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Purpose: To document enlarged neovascularization elsewhere (NVE) quantitatively and morphologically using widefield swept-source (SS) OCT angiography (OCTA) with vitreoretinal interface (VRI) slab images., Design: Retrospective, observational imaging study., Participants: The study included 46 NVE examples in 25 eyes of 21 consecutive patients who demonstrated severe proliferative diabetic retinopathy with NVE between March 2018 and June 2020 at Osaka University Hospital., Methods: All patients underwent ophthalmologic examination, including ultra-widefield fluorescein angiography and widefield SS OCTA scans., Main Outcome Measures: We evaluated the area and the vascular density (VD) of NVE lesions detected on five 12 × 12-mm 2 or two 15 × 9-mm 2 SS OCTA panoramic VRI slab images obtained at the first and final visits., Results: At baseline, the mean NVE area on OCTA was 1.85 ± 2.81 mm 2 , and the VD of the NVE lesions was 73.9 ± 14.6%. At the final visit, the mean NVE area on OCTA was 2.14 ± 3.14 mm 2 , and the mean VD of the NVE lesions was 65.3 ± 17.1%. The average NVE size change (square millimeters per month) was associated significantly with the ischemic index (P = 0.009). Growth of NVE area was classified into 2 patterns: round (61.8%) and ramified (38.2%). The round group tended to have a larger ischemic index at baseline than the ramified group (P = 0.0375)., Conclusions: We quantified the size and density of NVE lesions over time. The NVE size increase was associated significantly with the severity of ischemic changes. Furthermore, the round growth pattern was correlated significantly with the ischemic index. These findings suggest that the morphologic features of NVE are associated with more severe ischemia., (Copyright © 2021 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: Assessment of cardiovascular risk is the keystone of prevention in cardiovascular disease. The objective of this pilot study was to estimate the cardiovascular risk score (American Hospital Association [AHA] risk score, Syntax risk, and SCORE risk score) with machine learning (ML) model based on retinal vascular quantitative parameters., Methods: We proposed supervised ML algorithm to predict cardiovascular parameters in patients with cardiovascular diseases treated in Dijon University Hospital using quantitative retinal vascular characteristics measured with fundus photography and optical coherence tomography - angiography (OCT-A) scans (alone and combined). To describe retinal microvascular network, we used the Singapore "I" Vessel Assessment (SIVA), which extracts vessel parameters from fundus photography and quantitative OCT-A retinal metrics of superficial retinal capillary plexus., Results: The retinal and cardiovascular data of 144 patients were included. This paper presented a high prediction rate of the cardiovascular risk score. By means of the Naïve Bayes algorithm and SIVA + OCT-A data, the AHA risk score was predicted with 81.25% accuracy, the SCORE risk with 75.64% accuracy, and the Syntax score with 96.53% of accuracy., Conclusions: Performance of these algorithms demonstrated in this preliminary study that ML algorithms applied to quantitative retinal vascular parameters with SIVA software and OCT-A were able to predict cardiovascular scores with a robust rate. Quantitative retinal vascular biomarkers with the ML strategy might provide valuable data to implement predictive model for cardiovascular parameters., Translational Relevance: Small data set of quantitative retinal vascular parameters with fundus and with OCT-A can be used with ML learning to predict cardiovascular parameters.

Purpose: The purpose of this study was to evaluate the association between retinal laser burden and vascular oxygen saturation in patients with proliferative diabetic retinopathy (PDR) treated with different extent of retinal laser., Methods: The study was a prospective, interventional study of patients with treatment-naïve PDR. Patients were treated with navigated retinal laser (Navilas ® , OD-OS GmbH, Teltow, Germany) in different doses. Retinal oximetry was obtained at baseline (BL) prior to laser and after 6 months (M6). Patients were divided into three groups according to total laser spots applied: <1500 spots (Group 1), 1500-2000 spots (Group 2), and >2000 spots (Group 3)., Results: We included 33 eyes of 28 patients with treatment-naïve PDR. The groups did not differ according in BL characteristics. Between BL and M6, retinal arteriolar oxygen saturation did not change but retinal venular oxygen saturation (median with interquartile range) decreased in Groups 1 and 2 (1: 65.5 ± 8.8% versus 60.5 ± 9.5%, p = 0.04; 2: 65.3 ± 7.3% versus 63.0 ± 13.5%, p = 0.04). Focal retinal venular oxygen saturation, located to quadrants with retinal neovascularization, decreased in Group 2 from BL to M6 (67.5 ± 13.3% versus 61.5 ± 8.8%, p = 0.04). Retinal venular diameter decreased from BL to M6 in Group 1 (174.5 ± 15.3 μm versus 165.1 ± 28.7 μm, p = 0.01)., Conclusions: In this study of patients with treatment-naïve PDR, we showed that a less extensive laser treatment caused a reduction in retinal venular oxygen saturation and diameter 6 months after treatment. Our results suggest that less extensive laser treatment may be sufficient to improve the retinal metabolic environment conducive to PDR regression., (© 2020 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

The Glaucoma Stereo Analysis Study (GSAS) is a multicenter collaborative study of the characteristics of glaucomatous optic disc morphology using a stereo fundus camera. This study evaluated the retinal vessel calibers and correlations using GSAS fundus photographs between retinal vessels and 38 optic nerve head (ONH) morphologic parameters comprehensively. In all 240 eyes, the mean central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) were 138.4 and 216.5 μm, respectively; the CRAE correlated with age, visual field scores and 19 ONH parameters and CRVE correlated with age, intraocular pressure, visual field scores and 11 ONH parameters. Among the different optic disc appearances including focal ischemia (FI) (n = 53, 22%), generalized enlargement (GE) (n = 53, 22%), myopic glaucoma (MY) (n = 112, 47%), and senile sclerosis (SS) (n = 22, 9%), the CRAE did not differ significantly; CRVE was significantly narrower in SS than in FI and MY. In FI, GE, MY, and SS disc types, CRAE correlated with 3, 14, 9, and 2 ONH parameters, respectively, and CRVE corelated with 9, 0, 12, and 6 ONH parameters, respectively. We confirmed previous observations on the effect of retinal vessel narrowing on glaucomatous changes in the ONH and visual field. The associations between retinal vessel caliber and ONH morphologic parameters vary among different optic disc appearances, suggesting different effects of vascular changes in each disc type., Competing Interests: Drs. Maki Katai, Yasushi Kitaoka, Yu Yokoyama, Kazuko Omodaka, Tomoko Naito, Takehiro Yamashita, Shiro Mizoue, and Toru Nakazawa used a stereo fundus camera provided by Kowa Company, Ltd., to conduct the study. Drs. Masaki Tanito, Koji Nitta, Yu Yokoyama, and Toru Nakazawa have received lecture honoraria and/or consultation fees from Kowa Company, Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors have no conflict to declare.

Purpose: To determine the presence or absence of interocular differences in the foveal avascular zone (FAZ) area in healthy eyes., Study Design: Cross-sectional study., Methods: We examined 236 healthy eyes of 118 consecutive subjects (mean age, 39.1 ± 18.9 years). We used swept-source optical coherence tomography angiography (OCTA) images of the FAZ to measure its area from both the superficial capillary plexus (SCP-FAZ) and the whole retinal capillary plexus (WCP-FAZ). We also investigated the relationship between interocular differences in SCP-FAZ and other factors such as: axial length, spherical equivalent, central retinal thickness, and retinal vascular density., Results: There was no significant difference in the FAZ area between the right and left eyes in either the SCP-FAZ (P = 0.61) or WCP-FAZ (P = 0.80), and the FAZ areas of both eyes showed significant positive correlations (SCP-FAZ; P < 0.001, R 2  = 0.884, WCP-FAZ; P < 0.001, R 2  = 0.856). Bland-Altman plots showed that the mean interocular difference in SCP-FAZ area was 0.002 ± 0.037 mm 2 (95% confidence interval, -0.072-0.075 mm 2 ), and in the WCP-FAZ area, 0.050 ± 0.044 mm 2 (95% confidence interval, -0.036-0.137 mm 2 ). Multivariate regression analysis showed that none of the investigated factors were significantly associated with interocular differences in SCP-FAZ (P = 0.61, R 2  = 0.138)., Conclusions: There was no significant interocular difference in SCP- and WCP-FAZ areas in healthy eyes. The normal range of values for interocular difference in SCP-FAZ area was 0.002 ± 0.037 mm 2 and in the WCP-FAZ area, 0.050 ± 0.044 mm 2 .

Purpose: Ocular and brain microcirculation share embryological and histological similarities. The retinal vascular fractal dimension (FD) is a marker of retinal vascular complexity of the vascular tree. The purpose of this study was to explore the relationship between cerebral blood flow (CBF), retinal vascular FD and other retinal vascular markers., Methods: Cross-sectional analysis comprising 26 individuals ≥65 years old from the Cognitive REServe and Clinical ENDOphenotype (CRESCENDO) cohort of relative healthy older adults. Retinal vascular FD was measured from fundus photographs by using the semi-automated Singapore Eye Vessel Assessment (SIVA) software. CBF was estimated using a 2D pulsed ASL MRI sequence. Associations between blood flow and retinal parameters were analysed using linear regression models adjusted for age and sex., Results: Cerebral blood flow was positively associated with venular FD (R 2  = 0.32, p = 0.03). This association was stronger in the anterior versus posterior brain territories (R 2  = 0.35 [p = 0.001] versus R 2  = 0.16 [p = 0.07], respectively). Global CBF was correlated with arteriolar branching angle (R 2  = 0.23, p = 0.01) and tortuosity (R 2  = 0.20, p = 0.02). Global CBF was not correlated with other SIVA parameters., Conclusions: Retinal venular complexity summarized by the FD was associated with cerebral blood flow as well as retinal arteriolar tortuosity and branching angle. Larger prospective clinical studies are needed to confirm these results., (© 2019 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background/aims: With the perspective to provide individualised panretinal laser photocoagulation (PRP) for proliferative diabetic retinopathy (PDR), we evaluated if retinal peripheral capillary non-perfusion (PCNP) and oximetry, as non-invasive markers of retinal metabolism and function, could predict disease activity 6 months after PRP., Methods: We performed a prospective, interventional study of patients with treatment-naïve PDR. Retinal oximetry and ultra-widefield fluorescein angiography were performed at baseline (BL) and three (3M) and 6 months (6M) after PRP by a navigated laser system. At 6M follow-up, patients were divided according to disease activity: active or inactive., Results: We included 33 eyes, and 69.6% were men. At BL, the median age and duration of diabetes (with IQRs) were 51.6±23.4 and 20.0±15.0 years. Haemoglobin A 1c was 63.0±17.0 mmol/mol and blood pressure was 152±37/82±24 mm Hg. At BL and M6, patients with postoperative disease activity (30.3.%, n=10) had a larger area with PCNP than those with inactive PDR (BL: 51%-75% vs 26%-50%, p=0.03; 6M: 51%-75% vs 26%-50%, p=0.03). The area of PCNP did not change from BL to 6M in either group (inactive PDR: p=0.38, active PDR: p=0.87). Changes in retinal oxygen saturation were not found to be clinical relevant., Conclusion: We found the area of PCNP at all timepoints to be statistically larger in patients with active PDR 6 months after PRP treatment. Therefore, the area of PCNP, at baseline, may serve as a potential predictive marker for PDR activity after treatment., Competing Interests: Competing Interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: We aimed to investigate changes in retinal vascular geometry over time after panretinal photocoagulation (PRP) in patients with proliferative diabetic retinopathy (PDR)., Methods: Thirty-seven eyes with PDR were included. Wide-field fluorescein angiography (Optomap, Optos PLC., Dunfermline, Scotland, UK) was used to diagnose PDR at baseline and to assess activity at follow-up month three and six. At each time-point, a trained grader measured retinal vessel geometry on optic disc (OD) centred images using semiautomated software (SIVA, Singapore I Vessel Assessment, National University of Singapore, Singapore) according to a standardized protocol., Results: At baseline, the mean age and duration of diabetes were 52.8 and 22.3 years, and 65% were male. Mean HbA1c was 69.9 mmol/mol, and blood pressure was 155/84 mmHg. Of the 37 eyes with PDR, eight (22%) eyes had progression at month three and 13 (35%) progressed over six months. Baseline characteristics, including age, sex, duration of diabetes, HbA1c, blood pressure, vessel geometric variables and total amount of laser energy delivered did not differ by progression status. However, compared to patients with progression of PDR, patients with favourable treatment outcome had alterations in the retinal arteriolar structures from baseline to month six (calibre, 154.3 μm versus 159.5 μm, p = 0.04, tortuosity 1.12 versus 1.10, p = 0.04) and in venular structures from baseline to month three (fractal dimension 1.490 versus 1.499, p = 0.04, branching coefficient (BC) 1.32 versus 1.37, p = 0.01)., Conclusion: In patients with PDR, successful PRP leads to alterations in the retinal vascular structure. However, baseline retinal vascular geometry characteristics did not predict treatment outcome., (© 2017 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: To identify patterns summarizing the retinal vascular network in the elderly and to investigate the relationship of these vascular patterns with cardiovascular history., Methods: We conducted a population-based study, the Montrachet study (Maculopathy Optic Nerve nuTRition neurovAsCular and HEarT diseases), in participants older than 75 years. The history of cardiovascular disease and a score-based estimation of their 10-year risk of cardiovascular mortality (Heart SCORE) were collected. Retinal vascular network analysis was performed by means of Singapore "I" Vessel Assessment (SIVA) software. Principal component analysis was used to condense the information contained in the high number of variables provided and to identify independent retinal vascular patterns., Results: Overall, 1069 photographs (1069 participants) were reviewed with SIVA software. The mean age was 80.0 ± 3.8 years. We extracted three vascular patterns summarizing 41.3% of the vascular information. The most clinically relevant pattern, Sparse vascular network, accounted for 17.4% of the total variance. It corresponded to a lower density in the vascular network and higher variability in vessel width. Diabetic participants with hypoglycemic treatment had a sparser vascular network pattern than subjects without such treatment (odds ratio, [OR], 1.68; 95% CI, 1.04-2.72; P = 0.04). Participants with no history of cardiovascular disease who had a sparser vascular network were associated with a higher Heart SCORE (OR, 1.76; 95% CI, 1.08-2.25; P = 0.02)., Conclusions: Three vascular patterns were identified. The Sparse vascular network pattern was associated with having a higher risk profile for cardiovascular mortality risk at 10 years.

Purpose: To investigate a novel optical coherence tomography (OCT)-derived variable, circumpapillary mean retinal shadow width (cpMRSW), and to elucidate its association with normal-tension glaucoma (NTG)., Methods: For the purpose of validation, we measured retinal vascular calibers in 68 arterioles and 100 venules of 12 NTG patients and 12 healthy subjects and compared the width of the visible retinal shadows in spectral-domain OCT images and the caliber of retinal vessels in retinal photographs. Then we calculated cpMRSW in 78 NTG eyes and 25 age-matched healthy control eyes. Additionally, we divided the patients into early (mean deviation: MD > -6 dB), moderate (MD -6 to -12 dB), and severe (MD < -12 dB) NTG groups, and compared cpMRSW in these groups. Finally, we calculated the area under the receiver operating characteristic (ROC) curve in order to determine the power of mean retinal shadow width to distinguish the groups., Results: OCT retinal shadow width was significantly correlated with photography-measured retinal caliber (r = 0.82, P < 0.001). CpMRSW was significantly different between the control and NTG patients (control: 107.3 ± 7.0 µm, mild: 99.4 ± 8.6 µm, moderate: 99.7 ± 9.5 µm, severe: 90.5 ± 12.0 µm, P < 0.001), despite similar distributions in systemic variables. An ROC analysis revealed that cpMRSW could differentiate NTGs from normal eyes (area under the ROC curve: 0.81)., Conclusions: Our new software for measuring mean retinal shadow width in OCT images may be a valuable tool for detecting NTG and diagnosing its severity.

Purpose: Pseudoexfoliation syndrome (PEX), the most common identifiable cause of open-angle glaucoma, might affect the retinal hemodynamics. To test this, we compared retinal vessel diameter and glaucoma-related parameters between eyes with pseudoexfoliation material (PE+) and fellow unaffected (PE-) eyes of patients with clinically unilateral PEX., Methods: The medical records of 30 consecutive Japanese subjects were reviewed retrospectively. The retinal vessel diameters were measured and expressed as the central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) using standardized software. During the chart review, we recorded glaucoma-related parameters including intraocular pressure (IOP), visual field mean deviation (MD) value, planimetrically measured vertical cup-to-disc (C/D) ratio, circumpapillary retinal nerve fiber layer thickness (cpRNFLT) and macular inner retinal thickness (mIRT) measured by spectral-domain optical coherence tomography, anterior chamber flare (ACF), corneal endothelial cell density (CECD), and number of antiglaucoma medications., Results: Compared with PE- eyes, the CRAE, CRVE, MD, cpRNFLT and mIRT, and CECD were significantly lower in PE+ eyes; the IOP, vertical C/D ratio, number of antiglaucoma medications, and ACF were significantly higher in PE+ eyes (P<0.0001 for all comparisons). The CRAE, cpRNFLT, and MD were correlated positively with each other (ρ = 0.456-0.499, P<0.0001-0.0002) and negatively with the IOP (ρ = -0.562- -0.432, P<0.0001-0.0006). The vertical C/D ratio was correlated positively with the IOP (ρ = 0.483, P<0.0001) and negatively with the CRAE, cpRNFLT, and MD (ρ = -0.745--0.479, P<0.0001-0.0001)., Conclusions: Deposition of PE can cause retinal vessel narrowing in arterioles and venules. The roles and mechanisms of retinal vessel narrowing in glaucoma pathogenesis need clarification.

Objective: The aim of this study was to assess the relationship between retinal vascular caliber and target organ damage in HT patients., Methods: Data were collected on cardiac, renal, vascular, and retinal variables in 88 consecutive never-treated HT subjects. Retinal vascular calibers were measured from fundus photographs by using a semi-automated computer-assisted program and summarized as CRAE and CRVE., Results: Mean CRAE and CRVE were significantly lower in patients with left ventricular hypertrophy (left ventricular mass ≥110 g/m² for women, 125 g/m² for men) than in those with normal left ventricular (CRAE: 129.4±3.7 vs 138.2±2.3 μm; P=.04; CRVE: 195.6±4.4 vs 209.8±2.7 μm; P=.008). CRAE and CRVE were negatively correlated with urinary albumin excretion (β±SE=-15.4±3.2, P<.0001 and β±SE=-11.9±4.4, P=.001, respectively) but were not correlated with estimated glomerular filtration rate (P=.21 and P=.75, respectively), carotid-to-femoral pulse wave velocity (P=.24 and P=.14), or carotid augmentation index (P=.43 and P=.16)., Conclusion: In never-treated HT patients, reduced CRAE and CRVE were associated with cardiac and renal preclinical damage, ie, left ventricular hypertrophy and albuminuria, but not estimated glomerular filtration rate or vascular stiffness., (© 2016 John Wiley & Sons Ltd.)

Purpose: To report a semiautomated retinal vessel caliber measurement system that measures central retinal artery (vein) equivalent (CRAE [CRVE]) with individual correction for magnification errors under conditions assuming optimal focus., Methods: The focusing condition of the subject eye fundus camera optical system was individually determined by constructing an optical model of each eye applying its refractive error, corneal curvature, and axial length (AL) to Gullstrand's schematic eye, and by adjusting the position of the camera's focusing lenses using each eye's refractive error. Once the focusing condition of the entire optical system was fulfilled, magnification of the fundus images was calculated using paraxial ray tracing. Measurements of CRAE (CRVE) were performed in an annular area centered on the optic disc with magnification-corrected diameter from 1.8 to 2.7 mm. Reproducibility of the measurements of the results using the new method and comparison with those using interactive vessel analysis (IVAN) were performed in normal Japanese eyes., Results: Intra- and interexaminer intraclass correlation coefficient (ICC) for CRAE (CRVE) measurements was greater than 0.978. CRAE (CRVE) using the new method averaged 148.9 ± 10.9 μm (225.0 ± 13.9 μm; mean ± SD, N = 99). Differences between the new method and IVAN were greater with increasing AL (P < 0.001). The new method yielded CRAE (CRVE) in good agreement with IVAN in eyes with AL of approximately 24 mm. However, the new method yielded smaller values in eyes with shorter AL and vice versa., Conclusions: A new accurate and reproducible method to measure CRAE (CRVE) from fundus photographs was reported.

Purpose/aim: To investigate the association between retinal vascular tortuosity and traditional- and vascular-related risk factors in persons with diabetes., Methods: We recruited 224 diabetic patients. Retinal vascular tortuosity was measured from fundus photographs. Association of tortuosity with the following factors was assessed after adjusting for significant co-factors: diabetes duration, HbA1c, systolic blood pressure (SBP), cholesterol and body mass index (BMI), flicker-light induced retinal vasodilatation, and markers of endothelial function and inflammation (skin microvacular responses to acetylcholine iontophoresis, soluble e-selectin, inter-cellular adhesion molecule-1, vascular cell adhesion molecule-1, endothelin-1, total nitrite, C-reactive protein)., Results: Adjusting for age and gender, longer diabetes duration was associated with more tortuous retinal arterioles (mean difference in arteriolar tortuosity 5.85 × 10(-5), 95% Confidence Interval 1.44-10.3 × 10(-5); p = 0.016; ≤10 versus >10 years duration). Reduced flicker-light induced retinal vasodilatation was associated with tortuous arterioles and venules (mean difference in arteriolar tortuosity 5.62 × 10(-5), 4.50-6.72 × 10(-5); p < 0.001 and in venules 5.94 × 10(-5), 3.33-8.55 × 10(-5); p < 0.001; comparing highest versus lowest tertile of flicker-light vasodilatation). These associations remained after adjusting for co-factors. Diabetes duration explained about 36% and flicker-light vasodilatation 25% of the variation in retinal arteriolar tortuosity. No associations were found between retinal arteriolar or venular tortuosity and HBA1c, SBP, cholesterol, BMI and serum markers of endothelial function., Conclusions: Increased retinal arteriolar tortuosity was related to longer diabetes duration and reduced flicker-light induced vasodilatory response, suggesting that retinal vascular tortuosity in adults with diabetes may be influenced by multiple diabetes-related physio-pathological changes.

Endothelial dysfunction is a key feature of atherosclerosis. Retinal microvascular endothelial function can be assessed using noninvasive dynamic vessel imaging techniques. Whether it is impaired in subjects with coronary artery disease (CAD) is unknown. The aim of this study was to examine the relation of retinal microvascular endothelial function with CAD. Vascular studies were performed in 197 prospectively recruited subjects divided into 2 groups: those without CAD but ≥2 cardiovascular risk factors (non-CAD controls; n = 119) and those with stable CAD (n = 78). Retinal microvascular endothelial dysfunction was assessed by measuring retinal arteriolar and venular dilatation to flicker light, a nitric oxide-dependent phenomenon, expressed as percentage increase over baseline diameter. Fingertip pulse-volume amplitude was measured to calculate reactive hyperaemia index and brachial artery flow-mediated dilatation assessed as measures of peripheral microvascular and conduit vessel endothelial function, respectively. Mean retinal arteriolar dilatation was attenuated in patients with CAD compared with non-CAD controls (1.51 ± 1.51% vs 2.37 ± 1.95%, p = 0.001). Retinal arteriolar dilatation was independently associated with CAD after adjustment for age, gender, cardiovascular risk factors, and medication use (odds ratio 1.60, 95% confidence interval 1.14 to 2.25, p = 0.007). Reactive hyperaemia index and flow-mediated dilatation were not different. In conclusion, the capacity of retinal arterioles to dilate in response to flicker light is an independent predictor of the presence of CAD and suggests that retinal microvascular endothelial dysfunction is a marker for underlying CAD., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: There are limited data available on the variables that might affect retinal vessel oxygen saturation (SO₂) in diabetes. Therefore, the aim of this study is to assess factors associated with retinal oximetry values in persons with diabetes., Design: Clinic-based cross-sectional study., Participants: Fifty-eight persons with diabetes aged 18+ years, recruited from the University of Melbourne, the Royal Victorian Eye and Ear Hospital, and St. Vincent's Hospital (Melbourne), Australia., Methods: Retinal oximetry was performed using the oximetry module of the Vesselmap system (Imedos UG, Jena, Germany) in 92 diabetic eyes. Generalized estimating equation models were used to estimate the associations between candidate variables (age; gender; retinal capillary flow; duration of diabetes; hypertension; smoking status; presence of diabetic retinopathy [DR]; glycated haemoglobin; triglyceride; total cholesterol; finger SO₂ and ocular perfusion pressure) with retinal oximetry measures., Main Outcome Measure: Arteriolar SO₂, venular SO₂ and the arterio-venous (A-V) difference., Results: Of the candidate factors assessed, only the presence of DR was significantly associated with increased venular SO₂ and decreased A-V difference in unadjusted analyses. In models adjusting for age and gender and significant variables from unadjusted analyses, compared with no DR, the presence of DR was significantly associated with greater retinal venular SO₂ values (β = 3.65%, 95% confidence interval: 0.67-6.63%) and decreased A-V difference (β = -2.00%, 95% confidence interval: -3.46 to -0.53%)., Conclusion: In patients with diabetes, eyes with DR were associated with increased venular SO₂ and decreased A-V difference compared with eyes without DR, suggesting an altered metabolic state in DR., (© 2014 Royal Australian and New Zealand College of Ophthalmologists.)

Purpose: Retinal vascular fractal dimension, a measure of the density of the retinal vasculature, has been suggested as a marker of systemic microvascular disorders in diabetes. As hemoglobin concentration is tightly related to vascular physiology and hypoxia, the hypothesis was that hemoglobin concentration would be associated with retinal vascular fractals in a relevant population., Methods: In a cross-sectional study of 204 long-term type 1 diabetes patients from a population-based cohort, retinal digital photos were captured and graded for fractal dimension (Df) by International Retinal Imaging Software - Fractal (IRIS-Fractal). Df was calculated from a disc-centered retinal photo from the right eye. Hemoglobin concentrations were measured using routine equipment., Results: Of 175 patients with gradable images, median age was 57.7 years and median duration of diabetes was 42 years. Median retinal Df was 1.4606 (inter-quartile range 0.0264). A positive correlation was found between hemoglobin concentration and retinal vascular Df (r = 0.23, p = 0.0018). In a multiple linear regression model, Df was associated with hemoglobin (coefficient 0.0054 per 1.0 mmol/L increase in hemoglobin, p = 0.01) and age (coefficient -0.0046 for each 10-year increase in age, p = 0.04)., Conclusion: Hemoglobin correlated independently with retinal vascular fractals indicating a relationship between hemoglobin availability and retinal vascular structure.

Purpose: The pathway linking late-life malnutrition to greater risk of cardiovascular disease is unclear. Microcirulatory changes assessed by retinal vascular caliber have been linked with increased risk of stroke and coronary heart disease. The purpose of this study was to examine whether retinal vascular calibers are associated with malnutrition in elderly subjects free of cardiovascular diseases., Methods: This was a cross-sectional analysis of a community-dwelling cohort comprising 1145 individuals aged 60 years and older. Retinal vascular caliber was measured from fundus photographs using a semiautomated, standardized imaging software. Malnutrition was assessed using body mass index (BMI) < 18.5 kg/m(2) and biomarkers of protein malnutrition: plasma albumin and transthyretin., Results: In a multivariate model controlling for cardiovascular risk factors, retinal venular caliber was related to BMI (P = 0.0002) with an increased mean caliber for individuals with obesity and for those with low BMI. After multivariate adjustment for age, sex, hypertension, smoking, high-density lipoprotein (HDL) cholesterol, glomerular filtration rate and BMI, lower levels of albumin or transthyretin were associated with larger retinal venular caliber (P = 0.026 and P = 0.0018, respectively), that remain significant when adjusting for CRP (P = 0.040 and P = 0.0060, respectively) or orosomucoid (P = 0.034 and P = 0.0020, respectively). The relationships between retinal arteriolar caliber and BMI, albumin and transthyretin did not reach significance (P = 0.14, P = 0.12, and P = 0.15, respectively)., Conclusions: Protein malnutrition was identified as an additional factor associated with retinal venular dilatation beyond inflammation. This suggests that early microvascular changes may be one of the underlying mechanisms of increased risk of cardiovascular disease observed in elderly subjects suffering from malnutrition., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

Objective: Retinal microvascular signs are markers of cardiovascular disease risk. There are limited data, on relationships between retinal microvascular signs and retinal microvascular endothelial function. We sought to determine the relationship of retinal vascular signs with retinal microvascular endothelial function in patients with or at high risk of coronary artery disease., Methods: Participants with atherosclerosis risk factors and coronary disease (n=258; mean age 57±11 years) were recruited to have static and dynamic retinal vascular assessment. Retinal arteriolar dilatation in response to flicker light (FI-RAD) was measured using the Digital Vessel Analyser and expressed as percentage increase over baseline diameter. Static retinal photographs were acquired utilising a digital fundus camera for measurement of central retinal artery and vein equivalent (CRAE and CRVE), arteriovenous nicking (AVN) and focal arteriolar narrowing (FAN)., Results: Intra-class correlation coefficient was 0.82 for flicker-light induced retinal arteriolar dilatation. There were modest associations in retinal vascular measurements between eyes. For each 10 μm decrease in retinal arteriolar diameter, the absolute increase in FI-RAD was 0.28% (95% CI 0.11, 0.45; p=0.002) independent of age, gender and atherosclerosis risk factors. AVN and FAN were associated with attenuated FI-RAD (β=-0.67%; 95% CI -1.20, -0.15; p=0.012) and (β=-0.83%; 95% CI -1.44, -0.23; p=0.007) respectively after adjustment for age and gender., Conclusion: Assessment of retinal microvascular endothelial function is reproducible and correlated with retinal microvascular structure and signs, independent of atherosclerosis risk factors. Assessment of retinal vascular structure and function may provide insights into atherosclerotic disease., (Crown Copyright © 2014. Published by Elsevier Ireland Ltd. All rights reserved.)

Objective: Microvascular dysfunction has been suggested to be a major pathogenic factor for the development of hypertension. We examined the association between retinal vascular caliber, a marker of systemic microvascular dysfunction, and incident hypertension on a meta-analysis of individual participant data., Methods: We performed a systematic review with relevant studies identified through a search of electronic databases, a review of reference lists, and correspondence with experts. Studies were included if participants were selected from a general population, retinal vascular caliber was measured from photographs using computer-assisted methods at baseline, and individuals were followed up to ascertain the incidence of hypertension. Prespecified individual recorded data from six population-based prospective cohort studies were included. Discrete time proportional odds models were constructed for each study with adjustment for hypertension risk factors. Log odds ratios (ORs) per 20-μm difference were pooled using random-effects meta-analysis., Results: Among 10 229 participants without prevalent hypertension, diabetes, or cardiovascular disease, 2599 developed new-onset hypertension during median follow-up periods ranging from 2.9 to 10 years. Both narrower retinal arterioles [pooled multivariate-adjusted OR per 20-μm difference 1.29, 95% confidence interval (CI) 1.20-1.39] and wider venules (OR per 20-μm difference 1.14, 95% CI 1.06-1.23) were associated with an increased risk of hypertension. Each 20 μm narrower arterioles at baseline were associated with a 1.12 mmHg (95% CI 0.25-1.99) greater increase in SBP over 5 years., Conclusions: Retinal arteriolar narrowing and venular widening were independently associated with an increased risk of hypertension. These findings underscore the importance of microvascular remodeling in the pathogenesis of hypertension.

The fractal dimension is a global measure of complexity and is useful for quantifying anatomical structures, including the retinal vascular network. A previous study found a linear declining trend with aging on the retinal vascular fractal dimension (DF); however, it was limited to the older population (49 years and older). This study aimed to investigate the possible models of the fractal dimension changes from young to old subjects (10–73 years). A total of 215 right-eye retinal samples, including those of 119 (55%) women and 96 (45%) men, were selected. The retinal vessels were segmented using computer-assisted software, and non-vessel fragments were deleted. The fractal dimension was measured based on the log–log plot of the number of grids versus the size. The retinal vascular DF was analyzed to determine changes with increasing age. Finally, the data were fitted to three polynomial models. All three models are statistically significant (Linear: R(2) = 0.1270, 213 d.f., p < 0.001, Quadratic: R(2) = 0.1536, 212 d.f., p < 0.001, Cubic: R(2) = 0.1529, 211 d.f., p < 0.001). The quadratic regression is significantly better than the linear regression (p < 0.001); however, the increase in R(2) from the quadratic model to the cubic model is not significant (p = 0.97). These results suggest that the decreasing trend of the fractal dimension associated with aging is better explained by the quadratic model than by the linear and cubic models in a sample with a broader age spectrum.

Retinal arteriovenous (AV) nicking is one of the prominent and significant microvascular abnormalities. It is characterized by the decrease in the venular caliber at both sides of an artery-vein crossing. Recent research suggests that retinal AV nicking is a strong predictor of eye diseases such as branch retinal vein occlusion and cardiovascular diseases such as stroke. In this study, we present a novel method for objective and quantitative AV nicking assessment. From the input retinal image, the vascular network is first extracted using the multiscale line detection method. The crossover point detection method is then performed to localize all AV crossing locations. At each detected crossover point, the four vessel segments, two associated with the artery and two associated with the vein, are identified and two venular segments are then recognized through the artery-vein classification method. The vessel widths along the two venular segments are measured and analyzed to compute the AV nicking severity of that crossover. The proposed method was validated on 47 high-resolution retinal images obtained from two population-based studies. The experimental results indicate a strong correlation between the computed AV nicking values and the expert grading with a Spearman correlation coefficient of 0.70. Sensitivity was 77% and specificity was 92% (Kappa κ = 0.70) when comparing AV nicking detected using the proposed method to that detected using a manual grading method, performed by trained photographic graders.

Purpose: Retinal vascular caliber has been linked with increased cardiovascular risk and is predictive of cardiovascular pathology, including stroke and coronary heart disease. Oxidative stress, as well as inflammatory mechanisms, plays a major role in the pathogenesis and progression of atherosclerosis, plaque rupture and vascular thrombotic propensity. The purpose of this study is to explore the relationship between retinal vascular calibers and biomarkers of oxidative stress and inflammation, in subjects free of cardiovascular pathology., Patients and Methods: Cross-sectional analysis from a community-dwelling cohort comprising 1224 individuals aged 60 years and over, without a history of coronary or peripheral artery disease or stroke. Retinal vascular caliber was measured from fundus photographs using semi-automated standardized imaging software. Oxidative stress was evaluated using plasma superoxide dismutase 2 and glutathione peroxidase (GPx-3) activities, and inflammatory state was assessed using plasma high sensitivity C-reactive protein (hsCRP) and orosomucoid., Results: In a multivariate model controlling for cardiovascular risk factors, larger retinal arteriolar caliber was independently related to higher level of GPx-3 activity (p = 0.003) whereas larger venular caliber was associated with higher levels of hsCRP (p = 0.0001) and orosomucoid (p = 0.01)., Conclusion: In the present study, biomarkers of oxidative stress regulation and inflammation were independently associated with retinal vascular calibers. This suggests that an assessment of retinal vessels may offer early and non-invasive detection of subclinical vascular pathology.

Purpose: To assess the relation between retinal vascular caliber and renal function., Patients and Methods: Eighty apparently healthy subjects screened for cardiovascular risk factors (mean age 47 years, 51% female, 36% hypertensive, without diabetes or renal dysfunction) were recruited. Retinal vascular calibers were measured from fundus photographs and expressed as central retinal artery and venular equivalent. Renal function was assessed by measurement of glomerular filtration rate (urinary clearance of 99mTc-DTPA) and urinary albumin/creatinine ratio., Results: Mean glomerular filtration rate was 117 ml/min/1.73m(2). Overall, central retinal artery and venular equivalent were positively correlated with glomerular filtration rate (r = +0.31, p = 0.005 and r = +0.30, p = 0.006, respectively). In addition, central retinal artery equivalent was negatively correlated with urinary albumin/creatinine ratio (r = -0.34, p = 0.002). No significant relationship was found between central retinal venular equivalent and urinary albumin/creatinine ratio (r = +0.12, p = 0.32). The observed relations between retinal vascular calibers and renal function parameters remained significant after adjusting for potential confounding factors., Conclusion: In apparently healthy subjects with normal renal function, retinal arteriolar and venular calibers were negatively correlated with kidney function, suggesting common determinants of these preclinical target organ damages., (© 2013 The Authors. Acta Ophthalmologica © 2013 Acta Ophthalmologica Scandinavica Foundation. Published by Blackwell Publishing Ltd.)

Purpose: To examine associations between quantitatively measured retinal vessel caliber and the 10-year incidence of primary open-angle glaucoma (OAG)., Design: Population-based cohort study., Participants: The Blue Mountains Eye Study examined 3654 persons at baseline and 2461 persons at either 5 years, 10 years, or both times. After excluding 44 subjects with OAG at baseline, 2417 participants at risk of OAG at the 5- or 10-year examinations were included., Methods: Retinal vessel calibers of baseline retinal photographs were measured using a computer-based program and summarized as central retinal artery and vein equivalents (CRAE, CRVE). Incident OAG was defined as the development of typical glaucomatous visual field loss combined with matching optic disc rim thinning and an enlarged cup-to-disc (C:D) ratio of >0.7 or C:D asymmetry between the 2 eyes (≥0.3) at either the 5- or 10-year examination. Generalized estimating equation models were used to account for correlation between eyes while adjusting for glaucoma risk characteristics including intraocular pressure (IOP) or ocular perfusion pressure (OPP)., Main Outcome Measures: We assessed the 10-year incidence of OAG., Results: There were 82 persons (104 eyes) who developed incident OAG over the 10-year follow-up. After adjusting for age, sex, family history of glaucoma, smoking, diabetes, hypertension, hypercholesterolemia, body mass index, spherical equivalent refraction, and C:D ratio, narrower CRAE was associated with higher risk of incident OAG (adjusted odds ratio [OR], 1.77; 95% confidence interval [CI], 1.12-2.79, per standard deviation decrease in CRAE). This association persisted after further adjustment for IOP (adjusted OR, 1.87; 95% CI, 1.14-3.05) or OPP (adjusted OR, 1.76; 95% CI, 1.11-2.78), and remained significant when analyses were confined to eyes with IOP<20 mmHg and C:D ratio<0.6 at baseline. There were no independent associations between CRVE and incident OAG., Conclusions: Retinal arteriolar narrowing, quantitatively measured from retinal photographs, was associated with long-term risk of OAG. These data support the concept that early vascular changes are involved in the pathogenesis of OAG and suggest that computer-based measurements of retinal vessel caliber may be useful to identify people with an increased risk of developing the clinical stage of glaucoma., Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article., (Copyright © 2013 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: Whether the increase in vascular disease prevalence and mortality in OA populations is a result of co-occurrence of cardiovascular disease and OA, which are both common in the older population, is due to OA treatments or to the common association with reduced physical activity and/or obesity is unclear. One way to explore this non-invasively is to examine the cross-sectional relationship between changes in retinal microvasculature, which have been shown to be markers of generalized vascular pathology, and knee structural changes in an asymptomatic community-based population., Methods: A community sample of 289 (61% women) aged 50-79 years with no knee symptoms underwent magnetic resonance imaging (MRI) of their dominant knee in 2003. Cartilage volume and bone marrow lesions (BMLs) were determined. All subjects also had retinal photographs taken from which retinal arteriolar and venular diameters were determined and summarized as the central retinal arteriolar equivalent (CRAE) and the central retinal venular equivalent (CRVE)., Results: Retinal venular diameter was significantly wider in subjects with a BML compared with subjects without a BML (mean (SD) 214.2 (2.8) μm versus 207.5 (1.1) μm respectively independent of age, gender and BMI. A trend for decreased medial tibial cartilage with increasing CRAE was also observed (regression coefficient -2.70 μl, 95%CI-5.74, 0.5, p=0.08)., Conclusion: These findings suggest that vascular pathology, indicative of inflammatory processes, is associated with early structural knee changes. The role of micro-vascular changes in the pathogenesis of OA warrants further investigation.

Background and Purpose: Small-vessel disease contributes to the pathophysiology of stroke, and retinal microvascular signs have been linked to the risk of stroke. We examined the relationship of retinal signs with incident stroke in a multiethnic cohort., Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) is a prospective cohort study that enrolled participants without clinical cardiovascular diseases from 6 US communities between 2000 and 2002. Of the participants, 4849 (71.2%) had fundus photography performed in 2002 to 2004. Retinopathy and retinal vessel caliber were assessed from retinal images. Stroke risk factors including high-sensitivity C-reactive protein, carotid artery intima-media thickness, and coronary artery calcium were measured using standardized protocols. Incident stroke was confirmed from medical record review and death certificates., Results: After 6 years of follow-up, there were 62 incident strokes. Narrower retinal arteriolar caliber was associated with increased risk of stroke after adjusting for conventional cardiovascular risk factors (adjusted incidence rate ratio, 2.83; 95% CI, 1.34-5.95; P=0.006; adjusted hazard ratio, 3.01; 95% CI, 1.29-6.99; P=0.011). Retinopathy in persons without diabetes was associated with increased risk of stroke (adjusted adjusted incidence rate ratio, 2.96; 95% CI, 1.50-5.84; P=0.002; adjusted hazard ratio, 3.07; 95% CI, 1.17-8.09; P=0.023). These associations remained significant after adjusting for high-sensitivity C-reactive protein, carotid intima-media thickness, or coronary artery calcium., Conclusions: Narrower retinal arteriolar caliber and retinopathy in nondiabetic persons were associated with increased risk of stroke in this relatively healthy multiethnic cohort independent of traditional risk factors and measures of atherosclerosis. The association between narrower retinal arteriolar caliber and stroke warrants further investigation.

Serum apolipoprotein (apo)AI and -B have been shown to be associated with diabetic retinopathy, but the underlying mechanisms are unclear. We investigated whether apoAI and apoB levels are associated with measures of systemic and retinal microvascular function in patients with diabetes. We recruited 224 diabetic patients (85 type 1 and 139 type 2) and assessed serum lipids and lipoproteins from fasting blood, skin responses to sodium nitroprusside (endothelium independent) and acetylcholine (ACh) (endothelium dependent) iontophoresis, flicker-light-induced retinal vasodilatation, and retinal vascular tortuosity. After adjustment for age and sex, every SD increase in apoAI level was associated with ACh-induced skin perfusion (mean change 1.27%; P < 0.001 for apoAI) and flicker-light retinal arteriolar vasodilatation (0.33%; P = 0.003) and was associated inversely with arteriolar tortuosity (-2.83 × 10(-5); P = 0.044). Each SD increase in apoB was associated with arteriolar tortuosity only (1.75 × 10(-5); P = 0.050). These associations, except for apoB, remained in multivariate models. Serum apoAI was associated with increased vasomotor responsiveness to ACh and flickering light and inversely related to retinal vessel tortuosity--a characteristic that has both structural and functional dimensions. These findings provide additional insights into the potential mechanisms of apos in the pathogenesis of diabetic retinopathy and other diabetic microvascular complications.

Purpose: Retinal vessel attenuation is a key finding in the diagnosis of retinitis pigmentosa (RP), but there have been no studies to determine whether quantitative measurement of this retinal sign is useful. We aimed to investigate retinal vessel caliber and its relationship with the severity of RP., Methods: This is a cross-sectional study based on 74 patients (145 eyes) with RP who had visual field assessment with Goldmann permeter and good-quality retinal images for vessel size measurements identified by retrospective medial chart review (1973-2007) in the electrophysiology clinic of a tertiary eye hospital in Australia. Retinal vessel calibers were measured using a computer-based program as the central retinal artery and vein equivalent (CRAE and CRVE). Goldmann visual field area for III4e white test light was measured quantitatively using ImageJ software as a clinical parameter to indicate the severity of RP. We used the generalized estimating equation models to estimate the difference in retina vessel calibers accounting for correlation between right and left eyes., Results: Mean CRAE and CRVE were significantly narrower in persons with smaller visual field area. For each 100 cm2 decrease in visual field area, CRAE and CRVE decreased by -15.2 μm (95% confidence interval -20.7, -9.78) and -26.8 μm (-35.1, -18.5), respectively (both P<0.001)., Conclusions: In RP patients, the severity of visual field loss is correlated with retinal vessel attenuation. Quantitative retinal vessel caliber measurement may be a useful additional clinical marker for monitoring progression of RP or potential treatment response.

Recent advances in medical imaging modality have enabled us to identify new features in retinal vasculature. One of the features is retinal vascular tortuosity which has been shown to become a predictive factor for cardiovascular diseases and diabetes. The changes in retinal vascular tortuosity might be a sign of severity or improvement of the disease. In this paper, we propose a new method for measuring retinal vascular tortuosity. We adopt a new technique to analyze tortuosity that consider vessel-segment's width simultaneously. Our proposed method measures vessel-segment's tortuosity on its edge. A qualitative assessment shows that the method is appropriate for measuring the tortuosity of the vessels in different widths and directions in the image. Finally, a comparison distinguishing tortuous vs. non tortuous vessels demonstrates that the proposed approach may be suitable for predicting or earlier diagnosis of diabetes or cardiovascular diseases.

Background/aims: The effects of haemodialysis on the microcirculation are poorly understood. This study examined the changes in small vessel calibre., Methods: 24 patients (including 12 males, median age 62.5 years, range 30-87) underwent digital retinal photography immediately before and after routine haemodialysis. Arteriolar and venular calibres were measured from the images by a trained grader using a highly reproducible, computer-assisted method., Results: Patients had an average 2.0 ± 0.3 litres of fluid removed with dialysis, and their mean arterial blood pressure fell by 6.8 mm Hg (CI 13.8-0.2, p = 0.06). Retinal arteriole calibre did not change (mean difference 2.3 µm, CI -1.1 to 5.7, p = 0.17) but the venules dilated (mean difference 12.7 µm, CI 7.3-18.3, p < 0.001). Calibre returned to baseline by 2 h. Venules dilated less in diabetics than non-diabetics (mean difference -6.2 µm, CI -9.6 to -2.9, p < 0.01). Retinal venular dilatation correlated positively with the volume of fluid removed per kilogramme body weight (5.9, CI 0.2-11.5, p = 0.04), and negatively with the fall in mean arterial pressure (-0.36, CI -0.72 to -0.01, p < 0.05) after adjusting for age, gender, diabetes and dyslipidaemia., Conclusion: Haemodialysis is associated with systemic venular dilatation., (Copyright © 2012 S. Karger AG, Basel.)

Previous work suggests a general reduction in complexity with aging, referred to as the aging-complexity theory. Fractal dimension (FD) of the vessels in the retina is a global measure of the complexity of the vasculature. However, earlier works did not find any correlation between aging and FD of the retinal vasculature, in contrast to the findings of reduced complexity in other parts of the body. The authors tested the hypothesis that reduced complexity develops with advancing age in the structure of the retinal vasculature. To overcome the limitations of earlier works, a three-dimensional representation of the vasculature, together with Fourier fractal dimension (FFD) techniques, was used. Based on the analysis of 748 retinal images taken of persons aged 49-89 years, we observed a significant decrease in the FFD with aging (p < 0.0001). These data provide evidence supporting rarefaction (i.e. reduction) of the retinal vasculature with aging, consistent with observations from other human organ systems., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Retinal microvasculature provides a direct means to assess microvascular health in vivo. We examined whether retinal vessel caliber is associated with the presence of metabolic syndrome in Japanese adults in a health screening program., Methods: We examined 1,003 Japanese adults through the health screening program conducted at the Shinoda General Hospital. Retinal vessel caliber was measured from digital fundus images using validated, semiautomated computer-assisted software. Metabolic syndrome was defined according to the definition proposed by the Joint Interim Statement in 2009. Cross-sectional associations between retinal vascular caliber and metabolic syndrome or its individual components were determined as odds ratios (ORs) using multiple logistic regression models., Results: The overall prevalence of metabolic syndrome in the study sample was 29.9%. Persons with increased waist circumference and elevated triglycerides and blood pressure had significantly narrower retinal arterial diameters. Persons with increased waist circumference also had wider retinal venular diameters. Narrower retinal arterial diameters and wider retinal venular diameters were associated with a higher prevalence of metabolic syndrome (OR per -1 standard deviation (SD) change in arteriolar caliber=2.15, 95% confidence interval (CI) 1.45-3.18; OR per +1 SD change in venular caliber=1.53, 95% CI 1.04-2.26)., Conclusions: We observed cross-sectional associations between retinal vessel caliber changes and metabolic syndrome and its components. We demonstrated that retinal vessel caliber assessments are feasible in health screening programs in a timely manner. Further longitudinal studies are warranted to determine whether retinal vessel caliber measurements can be used as noninvasive assessment to evaluate vascular health related to metabolic syndrome and cardiovascular diseases in health screening program.

Background: Microvascular disease is a major pathogenic factor for chronic kidney disease (CKD) in persons with diabetes, but the role of microvascular disease in the development of CKD in the general population is unclear. The aim of this study is to examine whether microvascular disease precedes the development of CKD stage 3 in participants of the Multi-Ethnic Study of Atherosclerosis (MESA)., Study Design: Population-based cohort study., Setting & Participants: MESA is a prospective cohort study of adults aged 45-84 years living in 6 US communities; 4,594 adults with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m(2) when they underwent retinal photography (visit 2: in 2002-2004) were examined., Predictor: Retinal microvascular caliber measured from fundus photographs., Outcomes: Incident CKD stage 3 (ie, eGFR <60 mL/min/1.73 m(2)) at 2 subsequent follow-up examinations (visit 3 in 2004-2005, and visit 4 in 2005-2007) and an annual eGFR decrease >1 mL/min/1.73 m(2) computed using the CKD Epidemiology Collaboration (CKD-EPI) equation., Results: After a median follow-up of 4.8 years, there were 232 incident CKD stage 3 cases. Overall, retinal microvascular caliber was not associated with incident CKD stage 3. However, in race-stratified analysis, narrower arterioles in whites was associated with a higher risk of developing CKD stage 3 after adjusting for age, sex, blood pressure, diabetes, and other factors (HR, 1.78; 95% CI, 1.01-3.15; P = 0.04, lowest vs highest arteriolar caliber tertile). This association was seen even in whites without hypertension and diabetes (HR, 2.95; 95% CI, 1.10-7.98; P = 0.03). Retinal arteriolar caliber was not associated with incident CKD stage 3 in African Americans, Chinese, or Hispanics., Limitations: Analyses were based on a single eGFR measurement, and retinal microvascular caliber and eGFR measurements were not ascertained concurrently., Conclusion: Microvascular changes as manifest in the eye may contribute to the development of CKD stage 3 in whites., (Published by Elsevier Inc.)

Objectives: Alterations in retinal vascular calibre, particularly wider venular calibre, have been independently associated with elevated markers of inflammation and cardiovascular risk in the general population. We hypothesized that retinal vascular calibre would be altered in patients with RA, who are known to have both elevated cardiovascular risk and chronic, systemic inflammation., Methods: Retinal vascular calibre was measured from digital retinal photographs using computerized methods in 51 RA patients and 51 age- and gender-matched controls. Retinal vascular calibre was compared between RA and control patients with adjustment for relevant variables including cardiovascular risk factors and companion vessel calibre. The relationship between retinal venular calibre and inflammation was assessed by comparing controls and RA patients with high and lower disease activity., Results: Retinal venular calibre [mean (s.d.)] was significantly wider in RA patients than in controls [235.9 (24.6) vs. 211.6 (21.0) µm, P < 0.001]. After adjustment for all relevant variables, mean venular calibre remained 20.3 µm (95% CI 10.4, 30.3) wider in RA patients compared with controls. Retinal venular calibre [mean (s.d.)] also increased with increasing levels of systemic inflammation: 211.6 (21.0) µm in controls, 232.3 (22.4) µm in RA patients with moderate or lower disease activity and 255.5 (28.3) µm in RA patients with high disease activity (P for trend < 0.0001)., Conclusions: This study demonstrates that RA patients have dilated retinal venular calibre, reflecting systemic inflammation and possibly increased cardiovascular risk. Longitudinal studies correlating retinal vascular calibre with subsequent cardiovascular events will clarify the clinical utility of this test in patients with RA.

We have developed a robust method to perform retinal vascular fractal analysis from digital retina images. The technique preprocesses the green channel retina images with Gabor wavelet transforms to enhance the retinal images. Fourier Fractal dimension is computed on these preprocessed images and does not require any segmentation of the vessels. This novel technique requires human input only at a single step; the allocation of the optic disk center. We have tested this technique on 380 retina images from healthy individuals aged 50+ years, randomly selected from the Blue Mountains Eye Study population. To assess its reliability in assessing retinal vascular fractals from different allocation of optic center, we performed pair-wise Pearson correlation between the fractal dimension estimates with 100 simulated region of interest for each of the 380 images. There was Gaussian distribution variation in the optic center allocation in each simulation. The resulting mean correlation coefficient (standard deviation) was 0.93 (0.005). The repeatability of this method was found to be better than the earlier box-counting method. Using this method to assess retinal vascular fractals, we have also confirmed a reduction in the retinal vasculature complexity with aging, consistent with observations from other human organ systems.

Caliber of the retinal blood vessel is widely used for risk assessment of cardiovascular diseases. Accurate and automatic caliber measurement requires a precise model to be made for the vessel profile. In this paper, we present a new approach for retinal vessel profiling in which the background noise, uneven illuminations and specular reflections have all been considered. In this method, regression analysis is performed with a series of second-order Gaussians to filter and up-sample the original vessel profile. This is then segmented to identify and represent the vessel edges by two Generalized Gaussian functions. The technique has been applied to retinal images and the results have been verified and compared with the state of the art automatic techniques.

Aims/hypothesis: The fractal dimension (D(f)) of the retinal vasculature is a global measure of its branching pattern complexity. We examined the relationship of retinal D(f) with diabetes., Methods: We conducted a cross-sectional study of 1,577 participants with diabetes and impaired glucose metabolism and normal controls from the population-based Australian Diabetes, Obesity and Lifestyle (AusDiab) study. Retinal D(f) was quantified from fundus photographs using a computer-based programme and diabetes status was determined by oral glucose tolerance test based on the WHO criteria., Results: After adjustment for age, sex and vascular risk factors, persons with higher retinal D(f) were more likely to have diabetes (OR 1.56; 95% CI 1.14-2.14, highest vs lowest fractal tertile). This relationship remained with further adjustment for retinal arteriolar calibre and presence of retinopathy (OR 1.64; 95% CI 1.19-2.27), and after excluding participants with retinopathy (OR 1.60; 95% CI 1.16-2.21). Retinal D (f) was not related to impaired glucose tolerance or impaired fasting glucose (OR 1.19; 95% CI 0.85-1.67)., Conclusions/interpretation: Individuals with diabetes, but not with impaired glucose metabolism, have greater retinal D(f), reflecting greater complexity of the retinal vasculature. Our findings suggest the presence of early microvascular changes in the retinal vasculature of persons with diabetes, even in the absence of overt retinopathy.

Silent brain infarct and white matter lesions are common radiological findings associated with the risk of clinical stroke and dementia; however, our understanding of their underlying pathophysiology and risk factors remains limited. This study aimed to determine whether assessment of retinal microvascular abnormalities could provide prognostic information regarding the risk of brain infarct and white matter lesions on magnetic resonance imaging. This study is based on a subset of 810 middle-aged persons without clinical stroke or baseline magnetic resonance imaging infarct enrolled in the Atherosclerosis Risk in Communities Brain Magnetic Resonance Imaging Study, a prospective, population-based study. Participants had a baseline magnetic resonance imaging brain examination and retinal photography in 1993-1995, and returned for a repeat magnetic resonance imaging examination in 2004-2006. Magnetic resonance images were graded for presence of any cerebral infarct, infarct with lacunar characteristics and white matter lesions according to standardized protocols. Retinal photographs were graded for presence of retinopathy lesions and retinal arteriolar abnormalities following a standardized protocol. Over a median follow-up of 10.5 years, 164 (20.2%) participants developed cerebral infarct, 131 (16.2%) developed lacunar infarct, 182 (24.2%) developed new white matter lesions and 49 (6.1%) had evidence of white matter lesion progression. After adjusting for age, gender, race, cardiovascular risk factors and carotid intima-media thickness, retinopathy was associated with incident cerebral infarct (odds ratio 2.82; 95% confidence interval 1.42-5.60) and lacunar infarct (odds ratio 3.19; 95% confidence interval: 1.56-6.50). Retinal arteriovenous nicking was associated with incident cerebral infarct (odds ratio 2.82; 95% confidence interval: 1.66-4.76), lacunar infarct (odds ratio 2.48; 95% confidence interval: 1.39-4.40) and white matter lesion incidence (odds ratio 2.12; 95% confidence interval: 1.18-3.81) and progression (odds ratio 2.22; 95% confidence interval: 1.00-5.88). In conclusion, retinal microvascular abnormalities are associated with emergence of subclinical magnetic resonance imaging brain infarcts and white matter lesions, independent of shared risk factors. Retinal vascular imaging may offer a non-invasive tool to investigate the pathogenesis and natural history of cerebral small-vessel disease.

Objective: To determine whether retinal arteriolar narrowing, possibly reflecting peripheral arteriolar vasoconstriction, predicts risk of hypertension in Japanese persons., Methods: The Funagata study is a population-based cohort study of Japanese aged 35+ years. Baseline examinations were conducted in 2000-2002 among 1058 persons without hypertension. Of these, 581 persons (55%) returned for a 5-year follow-up examination, with data on 563 available for analyses. Retinal photographs taken at the baseline visits were assessed for retinal arteriolar or venular diameter and retinal vessel wall signs using standardized protocols. Hypertension was defined if systolic blood pressure > or =140 mmHg, diastolic blood pressure > or =90 mmHg or from self-reported clinical diagnosis, including the use of antihypertensive medications. Incident hypertension was defined as an absence of hypertension at baseline but presence of hypertension at the follow-up visit., Results: One hundred ninety-three subjects (34.3%) had developed hypertension at 5-year follow-up. After adjusting for age, gender, baseline blood pressure and other risk factors, narrower retinal arterioles at baseline was significantly associated with an increased risk of incident hypertension (odds ratio per standard deviation decrease in arteriolar diameter: 1.53, 95% confidence interval: 1.08-2.18)., Conclusions: Our findings support the concept that arteriolar narrowing, evident in the retina, signals an increased risk of developing hypertension in Japanese persons.

Purpose: Dilation of retinal vessels in response to diffuse luminance flicker may reflect endothelial function. Although this has previously been shown to be reproducible in whites, there have been no similar data in Asians. We assess the reproducibility of repeated measurements of this response in Asians., Material and Methods: Healthy Asians (n = 33) with normal vision and no history of glaucoma, age-related macular degeneration, cataract, or retinal arterial/venous occlusion participated in this study. Repeated measures from the same subjects were taken 30-60 min apart using the Dynamic Vessel Analyser (DVA, IMEDOS, Jena, Germany). Modification was made to the shape of the light source for Asian participants. Correlations of the first and second measures were assessed using Pearson correlation (R(2)), and agreement between the two measures was shown using Bland-Altman plots., Results: After modification to the shape of the light source, almost perfect correlation was found between the 1st and 2nd measurements of baseline arteriolar (R(2) = 0.95) and venular diameters (R(2) = 0.98) of arteriolar maximum dilation (R(2) = 0.85). Substantially high correlation between the 1st and 2nd measurements of venular maximum dilation was found (R(2) = 0.80)., Conclusions: Measurements of the dilation response of retinal vessels to diffuse luminance flicker an Asian sample using the DVA show high reproducibility for repeated measures over a short period of time. Such measurements may allow non-invasive quantification of endothelial function to study its association with systemic and ocular diseases.

Purpose: Subtle changes in retinal vascular caliber have been shown to predict diabetic retinopathy and other diabetic complications. This study was undertaken to investigate whether retinal vascular caliber correlates with light-flicker-induced retinal vasodilation, a measure of endothelial function., Methods: The participants were 224 persons with diabetes (85 type 1 and 139 type 2) and 103 persons without diabetes (controls). Flicker-induced retinal vasodilation (percentage increase over baseline diameter) was measured with a vessel analyzer. Retinal vascular caliber was measured from digital retinal photographs according to a standardized, validated protocol. Data from both right and left eyes were used and modeled with generalized estimating equations to account for correlation between eyes., Results: In persons with diabetes, after adjustment for age and sex, reduced flicker-induced vasodilation was associated with wider retinal vascular caliber. Eyes with the lowest tertiles of flicker-induced arteriolar dilation had wider arteriolar caliber (5.40 mum; 95% confidence interval [CI], 1.76-9.05) and eyes with the lowest tertiles of flicker-induced venular dilation had corresponding wider venular caliber (12.4 mum; 95% CI, 6.48-18.2), respectively, than eyes with the highest tertile of vasodilation. These associations persisted after further adjusting for diabetes duration, systolic blood pressure, fasting glucose, lipids, body mass index, current smoking, and presence of diabetic retinopathy. No associations were evident in persons without diabetes., Conclusions: Changes in retinal vascular caliber (wider arterioles and venules) are associated with impaired flicker-induced vasodilation in persons with diabetes. Determining whether endothelial dysfunction explains the link between retinal vascular caliber and risks of diabetic microvascular complications calls for further study.

Objective: To describe the prospective relationship of retinal vessel diameters with risk of hypertension in a multiethnic population-based cohort., Methods: The Multi-Ethnic Study of Atherosclerosis is a population-based study of subclinical cardiovascular disease among white, African-American, Hispanic, and Chinese American adults aged 45-84 years. Retinal vessel diameters were measured using a standardized imaging software at the second examination (considered baseline in this analysis) and summarized as the central retinal artery/vein equivalent. Presence of retinopathy and retinal focal arteriolar narrowing and arteriovenous nicking was assessed by trained graders. Incidence of hypertension was defined among participants at risk as systolic blood pressure at least 140 mmHg, diastolic blood pressure at least 90 mmHg, or use of an antihypertensive medication., Results: Of the initial 6237 participants at baseline, 2583 were at risk of hypertension. After 3.2 +/- 0.5 years of follow-up, 448 (17.3%) participants developed hypertension. After adjusting for age, sex, race/ethnicity, the average of mean arterial blood pressure in the first and second examination, and other vascular risk factors, persons with narrower retinal arteriolar diameter and wider venular diameter at baseline were more likely to develop hypertension [odds ratio per SD decrease in central retinal artery equivalent 1.20, 95% confidence intervals 1.02, 1.42; and odds ratio per SD increase in central retinal vein equivalent 1.18, 95% confidence interval 1.02, 1.37]. Persons with focal arteriolar narrowing were also more likely to develop hypertension (odds ratio 1.80, 95% confidence interval 1.09, 2.97)., Conclusion: Findings from this multiethnic population confirm that narrower retinal arteriolar diameter and wider venular diameter are associated with the development of hypertension independent of traditional risk factors.

Blood pressure has a significant effect on retinal arterioles. There are few data on whether this effect varies by race/ethnicity. We examined the relationship of blood pressure and retinal vascular caliber in a multi-ethnic Asian population. The study is population-based and cross sectional in design. A total of 3749 Chinese, Malay and Indian participants aged > or =24 years residing in Singapore were included in the study. Retinal vascular caliber was measured using a computer program from digital retinal photographs. The associations of retinal vascular caliber with blood pressure and hypertension in each racial/ethnic group were analyzed. The main outcome measures are retinal arteriolar caliber and venular caliber. The results show that retinal arterioles were narrower in persons with uncontrolled/untreated hypertension (140.0 microm) as compared with persons with controlled hypertension (142.1 microm, P=0.0001) and those with no hypertension (146.0 microm, P<0.0001). On controlling for age, gender, body mass index, lipids and smoking, each 10 mm Hg increase in mean arterial blood pressure was associated with a 3.1 microm decrease in arteriolar caliber (P<0.0001), with a similar magnitude seen in all three racial/ethnic groups: 3.1 microm in Chinese, 2.8 microm in Malays and 3.2 microm in Indians (P<0.0001 for all). Each 10 mm Hg increase in mean arterial blood pressure was associated with a 1.8 microm increase in venular caliber (P<0.0001); furthermore, the magnitude of this effect was similar across the three racial/ethnic groups. The effect of blood pressure on the retinal vasculature was similar across three major racial/ethnic groups in Asia.

Aims/hypothesis: The purpose of the study was to evaluate the association between retinal vascular calibre and micro- and macrovascular complications in a population-based cohort of Danish type 1 diabetic patients., Methods: This was a cross-sectional study of 208 long-surviving type 1 diabetic patients from a population-based Danish cohort. Retinal photographs were obtained at a clinical examination attended by each participant in 2007-2008, and retinal vascular calibre was measured and summarised as the central retinal artery or vein equivalent (CRAE or CRVE) using a computer-based program and a standardised protocol. Associations between retinal vascular calibre and micro- and macrovascular complications were examined after adjusting for confounding clinical characteristics., Results: Retinal photographs were gradable for 188 of 208 patients (90.3%). The median age and duration of diabetes for patients with gradable photos were 57.9 and 42 years, respectively. After multivariate adjustments, individuals with narrower retinal arterioles were more likely to have nephropathy (OR 2.17, 95% CI 1.29-3.68, per SD decrease in CRAE) and macrovascular disease (OR 3.17, 95% CI 1.59-6.34, per SD decrease in CRAE), but not neuropathy (OR 1.10, 95% CI 0.70-1.71, per SD decrease in CRAE). Retinal venular calibre was not associated with any micro- or macrovascular complications., Conclusions/interpretation: In type 1 diabetic patients, retinal arteriolar narrowing is associated with nephropathy and macrovascular disease independently of other clinical characteristics. If supported by further prospective studies, measurement of retinal vessel diameter may allow a non-invasive evaluation of the risk of diabetes-related complications.

Objective: The aim of this study was to examine the relationship of retinal vascular caliber with diabetes and impaired fasting glucose (IFG) in a multiethnic Asian population., Methods: This work was a population-based cross-sectional study comprising 3,404 Singaporean Chinese, Indian, and Malay participants. Retinal arteriolar and venular diameters, CRAE and CRVE, respectively were measured from digital retinal photographs. Diabetes was defined as physician-diagnosis of diabetes, self-reported use of diabetic medication, or fasting plasma glucose (FPG) > or = 7 mmol/L; IFG as FPG 6.1-6.9 mmol/L., Results: After adjusting for age, gender, ethnicity, systolic blood pressure, body mass index, total cholesterol, triglycerides, smoking, and vascular caliber (Model 3), participants with diabetes had both larger CRAE and CRVE, compared to those with normal fasting glucose (NFG) or IFG. In a multivariate analysis, including clinical risk factors and CRVE, mean CRAE increased from 143.6 microm in NFG to 145.3 microm with diabetes (P for trend = 0.01). On the other hand, each mmol/L increase in FPG was associated with a 0.51-microm increase in CRVE (P=0.006). In a subgroup analysis stratified by ethnicity, the association between FPG and larger CRVE was predominantly present among ethnic Indians (0.9-microm increase in CRVE per mmol/L increase in FPG)., Conclusion: Diabetes was associated with larger retinal arteriolar diameters and glucose level was associated with larger retinal venular diameters in this multiethnic Asian population. The magnitude of association between glucose level and venular widening was stronger among ethnic Indians.