Retinal Microvascular Damage Research Articles

Differential associations between retinal signs and CMBs by location: The AGES-Reykjavik Study.

ObjectiveTo test the hypothesis that age-related macular degeneration (AMD) and retinal microvascular signs are differentially associated with lobar and deep cerebral microbleeds (CMBs).MethodsCMBs in lobar regions indicate cerebral amyloid angiopathy (CAA). β-Amyloid deposits are implicated in both CAA and AMD. Deep CMBs are associated with hypertension, a major risk factor for retinal microvascular damage. This population-based cohort study included 2,502 participants in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study who undertook binocular digital retinal photographs at baseline (2002–2006) to assess retinal microvascular signs and AMD and brain MRI scan at both baseline and follow-up (2007–2011) to assess CMBs. We assessed retinal microvascular lesion burden by counting the 3 retinal microvascular signs (focal arteriolar narrowing, arteriovenous nicking, and retinopathy) concurrently present in the participant. We used multiple logistic models to examine the association of baseline retinal pathology to incident CMBs detected at follow-up.ResultsDuring an average 5.2 years of follow-up, 461 people (18.3%) developed new CMBs, including 293 in exclusively lobar regions and 168 in deep regions. Pure geographic atrophy was significantly associated with strictly lobar CMBs (multivariable-adjusted odds ratio 2.59, 95% confidence interval [CI] 1.01–6.65) but not with deep CMBs. Concurrently having ≥2 retinal microvascular signs was associated with a 3-fold (95% CI 1.73–5.20) increased likelihood for deep CMBs but not exclusively lobar CMBs.ConclusionsRetinal microvascular signs and pure geographic atrophy may be associated with deep and exclusively lobar CMBs, respectively, in older people. These results have implications for further research to define the role of small vessel disease in cognitive impairment.

Application of optical coherence tomography angiography in evaluation of retinal microvascular changes in patients with obstructive sleep apnea syndrome

Objective: To assess the changes of retinal microvasculature in patients with obstructive sleep apnea syndrome (OSAS) evaluated by optical coherence tomography (OCTA). Methods: Adult OSAS patients who visited Beijing Tongren Hospital from Jan 2016 to Apr 2016 and complained of snoring were included in this study. The patients' general information, results of polysomnography, and OCTA parameters were collected. Patients were divided into three groups according to their apnea hypopnea index (AHI) results: Mild-moderate group, AHI≤30/h; Severe group, 30/h<AHI≤60/h; Extremely severe group, AHI>60/h, and clinical characteristics, polysomnography and OCTA parameters among the three groups were compared. Results: A total of 27 patients were included in this study with 21 males (77.8%) and 6 females (22.2%). Mean age was (41.7±10.0) years, and the mean body mass index was (27.9±4.5) kg/m(2;) Neck circumference was 31-48 cm, mean (39.8±4.3) cm; 8 patients (29.6%) suffered from hypertension that could be controlled; Epworth sleepiness scale scored 1-18 points and mean (8.5±4.4) scores; AHI ranged between 5.5 and 92.1/h with a mean of (46.4±28.6)/h. There were 9 (33.3%), 7 (25.9%), and 11 (40.7%) patients in mild-moderate group, severe group, and extremely severe group, respectively. Compared with severe group, the optic nerve head and radial peripapillary capillaries (RPC) peripapillary vascular density in extremely severe group were significantly decreased (62.4%±1.9% vs 60.3%±1.9%, P=0.041; 64.7%±1.7% vs 62.2%±2.3%, P=0.036). Conclusions: OCTA has rapid, safe, and objective characteristics in assessing the retinal microvascular changes in OSAS patients. Retinal microvascular damage in patients with OSAS is associated with the disease severity. Reduction of retinal microvascular density in patients with OSAS may be associated with intermittent hypoxia.

The retinal microcirculation in migraine: The Rotterdam Study.

BackgroundTo explore the role of microvascular pathology in migraine, we investigated the association between migraine and retinal microvascular damage.MethodsWe included 3270 participants (age ≥ 45 years, 63% women) from the population-based Rotterdam Study (2006–2009). Participants with migraine were identified using a validated questionnaire based on ICHD-II criteria (n = 562). Retinopathy signs were graded on fundus photographs. Retinal arteriolar and venular caliber were measured by semi-automatic assessment of fundus photographs. Associations of migraine with retinopathy and retinal microvascular calibers were examined using logistic and linear regression models, respectively, adjusting for age, sex, and cardiovascular risk factors.ResultsMigraine was not associated with the presence of retinopathy (odds ratio (OR): 1.09, 95% confidence interval (CI) 0.62; 1.92). In the fully adjusted model, adjusting for the companion vessel, persons with migraine did not differ in retinal arteriolar or venular caliber compared to persons without migraine (mean difference in standardized arteriolar caliber −0.05 (95%CI −0.13; 0.03); in standardized venular caliber −0.00 (95%CI −0.09; 0.08)). Migraine subtypes, including migraine with aura, were also not associated with retinal microvascular damage.ConclusionsOur findings suggest that migraine is not associated with retinopathy or difference in retinal microvascular caliber. Further studies are needed to confirm these results.

Study of retinal microvascular perfusion alteration and structural damage at macular region in primary open-angle glaucoma patients

Objective: To investigate the alteration of retinal microcirculation and structural damage at macular region and evaluate their associations in primary open angle glaucoma (POAG) eyes. Methods: Cross-sectional study. Fifty-nine POAG patients (male/femal=35/24) were recruited from July 2015 to December 2015 in Eye, Ear, Nose and Throat Hospital of Fudan University. Twenty-eight eyes of early-stage POAG group (EG), 11 eyes of moderate-stage POAG group (MG) and 20 eyes of severe-stage POAG group (SG) were enrolled in this study. All patients underwent complete ophthalmological examinations and the general information was collected. The macular perfusion parameters (flow index & vessel area density) and the global/hemimacular retina thickness were derived from the 3D angio-retina and retina map procedures in the single optic coherence tomography (OCT) system with split-spectrum amplitude decorrelation angiography (SSADA) algorithm, respectively. One-way ANOVA analysis was conducted to compare the macular perfusion parameters, retinal thickness and visual field defects among three groups. Pearson partial regression analysis was used to calculate the correlations between different variables. Results: The mean flow index and vessel area density of MG eyes were 0.05±0.01 and 60.8%±7.9%, which were significantly lower than those indexes (0.06±0.01; 71.9%±4.6%) in EG eyes (t=5.11, P=0.001; t=5.05, P<0.01). The full and inner retinal layer thicknesses of MG eyes were (270.3±24.6) μm and (98.4±13.3) μm, which were obviously thinner than those indexes (293.0±12.0 μm, 113.0±7.4 μm) in EG eyes (t=3.60, P<0.01; t=4.06, P<0.01). However, there was no significant alteration of macular perfusion parameters and retinal thickness between MG and SG eyes. Furthermore, there was a significantly positive correlation between macular perfusion (flow index/vessel area density) and the macular retina thickness (full/inner thickness) (R=0.35-0.71, All P<0.01). Conclusions: The microvascular perfusion and retinal thickness in MG eyes were lower than those in EG eyes. There was significant positive association between the retinal microvascular perfusion and structural damage. Furthermore, the association between microvascular perfusion and inner inferior retinal thickness is the strongest. (Chin J Ophthalmol, 2017, 53: 98-103).

Zerumbone, a Bioactive Sesquiterpene, Ameliorates Diabetes-Induced Retinal Microvascular Damage through Inhibition of Phospho-p38 Mitogen-Activated Protein Kinase and Nuclear Factor-κB Pathways.

Zerumbone ameliorates retinal damage by blocking advanced glycation end products and their receptor system in streptozotocin-diabetic rats. Because of the multiple factors involved in diabetic retinopathy (DR) etiology, the mechanisms of zerumbone that are mainly responsible for its ameliorative effect on DR need to be further clarified. In the present study, zerumbone (20 mg or 40 mg/kg) or fenofibric acid (100 mg/kg) was orally administered to diabetic rats by intragastric gavage once daily for three consecutive months. Zerumbone displayed similar characteristics to fenofibric acid in reducing retinal vascular permeability and leukostasis in diabetic rats. Fundus photographs showed that large retinal vessel diameters were decreased in zerumbone-treated diabetic rats. Zerumbone not only down-regulated the gene expression of retinal angiogenic parameters, but also reduced the expression of inflammatory cytokines and chemokines in the retina of diabetic rats. Moreover, zerumbone reduced the p38 MAPK phosphorylation and abrogated the nuclear translocation of NF-κB p65 in the retina of diabetic rats. In conclusion, treatment of diabetic rats with zerumbone attenuates the severity of retinal inflammation and angiogenesis, via inhibition of p38 MAPK and NF-κB signaling pathways. These benefits of zerumbone for DR appear to be linked to its antihyperglycemic and antihyperlipidemic effects.

Vitamin D and retinal microvascular damage: The Rotterdam Study.

Vitamin D has been linked to various cardiovascular risk factors including indices of large-vessel disease. However, it remains unclear whether vitamin D is also associated with microvascular damage. In a community-dwelling population, we studied associations between vitamin D serum levels and retinal microvascular damage defined as retinopathy signs, narrower arterioles, and wider venules.From the population-based Rotterdam Study, we included 5675 participants (age ≥45 years) with vitamin D data and gradable retinal photographs. Serum levels of vitamin D were measured using an antibody-based assay. Retinal exudates, microaneurysms, cotton wool spots, and dot/blot hemorrhages were graded on fundus photographs by experienced graders in the whole sample; retinal vascular calibers, that is, arteriolar and venular diameters, were semiautomatically measured in a subsample (n = 2973). We examined the cross-sectional association between vitamin D and retinal microvascular damage using logistic and linear regression models, adjusting for age, sex, and cardiovascular risk factors.We found that persons with lower vitamin D levels were more likely to have retinopathy (adjusted odds ratio per standard deviation (SD) decrease of vitamin D = 1.30; 95% confidence interval (CI): = 1.12–1.49). Furthermore, lower vitamin D levels were associated with wider venular calibers (adjusted mean difference per SD decrease in vitamin D = 1.35; 95% CI = 0.64–2.06). This association was strongest among men (P for interaction = 0.023).Lower levels of vitamin D are associated with retinal microvascular damage, suggesting that the link with cardiovascular risk may partly run through changes in the microvasculature.

Nap Interferes with Hypoxia-Inducible Factors and VEGF Expression in Retina of Diabetic Rats.

The retinal microvascular damage is a complication of diabetic retinopathy (DR). Hyperglycemia and hypoxia are responsible of aberrant vessel's proliferation. The cellular response to hypoxia is mediated through activation of hypoxia-inducible factors (HIFs). Among these, HIF-1α modulates expression of its target gene, VEGF, whose upregulation controls the angiogenic event during DR development. In a previous study, we have demonstrated that a small peptide, NAP, is able to protect retina from hyperglycemic insult. Here, we have demonstrated that its intraocular administration in a rat model of diabetic retinopathy has reduced expression of HIF-1α, HIF-2α, and VEGF by increasing HIF-3α levels. These data have been also confirmed by immunolocalization study by confocal microscopy. Although these evidences need to be further deepened to understand the molecular mechanism involved in the protective NAP action, the present data suggest that this small peptide may be effective to prevent the development of this ocular pathology.

Retinal microvasculature and white matter microstructure: The Rotterdam Study.

To investigate whether retinal microvascular damage is related to normal-appearing white matter microstructure on diffusion tensor MRI. We included 2,436 participants (age ≥45 years) from the population-based Rotterdam Study (2005-2009) who had gradable retinal images and brain MRI scans. Retinal arteriolar and venular calibers were measured semiautomatically on fundus photographs. White matter microstructure was assessed using diffusion tensor MRI. We used linear regression models to investigate the associations of retinal vascular calibers with markers of normal-appearing white matter microstructure, adjusting for age, sex, the fellow vascular caliber, and additionally for structural MRI markers and cardiovascular risk factors. Narrower arterioles and wider venules were associated with poor white matter microstructure: adjusted difference in fractional anisotropy per SD decrease in arteriolar caliber -0.061 (95% confidence interval -0.106 to -0.016), increase in venular caliber -0.054 (-0.096 to -0.011), adjusted difference in mean diffusivity per SD decrease in arteriolar caliber 0.048 (0.007-0.088), and increase in venular caliber 0.047 (0.008-0.085). The associations for venules were more prominent in women. Retinal vascular calibers are related to normal-appearing white matter microstructure. This suggests that microvascular damage in the white matter is more widespread than visually detectable as white matter lesions.

N-Terminal Pro-B-Type Natriuretic Peptide Is Related to Retinal Microvascular Damage: The Rotterdam Study.

N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a marker of cardiac dysfunction and has been linked to various indices of large vessel disease. However, it remains unclear whether NT-proBNP also relates to microvascular damage. In a community-dwelling population, we studied the association between NT-proBNP and retinal microvascular damage. From the population-based Rotterdam Study, we included 8437 participants (mean age 64.1 years and 59% women) without a history of cardiovascular disease, with NT-proBNP data and gradable retinal images. NT-proBNP serum levels were measured using an immunoassay. Retinopathy signs, that is, exudates, microaneurysms, cotton wool spots, and dot/blot hemorrhages, present on fundus photographs were graded in the total study population; retinal vascular calibers, that is, arteriolar and venular calibers, were semiautomatically measured in a subsample (n=2763) of the study population. We conducted cross-sectional analyses on the association between NT-proBNP and retinal microvascular damage using logistic and linear regression models, adjusting for age, sex, and cardiovascular risk factors. We found that NT-proBNP was associated with the presence of retinopathy (adjusted odds ratio [95% confidence interval] per SD increase in natural log-transformed NT-proBNP: 1.14 [1.03-1.27]). We also found that higher NT-proBNP was associated with narrower arteriolar calibers (adjusted mean difference in arteriolar caliber per SD increase in natural log-transformed NT-proBNP: -0.89 µm [-1.54 to -0.24]). This association remained unchanged after excluding participants with retinopathy signs. In participants free of clinical cardiovascular disease, higher levels of NT-proBNP are associated with retinal microvascular damage, suggesting a potential role for NT-proBNP as marker for small vessel disease.

Retinal microvascular damage and vasogenic edema produced by Clostridium perfringens type D epsilon toxin in rats.

When the brain is exposed to large circulating levels of Clostridium perfringens type D epsilon toxin (EXT), microvascular damage with resulting severe, generalized, vasogenic edema seems to be principally responsible for the ensuing acute, and frequently fatal, neurologic disorder. However, although the blood-retinal barrier resembles in many respects the blood-brain barrier, retinal changes in livestock with acute epsilon intoxication have not, to the authors' knowledge, been previously reported. In rats given an acute dose of ETX, retinal microvascular endothelial injury led to widespread vasogenic edema as assessed immunohistochemically by marked plasma albumin extravasation. As laboratory rodents are a good model of the domestic livestock disease produced by ETX, it is probable that the latter sustain some visual deficit when exposed to large doses of this potent neurotoxin.

Anti-vascular endothelial growth factor therapy for diabetic macular edema.

Diabetes mellitus is a serious health problem that affects over 350 million individuals worldwide. Diabetic retinopathy (DR), which is the most common microvascular complication of diabetes, is the leading cause of new cases of blindness in working-aged adults. Diabetic macular edema (DME) is an advanced, vision-limiting complication of DR that affects nearly 30% of patients who have had diabetes for at least 20 years and is responsible for much of the vision loss due to DR. The historic standard of care for DME has been macular laser photocoagulation, which has been shown to stabilize vision and reduce the rate of further vision loss by 50%; however, macular laser leads to significant vision recovery in only 15% of treated patients. Mechanisms contributing to the microvascular damage in DR and DME include the direct toxic effects of hyperglycemia, sustained alterations in cell signaling pathways, and chronic microvascular inflammation with leukocyte-mediated injury. Chronic retinal microvascular damage results in elevation of intraocular levels of vascular endothelial growth factor A (VEGF), a potent, diffusible, endothelial-specific mitogen that mediates many important physiologic processes, including but not limited to the development and permeability of the vasculature. The identification of VEGF as an important pathophysiologic mediator of DME suggested that anti-VEGF therapy delivered to the eye might lead to improved visual outcomes in this disease. To date, four different inhibitors of VEGF, each administered by intraocular injection, have been tested in prospective, randomized phase II or phase III clinical trials in patients with DME. The results from these trials demonstrate that treatment with anti-VEGF agents results in substantially improved visual and anatomic outcomes compared with laser photocoagulation, and avoid the ocular side effects associated with laser treatment. Thus, anti-VEGF therapy has become the preferred treatment option for the management of DME in many patients.

Pathophysiology of diabetic retinopathy.

Diabetes is now regarded as an epidemic, with the population of patients expected to rise to 380 million by 2025. Tragically, this will lead to approximately 4 million people around the world losing their sight from diabetic retinopathy, the leading cause of blindness in patients aged 20 to 74 years. The risk of development and progression of diabetic retinopathy is closely associated with the type and duration of diabetes, blood glucose, blood pressure, and possibly lipids. Although landmark cross-sectional studies have confirmed the strong relationship between chronic hyperglycaemia and the development and progression of diabetic retinopathy, the underlying mechanism of how hyperglycaemia causes retinal microvascular damage remains unclear. Continued research worldwide has focussed on understanding the pathogenic mechanisms with the ultimate goal to prevent DR. The aim of this paper is to introduce the multiple interconnecting biochemical pathways that have been proposed and tested as key contributors in the development of DR, namely, increased polyol pathway, activation of protein kinase C (PKC), increased expression of growth factors such as vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1), haemodynamic changes, accelerated formation of advanced glycation endproducts (AGEs), oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and subclinical inflammation and capillary occlusion. New pharmacological therapies based on some of these underlying pathogenic mechanisms are also discussed.

A simple algorithm to estimate the time to development of sight-threatening diabetic retinopathy

BackgroundMore than 3 million people with diabetes in the UK are at risk of vision loss because of diabetic eye disease. Present UK recommendations specify annual diabetic eye screening in those aged 12 years or older with diabetes. Patients identified with potentially sight-threatening diabetic retinopathy are referred to ophthalmology services. Those with no retinopathy and those with non-referable retinal microvascular damage continue to be invited for annual screening irrespective of risk. Models for risk stratification require clinical information, including a measure of glycaemic control that may not be available to screening programmes. With use of data only from retinal photographs we aimed to identify patients at low, intermediate, and high risk of those offered annual appointments, to inform discussion about potential changes to recommended screening intervals. MethodsWe reviewed all patients referred from primary care to one local screening programme with assessable images of both eyes from at least three screening episodes between Jan 1, 2005, and Dec 31, 2010. Digital images were captured after dilation and were graded by a central quality assured team with NHS diabetic eye screening programme protocols. We included patients who at the first and second (index) screenings had no retinopathy or microaneuryms in one or both eyes. They were followed up until any sight-threatening diabetic retinopathy was detected or until the last available photograph with no sight-threatening diabetic retinopathy. Patients were categorised by presence of microaneuryms in neither, one, or both eyes at each screening. We excluded those with any missing data. By design, no confounding variables were included in the model. We derived life table survival plots with Kaplan-Meier estimates and calculated hazard ratios (HRs) with Cox proportional hazards models. We used log logistic models to estimate the proportion of patients with microaneuryms every year after baseline. Data were analysed with SAS (version 9.1). FindingsFrom 2005, 18–254 patients with non-referable diabetic retinopathy at two consecutive screenings were available, of whom 3700 had no further assessable images. Hence 14–554 patients were followed up for further median 2·8 years (IQR 1·3–3·3). Their median age was 65 years (IQR 56–73), and 8188 (55%) were men. Of 7246 with no evidence of retinal microvascular damage at both screenings, 120 progressed to sight-threatening diabetic retinopathy, 0·7% by 1 year. Of 1778 with microaneuryms in neither eye at first screening and in one eye at second screening, 80 progressed to sight-threatening diabetic retinopathy, 1·9% by 1 year (HR 2·9, 95% CI 2·2–3·8). Of 1159 with microaneuryms in both eyes at both screenings, 299 progressed to sight-threatening diabetic retinopathy, 11% by 1 year (HR 18·2, 95% CI 14·7–22·5). Those in higher risk groups were more likely to progress to more serious diabetic retinopathy than were those in lower risk groups. InterpretationThis screening programme of a mainly northern European population has robust quality controlled imaging and grading. Hence it needs to be validated in other populations and programmes to be generalisable. Two sequential image sets can differentiate levels of risk and could modify the interval for screening. The addition of these data to clinical indices could improve risk stratification compared with either method alone. FundingNone

Retinal Microvascular Abnormalities and Age-Related Hearing Loss: The Blue Mountains Hearing Study

Microvascular disease may contribute to hearing loss. We tested this hypothesis by examining the relation of retinal microvascular abnormalities and hearing loss. This was a cross-sectional, population-based study. We performed retinal photography and pure-tone audiometry on 1511 older individuals (ages 54+ years) from the Blue Mountains Eye Study population. Examination of the retinal microvasculature provides a noninvasive means of assessing systemic microvascular changes associated with cardiovascular disease, especially since reliable methods of quantifying retinal microvascular abnormalities from retinal photographs have recently been developed. Trained graders masked to audiometry data assessed retinal photographs for signs of retinal microvascular damage, for example, focal arteriolar narrowing, arteriovenous nicking, and retinopathy (microaneurysms, retinal hemorrhages), and used a computer-assisted method to measure arteriolar and venular calibers. We defined moderate or profound hearing loss as pure-tone average air-conducted hearing thresholds in the better ear worse than 40 dB at 0.5, 1, 2, and 4 kHz. We used odds ratios (OR), 95% confidence intervals (CI), and probability values to present the associations between retinal microvascular abnormalities and hearing loss; an OR >1 indicates that persons with the microvascular abnormality are more likely to have hearing loss, a CI that includes 1.00 (e.g., 0.85 to 2.34) indicates no statistically significant association (i.e., the association may have occurred due to chance), whereas a value of p < 0.05 indicates that an association is unlikely to have occurred due to chance. The proportion of women and men with moderate or profound hearing loss was 10.4% (90/862) and 15.4% (100/649), respectively. After adjustment for age, sex, blood pressure, and other risk factors for hearing loss, retinopathy in women was associated with hearing loss (adjusted OR, 2.10; 95% CI, 1.09 to 4.06, p = 0.002) but not in men. Associations were stronger for moderate or worse low-frequency (0.25 to 1.0 kHz) hearing loss in women (adjusted OR, 3.00; 95% CI, 1.25 to 7.19, p = 0.0005) but were absent for high-frequency hearing loss. In men, no retinal microvascular abnormalities were associated with hearing loss at either low or high frequencies. Retinopathy, a sign of retinal microvascular damage, was associated with hearing loss in women but not in men. Our results provide modest support to the hypothesis that microvascular disease may play a role in age-related hearing loss in women, particularly low-frequency losses.

Hemorheologic Abnormalities Associated with HIV Infection: Altered Erythrocyte Aggregation and Deformability

To investigate possible alterations of erythrocyte aggregation and deformability, which are factors that can influence blood flow, in human immunodeficiency virus (HIV)-infected individuals and to determine whether these factors are related to the severity of immunodeficiency. Laboratory evaluations were performed on 46 HIV-infected individuals and 44 HIV-negative control subjects. Current and nadir (lowest previous) CD4+ T-lymphocyte counts were identified for each subject. Erythrocyte aggregation was measured using a fully automatic erythrocyte aggregometer. Factors related to erythrocyte aggregation were also determined: erythrocyte sedimentation rate (ESR), zeta sedimentation ratio (ZSR), and plasma fibrinogen levels. Erythrocyte deformability was observed at various fluid shear stress levels, with a laser diffraction ektacytometer. Correlations were sought between each of these measures and current or nadir CD4+ T-lymphocyte counts, and each measure was compared between three subgroups based on current and nadir CD4+ T-lymphocyte counts (severely immunosuppressed, immune reconstituted, never severely immunosuppressed). The following parameters were significantly different between HIV-infected subjects and controls: increased erythrocyte aggregation, at stasis (P < 0.001) and low shear stress (P < 0.001), increased ESR (P < 0.001), increased ZSR (P < 0.028), increased serum fibrinogen (P = 0.015), and decreased erythrocyte deformability (P < 0.001). Only erythrocyte aggregation at stasis correlated significantly with current CD4+ T-lymphocyte count (r = - 0.344, P = 0.022). None of the parameters was significantly different between HIV-infected subgroups. Increased aggregation and decreased deformability of erythrocytes are associated with HIV-infection regardless of the severity of immunodeficiency. HIV-infected individuals may be at risk for progressive retinal microvascular damage from persistent hemorheologic abnormalities, despite immune reconstitution associated with potent antiretroviral drug therapies.

Endothelin antagonism prevents diabetic retinopathy in NOD mice: a potential role of the angiogenic factor adrenomedullin.

Altered activity of retinal endothelin-1 (ET-1) and nitric oxide may play a causal role in the hemodynamic and histopathological changes of diabetic retinopathy. This study evaluated the therapeutic potential of long-term selective blockade of the ET-1(A) receptor (ETRA) to prevent the development of retinopathy in a genetic mouse model of nonobese type 1 diabetes (NOD). Mice with NOD that received subcutaneous implantation of insulin pellets and wild-type control mice were treated for 4 months with the selective ETRA antagonist LU208075 (30 mg/kg/day) via drinking water. At the end of the study, blood glucose levels were evaluated, and animals were anesthetized and perfused intracardially with FITC-labeled dextran. Retinas were removed and either fixed in formalin for confocal microscope evaluation of retinal vascular filling or transferred to RNALater for quantitative reverse transcriptase-polymerase chain reaction to evaluate expression of NOS-3, NOS-1, ET-1, ETRA, ETRB, and the angiogenic factor adrenomedullin. Compared with wild-type controls, expression of ET-1, ETRA, ETRB, and adrenomedullin in mice with NOD were markedly upregulated in the retinas of nontreated mice (cycle time values relative to GAPDH [deltaCt], 14.8 vs. 13.7, 18.57 vs. 17.5, 10.76 vs. 9.9, and 11.7 vs. 9.1, respectively). Mean integral fluorescence intensity (MIFI) of retinal vascular filling was reduced from normal values of 24 to 12.5 in nontreated animals. LU208075 treatment normalized the upregulated expression of ET-1 and adrenomedullin, as well as the deficit in MIFI, but did not affect the increased ETRA and ETRB expression or the elevated plasma glucose levels found in nontreated animals. NOS isoform expression was essentially unchanged. ETRA antagonists may provide a novel therapeutic strategy to slow or prevent progression of retinal microvascular damage and proliferation in patients for whom there is clear evidence of activation of the ET-1 system.

Retinal and Cerebral Microembolization During Coronary Artery Bypass Surgery

Background— We sought to compare the effects on ophthalmic function of coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB) and off-pump (OPCAB) grafting and to investigate whether retinal microvascular damage is associated with markers of cerebral injury. Methods and Results— Retinal microvascular damage was assessed by fluorescein angiography and color fundus photography. Ophthalmic function was tested by the logarithm of the minimum angle of resolution visual acuity (VA), and cerebral injury, by transcranial Doppler ultrasound–detected emboli and S100 protein values. Twenty patients were randomized. Fluorescein angiography and postoperative VA could not be obtained for 1 CABG-CPB patient. Retinal microvascular damage was detected in 5 of 9 CABG-CPB but in none of 10 OPCAB patients (risk difference, 55%; 95% confidence interval [CI], 23% to 88%; P =0.01). Color fundus photography detected microvascular damage in 1 CABG-CPB patient but in no OPCAB patients; this lesion was associated with a field defect, which remained after 3 months of follow-up. There was no difference in postoperative VA. Doppler high-intensity transient signals (HITS) were 20.3 times more frequent in the CABG-CPB than in the OPCAB group (95% CI, 9.1 to 45; P &lt;0.0001). Protein S100 levels were higher in the CABG-CPB than in the OPCAB group 1 hour after surgery ( P &lt;0.001). HITS were 14.7 times more frequent (95% CI, 3.5 to 62; P =0.001) and S100 level 2.1 times higher (95% CI, 1.3 to 3.5; P =0.005) when retinal microvascular damage was present. Conclusions— The relative frequency of retinal microvascular damage between groups shows the extent to which the risk of cerebral injury is reduced with OPCAB. Imaging of part of the cerebral circulation provides evidence to validate markers of cerebral injury.

Dyslipidemia, but not hyperglycemia, induces inflammatory adhesion molecules in human retinal vascular endothelial cells.

The initial determinants of retinal microvascular damage in diabetic retinopathy are not well understood, but are likely to be induced by hyperglycemia and/or dyslipidemia. The purpose of this study was to examine the effect of fatty acids and hyperglycemia on human retinal vascular endothelial (hRVE) cells as a means of mimicking diabetic metabolic disorders. The expression of adhesion molecules in hRVE and human umbilical vein endothelial cells (HUVECs) was assayed by Western blot analysis and confirmed by leukocyte adhesion assay. The mechanisms underlying the induction of adhesion molecules by fatty acids were further investigated by using cyclooxygenase (COX), lipoxygenase (LOX), and P450 monooxygenase (MOX) inhibitors. Treatment of hRVE cells with the n6 polyunsaturated fatty acids (PUFAs) 18:2n6 and 20:4n6 for up to 24 hours resulted in a significant induction of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 protein levels. In contrast, treatment with high glucose (22 mM) for 24 hours did not affect CAM expression. Induction of CAM by n6 PUFA correlated with enhanced leukocyte binding to hRVE cells. The effect of n6 PUFA on ICAM-1 and VCAM-1 was blocked by an inhibitor of LOX, but not by COX or MOX inhibitors. In contrast to hRVE cells, n6 PUFA did not induce ICAM-1 or VCAM-1 in HUVECs. The data obtained in this study demonstrate that acute exposure to linoleic or arachidonic acid, but not hyperglycemia, induces inflammatory adhesion molecule expression in the presence of LOX in microvascular hRVE cells, but not in HUVECs. These results are consistent with the emerging hypothesis recognizing early-stage diabetic retinopathy as a low-grade chronic inflammatory disease.