Pathogenesis Of Retinal Vein Occlusion Research Articles

PON1, APOE and SDF-1 Gene Polymorphisms and Risk of Retinal Vein Occlusion: A Case-Control Study.

Numerous studies have tried to evaluate the potential role of thrombophilia-related genes in retinal vein occlusion (RVO); however, there is limited research on genes related to different pathophysiological mechanisms involved in RVO. In view of the strong contribution of oxidative stress and inflammation to the pathogenesis of RVO, the purpose of the present study was to investigate the association of inflammation- and oxidative-stress-related polymorphisms from three different genes [apolipoprotein E (APOE), paraoxonase 1 (PON1) and stromal cell-derived factor 1 (SDF-1)] and the risk of RVO in a Greek population. Participants in this case-control study were 50 RVO patients (RVO group) and 50 healthy volunteers (control group). Blood samples were collected on EDTA tubes and genomic DNA was extracted. Genotyping of rs854560 (L55M) and rs662 (Q192R) for the PON1 gene, rs429358 and rs7412 for the APOE gene and rs1801157 [SDF1-3'G(801)A] for SDF-1 gene was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Multiple genetic models (codominant, dominant, recessive, overdominant and log-additive) and haplotype analyses were performed using the SNPStats web tool to assess the correlation between the genetic polymorphisms and the risk of RVO. Binary logistic regression analysis was used for the association analysis between APOE gene variants and RVO. Given the multifactorial nature of the disease, our statistical analysis was adjusted for the most important systemic risk factors (age, hypertension and diabetes mellitus). The dominant genetic model for the PON1 Q192R single nucleotide polymorphism (SNP) of the association analysis revealed that there was a statistically significant difference between the RVO group and the control group. Specifically, after adjusting for age and hypertension, the PON1 192 R allele (QR + RR) was found to be associated with a statistically significantly higher risk of RVO compared to the QQ genotype (OR = 2.51; 95% CI = 1.02-6.14, p = 0.04). The statistically significant results were maintained after including diabetes in the multivariate model in addition to age and hypertension (OR = 2.83; 95% CI = 1.01-7.97, p = 0.042). No statistically significant association was revealed between the other studied polymorphisms and the risk of RVO. Haplotype analysis for PON1 SNPs, L55M and Q192R, revealed no statistically significant correlation. In conclusion, PON1 192 R allele carriers (QR + RR) were associated with a statistically significantly increased risk of RVO compared to the QQ homozygotes. These findings suggest that the R allele of the PON1 Q192R is likely to play a role as a risk factor for retinal vein occlusion.

Potential Mechanism of Platelet GPIIb/IIIa and Fibrinogen on Retinal Vein Occlusion

Purpose To explore the role of coagulation and fibrinolytic factors, and the potential mechanism of platelet aggregation in the pathogenesis of retinal vein occlusion. Methods Coagulation and fibrinolytic parameters in patients with retinal vein occlusion were determined using hemagglutinin and HISCL-5000. Relationships between these elevated parameters and factors representing typical clinical manifestations of retinal vein occlusion were examined, and these parameters were analyzed using a STRING database to indicate the potential role of platelet aggregation. Platelet glycoprotein IIb/IIIa (GPIIb/IIIa) levels were evaluated by flow cytometry after antiplatelet treatment in patients and mouse models. Furthermore, the GPIIb/IIIa ligand fibrinogen in peripheral blood and retina of mouse models was assessed by the turbidimetric method and real-time PCR, respectively. Results In patients, significant increases in peripheral blood fibrinogen and GPIIb/IIIa levels were observed (p = 0.0040, p < 0.0001, respectively). A positive correlation was observed between macular thickness (MT) and both fibrinogen and GPIIb/IIIa (r = 0.4528, p = 0.0063; r = 0.3789, p = 0.0427, respectively). After intravitreal injections of anti-vascular endothelial growth factor drugs, a significant reduction in fibrinogen levels was observed (p = 0.0072). In addition, the use of antiplatelet drugs resulted in a significant decrease in GPIIb/IIIa (p < 0.0001). In a mouse model, antiplatelet therapy significantly reduced both peripheral blood and retina fibrinogen levels and the overall rate of vein occlusion 3 days after occlusion (p < 0.0005). In addition, the reduction in GPIIb/IIIa levels after antiplatelet therapy was remarkable. Conclusion Fibrinogen and GPIIb/IIIa may be involved in retinal vein occlusion and blocking platelet aggregation may be a new therapeutic approach for retinal vein occlusion.

Роль геомагнитных возмущений в развитии окклюзионных поражений ретинальных вен (обзор литературы)

The review presents modern information on pathogenesis of retinal vein occlusions and risk factors for their formation. An in-depth analysis of role of external factors, among which influence of geomagnetic field and geomagnetic disturbances, has been carried out. The definition is given to such notions as magnetosensitivity, its pathogenetic mechanisms, and their role in formation of acute vascular events. Information about influence of geomagnetic disturbances on the formation of retinal vein occlusion is presented. Key words: geomagnetic disturbancies; magnetosensitivity; retinal vein occlusion.

Complete Blood Count-Derived Inflammation Indices and Retinal Vein Occlusion: A Case–Control Study

IntroductionThis study evaluated complete blood count-derived inflammation indices in patients with retinal vein occlusion (RVO).MethodsParticipants in this case–control study were 54 patients with RVO and 54 age- and sex-matched control subjects. All participants underwent a thorough ophthalmic examination, as well as blood sample testing for complete blood count. Comparison of all parameters derived from complete blood count as well as calculation of specific indices was performed between patients with RVO and controls.ResultsPatients with RVO presented significantly higher white blood cell count (p = 0.033), neutrophil count (p = 0.003), neutrophil-to-lymphocyte ratio (NLR, p = 0.002), red cell distribution width (RDW, p = 0.009), mean platelet volume (MPV, p = 0.023), and systemic immune-inflammatory index (SII, p = 0.007) compared to controls. Receiver operator characteristic curve (ROC) analysis showed that NLR was superior to other inflammatory indices, having the greatest area under the curve. The optimal cutoff value for NLR to predict RVO was 2.29 with 46.2% sensitivity and 77.8% specificity.ConclusionPatients with RVO presented increased NLR, RDW, MPV, and SII, providing evidence that inflammation plays an important role in the pathogenesis of RVO. Complete blood cell count-derived indices can be easily calculated and may serve as an easy, simple, and cost-effective tool to evaluate the degree of systemic inflammation in patients with RVO, so as to potentially guide treatment.

A Review of Intraocular Biomolecules in Retinal Vein Occlusion: Toward Potential Biomarkers for Companion Diagnostics.

Retinal vein occlusion (RVO) is one of the most common retinal vascular diseases. The pathogenesis of RVO is multifactorial and involves a complex interplay among a variety of vascular and inflammatory mediators. Many cytokines, chemokines, growth factors, and cell adhesion molecules have been reported to be implicated. Treatments for RVO are directed at the management of underlying risk factors and vision-threatening complications, including macula edema (ME) and neovascularization. Intravitreal anti-VEGF agents are currently considered as the first-line treatment for ME secondary to RVO (RVO-ME), but a substantial proportion of patients responded insufficiently to anti-VEGF agents. Since RVO-ME refractory to anti-VEGF agents generally responds to corticosteroids and its visual outcome is negatively correlated to disease duration, prediction of treatment response at baseline in RVO-ME may significantly improve both cost-effectiveness and visual prognosis. Several bioactive molecules in the aqueous humor were found to be associated with disease status in RVO. This review aims to present a comprehensive review of intraocular biomolecules reported in RVO, including VEGF, IL-6, IL-8, MCP-1, sICAM-1, IL-12, IL-13, sVEGFR-1, sVEGFR-2, PDGF-AA, etc., highlighting their association with disease severity and/or phenotype, and their potential roles in prognostic prediction and treatment selection. Some of these molecules may serve as biomarkers for aqueous humor-based companion diagnostics for the treatment of RVO in the future.

Evaluation of Systemic Endothelial Dysfunction in Retinal Vein Occlusions.

Objectives:Our aim in this study was to evaluate the systemic endothelial dysfunction status and carotid intima-media thickness (CIMT) in patients with retinal vein occlusion (RVO).Methods:Seventy-six patients who presented to the clinic with the diagnosis of RVO and 76 age- and gender-matched healthy individuals without a RVO history were included in the study. The patients’ best-corrected visual acuity (BCVA) and central macular thickness (CMT) were measures, and diabetes, hypertension, hyperlipidemia, carotid artery disease, body mass index, and smoking histories were recorded. The endothelial function levels of the patients, pulse wave velocity (PWV), flow-mediated dilation (FMD), and CIMT were measured. Endothelial dysfunction was detected by applying the FMD technique to the brachial artery. CIMT was evaluated by B-mode ultrasonography. Serum hematological parameters were evaluated.Results:BCVA (logMAR) was 1.39±1.30 in patients with RVO and 0.028±1.22 in the control group (p<0.001). CMT was 588.76±104.02 µm in patients with RVO and 265.20±45.11 µm in the control group (p=0.001). Hypertension, diabetes, and hyperlipidemia were found to be significantly higher in patients with RVO (p-value 0.001, 0.002, and 0.001, respectively). There was a significant difference between the groups in terms of FMD, PWV, and CIMT (all of them, p<0.001).Conclusion:The deterioration of FMD and PWV, which are indicators of endothelial dysfunction in patients with RVO, suggests that systemic endothelial dysfunction may play a role in the pathogenesis of RVO. Comprehensive studies with more patient participation are needed.

Optical Coherence Tomography Angiography Characteristics Serve as Retinal Vein Occlusion Therapeutic Biomarkers for Dexamethasone Intravitreal Implant.

Background Retinal vein occlusion (RVO) is the second most common vision-threatening retinal vascular disease. Intravitreal dexamethasone implant has been applied to treat macular edema secondary to RVO (RVO-ME). However, the alteration of morphologic features detected with optical coherence tomography angiography (OCTA) has not been fully studied in RVO-ME patients before and after the treatment. Objective This study is aimed at identifying potential therapeutic targets in RVO with integrative bioinformatic analysis and compares the OCTA characteristics alterations in patients with RVO-ME receiving injection of dexamethasone intravitreal implant. Methods Bioinformatic analysis was analyzed in GSE101398 dataset from the Gene Expression Omnibus database. Multiple functional enrichment analyses were performed, and protein-protein interaction network was constructed to visualize the key node genes. Eleven eyes with RVO-ME were examined with OCTA before and after intravitreal dexamethasone implant. The OCTA parameters, including macular thickness, vessel density, foveal avascular zone parameters, the number of hyperreflective foci (HRF), area of cystoid edema, and subretinal fluid (SRF), were compared. The correlation was analyzed between best-corrected visual acuity (BCVA) and OCTA parameters. Results A total of 79 differentially expressed genes were identified. Functional enrichment analyses revealed the enriched inflammatory events in RVO. In RVO-ME, Pearson correlation revealed that baseline BCVA was positively correlated with the area of SRF and central macular thickness, while no correlation was detected between baseline BCVA and HRF number or the area of cystoid edema. The visual acuity improved, and the central macular thickness was decreased after intravitreal dexamethasone implant injection. Besides, the number of HRF, the area of cystoid edema, and SRF were significantly alleviated after dexamethasone intravitreal injection. Conclusion Retinal inflammation plays a crucial role in RVO pathogenesis. The imaging biomarkers of RVO including Müller glial intracellular edema, and retinal pigment epithelium dysfunction, could be assessed in OCTA and attenuated by intravitreal dexamethasone implant effectively.

Retinal vein occlusion: drug targets and therapeutic implications

Introduction The pathogenesis of retinal vein occlusion (RVO) is extremely complex and includes several mediators. These mediators represent potential drug targets that can be used in the development of intravitreal drugs. Areas covered PubMed/MEDLINE databases were accessed between April-May 2021 to find the most relevant scientific papers regarding drug targets and therapeutic implications in RVO, focusing on current therapeutic options and potential cornerstones of future advances in treatment. Expert opinion Before the introduction of intravitreal therapies, the visual outcome following a diagnosis of RVO was extremely poor. Anti-VEGF and corticosteroid treatments have radically changed RVO prognosis, helping to preserve patients’ visual function and their quality of life. According to current clinical data, anti-VEGF and corticosteroid drugs are associated with both pros and cons; the present recommendation is to employ anti-VEGF molecules as a first-line treatment. Advances in our understanding of the biomolecular characteristics of RVO offer a solid basis for the development of new therapeutic targets and treatments.

Methods for making animal models of retinal vein occlusion

Retinal vein occlusion (RVO) is divided into branch retinal vein occlusion and central retinal vein occlusion. It is characterized by retinal vein dilatation and tortuosity, blood flow stasis, bleeding and edema. It is often accompanied by macular edema (ME) and neovascularization. Neovascular glaucoma is the most serious complications. RVO is the second most common cause of visual loss classified under retinal vascular disorders after diabetic retinopathy. So far, the number of patients suffering from retinal vein occlusion has increased, but the pathogenesis of retinal vein occlusion has not been fully understood and there are no treatments that are very long-lasting. The research of animal models on the pathogenesis and treatment of the RVO is very important. Therefore, this article gives a briefly review to the animals and model making methods used in retinal vein occlusion experiments, and discusses the advantages and disadvantages of various RVO animal models.

Platelet and Thrombophilia-Related Risk Factors of Retinal Vein Occlusion.

Retinal vein occlusion (RVO) is a heterogenous disorder in which the formation of a thrombus results in the retinal venous system narrowing and obstructing venous return from the retinal circulation. The pathogenesis of RVO remains uncertain, but it is believed to be multifactorial and to depend on both local and systemic factors, which can be divided into vascular, platelet, and hypercoagulable factors. The vascular factors include dyslipidaemia, high blood pressure, and diabetes mellitus. Regarding the platelet factors, platelet function, mean platelet volume (MPV), platelet distribution width (PDW), and platelet large cell ratio (PLCR) play key roles in the diagnosis of retinal vein occlusion and should be monitored. Nevertheless, the role of a hypercoagulable state in retinal vein occlusion remains unclear and requires further studies. Therefore, the following article will present the risk factors of RVO associated with coagulation disorders, as well as the acquired and genetic risk factors of thrombophilia. According to Virchow’s triad, all factors mentioned above lead to thrombus formation, which causes pathophysiological changes inside venous vessels in the fundus of the eye, which in turn results in the vessel occlusion. Therefore, a diagnosis of retinal vein occlusion should be based on both eye examination and general examination, including laboratory tests.

Fatty acid-binding protein 4 is an independent factor in the pathogenesis of retinal vein occlusion.

The main objective of current study was to identify the fatty acid-binding protein 4 (FABP4) expressed in both adipocytes and macrophages in vitreous fluid from patients with retinal vein occlusion (RVO). Patients with RVO (n = 14, CRVO; central RVO n = 5, BRVO; branch RVO n = 9) and non-RVO (macular hole or epiretinal membrane, n = 18) were surgically treated by a 25 or 27G vitrectomy. Undiluted vitreous fluid samples obtained as the result of surgery were subjected to enzyme-linked immunosorbent assays to measure the levels of FABP4 and vascular endothelial growth factor A (VEGFA).Data including ocular blood flow by laser speckle flow graphy (LSFG), height and weight, systemic blood pressures and several blood biochemistry values were collected. Among the LSFG mean blur rate (MBR) values of the optic nerve head (ONH) at baseline, MA (MBR of all area), MV (MBR of the vascular area), and MV-MT (MBR of the tissue area) were significantly decreased in patients with CRVO. The levels of V-FABP4 and V-VEGFA were relatively or significantly (P< 0.05) higher in the BRVO or CRVO patients compared to the non-RVO patients, respectively. A positive correlation (r = 0.36, P = 0.045) or a negative correlation (r = -0.51, P = 0.006) was observed between Log V-FABP4 and Log V-VEGF, or Log V-FABP4 and MV-MT at post-operative 1-week, respectively. Furthermore, neither of these factors were affected with respect to sex, body mass index and several clinical parameters that were collected, except that a positive correlation was observed for Log V-FABP4 with blood urea nitrogen. Stepwise multivariable regression analyses indicated that MV-MT at post-operative 1week was independently associated with Log V-FABP4 after adjustment for age and gender, and gender and Log V-FABP4 were independently associated with Log V-VEGFA after adjustment for age. The findings reported herein suggest that an independent factor, FABP4 may be synergistically involved in the pathogenesis of RVO with VEGFA.

Results from the Population-Based Gutenberg Health Study Revealing Four Altered Autoantibodies in Retinal Vein Occlusion Patients.

Purpose Retinal vein occlusion (RVO) is the second most common retinal vascular disease and a major cause of visual impairment. In this study, we aimed to observe whether RVO cases have different antibody profiles as a new potential risk factor and whether a conversion of retinal vein occlusion (RVO) to neovascular glaucoma (NVG), one of the major complications, is occurring within a 5-year timeframe. Methods We performed a nested case-control study (1 : 4) within the Gutenberg Health Study (GHS), a population-based, prospective cohort study in the Rhine-Main Region of Germany including 15,010 participants. RVO subjects (n = 59) were identified by grading of fundus photographs. Optic nerves of RVO subjects and age- and sex-matched controls (n = 229) at baseline and their follow-up examination after 5 years were analyzed for glaucomatous alterations. Of all RVO subjects and controls, serum autoantibody profiles were measured using in-house manufactured antigen-antibody microarrays. Results Of the 59 RVO patients, 3 patients (5%) showed glaucomatous optic disc alterations at baseline, whereas no new glaucoma case was detected at 5-year follow-up. Four of the autoantibodies measured (against dermcidin, neurotrophin-3, superoxide dismutase 1, and signal recognition particle 14 kDa protein) were significantly increased in the serum of RVO patients (p < 0.001). Multivariable conditional logistic regression analysis showed that 3 of these 4 antibodies were independent of cardiovascular risk factors. Conclusions We found several autoantibodies associated with RVO, targeting proteins and structures possibly involved in RVO pathogenesis.

Endothelial dysfunction and impaired arterial wall properties in patients with retinal vein occlusion.

Retinal vein occlusion (RVO) is a common retinal vascular lesion, and a leading cause of visual impairment. Patients with RVO have an increased risk for cardiovascular disease and share multiple common risk factors. In this study, we investigated the endothelial function and arterial stiffness of patients with RVO compared to healthy-control (CL) subjects. We enrolled 40 consecutive patients with RVO and 40 CL subjects. RVO was diagnosed by an ophthalmologist, endothelial function was evaluated by flow mediated dilation (FMD) in the brachial artery, and carotid-femoral pulse wave velocity (PWV) and augmentation index (AIx) of the radial artery were measured to evaluate arterial stiffness and reflected waves, respectively. No significant differences were detected between the studied groups in sex, age, presence of hypertension or dyslipidemia, body mass index, systolic and diastolic blood pressure levels, total cholesterol levels, and smoking habits (p > 0.05 for all). However, patients with RVO had impaired FMD (p = 0.002) and increased PWV (p = 0.004), even after adjustment for several confounders. Both FMD and PWV were also significantly and independently associated with the development of RVO. Furthermore, a significant and positive correlation between PWV and systolic blood pressure existed only in the CL group. Therefore, we have shown that RVO is associated with significant endothelial dysfunction and increased arterial stiffness. Our results strengthen the vascular theory, according to which, systemic endothelial dysfunction and arteriosclerosis play a significant role in the pathogenesis of RVO.

Changes in Aqueous and Vitreous Inflammatory Cytokine Levels in Retinal Vein Occlusion: A Systematic Review and Meta-analysis.

Evidence suggests that inflammatory cytokines not only play a role in the pathogenesis of retinal vein occlusion (RVO) but also may be useful as biomarkers to predict disease severity and response to treatment. We aimed to quantitatively summarize data on inflammatory cytokines associated with RVO. A systematic search of peer-reviewed English-language articles was performed without year limitation up to August 19, 2019. Studies were included if they provided data on aqueous or vitreous cytokine concentrations in patients with RVO. Data were extracted from 116 studies that encompassed 3242 study eyes with RVO and 1402 control eyes. Effect sizes were generated as standardized mean differences (SMDs) of cytokine concentrations between patients with RVO vs controls. Among the 4644 eyes in 116 studies, aqueous and vitreous concentrations (SMD, 95% CI, and P value) of interleukin (IL)-6 (aqueous: 1.23, 0.65 to 1.81, P < .001 vitreous: 0.70, 0.49 to 0.90, P < .001), IL-8 (aqueous: 1.11, 0.73 to 1.49, P < .001; vitreous: 1.19, 0.73 to 1.65, P < .001), monocyte chemoattractant protein 1(aqueous: 1.22, 0.72 to 1.72, P < .001; vitreous 1.42, 0.92 to 1.91, P < .001), vascular endothelial growth factor (VEGF) (aqueous: 1.52, 1.09 to 1.94, P < .001; vitreous: 0.99, 0.78 to 1.21, P < .001) were significantly higher in patients with RVO than in healthy controls. Only aqueous concentrations of IL-10 (0.81, 0.45 to 1.18, P < .001), angiopoietin 4 (1.96, 0.92 to 3.00, P < .001), and platelet-derived growth factor (PDGF)-AA (0.82, 0.35 to 1.30, P < .001) were significantly higher in patients with RVO than in healthy controls. Only the vitreous concentration of soluble intercellular adhesion molecule-1 (sICAM-1) (1.23, 0.83 to 1.63, P < .001) was significantly higher in patients with RVO. No differences, failed sensitivity analyses, or insufficient data were found between patients with RVO and healthy controls for the concentrations of the remaining cytokines. Several cytokines in addition to VEGF have the potential to be useful biomarkers and therapeutic targets in RVO.

Mapping research trends of retinal vein occlusion from 2009 to 2018: a bibliometric analysis.

ObjectivesTo map publication trends and explore research hotspots of retinal vein occlusion (RVO) study.MethodsBased on Web of Science Core Collection (WoSCC), a bibliometric analysis was carried out. The knowledge map was constructed by VOSviewer v.1.6.10 to visualize the annual publication number, the distribution of countries, international collaborations, author productivity, source journals, cited reference and keywords in this field.ResultsA total of 2,135 peer-reviewed papers were retrieved on RVO from 2009 to 2018. The United States ranks highest among countries with the most publications and the most active institution was Kyoto University. Noma H contributed the most publications in this field. Retina—The Journal of Retinal and Vitreous Disease was the most prolific journal in RVO research. The top cited references mainly presented anti-VEGF medications on the management of RVO. The keywords formed six clusters: (1) Risk factors and pathogenesis of RVO; (2) Metabolismof RVO; (3) Therapeutic use of corticosteroids on RVO; (4) Diagnostic methodsof RVO; (5) Management of macular edema secondary to RVO (6) Anti-VEGFtreatment of RVO.ConclusionsThe six major research hotspots could provide an insight into RVO research and valuable information for researchers to identify potential collaborators and partner institutions.

Vasoactivity of retinal veins: A potential involvement of endothelin-1 (ET-1) in the pathogenesis of retinal vein occlusion (RVO)

PurposeWhilst the pathogenesis of retinal vein occlusion (RVO) is still unclear, systemic hypertension and increased level of endothelin-1 (ET-1) are known risk factors. Therefore, we studied the influence of ET-1 on the retinal veins in hypertensive rats. MethodsWe focused on the behavior of retinal veins in spontaneous hypertensive rats (SHR). To determine whether ET-1 was associated with the blood flow in eyes of SHRs, the chorioretinal blood flow in the rats was assessed using laser speckle flowgraphy (LSFG-Micro, Softcare, Fukuoka, Japan) before and after an intravenous injection of ET-1 under general anesthesia. In addition, retinas from SHRs and age-matched normotensive Wistar-Kyoto rats (WKYs) were removed, and retinal sections were immunostained for the ET-A and ET-B receptors. The protein levels of both ET-1 receptors and hypoxia-inducible factor 1 (HIF-1) in the retinal tissues were also determined by western blot analysis. ResultsOne of the retinal veins became exceptionally constricted and was nearly occluded, and the chorioretinal blood flow significantly decreased in the retinas of SHRs following the injection of ET-1. Immunoreactivity to ET-A receptor was higher in SHR retinas than in WKY retinas. The protein levels of ET-A receptor and HIF-1 were also significantly higher in SHR retinas than in WKY retinas. ConclusionsAn increase of ET-1 in circulating blood leads to the local constriction of retinal veins and this effect is accentuated in hypertensive rats by an upregulation of ET-A receptor. It is plausible that such a constriction of retinal veins increases retinal venous pressure, and may even contribute to the pathogenesis of RVO.

STUDIES OF SYSTEMIC AND LOCAL CYTOKINE LEVEL IN RETINAL VEIN OCCLUSION ASSOCIATED WITH ANTIANGIOGENIC THERAPY

The paper presents results of studying systemic and local level of cytokines in retinal vein occlusion following antiangiogenic therapy. The study of cytokine concentrations was conducted in the general group of patients, and depended on the type of retinal vein occlusion before and after intravitreal injections of Ranibizumab. We examined thirty-two patients with retinal vein occlusion. We performed standard ophthalmological examinations, spectral optical coherence tomography, fluorescent angiography in order to establish the type of retinal vein occlusion. We determined concentration of vascular endothelial growth factor (VEGF), endothelin-1, interleukin-1, interleukin-6 and tumor necrosis factor-α in serum and tears by enzyme immunoassay before treatment, and 3 months after regular injections of Ranibizumab. The obtained data prove that all the patients with retinal vein occlusion had significantly increased VEGF levels in blood serum and tear fluid compared to the control group. We have revealed a positive correlation between levels of VEGF in tear fluid, and interleukin-1, interleukin-6 and endothelin-1 in the tears, as well as with VEGF concentrations and endothelin-1 in serum. We have found an increase of endothelin-1 in tear and serum, alongd with interleukins and tumor necrosis factor-α in tear fluid, with maximal concentrations of some factors in ischemic type of retinal vein occlusion. Following antiangiogenic therapy in patients with non-ischemic type, there was a significant decrease in VEGF level, interleukin-6 and tumor necrosis factor-α in the serum, vascular endothelial growth factor and interleukin-1 in tears. In patients with ischemic type, a significant decrease in VEGF and interleukin-6 concentrations in tears, endothelin-1 and interleukin-1 in blood serum. Thus, our research showed the role of interleukins, tumor necrosis factor-α, vascular endothelial growth factor and endothelin-1 in pathogenesis of retinal vein occlusion.

Reversible retinal vessel closure from VEGF-induced leukocyte plugging.

Clinical trials in patients with macular edema due to diabetic retinopathy or retinal vein occlusion (RVO) have shown that suppression of VEGF not only improves macular edema, but also reopens closed retinal vessels, prevents progression of vessel closure, and improves retinopathy. In this study, we show the molecular basis for those clinical observations. Increased retinal levels of VEGF in mice cause plugging of retinal vessels with leukocytes, vessel closure, and hypoxia. Suppression of VEGF reduces leukocyte plugging, causing reperfusion of closed vessels. Activation of VEGFR1 contributes to leukocyte recruitment, because it is significantly reduced by an anti-VEGFR1-neutralizing antibody. High VEGF increases transcriptional activity of NF-κB and expression of NF-κB target genes, particularly Vcam1. Injection of an anti-VCAM-1-neutralizing antibody reduces VEGF-induced leukocyte plugging. These data explain the broad range of benefits obtained by VEGF suppression in patients with ischemic retinopathies, provide an important insight into the pathogenesis of RVO and diabetic retinopathy, and suggest that sustained suppression of VEGF early in the course of these diseases may prevent vessel closure, worsening ischemia, and disease progression. This study also identifies VEGFR1 and VCAM-1 as molecular targets whose suppression could supplement VEGF neutralization for treatment of RVO and diabetic retinopathy.

Erythrocyte oxidative stress is associated with cell deformability in patients with retinal vein occlusion

Background Retinal vein occlusion (RVO) is characterized by vision loss resulting from hypoperfusion and hypoxia of the retina. RVO pathogenesis is not yet fully understood, although blood hyperviscosity has been observed. Erythrocyte deformability plays a key role in determining blood viscosity, and it is critical to microvascular perfusion and oxygen delivery. It has been shown that oxidative stress-induced erythrocyte membrane fluidity alterations are linked to the progression of cardiovascular diseases. Objectives To determine whether erythrocytes from RVO patients show signs of oxidative stress, and whether this condition can modify the hemorheologic profile in these patients. Patients and Methods We analyzed the entire hemorheologic profile and erythrocyte oxidative stress - reactive oxygen species (ROS) production and membrane lipid peroxidation - in 128 RVO patients and 128 healthy subjects, matched for age and sex. Fluorescence anisotropy was used to evaluate the fluidity of erythrocyte membranes. Results In RVO patients, erythrocyte oxidative stress was present and positively correlated with whole blood viscosity and erythrocyte deformability. Multivariate linear regression analysis after adjustment for age, cardiovascular risk factors, medications, leukocyte number and mean corpuscular volume indicated that erythrocyte-derived ROS and erythrocyte lipid peroxidation were significantly and positively correlated with erythrocyte membrane viscosity and deformability. Moreover, in vitro experiments demonstrated that ROS have a key role in erythrocyte membrane fluidity. Conclusions Our findings indicate that erythrocyte oxidative stress plays a key role in the pathogenesis of RVO, and pave the way to new therapeutic interventions.

Percentage of primary open angle glaucoma in retinal vein occlusion patients

Background Researches determined that the pathogenesis of retinal vein occlusion (RVO) is associated with primary open angle glaucoma (POAG) in Caucasian population.However, the relationship between RVO and POAG in Asian population is unclear. Objective This study was to survey the percentage of POAG in RVO patients in China. Methods A prospective cross-sectional observational study based on hospital was performed.Three hundred and seventy five patients with newly diagnosed RVO by fluorescein fundus angiography (FFA) were consecutively enrolled in Peking University Third Hospital from October 2011 to May 2013, and gonioscopy was carried out in all the patients.Glaucoma was diagnosed according to the criteria of the International Society of Geographical and Epidemiological Ophthalmology (ISGEO). RVO was classified into central retinal vein occlusion (CRVO), hemicentral retinal vein occlusion (HRVO) and branch retinal vein occlusion (BRVO) based on fundus photograph and FFA, or classified into arteriovenous crossing RVO (AV-RVO), optic cup RVO(OC-RVO), optic nerve RVO without optical nerve head swelling (NONHS-RVO) and RVO with optical nerve head swelling (ONHS-RVO) based on the sites of venous occlusion.The percentages of POAG in different types of RVO were calculated.This study was approved by Ethic Committee of Peking University Third Hospital, and written informed consent was obtained from each patient before entering study cohort. Results Three hundred and seventeen RVO patients finished screening of glaucoma, with the response rate 84.5%.The percentage of POAG is 8.2% in RVO patients, including 7.1% in the CRVO patients, 23.5% in HRVO patients and 6.2% in BRVO patients.The percentage of POAG was significantly higher in OC-RVO patients (27.9%) and NONHS-RVO patients (13.2%) than that in AV-RVO patients (4.7%) and ONHS-RVO patients (1.3%) (all at P<0.05). Conclusions The overall percentage of POAG in RVO patients in China is 3-4 times higher than general population.Higher percentage of POAG is found in OC-RVO patients and NONHS-RVO patients, suggesting that pathogenesis of RVO is probably associated with the glaucomatous anatomic changes of optical nerve head. Key words: Glaucoma/statistics & numerical data; Retinal vein; Thrombosis/statistics & numerical data; Glaucoma, open angle; Retinal vein occlusion; Humans