Lauren Hodgson

Retinal Vascular Fractals and Microvascular and Macrovascular Complications in Type 1 Diabetes

PURPOSE Fractal analysis is a method to quantify the geometric pattern and complexity of the retinal vessels. This study examined the association of retinal fractal dimension (D(f)) and microvascular and macrovascular complications in a population-based cohort of Danish patients with type 1 diabetes. DESIGN Cross-sectional study. PARTICIPANTS This was a cross-sectional study of 208 long-term surviving type 1 diabetes patients from a population-based Danish cohort identified in 1973. METHODS Retinal photographs were obtained at a clinical examination in 2007 or 2008. D(f) was measured with a semiautomatic computer-based program (International Retinal Imaging Software; National University of Singapore, Republic of Singapore; University of Sydney, Sydney, and University of Melbourne, Melbourne, Australia). D(f) of the retinal vasculature was measured within a predefined circular region of 3.5 optic disc radii centered on the optic disc. Line tracing of the vasculature was provided by the program. Any artifacts were removed by the grader, and the box-counting method then was used by the program to calculate D(f). MAIN OUTCOME MEASURES The association of D(f) with proliferative retinopathy, nephropathy, neuropathy, and macrovascular disease (coronary heart disease, stroke, peripheral artery disease) was examined. RESULTS Retinal fractals were gradable in at least 1 eye in 178 (86.6%) of 208 patients. Median age and duration of diabetes for these patients were 57.8 years and 42 years, respectively. Median D(f) was 1.4610 (range, 1.3774-1.5188). After adjustments for age, gender, duration of diabetes, systolic blood pressure, and smoking, persons with lower D(f) were more likely to have proliferative retinopathy (odds ratio [OR], 1.45 per standard deviation [SD] decrease in D(f); 95% confidence interval [CI], 1.04-2.03) and neuropathy (OR, 1.42 per SD decrease in D(f); 95% CI, 1.01-2.01). There was also a trend of an association between lower D(f) and nephropathy (OR, 1.39 per SD decrease in D(f); 95% CI, 0.97-2.01) but not macrovascular disease. Furthermore, persons with lower D(f) were older. CONCLUSIONS This study adds to the evidence that D(f) may have some role as a global measure of retinal vasculature and its association with systemic disease. Prospective studies clarifying this role are needed. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Does Retinal Vascular Geometry Vary with Cardiac Cycle

PURPOSE Changes in retinal vascular parameters have been shown to be associated with systemic vascular diseases. In this study, we assessed the physiologic variations in retinal vascular measurements during the cardiac cycle. METHODS Fundus images were taken using electrocardiogram-synchronized retinal camera at nine distinct cardiac points from 15 healthy volunteers (135 images). Analyses of retinal vessel geometric measures, including retinal vessel caliber (individual and summary), tortuosity, branching angle, length-diameter ratio (LDR), and optimality deviation, were performed using semiautomated computer software. Repeated-measures ANOVAs were used to obtain the means and to estimate the variation of each cardiac point compared with cardiac point 1. RESULTS There was a significant variation of the caliber of the individual arteriolar and venular vessels. However, there was no significant variation found for vessel caliber summary, represented by the central retinal arteriolar equivalent (CRAE) and the central retinal venular equivalent (CRVE). There was also no significant variation found for tortuosity and branching angle, and LDR showed none or very little variations at different cardiac points: variations in caliber ranges between 0 and 4.1%, tortuosity 0 and 1.5%, branching angle 0 and 3.5%, and LDR 0 and 2%; all values for variations, P > 0.1; linear trend, P > 0.5; and nonlinear trend, P > 0.8. CONCLUSIONS This study showed that there were minimal variations in the CRAE, CRVE, tortuosity, and branching angle that are clinically used for two-dimensional measures of retinal vascular geometry during cardiac cycles. However, there was significant variation in the caliber of the individual vessels over the cardiac cycle.

Quantitative genetic analysis of the retinal vascular caliber: The australian twins eye study

Research into the genetic effects and specific genes associated with retinal vascular caliber, a risk marker of cardiovascular diseases, may provide new insights into the genetic contribution of early microvascular disease. A combined 374 monozygotic and 536 dizygotic twin pairs and 322 siblings from the Twins Eye Study in Tasmania and the Brisbane Adolescent Twin Study underwent complete ophthalmic examinations, including retinal photography, and bilateral retinal vascular caliber was measured. Structural equation modeling was used to estimate the heritability. Genome-wide linkage analysis was conducted on 836 individuals from 381 Brisbane Adolescent Twin Study families, with adjustments for age, sex, and other covariates. The heritabilities for the retinal arteriolar caliber were 59.4% (95% CI: 53.2% to 64.7%) and 56.5% (95% CI: 50.1% to 61.9%) in the Twins Eye Study in Tasmania and the Brisbane Adolescent Twin Study, respectively, and for venular caliber they were 61.7% (95% CI: 55.6% to 67.0%) and 64.2% (95% CI: 58.7% to 68.8%), respectively, after adjusting for age, sex, and body mass index. Two multipoint peaks detected on chromosomes 3p12.3 and 8p23.1 for retinal arteriolar caliber had suggestive linkage, with the highest multipoint peak logarithm of odds score of 2.24 on chromosome 8p23.1 (genome-wide P=7.0×10−4). Two suggestive logarithm of odds scores for venular caliber were identified on chromosomes 2p14 and 9q21.13. The largest multipoint logarithm of odds score was 2.69 on chromosome 2p14 (genome-wide P=2.0×10−4). In this large twin population, genetic factors appear to play a significant role in the variation of retinal vascular caliber. Several putative loci were identified for the retinal vascular caliber.

Retinal Vessel Calibers Predict Long-term Microvascular Complications in Type 1 Diabetes: The Danish Cohort of Pediatric Diabetes 1987 (DCPD1987)

Diabetic neuropathy, nephropathy, and retinopathy cause significant morbidity in patients with type 1 diabetes, even though improvements in treatment modalities delay the appearance and reduce the severity of these complications. To prevent or further delay the onset, it is necessary to better understand common underlying pathogenesis and to discover preclinical biomarkers of these complications. Retinal vessel calibers have been associated with the presence of microvascular complications, but their long-term predictive value has only been sparsely investigated. We examined retinal vessel calibers as 16-year predictors of diabetic nephropathy, neuropathy, and proliferative retinopathy in a young population-based Danish cohort with type 1 diabetes. We used semiautomated computer software to analyze vessel diameters on baseline retinal photos. Calibers of all vessels coursing through a zone 0.5–1 disc diameter from the disc margin were measured and summarized as the central artery and vein equivalents. In multiple regression analyses, we found wider venular diameters and smaller arteriolar diameters were both predictive of the 16-year development of nephropathy, neuropathy, and proliferative retinopathy. Early retinal vessel caliber changes are seemingly early markers of microvascular processes, precede the development of microvascular complications, and are a potential noninvasive predictive test on future risk of diabetic retinopathy, neuropathy, and nephropathy.

Retinal vascular calibre is altered in patients with rheumatoid arthritis: a biomarker of disease activity and cardiovascular risk?

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.

Changes in Retinal Microvascular Caliber Precede the Clinical Onset of Preeclampsia

Preeclampsia is a leading cause of maternal morbidity and mortality. The degree of maternal cardiovascular dysfunction that precedes the onset of preeclampsia is largely unknown. This prospective cohort study aimed to characterize differences in vivo in retinal microvascular caliber and blood pressure throughout pregnancy in relation to preeclampsia development. Women were recruited from Royal Prince Alfred Hospital, Sydney, Australia, of which 92 women were included in the study. Retinal images and blood pressures were collected at 13, 19, 29, and 38 weeks of gestation. Retinal vessels were analyzed as the central retinal arteriolar equivalent corrected for mean arterial blood pressure and the central retinal venular equivalent corrected for mean arterial blood pressure, using generalized linear models adjusted for age and body mass index. The preeclampsia group were significantly older (P=0.002) and had a significantly higher mean body mass index (P=0.005). The central retinal arteriolar equivalent corrected for mean arterial blood pressure was significantly reduced at 13 (P=0.03), 19 (P=0.007), and 38 (P=0.03) weeks of gestation in the preeclampsia group. The central retinal venular equivalent corrected for mean arterial blood pressure was also significantly lower at 13 (P=0.04) and 19 (P=0.001) weeks of gestation in the women who progressed to preeclampsia. This study directly documents increased peripheral resistance in vivo, observed as the combination of constricted retinal arterioles or venules and elevated blood pressure, in women who later developed preeclampsia. This difference preceded the clinical signs of preeclampsia.

Hypertensive retinopathy: comparing the Keith-Wagener-Barker to a simplified classification

Purpose: This study assessed the interobserver and intraobserver grading reliability of the Keith–Wagener–Barker (KWB) system to the proposed Mitchell–Wong ‘simplified’ three-grade classification for hypertensive retinopathy. Methods: Digital retinal images of normal and hypertensive human fundii (n = 50 per group) were randomly graded by an optometrist and an ophthalmologist using the two systems. Interobserver agreement was compared to a ‘gold standard’ research grader. Intraobserver agreement was assessed through a repeat grading after 6 months. Cohens kappa coefficients were used to assess the degree of agreement. Results: Both clinicians demonstrated a good level of agreement with the KWB and simplified classification compared with a ‘gold standard’ grader; there was no significant difference in the level of agreement for either of the two classification methods for either observer. The simplified classification was found to be equally as efficacious as the KWB system with respect to interobserver and intraobserver agreement for both practitioners. Conclusion: These findings indicate that the simplified classification of hypertensive retinopathy is both reliable and repeatable. The advantage of the simplified method over the KWB system in correlating retinal microvascular signs to incident cardiovascular risk supports its adoption in clinical practice.

Measurement of macular fractal dimension using a computer-assisted program.

PURPOSE Macular diseases may be associated with an altered retinal vasculature. We describe and test new software for the measurement of retinal vascular fractal dimension to quantify the complexity of retinal vasculature at the macula (D mac) and to compare this with fractal dimension measured around the optic disc (D disc). METHODS A total of 342 macular-centered and optic disc-centered digital retinal photographs from 171 subjects was selected randomly from a population-based study. Retinal vascular fractional dimension (Df) was measured by two trained graders using a computer-assisted program (SIVA-FA, software version 1.0, National University of Singapore) on macula-centered (D mac) and optic disc-centered (D disc) photographs, to assess intergrader reliability. Measurements were repeated after two weeks to determine intragrader reliability. A separate 50 pairs of consecutively repeated images were selected and measured using SIVA-FA to assess intrasession reliability. Reliability analyses were conducted using intraclass correlation coefficients (ICC), and multiple linear regression analyses were performed to compare factors associated with D mac and D disc measurements. RESULTS The mean (SD) D mac and D disc values were 1.453 (0.060) and 1.484 (0.043), respectively, and were highly correlated (r = 0.70, P < 0.001). Intragrader, intergrader, and intrasession reliability for both Df measures was high (ICCs ranging from 0.88-0.99). In multiple regression analyses, age (both β = -0.03, P < 0.001) and hypertension (β = -0.02, P = 0.011; β = -0.02, P = 0.021, respectively) were independently associated with D mac and D disc. CONCLUSIONS The complexity of the retinal vasculature in the macula can be measured reliably and may be a useful tool to study parafoveal vascular networks in macula diseases, such as diabetic maculopathy.

Temporal Changes in Retinal Microvascular Caliber and Blood Pressure During Pregnancy

The microvasculature plays an important role in regulating cardiovascular changes in pregnancy, but changes in microvasculature have been difficult to document in vivo. This study objectively quantifies changes in the maternal retinal arteriolar and venular caliber over the course of healthy pregnancy. Healthy pregnant women (n=53) were recruited from Royal Prince Alfred Hospital, Sydney, Australia. Retinal images and mean arterial blood pressures (MAP) were collected at 13, 19, 29, and 38 weeks of gestation and at 6-month postpartum. Retinal vessels were analyzed and summarized as the central retinal arteriolar equivalent and central retinal venular equivalent. Central retinal arteriolar equivalent and central retinal venular equivalent were corrected for MAP. Paired t tests were performed comparing consecutive time points, with a significance level of P<0.01. There was a decrease in MAP between 13- and 19-week gestation (P=0.001) followed by a return to baseline from 19 weeks to delivery. This was correlated by an increase in vessel caliber between 13- and 19-week gestation (central retinal arteriolar equivalent: P<0.001, central retinal venular equivalent: P=0.007) and a return to baseline from 19 weeks to delivery. There were no differences in the central retinal arteriolar equivalent or central retinal venular equivalent (both uncorrected and corrected for MAP) between nulliparous and parous women. The pattern of dilatation and constriction in the microvasculature mirrored the changes in MAP throughout pregnancy, reflecting changes in peripheral resistance. This study provides insights into physiological changes in the microvasculature throughout a healthy pregnancy. These results can be used as a baseline with which to compare the changes observed in pathological conditions of pregnancy.

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.