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Prevention of retinal vessel changes associated with diabetic retinopathy in galactose-fed dogs by aldose reductase inhibitors.

Vascular changes associated with early diabetic retinopathy that include the selective degeneration of pericytes, the formation of microaneurysms and acellular capillaries, and vessel dilation have been experimentally investigated in age- and sex-matched beagle dogs fed a 30% galactose diet and treated with or without the aldose reductase inhibitors sorbinil and/or M79175. Eyes from dogs in each group were periodically enucleated during a 36-month period and their retinal capillaries were examined as trypsin-digested flat preparations. These studies reveal that the destruction of retinal pericytes to form pericyte ghosts is the earliest observable retinal vessel change occurring after 19 to 21 months of galactose feeding. By 24 months, both an irregular distribution of endothelial cell nuclei near pericyte ghosts and the presence of acellular capillaries containing neither endothelial cells nor pericytes can be observed. This was followed by the histologic appearance of microaneurysms after 27 months and the funduscopic appearance of intraretinal hemorrhages after 33 months. Varicose enlargements of capillaries were also observed in the trypsin-digested preparations from dogs fed galactose for 33 to 36 months. All of these changes are linked to the initial aldose reductase-associated destruction of pericytes. The onset and progression of these retinal changes were retarded in a dose-dependent manner with aldose reductase inhibitors.

Aldehyde Reductase↗

Observer sensitivity to retinal vessel diameter and tortuosity in retinopathy of prematurity: a model system.

BACKGROUND: Abnormally increased diameter and tortuosity of retinal blood vessels in the posterior pole, or "plus disease," is recognized as a powerful predictor of poor outcome in eyes with retinopathy of prematurity (ROP). Although the diagnosis of plus disease depends upon the examiner's ability to examine retinal blood vessels, the ability of the human observer to identify changes in retinal blood vessel diameter and tortuosity accurately has not been studied. METHODS: Using computer-aided analysis of fundus photographs from eyes with a wide range of ROP severity, we generated tracings of posterior pole blood vessels which varied by quintiles of mean vessel diameter and tortuosity. Subjects (23 naive and 12 expert observers) ranked groups of tracings in order of increasing mean vessel diameter and tortuosity. These ranking tests were performed on tracings derived from the same fundus and tracings derived from distinct fundi. In a similar fashion, subjects also compared one designated standard fundus tracing with 25 distinct fundus tracings. RESULTS: Vessel diameter was assessed correctly more often than vessel tortuosity, both among similar (> 99% vs 92% of the time, respectively, P < 0.001), or among distinct (88% vs 78% of the time, respectively, P < 0.001) fundus images. The mean vessel diameter and tortuosity of 25 distinct fundus images were correctly ranked versus a standard image in 89% of attempts. Assessments of increments in vessel diameter and tortuosity were independent. Naive and expert subjects performed indistinguishably on all tests. CONCLUSIONS: Intelligent human observers have considerable ability to discern clinically relevant increments in blood vessel diameter and tortuosity. This ability may facilitate standardization in the diagnosis of plus disease in ROP.

Computer Simulation↗

Retinal vessel wall signs and the 5 year incidence of age related maculopathy: the Blue Mountains Eye Study.

AIMS: To assess whether retinal arteriolar wall changes (focal narrowing and arteriovenous nicking) are associated with an increased 5 year risk of age related maculopathy (ARM). METHODS: The Blue Mountains Eye Study examined 3654 residents aged 49+ years living in a defined area, during 1992-4 (82.4% participation). After 5 years, 2335 surviving participants (75.1%) were re-examined during 1997-9. Retinal photographs were graded using the Wisconsin ARM grading system. Incident late (neovascular or atrophic) or early stage ARM was defined using a side by side grading method. Focal arteriolar narrowing (localised constricted arteriolar segments causing a sausage-like appearance), and arteriovenous (AV) nicking (constriction on both sides of the venule where crossed by an arteriole), were graded by comparison with standard photographs. All retinal vessels passing through a circumferential zone 0.5-1.0 disc diameters from the optic disc margin were measured from digitised images. Summarised estimates for central retinal arteriolar equivalent (CRAE) represent an average diameter of arterioles for that eye. Associations were assessed after adjusting for age, sex, smoking, mean arterial blood pressure, and other vascular risk factors. RESULTS: Of 2314 baseline participants at risk of late stage ARM, either late stage lesion developed in 34 participants (1.5%). Of 2203 at risk of early stage ARM, this sign developed in 197 participants (8.9%). Focal arteriolar narrowing was present at baseline in at least one eye of 162 survivors (6.9%) and severe AV nicking was present in 187 people (8.1%). Over 5 years, 4.9% of subjects with and 1.2% of those without focal narrowing developed either late stage ARM lesion, age adjusted relative risk (RR) 2.3, 95% confidence interval (CI) 1.0 to 5.1, multivariate adjusted odds ratios (OR) 2.1 (95% CI 0.9 to 4.9). Similarly, 3.7% of subjects with and 1.3% of those without severe AV nicking developed late ARM lesions, age adjusted RR 2.1 (95% CI 0.9 to 5.1), multivariate adjusted OR 2.2 (95% CI 0.9 to 5.6). Corresponding age adjusted RR and multivariate adjusted OR for development of early stage ARM were 1.4 (95% CI 0.9 to 2.0) and 1.3 (95% CI 0.8 to 2.1) for focal arteriolar narrowing, and 1.6 (95% CI 1.0 to 2.3) and 1.8 (95% CI 1.1 to 2.9) for severe AV nicking, respectively. No associations between baseline CRAE and 5 year incident late or early stage ARM were found. CONCLUSIONS: Although of borderline statistical significance, the consistent associations found in this study suggest that structural retinal arteriolar changes may either contribute to ARM progression or may share common pathological pathways with ARM.

Aged↗

The relation of retinal vessel caliber to the incidence and progression of diabetic retinopathy: XIX: the Wisconsin Epidemiologic Study of Diabetic Retinopathy.

OBJECTIVE: To describe the relation of retinal arteriolar and venular caliber to the incidence and progression of diabetic retinopathy in people with type 1 diabetes mellitus. DESIGN: Incidence findings in a population-based study of diabetic retinopathy in Wisconsin. Participants included 996 persons diagnosed as having diabetes mellitus before 30 years of age who took insulin and underwent the baseline examination, 891 in the 4-year follow-up, 765 in the 10-year follow-up, and 634 in the 14-year follow-up. Retinal photographs of 7 standard fields were taken at all examinations. Computer-assisted grading was performed from a digitized image of field 1 to determine the average diameter of retinal arterioles and venules and their ratio. Main outcome measures included incidence and progression of retinopathy, incidence of proliferative retinopathy, and macular edema. RESULTS: While adjusting for other factors, larger arteriolar (relative risk [RR] for the fourth vs first quartile range, 2.04; 95% confidence interval [CI], 1.20-3.47; test of trend, P =.008) and venular diameters (RR, 2.33; 95% CI, 1.37-3.95; test of trend, P =.005) were associated with greater 4-year progression of retinopathy. Larger venular diameters (RR, 4.28; 95% CI, 1.50-12.19; test of trend, P =.006) but not arteriolar diameters were associated with greater 4-year incidence of proliferative retinopathy. In multivariable analyses, arteriolar and venular calibers were not associated with the 4-year incidence of retinopathy. While adjusting for other factors, arteriolar and venular calibers were not associated with incidence of macular edema at 4 years. There were few associations of arteriolar or venular caliber with the 10- or 14-year incidence or the progression of retinopathy. CONCLUSIONS: Larger arteriolar and venular caliber, independent of retinopathy severity level, is related to the progression of retinopathy, and larger venular caliber is associated with the 4-year incidence of proliferative retinopathy. Caliber of retinal vessels is not associated with incident retinopathy. These data suggest a quantitative measure of retinal vascular caliber provides additional information regarding risk for progression of retinopathy.

Adult↗

Retinal vessel responses to exercise and hypoxia before and after high altitude acclimatisation.

Computerised microdensitometry was used to study diameter changes in 93 arterial and 91 venous vessel sites in the retinas of four mountain climbers before and after spending seven weeks in the Himalaya mountains. The vascular response to short-term strenuous exercise was measured at sea level, to acute hypoxia of simulated altitude of 15,000 ft (4,572 m) at rest, and to strenuous exercise while acutely exposed to the same hypoxic condition. Before the mountain exposure, retinal vessels constricted during exercise -1.9% (arteries); -3.3% (veins) and dilated in acute hypoxia 9.4% (arteries); 8.1% (veins). Superimposed exercise on hypoxic dilated arteries reduced the vasodilation (9.4% to 6%). After acclimatisation, the same physical work load at sea level constricted the arteries more (-5.4% vs -1.9%) but did not constrict the veins (0.2% vs -3.3%). Superimposed exercise on hypoxic dilated vessels, excessively dilated both arteries (8.4% vs 6.0%) and veins (13.7% vs 8.4%), compared to changes seen before the mountain sojourn. This study shows that physical conditioning and long adaptation to hypoxia, significantly change the vascular response of the retina to physical activity both in normal atmospheric conditions and during hypoxic stress. High altitude retinal hemorrhages (HARH) were present in one climber, and the study may indicate why HARH is seen often in young and physical well-trained subjects.

Acclimatization↗

[Prenatal development of human retinal vessels].

Feeding of the retina, whose thickness does not exceed 130 mu km, is possible at the account of chriocapillary diffusion. Should this threshold be topped (approximately by the 3.5th prenatal month), it will result in a relative hypoxia of the uttermost internal strata of the retina, which induces the appearance of new feeding source, i.e. retinal vessels. First, dense cellular steaks of the sequential fusiform cells originating from the visual-stem depth located near the wall of a. hyaloidea emerge in the surface retinal strata. These cells (angioblasts) formed the peripapillary plexus, shaped as a vascular pattern, and represented a non-lumenized prototype, or matrix, of a future capillary network. Later, main arterioles emerged, in the outward direction from them, and after that venules took shape from the above network through a partial reduction of vessels and a redistribution of blood circulation. The second deep capillary stratum was formed rather through a prolongation and "sagging" of the surface capillary loops than through gemmation; it is common for the entire retina and, unlike the surface stratum, is not divided by main arterioles into adjoining segments. By the 8th fetal-life month the evolution of the retinal bloodstream is not entirely completed, though it resembles, to a great extent, a definitive one.

Arterioles↗

Dorzolamide influences the autoregulation of major retinal vessels caused by artificial intraocular pressure elevation in patients with POAG: a clinical study.

PURPOSE: The study investigated whether dorzolamide influences the autoregulatory behavior of major retinal arterioles in glaucoma patients via a moderate perfusion pressure reduction. METHODS: The study included one eye each of 12 untreated patients with a primary open-angle glaucoma (POAG) (age 60.8 +/- 8.3, IOP 22.3 +/- 6.5 mmHg). Changes in the diameter of a retinal artery segment before (120 s), during (100 s), and after (380 s) artificial IOP elevation to 38 mmHg for 100 s were recorded continuously by means of a Retinal Vessel Analyzer. The measurement was repeated after 4-week treatment with dorzolamide eye drops t.i.d. RESULTS: Ocular perfusion pressure (mmHg) was reduced by the intraocular pressure (IOP) elevation from 58 (+/- 10) to 41 (+/- 11) in the pretreatment examination and from 60 (+/- 8) to 40 (+/- 8) posttreatment (differences between the examinations n.s.). Before IOP elevation, the arterial diameter was found to be +1.7 +/- 3.5% greater in the posttreated eyes than in the pretreated eyes (p < 0.02). During IOP elevation, the arterial diameter decreased by -1.8% +/- 3.8 in the pretreated eyes, whereas dilatation by +1.4% +/- 2.5 was observed in the posttreated eyes (p = 0.02). At the end of the observation period following IOP elevation, the vessel diameter in the pretreated eyes had increased by +1.8% +/- 4.2, whereas in the posttreated eyes it had decreased by -1.7% +/- 3.0. On average, dorzolamide reduced IOP by -5.6 mmHg (p = 0.001). CONCLUSIONS: The arterial diameter dilatation during IOP elevation in dorzolamide-treated eyes could be an accelerated counter-regulation on the induced elevated IOP and could constitute an additional therapeutic effect.

Aged↗

Treatment of an avulsed retinal vessel with infrared diode laser photocoagulation.

PURPOSE: To report the use of the infrared diode laser with long-duration pulses to successfully treat a patient with recurrent vitreous hemorrhages due to an avulsed retinal arteriole. DESIGN: Interventional case report. METHODS: A 70-year-old man presented with repeated, visually significant vitreous hemorrhages due to an avulsed retinal arteriole. Infrared diode laser photocoagulation with long-duration, large, overlapping spots was performed on either side of the avulsed segment. RESULTS: Resolution of the hemorrhage occurred within 1 month, without further episodes of bleeding. Two-year follow-up with fluorescein angiography showed complete cessation of blood flow through the treated segment. CONCLUSIONS: Infrared diode laser photocoagulation with long-duration pulses may be an effective, minimally invasive treatment of the avulsed retinal vessel syndrome.

Aged↗

Retinal vessel changes in galactose-fed dogs.

BACKGROUND: Retinal lesions similar to those in human early-stage diabetic retinopathy have been reported to occur in dogs fed galactose for long periods. Investigations of retinal changes, however, have been limited to studies of the intact retinal vasculature isolated by trypsin digestion. OBJECTIVE: To document the onset and progression of retinal lesions in galactose-fed dogs by the common clinical techniques of fundus color photography and fluorescein angiography. METHODS: Fourteen 6-month-old male beagles made aphakic in 1 eye were divided into a control group (4 dogs), receiving a diet containing 30% cellulose, and a galactosemic group (10 dogs), receiving a diet containing 30% galactose. The progression of retinal changes in these dogs was periodically monitored by color fundus photography and fluorescein angiography. RESULTS: Dogs fed a 30% galactose diet for 28 to 41 months were observed by fluorescein angiography and color fundus photography to develop, in order of frequency, microaneurysms, retinal hemorrhages, intraretinal microvascular abnormalities, retinal nonperfused areas, and varicose and serpiginous veins. These findings are similar to the early clinical retinal changes observed in humans with diabetes. CONCLUSION: These results confirm that galactosemic dogs are an appropriate and suitable animal model for investigating human diabetic retinopathy.

Animals↗

Computer data processing in the examination of retinal vessels in essential hypertension and atherosclerosis.

The mean retinal venoarterial width ratio in 100 healthy subjects was measured with a PZO stereoscopic microscope equipped with a calibrated ocular and with an automatic digital image transformer coupled with an ODRA 1204 computer. The mean value was estimated as equal to 1.21 with an SD of 0.071. The same study was performed in 75 atherosclerotic patients and 75 patients with essential hypertension. In the first group the mean retinal venoarterial width ratio amounted to 1.51 (SD 0.054), while in the second one it was equal to 1.53 (SD 0.079).

Adolescent↗

Angiopoietin-2 enhances retinal vessel sensitivity to vascular endothelial growth factor.

Increased expression of vascular endothelial growth factor (VEGF) in the retina starting after postnatal day (P)7 results in neovascularization originating from deep retinal capillaries, but not those in the superficial capillary bed. Doxycycline was administered starting P0 to double transgenic mice with inducible expression of VEGF in the retina. These mice showed proliferation and dilation of superficial retinal capillaries, indicating that at this stage of development, the superficial capillaries are sensitive to the effects of VEGF. Angiopoietin-2 (Ang2) is expressed along the surface of the retina for several days after birth, but by P7 and later, Ang2 is only expressed in the region of the deep capillary bed. In mice with ubiquitous doxycycline-inducible expression of Ang2, in the absence of doxycycline, intravitreous injection of a gutless adenoviral vector expressing VEGF (AGV.VEGF) resulted in neovascularization of the cornea and iris, but no retinal neovascularization. After treatment with doxycycline to induce Ang2 expression, intravitreous injection of AGV.VEGF caused retinal neovascularization in addition to corneal and iris neovascularization. The retinal neovascularization originated from both the superficial and deep capillary beds. These data suggest that Ang2 promotes sensitivity to the angiogenic effects of VEGF in retinal vessels.

Adenoviridae↗