Retinal Vascular Fractal Dimensions and Their Association with Macrovascular Cardiac Disease.

INTRODUCTION: As the only part of the human vasculature, the retina is available for direct, noninvasive inspection. Retinal vascular fractal dimension (DF) is a method to measure the structure of the retinal vascular tree, with higher noninteger values between 1 and 2 representing a more complex and dense retinal vasculature. Retinal vascular structure has been associated with a variety of systemic diseases, and this study examined the association of DF and macrovascular cardiac disease in a case-control design. METHODS: Retinal fundus photos were captured with Topcon TRC-50X in 38 persons that had coronary artery bypass grafting (CABG, cases) and 37 cardiovascular healthy controls. The semiautomatic software VAMPIRE was used to measure retinal DF. RESULTS: Patients with CABG had lower DF of the retinal main venular vessels compared to the control group (1.15 vs. 1.18, p = 0.01). In a multivariable regression model adjusted for gender and age, eyes in the fourth quartile with higher DF were less likely to have CABG compared to patients in the first (OR, 7.20; 95% confidence interval: 1.63-31.86; p = 0.009) and second (OR, 8.25; 95% confidence interval: 1.70-40.01; p = 0.009) quartiles. CONCLUSIONS: This study demonstrates that lower complexity of main venular vessels associates with higher risk of having CABG. The research supports the hypothesis that the retinal vascular structure can be used to assess nonocular macrovascular disease.

Retinal Vascular Geometry and the Prevalence of Atrial Fibrillation and Heart Failure in a Clinic-Based Sample.

BACKGROUND: We aimed to examine the cross-sectional association between a range of retinal vascular geometric variables and the prevalence of atrial fibrillation (AF) and heart failure. METHODS: The Australian Heart Eye Study (AHES) surveyed 1,680 participants presenting to a tertiary referral hospital for the evaluation of potential coronary artery disease by coronary angiography. Retinal vascular geometric variables (tortuosity, branching, and fractal dimension) were measured from retinal photographs using a computer-assisted program (Singapore I Vessel Assessment). Atrial fibrillation was determined based on a combination of: self-reported history of AF; self-reported use of rate-control and anti-arrhythmic medications; and/or screening electrocardiogram. Self-reported echocardiography-confirmed heart failure was also documented. RESULTS: A total of 1,169 participants had complete information on retinal vascular geometric variables and AF and of these 104 (8.9%) had AF. Participants in the second tertile of fractal dimension (Df) compared to those in the highest tertile (reference group), had 92% increased likelihood of having AF after multivariable adjustment. A threshold effect for Df was identified, and participants below versus those above a Df threshold value of 1.472, had greater odds of having AF: multivariable-adjusted OR 1.85 (95% CI 1.03-3.31). Measures of retinal tortuosity and branching were not associated with AF. Retinal vascular geometric variables were also not associated with prevalence of heart failure. CONCLUSIONS: A sparser retinal microvascular network (lower Df) was independently associated with greater likelihood of AF. Further studies are needed to investigate whether temporal changes to the retinal vascular geometry are predictive of AF in the longer term.

The Adolescent Cardio-Renal Intervention Trial (AdDIT): retinal vascular geometry and renal function in adolescents with type 1 diabetes.

AIMS/HYPOTHESIS: We examined the hypothesis that elevation in urinary albumin creatinine ratio (ACR) in adolescents with type 1 diabetes is associated with abnormal retinal vascular geometry (RVG) phenotypes. METHODS: A cross-sectional study at baseline of the relationship between ACR within the normoalbuminuric range and RVG in 963 adolescents aged 14.4 ± 1.6 years with type 1 diabetes (median duration 6.5 years) screened for participation in AdDIT. A validated algorithm was used to categorise log10 ACR into tertiles: upper tertile ACR was defined as 'high-risk' for future albuminuria and the lower two tertiles were deemed 'low-risk'. RVG analysis, using a semi-automated computer program, determined retinal vascular calibres (standard and extended zones) and tortuosity. RVG measures were analysed continuously and categorically (in quintiles: Q1-Q5) for associations with log10 ACR and ACR risk groups. RESULTS: Greater log10 ACR was associated with narrower vessel calibres and greater tortuosity. The high-risk group was more likely to have extended zone vessel calibres in the lowest quintile (arteriolar Q1 vs Q2-Q5: OR 1.67 [95% CI 1.17, 2.38] and venular OR 1.39 [0.98, 1.99]) and tortuosity in the highest quintile (Q5 vs Q1-Q4: arteriolar OR 2.05 [1.44, 2.92] and venular OR 2.38 [1.67, 3.40]). The effects of retinal vascular calibres and tortuosity were additive such that the participants with the narrowest and most tortuous vessels were more likely to be in the high-risk group (OR 3.32 [1.84, 5.96]). These effects were independent of duration, blood pressure, BMI and blood glucose control. CONCLUSIONS/INTERPRETATION: Higher ACR in adolescents is associated with narrower and more tortuous retinal vessels. Therefore, RVG phenotypes may serve to identify populations at high risk of diabetes complications during adolescence and well before onset of clinical diabetes complications.

Retinal vascular geometry and 6 year incidence and progression of diabetic retinopathy.

AIMS/HYPOTHESIS: We aimed to examine prospectively the association between a range of retinal vascular geometric variables measured from retinal photographs and the 6 year incidence and progression of diabetic retinopathy. METHODS: We conducted a prospective, population-based cohort study of Asian Malay individuals aged 40-80 years at baseline (n = 3280) who returned for a 6 year follow-up. Retinal vascular geometric variables (tortuosity, branching, fractal dimension, calibre) were measured from baseline retinal photographs using a computer-assisted program (Singapore I Vessel Assessment). Diabetic retinopathy was graded from baseline and follow-up photographs using the modified Airlie House classification system. Incidence of diabetic retinopathy was defined as a severity of ≥15 at follow-up among those without diabetic retinopathy at baseline. Incidence of referable diabetic retinopathy was defined as moderate or severe non-proliferative diabetic retinopathy, proliferative diabetic retinopathy or diabetic macular oedema at follow-up in participants who had had no or mild non-proliferative diabetic retinopathy at baseline. Progression of diabetic retinopathy was defined as an increase in severity of ≥2 steps at follow-up. Log-binomial models with an expectation-maximisation algorithm were used to estimate RR adjusting for age, sex, diabetes duration, HbA1c level, BP, BMI, estimated GFR and total and HDL-cholesterol at baseline. RESULTS: A total of 427 individuals with diabetes participated in the baseline and 6 year follow-up examinations. Of these, 19.2%, 7.57% and 19.2% developed incidence of diabetic retinopathy, incidence of referable diabetic retinopathy and diabetic retinopathy progression, respectively. After multivariate adjustment, greater arteriolar simple tortuosity (mean RR [95% CI], 1.34 [1.04, 1.74]), larger venular branching angle (RR 1.26 [1.00, 1.59]) and larger venular branching coefficient (RR 1.26 [1.03, 1.56]) were associated with incidence of diabetic retinopathy. Greater arteriolar simple tortuosity (RR 1.82 [1.32, 2.52]), larger venular branching coefficient (RR 1.46 [1.03, 2.07]), higher arteriolar fractal dimension (RR 1.59 [1.08, 2.36]) and larger arteriolar calibre (RR 1.83 [1.15, 2.90]) were associated with incidence of referable diabetic retinopathy. Greater arteriolar simple tortuosity (RR 1.34 [1.12, 1.61]) was associated with diabetic retinopathy progression. Addition of retinal vascular variables improved discrimination (C-statistic 0.796 vs 0.733, p = 0.031) and overall reclassification (net reclassification improvement 18.8%, p = 0.025) of any diabetic retinopathy risk beyond established risk factors. CONCLUSIONS/INTERPRETATION: Retinal vascular geometry measured from fundus photographs predicted the incidence and progression of diabetic retinopathy in adults with diabetes, beyond established risk factors.

Retinal vascular structure independently predicts the initial treatment response in neovascular age-related macular degeneration.

PURPOSE: Prediction of the early treatment response is important in neovascular age-related macular degeneration (nAMD). Hence, we aimed to test if non-invasive measurements of the retinal vascular structure were able to predict a successful outcome of initial intravitreal treatment. METHODS: In 58 eyes of 58 patients with treatment-naïve nAMD, advanced markers of retinal vascular structure were measured by Singapore I Vessel Assessment prior to initial intravitreal treatment with three monthly injections of aflibercept with subsequently categorization of patients as full treatment responders (FTR) or non/partial treatment responders (N/PR), with the former defined as loosing fewer than five Early Treatment Diabetic Retinopathy Study letters and having no residual intra- or subretinal fluid or macular haemorrhage. RESULTS: Of 54 eyes attending follow-up, 44.4% were categorized as FTR. Patients with FTR were older (81.5 vs. 77 years, p = 0.04), and prior to treatment those eyes had a lower retinal arteriolar fractal dimension (Fd) (1.21 vs. 1.24 units, p = 0.02) and venular length-diameter ratio (LDR) (7.3 vs. 15.9 units, p = 0.006), but did not differ with respect to other retinal vascular parameters. In multiple logistic regression models, a lower chance of FTR was independently predicted by a higher retinal venular LDR (odds ratio [OR] 0.91, 95% CI 0.82-0.99, p = 0.03, for each 1 unit increment) and marginally by a higher retinal arteriolar Fd (OR 0.83, 95% CI 0.68-1.00, p = 0.05, for each 0.01 unit increment). CONCLUSION: Retinal venular LDR independently predicted the initial treatment response in nAMD. If confirmed by long-term, prospective studies, this might help to guide treatment.

Correlation between retinal vascular geometric parameters and pathologically diagnosed type 2 diabetic nephropathy.

Background: Diabetic nephropathy (DN) and diabetic retinopathy (DR) are common microvascular complications of diabetes. The purpose of this study was to investigate the correlation between retinal vascular geometric parameters and pathologically diagnosed type 2 DN and to determine the capacity of retinal vascular geometric parameters in differentiating DN from non-diabetic renal disease (NDRD). Methods: The study participants were adult patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease who underwent a renal biopsy. Univariate and multivariable regression analyses were performed to evaluate associations between retinal vessel geometry parameters and pathologically diagnosed DN. Multivariate binary logistic regression analyses were performed to establish a differential diagnostic model for DN. Results: In total, 403 patients were examined in this cross-sectional study, including 152 (37.7%) with DN, 157 (39.0%) with NDRD and 94 (23.3%) with DN combined with NDRD. After univariate logistic regression, total vessel fractal dimension, arteriolar fractal dimension and venular fractal dimension were all found to be associated with DN. In multivariate analyses adjusting for age, sex, blood pressure, diabetes, DR and other factors, smaller retinal vascular fractal dimensions were significantly associated with DN (P < .05). We developed a differential diagnostic model for DN combining traditional clinical indicators and retinal vascular geometric parameters. The area under the curve of the model established by multivariate logistic regression was 0.930. Conclusions: Retinal vessel fractal dimension is of great significance for the rapid and non-invasive differentiation of DN. Incorporating retinal vessel fractal dimension into the diagnostic model for DN and NDRD can improve the diagnostic efficiency.

Differential effects of adiposity and childhood growth trajectories on retinal microvascular architecture.

OBJECTIVES: We hypothesized that trajectories of adiposity across childhood would be associated with retinal microcirculatory diameters at age 12 years, independent of BP. METHODS: The ALSPAC followed a cohort of children born in 1991-1992. The current study includes all children with retinal images acquired at the 12 years clinic and individual trajectories of PI from 0 to 2 years and BMI from 2 to 10 years. Retinal microvascular measures included retinal arteriolar and venular diameters. RESULTS: Children in this analysis had a birth weight of 3.5 ± 0.4 kg, a PI of 26.2 ± 2.4 kg/m(3) and a gestational age of 39.7 ± 1.4 weeks (mean ± SD). Analysis of growth trajectories showed that lower PI at birth was associated with narrower retinal arterioles. Higher PI at birth was associated with wider venular diameter, and a stronger positive association was evident between BMI change at 5-5.5 and 8.5-10 years with wider venular diameters. Current fat mass was also associated with wider venular diameters. CONCLUSIONS: Retinal arterioles and venules are differentially associated with growth in early life and childhood adiposity. Early adiposity may adversely affect the microcirculation, with important implications for cardiovascular risk in adulthood.

Retinal Vascular Geometry in Hypertension: cSLO-Based Method.

INTRODUCTION: We aim to introduce a method using confocal scanning laser ophthalmoscopy (cSLO) images for measuring retinal vascular geometry, including vessel branch angle (BA), vessel diameter, vessel tortuosity, and fractal dimension (Df), and to elucidate the relationship between hypertension and these metrics. METHODS: A total of 119 participants (119 eyes) were enrolled, among which 72 were normotensive and 47 were hypertensive. Infrared cSLO images were extracted from the circular scan around the optics disc using a commercial cSLO + optical coherence tomography instrument. Preprocessed cSLO images were further analyzed using the appropriate tool/macro/plugin of ImageJ. RESULTS: Intraclass correlation coefficients of selected methods used for conducting the cSLO-based geometric analyses were all higher than 0.80. Arterial/arteriolar BA, arteriolar vessel diameter, and total Df in normotensive subjects were 85.80 ± 7.79°, 116.80 ± 12.58 µm, and 1.430 ± 0.037, respectively, significantly higher than those of hypertensive subjects (82.13 ± 10.83°, 108.2 ± 11.12 µm, and 1.361 ± 0.044, all P < 0.05). The aforementioned metrics remained negatively correlated with hypertension even after adjusting for age alone or age and gender (P < 0.05). However, the difference between arteriolar tortuosity and all studied venous/venular geometric parameters in both subjects was insignificant (all P > 0.05). CONCLUSION: Proposed cSLO-based methods for assessing various vascular geometric parameters were highly repeatable and reproducible. Arterial/arteriolar BA, arteriolar vessel diameter, and total Df were retinal vascular parameters significantly correlated with hypertension in a negative manner.

Exploring Associations Between Cardiac Structure and Retinal Vascular Geometry.

Background Retinal arteriolar narrowing and venular widening has been widely suggested to be associated with subclinical changes in cardiac structure. The novel retinal vascular geometric indices might reflect more comprehensive information on microvasculature other than vascular caliber alone. However, the association between suboptimal retinal vascular geometry and cardiac structural alteration has not been studied. Methods and Results We recruited 50 participants without cardiovascular disease from the Cardiac Aging Study conducted between 2014 and 2016. We performed transthoracic echocardiography imaging to measure cardiac structure indices such as left ventricular internal diameter end diastole index, left ventricular internal diameter end systole index, left ventricular mass index, and left atrial volume index, and retinal imaging to measure retinal vascular geometric indices including branching angle, curvature tortuosity, and fractal dimension. We applied multiple linear regressions to examine associations between indices of cardiac structure and retinal vascular geometry, adjusting for age, sex, body mass index, mean blood pressure, and comorbidity. The average age of all participants was 62.54 years old and slightly more than half were male (27; 54%). Each unit increase in a set of cardiac structure indices was associated with larger retinal arteriolar branching angle (ß and 95% CI: for left ventricular internal diameter end systole index, 26.93°; 6.00-47.86; for left ventricular internal diameter end diastole index, 17.86°; 1.61-34.11; for left ventricular mass index, 0.39°; 0.10-0.67; for left atrial volume index, 0.91°; 0.24-1.58). Conclusions Adverse retinal arteriolar geometric morphology mirrored suboptimal cardiac structural alteration.

Sex differences in retinal microvasculature through puberty in type 1 diabetes: are girls at greater risk of diabetic microvascular complications?

PURPOSE: Adolescent females with type 1 diabetes (T1D) are reported to have greater risk of early microvascular complications than males. We hypothesize sex differences in retinal vascular geometry (RVG) through puberty are associated with earlier-onset microvascular complications. METHODS: Prepubertal patients (n = 64, 35 male) with T1D, complication-free at baseline, were followed through to sexual maturity with detailed Tanner-staging and repeated diabetes complications assessments. Retinal vascular geometry from digitized retinal photographs at each visit was assessed using a semiautomated computer program. Determinants of RVG measurements (pre-, during, and post puberty) were explored using generalized estimating equations (GEE). Factors associated with time to onset of retinopathy and albumin excretion rate (AER) were examined using multivariable Cox regression. RESULTS: Median follow-up was 7.2 years. Retinopathy developed in 69% and elevated albumin excretion in 56%. In multivariable GEE, female sex was associated with wider venular caliber (prepuberty: lowest-quartile, odds ratio 0.40 [95% confidence interval: 0.17, 0.96]); P = 0.04) and lower arteriolar length-to-diameter-ratio (LDRa) (during puberty: lowest-quartile 2.87 [1.01, 8.13]; P = 0.047 and post puberty: 2.93 [0.96, 8.64]; P = 0.06). In Cox-regression, females developed retinopathy earlier than males (8.1 vs. 9.6 years; P = 0.002). Female sex (hazard ratio [HR] 3.8 [1.6-8.6]; P = 0.002) and growth velocity (1.3 [1.1-1.5]; P = 0.001) were associated with earlier retinopathy. CONCLUSIONS: This is the first longitudinal study to repeatedly examine RVG through puberty in youth with T1D. Sex dimorphism was observed. Female sex was associated with lower LDRa, wider venules, and earlier onset of retinopathy. These RVG patterns have been associated with incident microvascular complications but did not reach statistical significance in this study. Larger studies are needed to investigate the RVG, microvascular complications, and sex associations early in the course of T1D.