Quantify retinal structure in high-altitude residents with and without high altitude polycythemia.

BACKGROUND: To assess retinal structural parameters in high-altitude (HA) residents with and without high altitude polycythemia (HAPC) and to elucidate the relationship between retinal structural parameters and hemoglobin (HGB). METHODS: This cross-sectional study included 55 HAPC patients and 52 healthy HA residents. Retinal structural parameters included retinal nerve fiber layer (RNFL) thickness, optic nerve head (ONH) parameters and retinal vessel diameter. RNFL thickness were acquired from spectral domain optical coherence tomography (SD-OCT) built-in software. ONH parameters including neuroretina rim height, cup area, disc area and vertical cup/disc ratio were obtained by OCT built-in software and ImageJ software. Retinal vessel measurements including central retinal artery equivalent (CRAE), central retinal vein equivalent (CRVE) and AVR (artery/vein ratio) were calculated by revised formulas for summarizing retinal vessel diameters. All parameters were compared between HAPC group versus healthy HA group. The associations between retinal parameters and HGB were assessed by Pearson correlation analyses. RESULTS: In comparison of HAPC group versus healthy HA group, RNFL thickness was thicker in the nasal quadrant of the optic disc in HAPC group (74.82 ± 14.4 VS. 66.06 ± 13.71 µm, P = 0.002). Bigger disc area and bigger cup area were also observed in HAPC group (all P < 0.05). Meanwhile, the value of CRVE was higher in HAPC group which suggested that retinal veins dilated significantly in HAPC patients (P < 0.001), however, CRAE and AVR were comparable between groups. Pearson analyses revealed that HGB was positive correlated with CRVE in HAPC group (r = 0.469, P = 0.003). CONCLUSIONS: long-term HA exposure secondary HAPC could result in thickened RNFL, enlarged ONH and dilated retinal veins. Moreover, increased blood viscosity caused by HGB should be responsible for dilated veins, but not for thickened RNFL and enlarged ONH. This study deepens the understanding of the impact of HA environment on retina.

Prevalence of and risk factors for diabetic retinopathy in residents with different types of abnormal glucose metabolism with or without hypertension: A suburban community-based cross-sectional study.

Aims: The present study examined the prevalence and risk factors for diabetic retinopathy (DR) in residents with abnormal glucose metabolism in a community. Methods: 6029 subjects were included and underwent standardized interviews and comprehensive examinations. Residents with diabetes were divided into nondiabetic retinopathy (NDR) and DR groups and non-hypertension and hypertension groups. Unconditional multivariate logistic regression models were used to analyze the risk factors for DR in different groups. Results: The prevalence of DR in diabetes was 9.9%, and the prevalence of retinopathy, which also has the typical signs of DRs, such as retinal microaneurysms, in prediabetes and normal glucose tolerance was 5.2% and 5.3%, respectively. An elevated waist-to-hip ratio (WHR) (female≥0.85, male≥0.9)[OR 1.683, 95% CI (1.016, 2.790)], systolic blood pressure (SBP)≥140 mmHg [OR 1.875, 95% CI (1.158, 3.034)], elevated HbA1c [OR 1.410, 95% CI (1.220, 1.629)], HbA1c ≥6.5% [OR 2.149, 95% CI (1.320, 3.498)], antidiabetic drug use [OR 3.798, 95% CI (2.209, 6.529)], elevated fasting blood glucose [OR 1.176, 95% CI (1.072, 1.289)], elevated postprandial blood glucose [OR 1.090, 95% CI (1.033, 1.150)] and nonspecific ST-T segment changes on electrocardiography [OR 2.555, 95% CI (1.556, 4.196)] were risk factors for DR. Duration of diabetes [OR 1.206, 95% CI (1.028, 1.415)], elevated WHR [OR 3.796, 95% CI (1.144, 12.603)], elevated waist circumference [OR 6.874, 95% CI (1.403, 33.665)], elevated HbA1c [OR 1.435, 95% CI (1.046, 1.970)], HbA1c ≥6.5% [OR 6.850, 95% CI (1.771, 26.501)], and concurrent metabolic syndrome [OR 3.975, 95% CI (1.144, 13.815)] were risk factors for DR in diabetes without hypertension, and elevated HbA1c [OR 1.395, 95% CI (1.183, 1.645)], HbA1c ≥6.5% [OR 1.745, 95% CI (1.027, 2.966)], use of antidiabetic drugs [OR 4.781, 95% CI (2.624, 8.711)], elevated fasting blood glucose [OR 1.146, 95% CI (1.034, 1.270)], elevated postprandial blood glucose [OR 1.083, 95% CI (1.020, 1.151)], and nonspecific ST-T segment changes on electrocardiography [OR 2.616, 95% CI (1.531, 4.469)] were risk factors for DR in diabetes with hypertension. Conclusion: Retinopathy was found in subjects with normal glucose tolerance and prediabetes. There were differences in risk factors for DR in diabetic patients with and without hypertension.

Effects of long-term high-altitude exposure on retinal and choroidal microcirculation.

PURPOSE: To quantify the effect of long-term high-altitude (HA) exposure on retinal and choroidal microcirculation and to relate these changes to high-altitude polycythemia (HAPC), as a proxy for etiopathogenesis of high-altitude related retinopathy (HAR). METHODS: Fifty-one HAPC patients, 50 healthy HA residents, and 43 low altitude (LA) residents were recruited in this study. Optical coherence tomography angiography (OCTA) and enhanced depth imaging (EDI)-OCT images were analyzed. Retinal microvascular metrics included vessel density (VD), skeleton density (SD), fractal dimension (FD), and foveal avascular zone (FAZ). Choroidal microvascular metrics included subfoveal choroidal thickness (SFCT) and choroidal vascularity index (CVI). All metrics were calculated by ImageJ software and compared among HAPC group, healthy HA group, and LA group. RESULTS: In HAPC group, VD (30.62 ± 3.67%), SD (13.25 ± 1.64%), FD (1.79 ± 0.04), and the CVI (63.01 ± 1.42%) were significant lower and SFCT (403.25 ± 94.3 µm) was significant thicker than healthy HA group (all P < 0.001). FAZ area was comparable between two groups (0.42 ± 0.1 vs. 0.4 ± 0.11 mm2, P = 0.411). However, these metrics were not different between healthy HA group and LA group (all P > 0.05) except for FD was lower in HA group (P < 0.001). Pearson's correlation analyses revealed HGB was negatively related with VD (r = - 0.562, P < 0.001) and positively related with SFCT (r = 0.505, P < 0.001) in healthy HA group; however, no associations between HGB and vascular metrics in HAPC group were detected (all P > 0.05). CONCLUSIONS: Long-term exposure to HA environment induces retinal and choroidal microcirculation disturbance in HAPC patients. However, these changes were not evident in healthy HA residents because of adaptation.

Elevated plasma and vitreous levels of leucine-rich-α2-glycoprotein are associated with diabetic retinopathy progression.

PURPOSE: To investigate the association of plasma and vitreous leucine-rich-α2-glycoprotein (LRG1) with diabetic retinopathy (DR) progression. METHODS: A total of 86 outpatients and 33 inpatients were recruited. Outpatients with type 2 diabetes mellitus (T2DM) were classified as T2DM without DR (n = 22), nonproliferative DR (NPDR) (n = 20) and proliferative DR (PDR) (n = 22) based on international clinical DR severity scales. A total of 86 plasma and 33 vitreous samples were collected and subjected to enzyme-linked immunosorbent assay. The diagnostic value of plasma LRG1 was tested using receiver operating characteristic (ROC) curves. RESULTS: Plasma LRG1 in PDR patients (9025 ± 1870 pg/ml) was significantly increased as compared with controls (5975 ± 2022 pg/ml), T2DM without DR (6550 ± 2359 pg/ml) and NPDR patients (6550 ± 2359 pg/ml) (p < 0.0001). Vitreous LRG1 in PDR patients was elevated by approximately 4.3-fold than that in controls (562.1 ± 273.5 ng/ml versus 130.0 ± 102.8 ng/ml, p = 0.000). The area under the ROC curve value for plasma LRG1 was 0.786 (p < 0.0001). The maximal Youden index was 0.4372 and the optimal cut-off value of LRG1 was 7357.043 pg/ml with 81.82% sensitivity and 61.90% specificity. CONCLUSION: Plasma and vitreous LRG1 levels were elevated in patients with PDR. Leucine-rich-α2-glycoprotein (LRG1) might be a potential risk-warning marker for PDR.

Fenofibrate Exerts Protective Effects in Diabetic Retinopathy via Inhibition of the ANGPTL3 Pathway.

Purpose: Fenofibrate has been demonstrated to exert a promising therapeutic effect against diabetic retinopathy. Angiopoietin-like 3 (ANGPTL3) has been shown to exert significant pathogenic effects on vascular endothelial cells, which are critically involved in the pathogenesis of diabetic retinopathy. The present study aimed to investigate the link between the therapeutic effects of fenofibrate and the pathogenic effects of ANGPTL3 in diabetic retinopathy. Methods: Diabetic and control rats were randomly assigned to the following treatments: intravitreal injection with ANGPTL3 small interfering RNA (siRNA), recombinant human (rh)ANGPTL3, fed with normal feeds, or fenofibrate-containing feeds for 8 weeks. Human retinal microvascular endothelial cells (HRMECs) were exposed to normal glucose or high glucose levels with ANGPTL3 siRNA, ANGPTL3 RNA overexpression, blank vector, cilengitide, or fenofibrate treatment. Expression levels of ANGPTL3, IL-1, IL-6, Bax, P53, VEGF, and integrin αVß3 in the retinas of rats and HRMECs were examined by Western blotting and real-time PCR. The apoptosis rates of HRMECs were examined using a TUNEL apoptosis assay kit. Results: Expression levels of ANGPTL3, IL-1ß, IL-6, Bax, P53, VEGF, and integrin αVß3 were found to be upregulated after high-glucose stimulation or ANGPTL3 overexpression in HRMECs or diabetic retinal tissue. However, expression levels of the above markers were downregulated following fenofibrate intervention, blockage of integrin αVß3 receptor, or ANGPTL3 siRNA interference. Conclusions: We identified fenofibrate exerts its protective effects by inhibiting ANGPTL3-induced apoptosis and inflammation in diabetic retinopathy, which is a novel mechanism.

Change of ranibizumab-induced human vitreous protein profile in patients with proliferative diabetic retinopathy based on proteomics analysis.

BACKGROUND: Preoperative treatment of anti-vascular endothelial growth factor (VEGF) agents is extensively used in proliferative diabetic retinopathy (PDR), but the molecular mechanism is not fully understood. The objective of this research is to observe change of protein profile induced by ranibizumab (an anti-VEGF agent) in vitreous humor from PDR patients and reveal the effects of anti-VEGF treatment on PDR. METHODS: A proteomic method was used to identify differentially expressed proteins in vitreous humor. Untreated PDR patients were defined as PDR group, while those who treated with intravitreal injection of ranibizumab (IVR) were defined as IVR. Gene Ontology (GO) annotation and REACTOME pathways were obtained from DAVID Bioinformatics Resources. Intravitreal level of apolipoprotein C-I (APOC1), serpin peptidase inhibitor clade A member 5 (SERPINA5), tissue inhibitor of metalloproteinases (TIMP2), and keratin 1 (KRT1) were determined by enzyme-linked immuno sorbent assay (ELISA). RESULTS: 339 differentially expressed proteins were identified in response to IVR. The most notable GO annotation describes the altered proteins was "innate immune response". The most notable REACTOME pathway was "platelet degranulation". ELISA result showed increased level of APOC1, SERPINA5, KRT1 and a decreased level of TIMP2 in PDR group compared with IVR. CONCLUSIONS: In addition to decreasing VEGF level, ranibizumab is associated with change of human vitreous protein profile in patients with PDR, in which the differential proteins are involved in immune response, platelet degranulation, complement activation etc., suggesting that the effects of VEGF are involved in these signaling pathways.

miR-23b-3p induces the cellular metabolic memory of high glucose in diabetic retinopathy through a SIRT1-dependent signalling pathway.

AIMS/HYPOTHESIS: The mechanisms underlying the cellular metabolic memory induced by high glucose remain unclear. Here, we sought to determine the effects of microRNAs (miRNAs) on metabolic memory in diabetic retinopathy. METHODS: The miRNA microarray was used to examine human retinal endothelial cells (HRECs) following exposure to normal glucose (N) or high glucose (H) for 1 week or transient H for 2 days followed by N for another 5 days (H→N). Levels of sirtuin 1 (SIRT1) and acetylated-nuclear factor κB (Ac-NF-κB) were examined following transfection with miR-23b-3p inhibitor or with SIRT1 small interfering (si)RNA in the H→N group, and the apoptotic HRECs were determined by flow cytometry. Retinal tissues from diabetic rats were similarly studied following intravitreal injection of miR-23b-3p inhibitor. Chromatin immunoprecipitation (ChIP) analysis was performed to detect binding of NF-κB p65 to the potential binding site of the miR-23b-27b-24-1 gene promoter in HRECs. RESULTS: High glucose increased miR-23b-3p expression, even after the return to normal glucose. Luciferase assays identified SIRT1 as a target mRNA of miR-23b-3p. Reduced miR-23b-3p expression inhibited Ac-NF-κB expression by rescuing SIRT1 expression and also relieved the effect of metabolic memory induced by high glucose in HRECs. The results were confirmed in the retina using a diabetic rat model of metabolic memory. High glucose facilitated the recruitment of NF-κB p65 and promoted transcription of the miR-23b-27b-24-1 gene, which can be suppressed by decreasing miR-23b-3p expression. CONCLUSIONS/INTERPRETATION: These studies identify a novel mechanism whereby miR-23b-3p regulates high-glucose-induced cellular metabolic memory in diabetic retinopathy through a SIRT1-dependent signalling pathway.