Retinal Microvascular Lesions Research Articles

Reduced macular thickness and vascular density in abnormal glucose metabolism patients: A meta-analysis of optical coherence tomography (OCT) and OCT angiography studies.

Alterations in macular thickness and vascular density before clinically visible diabetic retinopathy (DR) remain inconclusive. This study aimed to determine whether retinal manifestations in abnormal glucose metabolism (AGM) patients differ from those in the healthy individuals. PubMed, Embase, and Web of Science were searched between 2000 and 2021. The eligibility criteria were AGM patients without DR. Primary and secondary outcomes measured by optical coherence tomography (OCT) and OCT angiography (OCTA) were analyzed and expressed as standardized mean differences (SMDs) with 95% confidence intervals (CIs). A random-effects model was used in the data synthesis. The potential publication bias for the variables was evaluated using Egger's test. A total of 86 observational studies involving 13,773 participants and 15,416 eyes were included. OCT revealed that compared to healthy controls, the total macular thickness of AGM patients was thinner, including the thickness of fovea (-0.24, 95% CI [-0.39, -0.08]; P =0.002, I2 =87.7%), all regions of parafovea (-0.32, 95% CI [-0.54, -0.11]; P =0.003; I2 =71.7%) and the four quadrants of perifovea; the thickness of peripapillary retinal nerve fiber layer (pRNFL), macular retinal nerve fiber layer (mRNFL), and ganglion cell layer (GCL) also decreased. OCTA indicated that the superficial and deep vascular density decreased, the foveal avascular zone (FAZ) area enlarged, and the acircularity index (AI) reduced in AGM individuals. Retinal thinning and microvascular lesions have occurred before the advent of clinically detectable DR; OCT and OCTA may have the potential to detect these preclinical changes. PROSPERO; http://www.crd.york.ac.uk/prospero/ ; No. CRD42021269885.

Determining the Role of SGLT2 Inhibition with Dapagliflozin in the Development of Diabetic Retinopathy.

Diabetic retinopathy (DR) is a major cause of blindness globally. Sodium Glucose Cotransporter-2 (SGLT2) inhibitors have been demonstrated to exert cardiorenal protection in patients with diabetes. However, their potential beneficial effect on DR is less well studied. The aim of the present study was to determine the effects of the SGLT2 inhibition with Dapagliflozin (DAPA) on DR in well-characterised DR mouse models and controls. Dapagliflozin was administered to mice with and without diabetes for 8 weeks via their drinking water at 25 mg/kg/day. Urine glucose levels were measured weekly and their response to glucose was tested at week 7. After 8 weeks of treatment, eye tissue was harvested under terminal anaesthesia. The retinal vasculature and neural structure were assessed using immunofluorescence, immunohistochemistry and electron microscopy techniques. Dapagliflozin treated DR mice exhibited metabolic benefits reflected by healthy body weight gain and pronounced glucose tolerance. Dapagliflozin reduced the development of retinal microvascular and neural abnormalities, increased the beneficial growth factor FGF21 (Fibroblast Growth Factor 21). We highlight for the first time that SGLT2 inhibition results in the upregulation of SGLT1 protein in the retina and that SGLT1 is significantly increased in the diabetic retina. Blockade of SGLT2 activity with DAPA may reduce retinal microvascular lesions in our novel DR mouse model. In conclusion, our data demonstrates the exciting future potential of SGLT1 and/or SGLT2 inhibition as a therapeutic for DR.

Comparison of two ultra-widefield color-fundus imaging devices for visualization of retinal periphery and microvascular lesions in patients with early diabetic retinopathy

Comparison of two ultra-widefield (UWF) color-fundus (CF) imaging devices in diabetic patients for visualization of retinal periphery and detection of early microvascular lesions. The total gradable areas (TGA) seen on non-mydriatic CF-images of two UWF-imaging devices (Optos Daytona P200T; Zeiss Clarus 700) were compared and differences in projected area measured. Retinal periphery outside the 7 standard fields (7SF) was divided into: F3 temporal, F4 superotemporal, F5 inferotemporal, F6 superonasal, F7 inferonasal. DR stage was evaluated in the 7SF and the TGA on images of both devices and compared using Cohens κ. 67 eyes of 67 patients (52.5 ± 15.3 years) were analysed. DR stages in the 7SF were no (n = 36 Optos, n = 35 Clarus), mild (n = 16 Optos, n = 17 Clarus), and moderate DR (n = 15). Optos depicted significantly more area in F3 (median [interquartile range]; 2.41% [1.06–4.11] vs 0% [0–0], P < 0.001) and Clarus in F7 (3.29% [0–7.69] vs 0% [0–3.27], P = 0.002). In 4 eyes DR-stage was higher using Optos due to peripheral lesions not seen on the Clarus. Interrater reliability of DR-stage on both devices was almost perfect in the 7SF (κ = 0.975) and the TGA (κ = 0.855). Reliability in detecting signs of early DR is high on both devices. Clarus allowed for better visualization of the inferonasal field, Optos of the temporal field.

IL-17A injury to retinal ganglion cells is mediated by retinal M\xfcller cells in diabetic retinopathy

Diabetic retinopathy (DR), the most common and serious ocular complication, recently has been perceived as a neurovascular inflammatory disease. However, role of adaptive immune inflammation driven by T lymphocytes in DR is not yet well elucidated. Therefore, this study aimed to clarify the role of interleukin (IL)-17A, a proinflammatory cytokine mainly produced by T lymphocytes, in retinal pathophysiology particularly in retinal neuronal death during DR process. Ins2Akita (Akita) diabetic mice 12 weeks after the onset of diabetes were used as a DR model. IL-17A-deficient diabetic mice were obtained by hybridization of IL-17A-knockout (IL-17A-KO) mouse with Akita mouse. Primarily cultured retinal Müller cells (RMCs) and retinal ganglion cells (RGCs) were treated with IL-17A in high-glucose (HG) condition. A transwell coculture of RGCs and RMCs whose IL-17 receptor A (IL-17RA) gene had been silenced with IL-17RA-shRNA was exposed to IL-17A in HG condition and the cocultured RGCs were assessed on their survival. Diabetic mice manifested increased retinal microvascular lesions, RMC activation and dysfunction, as well as RGC apoptosis. IL-17A-KO diabetic mice showed reduced retinal microvascular impairments, RMC abnormalities, and RGC apoptosis compared with diabetic mice. RMCs expressed IL-17RA. IL-17A exacerbated HG-induced RMC activation and dysfunction in vitro and silencing IL-17RA gene in RMCs abolished the IL-17A deleterious effects. In contrast, RGCs did not express IL-17RA and IL-17A did not further alter HG-induced RGC death. Notably, IL-17A aggravated HG-induced RGC death in the presence of intact RMCs but not in the presence of RMCs in which IL-17RA gene had been knocked down. These findings establish that IL-17A is actively involved in DR pathophysiology and particularly by RMC mediation it promotes RGC death. Collectively, we propose that antagonizing IL-17RA on RMCs may prevent retinal neuronal death and thereby slow down DR progression.

Ultrawide Field Imaging in Diabetic Retinopathy: Exploring the Role of Quantitative Metrics.

Ultrawide field imaging (UWF) has allowed the visualization of a significantly greater area of the retina than previous standard approaches. In diabetic retinopathy (DR), significantly more lesions are seen on UWF imaging compared to the seven-standard ETDRS fields. In addition, some eyes have lesions that are located predominantly in the peripheral retina that are associated with an increased risk of DR progression. The current DR severity scales are still largely based on clinically visible retinal microvascular lesions and do not incorporate retinal periphery, neuroretinal, or pathophysiologic changes. Thus, current scales are not well suited for documenting progression or regression in eyes with very early or advanced DR, nor in the setting of vascular endothelial growth factor inhibitors (antiVEGF). In addition, the categorical system is highly subjective, and grading is variable between different graders based on experience level and training background. Recently, there have been efforts to quantify DR lesions on UWF imaging in an attempt to generate objective metrics for classification, disease prognostication and prediction of treatment response. The purpose of this review is to examine current quantitative metrics derived from UWF fluorescein angiograms and UWF color imaging to determine their feasibility in any potential future DR classification.

Efficacy and Safety of TangWang Prescription for Type 2 Non-Proliferative Diabetic Retinopathy: A Study Protocol for a Randomized Controlled Trial.

Background: Diabetic retinopathy (DR) is one of the most common and severe microvascular complications of diabetes mellitus (DM), which results in blindness among adults worldwide. Presently, the efficacy of drug treatments for diabetic retinopathy (DR) is not satisfactory, thus urgently necessitating effective drug treatment measures. TangWang prescription (TWP) has been found to have retinal protection effects in previous clinical and basic research. However, there is a lack of rigorous, randomized, and controlled studies. This study aims to evaluate the efficacy and safety of TWP in delaying the development of DR. Methods: This study is a randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial, consisting of 384 participants to be randomized in a 1:1 ratio in the treatment and control groups. Furthermore, the treatment and control groups will be administered the TangWang prescription and the placebo, respectively, each at a dose of one bag twice a day. The study period will last for 48 weeks. The primary outcome measure will be the changes in the degree of retinal microvascular lesions before and after treatment. The secondary outcome will be changes in the degree of hemangioma, microvascular bleeding, microvascular leakage, macular edema, and vision. All statistical tests will be two-sided, and a p < 0.05 will be considered statistically significant. Discussion: We hypothesize that the patients with DR will benefit from TangWang prescription, and in addition to the central random system and platform of dynamic information collection, the patients’ conditions will be monitored, and the data collected for analysis. If successful, this study will provide evidence that the TWP formulation delays in the progression of DR. Trial registration: The design of this trial has been registered with the ClinicalTrials.gov (NCT03025399).

Screening for Diabetic Retinopathy with Extended Intervals, Safe and Without Compromising Adherence: A Retrospective Cohort Study.

IntroductionScreening for diabetic retinopathy (DR) prevents blindness through the early detection of sight-threatening retinal microvascular lesions that respond to timely local treatment. However, the provision of easy and regular access to DR screening programs is currently being challenged by the increasing prevalence of diabetes. One proposed solution is to extend the screening interval for patients at low risk for progression of retinopathy. To date, most providers of screening programs have hesitated to implement a strategy of extended intervals due to the lack of data on whether adherence and safety are compromised when retinal examinations occur less frequently. In the study reported here, we investigated adherence to the screening program and progression of retinopathy in patients with type 2 diabetes participating in a DR screening program with extended intervals.MethodsThis was a retrospective study that included 1000 patients with type 2 diabetes mellitus who attended a screening program for DR. The patients were consecutively placed into a low-risk patient cohort with no retinopathy or into an intermediate-risk patient cohort with mild retinopathy (each cohort n = 500). Screening intervals were 36 months for the low-risk cohort and 18 months for the intermediate-risk cohort.ResultsThe 1000 subjects enrolled in the study had a median age of 68 (interquartile range 12) years and 60.4% were men. At the follow-up screening visit, data on 102 subjects were not included in the analysis of adherence rate due to death, severe systemic illness, other concurrent eye disease or migration. Among the 898 remaining subjects, adherence to the screening program was 93.7% (413/443) in the 36-month group and 98.3% (449/455) in the 18-month group (p < 0.0001). Non-adherence decreased with increasing age (odds ratio 0.92, 95% confidence interval 0.888–0.954, p = 0.0005). At follow-up, 65 subjects showed progression of retinopathy; none had worse than moderate retinopathy. Risk factors for DR and treatment for hyperglycemia, hypertension and hyperlipidemia were compared among subjects in the low-risk cohort: non-adherent subjects did not differ from their adherent counterparts without progression of DR, but the former had a shorter duration of diabetes and higher diastolic blood pressure than adherent subjects with progression of DR (4.5 vs. 7.5 years, p = 0.007; and 80 vs. 75 mmHg, p = 0.02, respectively).ConclusionThe results suggest that screening DR at extended intervals can be achieved with high adherence rates without compromising patient safety. However, younger subjects and those at higher risk of progression may require extra attention.

The Role of Angiogenesis Factors in the Formation of Vascular Changes in Scleroderma by Assessment of the Concentrations of VEGF and sVEGFR2 in Blood Serum and Tear Fluid.

Systemic sclerosis (SSc) is a connective tissue disorder characterized by tissue hypoxia, excessive fibrosis of skin and internal organs, and angiogenesis imbalance. The aim of the study was to evaluate in SSc patients the association between the retinal microcirculation disturbances and the presence of peripheral trophic changes and to determine the role of angiogenesis factors in the formation of vascular changes in scleroderma. Twenty-five SSc patients and 25 age- and sex-matched healthy controls were included to the study. Assay of vascular endothelial growth factor (VEGF) and soluble VEGF receptor-2 (sVEGFR-2) in blood serum and tears was done for all patients and controls using enzyme-linked immunosorbent assay. Retinal blood circulation was investigated with fluorescein angiography (FA) in the SSc patients only. In our research, proportion of mainly hypertensive patients presenting with a large spectrum of retinal microvascular lesions was 72%, while proportion of patients with skin microvascular lesions within distal phalanxes of fingers and toes was 76%. We noticed that patients with pathological changes in the FA examination had finger ulcerations significantly more often than patients without changes in the eye fundus. There were no statistically significant differences in the serum concentration of VEGF and sVEGFR2 between subjects in both analyzed groups. Analysis of lower levels of VEGF (p = <0.001) and sVEGFR-2 (p = <0.001) in blood serum accompanied by simultaneous higher levels of VEGF/sVEGFR-2 ratio in tears of SSc patients, as compared with the control group, indicates the superiority of proangiogenic factors in patients' tears.

Transducin1, Phototransduction and the Development of Early Diabetic Retinopathy.

PurposeRecent evidence suggests that retinal photoreceptor cells have an important role in the pathogenesis of retinal microvascular lesions in diabetes. We investigated the role of rod cell phototransduction on the pathogenesis of early diabetic retinopathy (DR) using Gnat1−/− mice (which causes permanent inhibition of phototransduction in rod cells without degeneration).MethodsRetinal thickness, oxidative stress, expression of inflammatory proteins, electroretinograms (ERG) and optokinetic responses, and capillary permeability and degeneration were evaluated at up to 8 months of diabetes.ResultsThe diabetes-induced degeneration of retinal capillaries was significantly inhibited in the Gnat1−/− diabetics. The effect of the Gnat1 deletion on the diabetes-induced increase in permeability showed a nonuniform accumulation of albumin in the neural retina; the defect was inhibited in diabetic Gnat1−/− mice in the inner plexiform layer (IPL), but neither in the outer plexiform (OPL) nor inner nuclear (INL) layers. In Gnat1-deficient animals, the diabetes-induced increase in expression of inflammatory associated proteins (iNOS and ICAM-1, and phosphorylation of IĸB) in the retina, and the leukocyte mediated killing of retinal endothelial cells were inhibited, however the diabetes-mediated induction of oxidative stress was not inhibited.ConclusionsIn conclusion, deletion of transducin1 (and the resulting inhibition of phototransduction in rod cells) inhibits the development of retinal vascular pathology in early DR.

The Relationship between Progression of Retinal Microvascular Lesions and Cerebral Small Vessel Disease Over Time

Background We investigated the mutual relationship of the progress of retinal microvascular lesions with that of cerebral small vessel diseases (CSVD) over time. Methods We prospectively included acute ischemic stroke patients. The presence of cerebral microbleeds (CMB), lacunar infarcts, leukoaraiosis and retinal microvascular lesions were interpreted. The retinal microvascular lesions through retinal photography included arterio-venular nicking, narrow arteriole, focal arterial narrowing, enhanced light reflex, and widened venule. Follow-up of the brain and eye evaluation was planned about one year after the initial examination. The progress of cerebral small vessel diseases and retinal microvascular lesions was assessed. Univariate analysis to test the relationship between retinal microvascular changes and CSVD changes was performed. Multiple logistic regression model was used to analyze the independent relationship between retinal microvascular changes and CSVD changes over time. Results Total 98 patients (63 male) were enrolled. The mean time interval between the initial and follow-up exam was 15.8 months. Initial eye exam showed arterio-venular nicking in 72/88 (81.8%), enhanced light reflex in 56/88 (63.6%), focal arterial narrowing in 71/88 (80.7%), narrow arteriole in 84/88 (95.5%), and widened venule in 78/88 (88.6%). Progression of retinal microvascular lesions could be evaluated in 55 patients. Among them, progression was observed in 22 (40%). CMB progressed in 13/66 (19.7%), lacunar infarct in 13/76 (17.1%) and leukoaraiosis in 10/76 (10.2%). The progression of retinal microvascular lesions was not correlated with the progression of any type of cerebral small vessel diseases. The presence of hypertension was the independent factor which is significantly associated with the progression of CSVD. Conclusion The progression of retinal microvascular lesions was not correlated with the progression of cerebral small vessel diseases. Key words: Retinal vessels; Stroke, Lacunar; Cerebral microbleeds; Leukoaraiosis

The association between retinal vasculature changes and stroke: a literature review and Meta-analysis.

To determine the association between retinal vasculature changes and stroke. MEDLINE and EMBASE were searched for relevant human studies to September 2015 that investigated the association between retinal vasculature changes and the prevalence or incidence of stroke; the studies were independently examined for their qualities. Data on clinical characteristics and calculated summary odds ratios (ORs) were extracted for associations between retinal microvascular abnormalities and stroke, including stroke subtypes where possible, and adjusted for key variables. Nine cases were included in the study comprising 20 659 patients, 1178 of whom were stroke patients. The retinal microvascular morphological markers used were hemorrhage, microaneurysm, vessel caliber, arteriovenous nicking, and fractal dimension. OR of retinal arteriole narrowing and retinal arteriovenous nicking and stroke was 1.42 and 1.91, respectively, indicating that a small-caliber retinal arteriole and retinal arteriovenous nicking were associated with stroke. OR of retinal hemorrhage and retinal microaneurysm and stroke was 3.21 and 3.83, respectively, indicating that retinal microvascular lesions were highly associated with stroke. Results also showed that retinal fractal dimension reduction was associated with stroke (OR: 2.28 for arteriole network, OR: 1.80 for venular network). Retinal vasculature changes have a specific relationship to stroke, which is promising evidence for the prediction of stroke using computerized retinal vessel analysis.

Ten-Year Longitudinal Changes in Retinal Microvascular Lesions: The Atherosclerosis Risk in Communities Study

There are limited data on the natural history and longitudinal changes of retinal microvascular lesions. We examined 10-year changes in retinal microvascular lesions, focusing on those related to hypertension and shown to predict development of cardiovascular disease. Prospective cohort. We included 1120 middle-aged participants without diabetes of the Atherosclerosis Risk in Communities (ARIC) Study in 1993 to 1995 and again 10 years later in 2003 to 2005. Retinal microvascular lesions were graded from retinal photographs using the same protocol at both examinations, with changes (incidence or disappearance) adjudicated by a side-by-side comparison of photographs. The study sample was stratified by carotid intima media thickness (IMT) and ARIC field center; thus, all analyses were weighted by these factors. Persons with diabetes were excluded because the frequency and pathophysiology of diabetic retinal lesions is different. Incidence and disappearance rates of lesions. The 10-year incidence of focal arteriolar narrowing, arteriovenous (AV) nicking, and retinopathy in persons without diabetes was 3.4% (95% confidence interval [CI], 2.3-4.9), 2.5% (95% CI, 1.6-3.9), and 2.2% (95% CI, 1.3-3.5) respectively. Over the 10-year period, of 32, 219, and 24 eyes with focal arteriolar narrowing, AV nicking and retinopathy at baseline, 50.3% (95% CI, 28.6-71.9), 40.7% (95% CI, 32.7-49.4), and 65.9% (95% CI, 42.4-83.5), respectively, disappeared. Higher baseline plasma fibrinogen and white cell counts were associated with incident focal arteriolar narrowing; antihypertensive medication use was associated with incident AV nicking, and higher diastolic blood pressure, carotid IMT, and white cell counts were associated with incident retinopathy. Higher fasting serum glucose was not significantly associated with incident retinopathy, although this may be related to the small number of lesions (odds ratio, 5.88; 95% CI, 0.74-46.64 per standard deviation difference). In this sample of middle-aged adults, new retinal microvascular lesions appeared at a rate between 2% and 4% over 10 years. A high percentage of lesions (≥40%) disappeared over the same period, suggesting considerable remodeling in the retinal microvasculature. The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Ten-year longitudinal changes in retinal microvascular lesions: The atherosclerosis risk in communities study

Ten-year longitudinal changes in retinal microvascular lesions: The atherosclerosis risk in communities study

Relation Between Grade II Hypertensive Retinopathy and Coronary Artery Disease in Treated Essential Hypertensives

It is known that in advanced hypertensive retinopathy, which changes advanced hypertensive retinopathy (Grade III or IV), there is a strong relation between retinal microvascular lesions and cardiac and macrovascular markers of target organ damage (TOD). The prevalence of grade II hypertensive retinopathy and its relationship to cardiovascular risk factors remain controversial. The subjects, a total of 437 hypertensive patients, were divided into three groups according to modified Keith, Wagener, and Barker (KWB) classification by two ophthalmologists: Grade 0 with normal retinal change (N = 169, 38.7%), Grade I with arteriolar narrowing (N = 215, 49.1%), Grade II with arteriovenous crossings (N = 49, 11.2%). The prevalence of Grade I and Grade II hypertensive retinopathy was significantly higher than that of advanced hypertensive retinopathy. The grade of hypertensive retinopathy was related to age, duration of hypertension, coronary artery disease (CAD), and left ventricular hypertrophy (LVH). The prevalence of LVH and CAD in Grade II was significantly higher than in Grade I and Grade 0. The hypertensive retinopathy Grade II was significantly correlated with LVH (odds ratio (OR) 2.3, 95% confidence interval (CI) 1.21–4.44, p < 0.05) and CAD (OR 4.2, 95% CI 1.97–8.95, p-<-0.001). Grade I and Grade II hypertensive retinopathy are frequently observed in hypertensive patients compared to Grade III and IV patients. We concluded that Grade II hypertensive retinopathy is closely related to CAD and should therefore not be ignored.

Emphasizes the research of diabetic retinal neurons lesions and retinal neuroprotection

Diabetic retinopathy includes retinal microangiopathy and retinal neuronopathy. Most of the clinical research has been primarily focused on the former. The retinal microvascular lesions and its complications has standardized in diagnosis and treatment. However, the emphasis on the latter has not been attached to the importance in clinic, and it has fewer studies on it. In recent years, studies have shown that the functional lesion of the retinal neurons and glial cells often can be detected earlier than microangiopathy in diabetic patients. Therefore, emphasis on the research of the diabetic retinal neurons lesions and retinal neuroprotection is beneficial to understand the essence of diabetic retinopathy rightly, and has great practical significance in preventing and reversing diabetic retinal neuronopathy in the early stage.

Retinal and Cerebral Microvascular Signs and Diabetes

Diabetes increases the risk for microvascular disease. The retina and the brain both have intricate microvascular systems that are developmentally similar. We sought to examine whether microvascular lesions in the retina and in the brain are associated and whether this association differs among people with and without diabetes. The analysis included 4,218 participants of the Icelandic population-based Age, Gene/Environment Susceptibility-Reykjavik Study who were born in 1907-1935 and who were previously followed as a part of the Reykjavik Study. Retinal focal arteriolar narrowing, arteriovenous (AV) nicking, and microaneurysms/hemorrhages were evaluated on digital retinal images of both eyes. Cerebral microbleeds (CMBs) were evaluated from magnetic resonance images. Data were analyzed with logistic and multinomial logistic regression models controlling for demographics, major cardiovascular risk factors, cerebral infarcts, and white matter lesions. Evidence of brain microbleeds was found in 485 (11.5%) people, including 192 with multiple (>or=2) microbleeds. Subjects with signs of retinal microvascular lesions were at a significantly increased likelihood for having multiple CMBs. People with diabetes in combination with the presence of either retinal AV nicking (odds ratio [OR] 2.47 [95% CI 1.42-4.31]) or retinal microaneurysms/hemorrhages (2.28 [1.24-4.18]) were significantly more likely to have multiple CMBs. Retinal microvascular abnormalities and brain microbleeds may occur together in older adults. People with both diabetes and signs of retinal microvascular lesions (AV nicking and microaneurysms/hemorrhages) are more likely to have multiple microbleeds in the brain. Microvascular disease in diabetes extends to the brain.

Retinopathy Is Reduced during Experimental Diabetes in a Mouse Model of Outer Retinal Degeneration

Diabetic patients who also have retinitis pigmentosa (RP) appear to have fewer and less severe retinal microvascular lesions. Diabetic retinopathy may be linked to increased inner retinal hypoxia, with the possibility that this is exacerbated by oxygen usage during the dark-adaptation response. Therefore, patients with RP with depleted rod photoreceptors may encounter proportionately less retinal hypoxia, and, when diabetes is also present, there may be fewer retinopathic lesions. This hypothesis was tested in rhodopsin knockout mice (Rho-/-) as an RP model in which the diabetic milieu is superimposed. The study was designed to investigate whether degeneration of the outer retina has any impact on hypoxia, to examine diabetes-related retinal gene expression responses, and to assess lesions of diabetic retinopathy. Streptozotocin-induced diabetes was created in male C57Bl6 (wild-type; WT) and Rho-/- mice, and hyperglycemia was maintained for 5 months. The extent of diabetes was confirmed by measurement of glycated hemoglobin (%GHb) and accumulation of advanced glycation end products (AGEs). Retinal hypoxia was assessed using the bioreductive drug pimonidazole. The retinal microvasculature was studied in retinal flatmounts stained by the ADPase reaction, and the outer retina was evaluated histologically in paraffin-embedded sections. Retinal gene expression of VEGF-A, TNF-alpha, and mRNAs encoding basement membrane component proteins were quantified by real-time RT-PCR. The percentage GHb increased significantly in the presence of diabetes (P < 0.001) and was not different between WT or Rho-/- mice. Hypoxia increased in the retina of WT diabetic animals when compared with controls (P < 0.001) but this diabetes-induced change was absent in Rho-/- mice. Retinal gene expression of VEGF-A was significantly increased in WT mice with diabetes (P < 0.05), but was unchanged in Rho-/- mice. TNF-alpha gene expression significantly increased (4.9-fold) in WT mice with diabetes (P < 0.05) and also increased appreciably in Rho-/- mice but to a reduced extent (1.5 fold; P < 0.05). The outer nuclear layer in nondiabetic Rho-/- mice was reduced to a single layer after 6 months, but when diabetes was superimposed on this model, there was less degeneration of photoreceptors (P < 0.05). Vascular density was attenuated in diabetic WT mice compared with the nondiabetic control (P < 0.001); however, this diabetes-related disease was not observed in Rho-/- mice. Loss of the outer retina reduces the severity of diabetic retinopathy in a murine model. Oxygen usage by the photoreceptors during dark adaptation may contribute to retinal hypoxia and exacerbate the progression of diabetic retinopathy.

Prevalence and correlates of advanced retinopathy in a large selected hypertensive population. The Evaluation of Target Organ Damage in Hypertension (ETODH) study

Objective. To describe the prevalence of advanced retinal microvascular lesions and their associations with cardiac and extracardiac signs of target organ damage (TOD) in a large selected hypertensive population. Methods. A total of 2172 non‐diabetic untreated and treated uncomplicated essential hypertensives consecutively attending for the first time our hospital outpatient hypertension clinic and included in the Evaluation of Target Organ Damage in Hypertension (ETODH), an observational ongoing registry of hypertension‐related TOD, were considered for this analysis. Advanced hypertensive retinopathy was defined by the presence of any of the following lesions: flame‐shaped haemorrhages, soft exudates or cotton wool spots and papilloedema. Left ventricular hypertrophy (LVH), carotid structural abnormalities, such as plaques and intima media (IM) thickening, and microalbuminuria were diagnosed according to the 2003 ESH/ESC guidelines criteria. Results. Among the whole study population, 33 patients (1.5%) were found to have advanced hypertensive retinopathy. Patients with these retinal lesions were similar to those without for age, body mass index, known duration of hypertension, smoking habit, total serum cholesterol, fasting blood glucose and prevalence of antihypertensive treatment; whereas mean systolic and diastolic blood pressures were higher in the former group. The prevalence rates of LVH, carotid plaques, carotid IM thickening and microalbuminuria in patients with and without retinopathy were 57%, 67%, 69%, 19% and 25%, 47%, 44%, 12%, respectively. In a multivariate logistic regression analysis, advanced retinopathy was significantly associated with LVH (OR = 4.0), carotid IM thickening (OR = 2.9), carotid plaques (OR = 2.8), but not with microalbuminuria. Conclusions. Our study indicates that: (i) advanced retinopathy is a rare finding in non‐diabetic hypertensive patients seen in a specialist setting; (ii) a strong relation exists between retinal microvascular lesions and cardiac and macrovascular markers of TOD.

Wong TY, Klein R, Couper DJ, et al. Retinal microvascular abnormalities and incident stroke: the Atherosclerosis Risk in Communities Study.

Wong TY, Klein R, Couper DJ, et al. Retinal microvascular abnormalities and incident stroke: the Atherosclerosis Risk in Communities Study. Lancet 2001;358:1134–40. Wong et al. obtained undilated retinal photographs in 10,358 men and women living in North Carolina, Mississippi, Minnesota, and Maryland. They followed the patients for an average of 3.5 years (range 3–5 years), and observed the frequency of stroke (ischemic or hemorrhagic), stratifying it with respect to retinal vessel abnormalities, predisposing systemic diseases (diabetes, hypertension, coronary artery disease), and other risk factors (smoking, alcohol use, cholesterol). There were 110 patients with stroke (96 ischemic, 13 hemorrhagic, and one ischemic/hemorrhagic). After adjusting for age, gender, race, and locality, each of the retinal microvascular lesions observed increased the relative risk of stroke above baseline (microaneurysm: RR 5.0 [95% CI 3.0–8.2], soft exudates: 5.6 [2.8–89], blot hemorrhage: 4.9 [2.7–8.8], flame hemorrhage: 4.6 [2.1–9.9], arteriovenous nicking: 1.9 [1.3–3.0]). Much of this could be expected because these lesions are commonly associated with hypertension, diabetes, and other vascular diseases, and these diseases are all risk factors for stroke. Surprisingly, when a multivariate analysis was done, adjusting for blood pressure, the use of antihypertensive medications, the presence of diabetes, smoking status, fasting glucose, and blood lipid measurements, each of the retinal abnormalities was still a significant risk factor for stroke, although to a lesser degree. A stratified analysis using the presence of diabetes and hypertension also showed that the retinal abnormalities were independent predictors of stroke, although the small number of patients in some of the groups meant that the confidence limits were wide. The biggest potential flaw of this study is that the confounding variables (presence of hypertension and other vascular diseases may not have been completely eliminated in the multivariate analyses. Nonetheless, an important implication of this study is that observation of a retinal microvascular abnormality in a patient should not only prompt a work-up for vascular disease, but even if no disease is present, suggest that the patient is at an increased risk of stroke. The retinal abnormalities may be markers of small vessel disease and may be indicative of vascular pathologic processes occurring in the cerebral circulation.

Retinal Photography for Stroke Risk Prediction

The article is about retinal photography and stroke risk prediction. It is an analysis of the study data that revealed a statistically significant correlation between the presence of retinal microvascular lesions and the occurrence of stroke.