerbates inflammation, oxidative stress, neurohormonal and EC activation and promotes unfavorable transcriptome remodeling in ECs of patients with HFrEF. A distinct biological sensitivity to VC appears to be associated with high risk for HF progression.

Serum Angiopoietin-2 Levels Predict the Development of Hepatocellular Carcinoma following Hepatitis C Virus Eradication Using Direct-Acting Antiviral Agents.

INTRODUCTION: Our previous studies showed that serum angiopoietin-2 (Ang-2) and C-X-C motif chemokine ligand 10 (CXCL10) levels predicted improvement in liver fibrosis following sustained virological response (SVR) of hepatitis C virus (HCV) obtained with administration of with direct-acting antiviral agents (DAAs). These levels were evaluated retrospectively as predictive indicators of hepatocellular carcinoma (HCC) development following SVR. METHODS: We enrolled individuals from a historical cohort of 89 chronic HCV patients without history of HCC at baseline and with SVR following DAA therapy and had baseline serum levels of Mac-2 binding protein glycosylation isomer ≥2.0 cut-off index (C.O.I.). RESULTS: Multivariate analyses revealed that only the Ang-2 level at 24 weeks following the end of treatment (EOT24W) was significantly related to HCC development (hazard ratio 2.27; p = 0.003). This result was reproduced in individuals without history of HCC and with advanced liver fibrosis (M2BPGi level ≥3.3 C.O.I. at baseline). Time-dependent receiver operating characteristic curve analyses for the future risk of developing HCC within 5 years of follow-up (5y-HCC) showed the best cut-off Ang-2 level at the EOT24W was 2,780 pg/mL, and significantly stratified the cumulative incidence of HCC (≥2,780 vs. < 2,780 pg/mL, 5y-HCC: 45.5 vs. 8.2%, p < 0.001). CONCLUSIONS: At the EOT24W, serum Ang-2 level predicts the likelihood of developing HCC following SVR to DAA therapy.

VEGF-A165a and angiopoietin-2 differently affect the barrier formed by retinal endothelial cells.

Exposure to VEGF-A165a over several days leads to a persistent dysfunction of the very tight barrier formed by immortalized endothelial cells of the bovine retina (iBREC). Elevated permeability of the barrier is indicated by low cell index values determined by electric cell-substrate impedance measurements, by lower amounts of claudin-1, and by disruption of the homogenous and continuous staining of vascular endothelial cadherin at the plasma membrane. Because of findings that suggest modulation of VEGF-A's detrimental effects on the inner blood-retina barrier by the angiogenic growth factor angiopoietin-2, we investigated in more detail in vitro whether this growth factor indeed changes the stability of the barrier formed by retinal endothelial cells or modulates effects of VEGF-A. In view of the clinical relevance of anti-VEGF therapy, we also studied whether blocking VEGF-A-driven signaling is sufficient to prevent barrier dysfunction induced by a combination of both growth factors. Although angiopoietin-2 stimulated proliferation of iBREC, the formed barrier was not weakened at a concentration of 3 nM: Cell index values remained high and expression or subcellular localization of claudin-1 and vascular endothelial cadherin, respectively, were not affected. Angiopoietin-2 enhanced the changes induced by VEGF-A165a and this was more pronounced at lower concentrations of VEGF-A165a. Specific inhibition of the VEGF receptors with tivozanib as well as interfering with binding of VEGF-A to its receptors with bevacizumab prevented the detrimental effects of the growth factors; dual binding of angiopoietin-2 and VEGF-A by faricimab was marginally more efficient. Uptake of extracellular angiopoietin-2 by iBREC can be efficiently prevented by addition of faricimab which is also internalized by the cells. Exposure of the cells to faricimab over several days stabilized their barrier, confirming that inhibition of VEGF-A signaling is not harmful to this cell type. Taken together, our results confirm the dominant role of VEGF-A165a in processes resulting in increased permeability of retinal endothelial cells in which angiopoietin-2 might play a minor modulating role.

The Role of Angiopoietins in Cardiovascular Outcomes of Kidney Transplant Recipients: An Ancillary Study from the FAVORIT.

INTRODUCTION: Kidney transplant recipients (KTRs) have increased risk of cardiovascular disease (CVD) mortality. We investigated vascular biomarkers, angiopoietin-1, and angiopoietin-2 (angpt-1, -2), in CVD development in KTRs. METHODS: This ancillary study from the FAVORIT evaluates the associations of baseline plasma angpt-1, -2 levels in CVD development (primary outcome) and graft failure (GF) and death (secondary outcomes) in 2000 deceased donor KTRs. We used Cox regression to analyze the association of biomarker quartiles with outcomes. We adjusted for demographic; CVD- and transplant-related variables; medications; urine albumin-to-creatinine ratio; and randomization status. We calculated areas under the curves (AUCs) to predict CVD or death, and GF or death by incorporating biomarkers alongside clinical variables. RESULTS: Participants' median age was 52 IQR [45, 59] years: with 37% women and 73% identifying as white. Median time from transplantation was 3.99 IQR [1.58, 7.93] years and to CVD development was 2.54 IQR [1.11-3.80] years. Quartiles of angpt-1 were not associated with outcomes. Whereas higher levels of angpt-2 (quartile 4) were associated with about 2 times the risk of CVD, GF, and death (aHR 1.85 [1.25-2.73], p < 0.01; 2.24 [1.36-3.70)], p < 0.01; 2.30 [1.48-3.58], p < 0.01, respectively) as compared to quartile 1. Adding angiopoietins to preexisting clinical variables improved prediction of CVD or death (AUC improved from 0.70 to 0.72, p = 0.005) and GF or death (AUC improved from 0.68 to 0.70, p = 0.005). Angpt-2 may partially explain the increased risk of future CVD in KTRs. Further research is needed to assess the utility of using angiopoietins in the clinical care of KTRs. CONCLUSION: Angpt-2 may be a useful prognostic tool for future CVD in KTRs. Combining angiopoietins with clinical markers may tailor follow-up to mitigate CVD risk.

How we use angiopoietin-2 in the diagnosis and management of vascular anomalies.

The diagnosis of vascular anomalies remains challenging due to significant clinical heterogeneity and uncertain etiology. Evaluation using biopsy and/or genetic testing for somatic variants is invasive, expensive, and prone to sampling error. There is great need for noninvasive and easily measured blood laboratory biomarkers that can aid not only in diagnosis, but also management of treatments for vascular anomalies. Angiopoietin-2, a circulating blood angiogenic factor, is highly elevated in patients with kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon and kaposiform lymphangiomatosis. Here, we describe our clinical experience using serum angiopoietin-2 as a biomarker for diagnosis and monitoring response to treatment.

Disturbed atrial metabolism, shear stress, and cardiac load contribute to atrial fibrillation after ablation: AXAFA biomolecule study.

AIMS: Different disease processes can combine to cause atrial fibrillation (AF). Their contribution to recurrent AF after ablation in patients is not known. Cardiovascular processes associated with recurrent AF after AF ablation were determined by quantifying biomolecules related to inflammation, metabolism, proliferation, fibrosis, shear stress, atrial pressure, and others in the AXAFA biomolecule study. METHODS AND RESULTS: Twelve circulating cardiovascular biomolecules (ANGPT2, BMP10, CA125, hsCRP, ESM1, FABP3, FGF23, GDF15, IGFBP7, IL6, NT-proBNP, and hsTnT) were quantified in plasma samples obtained prior to a first AF ablation using high-throughput, high-precision assays. Cox regression was used to identify biomolecules associated with recurrent AF during the first 3 months after AF ablation. In 433 patients (64 years [58, 70]; 33% women), baseline concentrations of ANGPT2, BMP10, hsCRP, FGF23, FABP3, GDF15, and NT-proBNP were elevated in patients with recurrent AF (120/433; 28%). After adjustment for 11 clinical features and randomized treatment, elevated NT-proBNP [hazard ratio (HR) 1.58, 95% confidence interval (1.29, 1.94)], ANGPT2 [HR 1.37, (1.12, 1.67)], and BMP10 [HR 1.24 (1.02, 1.51)] remained associated with recurrent AF. Concentrations of ANGPT2, BMP10, and NT-proBNP decreased in patients who remained arrhythmia free, but not in patients with recurrent AF, highlighting their connection to AF. The other eight biomarkers showed unchanged concentrations. CONCLUSION: Elevated concentrations of ANGPT2, BMP10, and NT-proBNP are associated with recurrent AF after a first AF ablation, suggesting that processes linked to disturbed cardiomyocyte metabolism, altered atrial shear stress, and increased load contribute to AF after AF ablation in patients.

The correlation between serum angiopoietin-2 levels and acute kidney injury (AKI): a meta-analysis.

INTRODUCTION: The correlation between serum angiopoietin-2 levels and acute kidney injury (AKI) is a topic of significant clinical interest. This meta-analysis aims to provide a comprehensive evaluation of this relationship. CONTENT: A systematic search was conducted in PubMed, Embase, Web of Science, and Cochrane databases up to October 11, 2023. The included studies were evaluated using the Newcastle-Ottawa Scale (NOS) and Methodological Index for Non-Randomized Studies (MINORS). Weighted mean differences (WMD) and odds ratios (OR) were calculated using random-effects models. Sensitivity analysis, funnel plots, and Egger's test were used to assess the robustness and publication bias of the findings. Subgroup analyses were performed to explore potential variations between adults and children. SUMMARY: Eighteen studies encompassing a total of 7,453 participants were included. The analysis revealed a significant elevation in serum angiopoietin-2 levels in patients with AKI compared to those without (WMD: 4.85; 95 % CI: 0.75 to 0.27; I²=93.2 %, p<0.001). Subgroup analysis indicated significantly higher angiopoietin-2 levels in adults with AKI (WMD: 5.17; 95 % CI: 3.51 to 6.83; I²=82.6 %, p<0.001), but not in children. Additionally, high serum angiopoietin-2 levels were associated with an increased risk of AKI (OR: 1.58; 95 % CI: 1.39 to 1.8; I²=89.1 %, p<0.001). Sensitivity analysis validated the robustness of these results, showing no substantial change in the overall effect size upon the exclusion of individual studies. OUTLOOK: This meta-analysis supports a significant association between elevated serum angiopoietin-2 levels and increased risk of AKI. The observed differential association between adults and children highlights the need for further targeted research to understand these age-specific variations.

Serum angiopoietin-2: a promising biomarker for early diabetic kidney disease in children and adolescents with type 1 diabetes.

Albuminuria has been considered the golden standard biomarker for diabetic kidney disease (DKD), but appears once significant kidney damage has already occurred. Angiopoietin-2 (Angpt-2) has been implicated in the development and progression of DKD in adults. We aimed to explore the association of serum Angpt-2 levels with DKD in children and adolescents with type 1 diabetes mellitus (T1DM) of short duration (3-5 years) and to evaluate the predictive power of serum Angpt-2 in the early detection of DKD prior to the microalbuminuric phase. The current cross-sectional study included 90 children divided into three age and sex-matched groups based on urinary albumin-to-creatinine ratio (UACR): microalbuminuric diabetic group (n = 30), non-albuminuric diabetic group (n = 30), and control group (n = 30). All participants were subjected to anthropometric measurements, serum Angpt-2 and fasting lipid profile (total cholesterol, triglycerides, LDL-C, HDL-C, and Non-HDL-C) assessment. Glomerular filtration rate was estimated based on serum creatinine (eGFR-Cr). Higher serum Angpt-2 levels were detected in both diabetic groups compared to controls and in microalbuminuric compared to non-albuminuric diabetic group. There was no detected significant difference in eGFR-Cr values across the study groups. Serum Angpt-2 was positively correlated with triglycerides, LDL, Non-HDL-C, HbA1c, and UACR, while UACR, HbA1c, and Non-HDL-C were independent predictors for serum Angpt-2. Serum Angpt-2 at level of 137.4 ng/L could discriminate between microalbuminuric and non-albuminuric diabetic groups with AUC = 0.960 and at level of 115.95 ng/L could discriminate between the non-albuminuric diabetic group and controls with AUC = 0.976.Conclusion: Serum Angpt-2 is a promising potent biomarker for the detection of early stage of DKD in childhood T1DM before albuminuria emerges. What is Known? • Urine albumin-to-creatinine ratio (UACR) and glomerular filtration rate (GFR) are the golden standard but late biomarkers for DKD. • Angiopoietin-2 has been implicated in the development and progression of DKD in adults with diabetes, but has not been explored in T1DM children with DKD. What is New? • Higher serum angiopoietin-2 was detected in diabetic groups compared to controls and in microalbuminuric compared to non-albuminuric group. • Angiopoietin-2 correlated positively with triglycerides, LDL, Non-HDL-C, HbA1c, and UACR. • Serum angiopoietin-2 is a promising early diagnostic biomarker for DKD in children with T1DM.

Six-month outcomes of switching from aflibercept to faricimab in refractory cases of neovascular age-related macular degeneration.

PURPOSE: To assess 6-month outcomes of switching from aflibercept to faricimab in eyes with refractory neovascular age-related macular degeneration (nAMD) previously requiring monthly injections. METHODS: This multicenter retrospective study examined nAMD eyes receiving monthly aflibercept injections switched to faricimab administered monthly up to 4 injections followed by injections at a minimum of 2-month intervals as per drug labeling. Data regarding age, sex, number of previous injections, treatment intervals, and best-corrected visual acuity (BCVA) were collected. Central retinal thickness (CRT), subfoveal choroidal thickness (SFCT), and maximal pigment epithelial detachment (PED) height were measured by optical coherence tomography. RESULTS: The study included 130 eyes of 124 patients. At 6 months, 53 eyes (40.8%) continued on faricimab treatment (Group 1), while 77 eyes (59.2%) discontinued faricimab for various reasons (Group 2) the most common being worse exudation. There were no significant differences between the two groups at baseline. In Group 1, CRT and SFCT significantly decreased at 1 month (P = 0.013 and 0.008), although statistical significance was lost at 6 months (P = 0.689 and 0.052). BCVA and maximal PED height showed no significant changes; however, mean treatment intervals were extended from 4.4 ± 0.5 weeks at baseline to 8.7 ± 1.7 weeks at 6 months (P < 0.001) in Group 1. No clear predictors of response were identified. CONCLUSION: Switching from aflibercept to faricimab allowed for extension of treatment intervals from monthly to bimonthly in roughly 40% of eyes, suggesting that faricimab may be considered in refractory nAMD cases.

Efficacy, durability, and safety of faricimab up to every 16 weeks in patients with neovascular age-related macular degeneration: 2-year results from the Japan subgroup of the phase III TENAYA trial.

PURPOSE: To evaluate 2-year efficacy, durability, and safety of faricimab in the TENAYA Japan subgroup and pooled global TENAYA/LUCERNE cohort of patients with neovascular age-related macular degeneration (nAMD). METHODS: Subgroup analysis of TENAYA/LUCERNE (NCT03823287/NCT03823300): phase III, multicentre, randomised, active comparator-controlled, double-masked, non-inferiority trials. Treatment-naïve patients aged ≥ 50 years with nAMD were randomised (1:1) to intravitreal faricimab (6.0 mg up to every 16 weeks [Q16W] after 4 initial Q4W doses) or aflibercept (2.0 mg Q8W after 3 initial Q4W doses). Outcomes were assessed through year 2 for the TENAYA Japan subgroup (N = 133) and global pooled TENAYA/LUCERNE cohort (N = 1329). RESULTS: Vision and anatomic improvements achieved with faricimab at year 1 were maintained over 2 years and were generally comparable between the TENAYA Japan subgroup and pooled TENAYA/LUCERNE cohort. Adjusted mean best-corrected visual acuity (BCVA) change from baseline at year 2 for the TENAYA Japan subgroup and global pooled TENAYA/LUCERNE cohort was +7.1 (3.7-10.5) and +4.4 (3.2-5.5) letters in the faricimab arm, respectively, and +5.2 (1.9-8.6) and +4.3 (3.1-5.4) letters in the aflibercept arm, respectively. At week 112, the proportion of faricimab-treated patients on Q16W dosing was 61.0% and 63.1% in the TENAYA Japan subgroup and pooled TENAYA/LUCERNE cohort. Faricimab was well tolerated through year 2. CONCLUSION: Year 2 TENAYA Japan subgroup findings for faricimab were generally consistent with the pooled global TENAYA/LUCERNE results in patients with nAMD. Vision and anatomical benefits with faricimab were similar to those with aflibercept but with fewer injections.

Faricimab for neovascular age-related macular degeneration and diabetic macular edema: from preclinical studies to phase 3 outcomes.

Intravitreal anti-vascular endothelial growth factor (VEGF) therapy is the standard of care for diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD); however, vision gains and anatomical improvements are not sustained over longer periods of treatment, suggesting other relevant targets may be needed to optimize treatments. Additionally, frequent intravitreal injections can prove a burden for patients and caregivers. Angiopoietin-2 (Ang-2) has been explored as an additional therapeutic target, due to the involvement of Ang-2 in DME and nAMD pathogenesis. Recent evidence supports the hypothesis that targeting both VEGF and Ang-2 may improve clinical outcomes in DME and nAMD compared with targeting VEGF alone by enhancing vascular stability, resulting in reduced macular leakage, prevention of neovascularization, and diminished inflammation. Faricimab, a novel bispecific antibody that targets VEGF-A and Ang-2, has been evaluated in clinical trials for DME (YOSEMITE/RHINE) and nAMD (TENAYA/LUCERNE). These trials evaluated faricimab against the anti-VEGFA/B and anti-placental growth factor fusion protein aflibercept, both administered by intravitreal injection. In addition to faricimab efficacy, safety, and pharmacokinetics, durability was evaluated during the trials using a treat-and-extend regimen. At 1 year, faricimab demonstrated non-inferior vision gains versus aflibercept across YOSEMITE/RHINE and TENAYA/LUCERNE. In YOSEMITE/RHINE, faricimab improved anatomic parameters versus aflibercept. Reduction of central subfield thickness (CST), and absence of both DME and intraretinal fluid were greater in faricimab- versus aflibercept-treated eyes. In TENAYA/LUCERNE, CST reductions were greater for faricimab than aflibercept at the end of the head-to-head phase (0-12 weeks), and were comparable with aflibercept at year 1, but with less frequent dosing. CST and vision gains were maintained during year 2 of both YOSEMITE/RHINE and TENAYA/LUCERNE. These findings suggest that dual Ang-2/VEGF-A pathway inhibition may result in greater disease control versus anti-VEGF alone, potentially addressing the unmet needs and reducing treatment burden, and improving real-world outcomes and compliance in retinal vascular diseases. Long-term extension studies (RHONE-X, AVONELLE-X) are ongoing. Current evidence suggests that dual inhibition with faricimab heralds the beginning of multitargeted treatment strategies inhibiting multiple, independent components of retinal pathology, with faricimab providing opportunities to reduce treatment burden and improve outcomes compared with anti-VEGF monotherapy.

Three-month outcomes of treatment with faricimab or aflibercept for neovascular age-related macular degeneration: a propensity score matching study in a Japanese population.

PURPOSE: This study aimed to compare the treatment outcomes of patients with neovascular age-related macular degeneration (nAMD) who initially received faricimab or aflibercept treatment using propensity score matching (PSM) to align patient backgrounds. METHODS: Patients with treatment-naïve nAMD who received either faricimab or aflibercept for three consecutive monthly injections as the loading phase were enrolled in this study. In the 1:1 PSM, sex, age, best-corrected visual acuity (BCVA), central macular thickness (CMT), central choroidal thickness (CCT), and AMD subtypes in the pre-treatment state were selected as covariates. We examined the BCVA, CMT, CCT, and remaining fluid at 1-, 2-, and 3-month after the first injection. RESULTS: After PSM, 43 eyes were included in the faricimab and aflibercept group each. Both groups showed significant improvements in BCVA, CMT, and CCT at 1-, 2-, and 3-month after the initial injection compared with baseline. Meanwhile, no significant differences were observed between the two groups at any time point regarding BCVA, CMT, and CCT. At 1-month, 18.6% of patients in the faricimab group and 41.9% in the aflibercept group demonstrated residual subretinal fluid or intraretinal fluid, with a significant difference between the groups (P = 0.03). CONCLUSION: The BCVA improved after three loading injections of both faricimab and aflibercept. Faricimab may provide a favorable early treatment response in reducing subretinal fluid in a Japanese cohort.

A new look at angiogenesis inhibition of geniposide in experimental arthritis by blocking angiopoietin-2 exocytosis.

Angiogenesis is a key player in the pathogenesis of rheumatoid arthritis. Exocytosis from Weibel-Palade bodies is a prerequisite for angiopoietin-2 (Ang-2) to activate endothelial cells and initiate angiogenesis. Geniposide (GE) was previously reported to exert anti-angiogenic effects. The aim of this study was to shed light on whether and how GE regulates Ang-2 exocytosis. A rat model of adjuvant arthritis (AA) was established to evaluate the therapeutic effect of GE (60 and 120 mg/kg) especially in synovial angiogenesis. In addition, the Matrigel plug assay was used to detect the effect of GE (120 and 240 mg/kg) on angiogenesis in AA mice. In vitro, sphingosine-1-phosphate (S1P)-stimulated human umbilical vein endothelial cells (HUVECs) were used to investigate the effect and mechanism of GE on Ang-2 exocytosis. It was found that GE improved the symptoms of AA rats and inhibited angiogenesis in AA, which may be related to the down-regulation of S1P receptors 1, 3 (S1PR1, S1PR3), phospholipase Cß3 (PLCß3), inositol 1,4,5-trisphosphate receptor (IP3 R) and Ang-2 expression. The results of in vitro experiments showed that S1P induced rapid release of Ang-2 from HUVECs with multigranular exocytosis. Suppression of the S1P/S1PR1/3/PLCß3/Ca2+ signal axis by the S1PR1/3 inhibitor VPC23019 and the IP3 R inhibitor 2-APB blocked Ang-2 exocytosis, accompanied by diminished angiogenesis in vitro. GE dose-dependently weakened S1P/S1PR1/3/PLCß3/Ca2+ signal axis activation, Ang-2 exocytosis and angiogenesis in HUVECs (p < 0.05, p < 0.01). Overall, these findings revealed that angiogenesis inhibition of GE was partly attributed to the intervention of Ang-2 exocytosis through negatively modulating the S1P/S1PR1/3/PLCß3/Ca2+ signal axis, providing a novel strategy for rheumatoid arthritis anti-angiogenic therapy.

Serum angiopoietin-2/angiopoietin-1 ratio is associated with cardiovascular and all-cause mortality in peritoneal dialysis patients: a prospective cohort study.

INTRODUCTION: Our objective was to examine the factors associated with the serum angiopoietin-2/angiopoietin-1 (Angpt-2/Angpt-1) ratio in peritoneal dialysis (PD) patients and to investigate the association between Angpt-2/Angpt-1 ratio and cardiovascular and all-cause mortality. METHODS: Patients on PD who were prevalent between January 2014 and April 2015 in the center of Renji Hospital were enrolled. At the time of enrollment, serum and dialysate samples were collected to detect biochemical parameters, serum angiopoietin-2 and angiopoietin-1 levels. Patients were dichotomized into two groups according to a median of Angpt-2/Angpt-1 ratio and followed up prospectively until the end of the study. RESULTS: A total of 325 patients were enrolled, including 168 males (51.7%) with a mean age of 56.9 ± 14.2 years and a median PD duration of 32.4 (9.8-55.9) months. Multiple linear regression showed pulse pressure (ß = 0.206, p < .001) and high-sensitivity C-reactive protein (hs-CRP) (ß = 0.149, p = .011) were positively correlated with serum Angpt-2/Angpt-1 ratio, while residual renal function (RRF) (ß= -0.219, p < .001) was negatively correlated with serum Angpt-2/Angpt-1 ratio. Multivariate Cox regression analysis showed the high serum Angpt-2/Angpt-1 ratio was an independent predictor of cardiovascular mortality (hazard ratio (HR)=2.467, 95% confidence interval (CI) 1.243-4.895, p = .010) and all-cause mortality (HR = 1.486, 95%CI 1.038-2.127, p = .031). In further subgroup analysis by gender, a significant association was shown in high Angpt-2/Angpt-1 ratio with all-cause mortality in male (p < .05), but not in female patients (p>.05). CONCLUSIONS: High Angpt-2/Angpt-1 ratio is an independent risk factor for cardiovascular and all-cause mortality in PD patients.