Gerald Liew

Retinal vascular imaging: a new tool in microvascular disease research.

The microcirculation is relatively inaccessible to direct visualization and investigation. Recent methods have been developed which use advanced retinal photographic imaging techniques and computer-assisted image analysis to characterize, measure and quantify subtle variations and abnormalities in the retinal vasculature. These quantitative and qualitative assessments demonstrate a close association of retinal vascular signs to both clinical and subclinical cerebrovascular, cardiovascular and metabolic outcomes. Retinal vascular imaging may thus offer potential as a noninvasive research tool to probe the role and pathophysiology of the microvasculature, and as a cardiovascular risk prediction tool. Key areas where retinal vascular imaging has contributed to increased understanding of microvascular pathology and major areas of current and new research are discussed in this review.

Meta-analysis: retinal vessel caliber and risk for coronary heart disease.

Coronary heart disease (CHD) remains the leading cause of death in the United States despite advances in prevention, diagnosis, and therapy. Further improvement in outcomes can be achieved through more accurate identification of persons at risk, enhanced understanding of pathogenesis, novel interventions, and better implementation of existing preventive and therapeutic strategies. Coronary microvascular dysfunction is increasingly recognized as an important contributor to CHD, particularly among women (1), and interest in noninvasive methods of assessing the coronary microcirculation is considerable (2). The coronary and retinal vessels undergo similar changes (such as sclerosis) in hypertension (3, 4), and assessment of retinal vessels may provide an indication of coronary microvascular damage (5). With the advent of computer-assisted methods for measuring retinal vessel caliber from retinal photographs, retinal vascular imaging has been found to independently predict increased risk for CHD in prospective epidemiologic studies (610), which raises the possibility of using retinal vessel assessment as a novel risk marker. However, the results reported thus far have not been consistent. The ARIC (Atherosclerosis Risk in Communities) study (6), the first large epidemiologic study to report associations of retinal vessel caliber with incident CHD, suggested that these associations were only present in middle-age women. Subsequent studies have produced conflicting results. The CHS (Cardiovascular Health Study) (9) reported associations of narrower retinal arterioles and wider venules with incident CHD in both older women and men, but other studies found associations mainly in younger women and men, with weak or no association in older persons (10). Differences in study populations and inclusion criteria may account for the varying findings. For example, participants with diabetes or prevalent CHD were included in some studies (10) but not others (9, 11), and analytic methods and adjustment for traditional cardiovascular risk factors varied considerably among studies. To provide robust evidence to address these discrepancies, we conducted a systematic review and an individual-participant meta-analysis of population-based cohort studies, adjusting for traditional risk factors, to determine the associations between retinal vessel caliber and CHD risk. We particularly examined whether the associations differed between women and men. Methods Data Extraction We reviewed the literature to identify all studies that measured retinal vessel caliber, documented CHD events, and were conducted in general populations. We conducted a search of MEDLINE and EMBASE of all studies published between 1950 and 4 June 2009. We used the MEDLINE search terms (exp Retinal Diseases/, (retina or retinal).tw., retinopathy.tw., Arteriolar narrowing.tw., Arterio-venous nicking.tw., Arteriovenous nicking.tw., venular dilatation.tw., venular dilation.tw., arterio-venular ratio.tw.) and (Cardiovascular Diseases/, exp Heart Diseases/, exp Vascular Diseases/, cardiovascular.tw., coronary.tw., heart.tw., mortality.tw.) and (incidence/, exp Mortality/, exp epidemiologic studies/, prognos

Relation between fasting glucose and retinopathy for diagnosis of diabetes: three population-based cross-sectional studies.

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Prediction of Incident Stroke Events Based on Retinal Vessel Caliber: A Systematic Review and Individual-Participant Meta-Analysis

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Retinal vascular calibre and the risk of coronary heart disease-related death

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A comparison of the causes of blindness certifications in England and Wales in working age adults (16–64 years), 1999–2000 with 2009–2010

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Genome-Wide Association Study of Retinopathy in Individuals without Diabetes

.tw.). We then searched the selected papers to identify studies that met our inclusion criteria: carried out in general populations, measured retinal vessel caliber from either photographic film or digital photographs by using computer-assisted methods, and recorded incident CHD events. We contacted the principal or lead investigators of the chosen studies and obtained individual-participant data from each study to investigate heterogeneity in the published results and, if appropriate, to calculate pooled estimates of the associations between retinal vessel caliber and CHD risk. If the investigators agreed to participate, we then requested original recorded data on individual retinal vessel caliber measurements, fatal and nonfatal CHD events and time to these events, baseline measurements of variables included in the Framingham Risk Score (age, sex, systolic blood pressure, serum total cholesterol and high-density lipoprotein [HDL] cholesterol levels, current smoking status, use of blood pressurelowering medications, and presence of diabetes), body mass index, diastolic blood pressure, leukocyte count, and previous CHD. Statistical Analysis We analyzed the data for women and men separately because our primary hypothesis was that retinal vessel caliber predicts incident CHD more strongly in women than in men (8). In addition, separate Framingham Risk Scores, with different coefficients for the variables in the score, are used for men and women (12). The standard deviation for the means of arteriolar and venular caliber was approximately 20 m. We estimated the hazard ratio associated with each 20-m decrease in arteriolar caliber and each 20-m increase in venular caliber, which were adjusted for the other retinal vessel caliber, the variables that make up the Framingham Risk Score, and other risk factors associated with CHD and retinal caliber (13, 14). We estimated these separately for each study by using a proportional hazards model. We then combined data from all studies and used a stratified proportional hazards model to test for interaction between the study stratification variable and retinal vessel caliber variables, as well as sex and the CHD risk factors. This tests heterogeneity across studies in associations with retinal vessel caliber. Where no heterogeneity was present, we obtained a pooled hazard ratio adjusted for the CHD risk factors. The stratified proportional hazards model allows the baseline hazard function to differ among the studies but assumes that the effect of the retinal vessel caliber and the other variables are fixed. We defined nonfatal CHD events as myocardial infarction, coronary artery bypass graft, or coronary angioplasty. For those events that were coded by using International Classification of Diseases, Tenth Edition, codes, we classified fatal events as CHD deaths if the main or underlying cause of death received a code from I21 to I25 or if the study-adjudicated cause of death was CHD. Within each study, we assessed the appropriate functional form of each of the continuous variables in the models by using fractional polynomials, and we tested the proportional hazards assumption by using plots of the Schoenfeld residuals and by testing for the effect of adding time-dependent covariates (15). We repeated the main analysis to examine the robustness of our results, this time standardizing the retinal vessel caliber measurements by dividing them by the study-specific standard deviations to allow for different means and standard deviations of the retinal vessel caliber measurements in the different studies (16). We also pooled the study-specific hazard ratios by using a random-effects model (17). Results Characteristics of the Studies Identified We found 3946 studies with our initial search strategy. We then identified 25 studies that had performed retinal assessments or vessel caliber measurements and had followed participants over time to monitor CHD events. Of these, 18 studies (1835) recorded only the presence of retinopathy and not retinal vessel caliber, were conducted exclusively in persons with diabetes, or recorded only fatal events (Figure 1). This left 7 studies that met our inclusion criteria. One study, MESA (Multi-Ethnic Study of Atherosclerosis) (36), had insufficient outcome data available at the time of the analysis. Investigators from the other 6 studies (ARIC, CHS, AusDiab [Australian Diabetes, Obesity and Lifestyle] study, BMES [Blue Mountains Eye Study], BDES [Beaver Dam Eye Study], and RS [Rotterdam Study]) agreed to provide data for the individual-participant meta-analysis. Figure 1. Literature search and selection. CHD = coronary heart disease. Table 1 shows the characteristics for 22159 participants from each of the 6 studies we included. The measurement of retinal vessel caliber was similar in each study with some slight variations (7, 3741). Briefly, participants in each study had retinal photographs (film or digital) taken for either a single eye or both eyes, centered on the optic disc and macula. The BDES and BMES both used the Zeiss FF3 camera (Carl Zeiss Meditec, Jena, Germany) and 30 fields (10), ARIC and CHS used the Canon CR6-45NM (Canon, Tokyo, Japan) with 45 fields (37, 41), AusDiab used the Canon CR45UAF (Canon) with 45 fields (38), and RS used the Topcon TRC-SS2 (Topcon, Tokyo, Japan) with 20 fields (11). Trained graders, who were masked to participant characteristics, then viewed the optic disc photographs. The graders measured the diameters of all arterioles and venules that coursed through a zone that surrounded the optic disc, one-half to one-whole disc diameter away from the optic disc margin, by using a computer-assisted software program specifically developed for this purpose (37). The measurement module was custom programmed in Khoros (public domain image-processing software from the University of New MexicoAlbuquerque, Albuquerque, New Mexico) and used the green channel of the digital image to enhance contrast of the retinal vessels against the retinal pigment epithelium. Table 1. Participant Characteristics The ARIC, BDES, and BMES used an earlier version of this software to measure the retinal vessel caliber, whereas AusDiab, CHS, and RS used a later version of the same software. Both versions are available on request from the reviewers or the Wisconsin Fundus Photograph Reading Center, University of WisconsinMadison, Madison, Wisconsin. For this meta-analysis, we summarized the individual mean retinal vessel calibers from each study by using the ParrHubbard formula (37). Reproducibility statistics were high for thes

Quantitative Assessment of Early Diabetic Retinopathy Using Fractal Analysis

BACKGROUND The WHO and American Diabetes Association criteria for diagnosing diabetes mellitus assume the presence of a glycaemic threshold with high sensitivity for identifying retinopathy. However, this assumption is based on data from three previous studies that had important limitations in detecting retinopathy. We aimed to provide updated data for the relation between fasting plasma glucose (FPG) and retinopathy, and to assess the diagnostic accuracy of current FPG thresholds in identifying both prevalent and incident retinopathy. METHODS We examined the data from three cross-sectional adult populations: those in the Blue Mountains Eye Study (BMES, Australia, n=3162), the Australian Diabetes, Obesity and Lifestyle Study (AusDiab, Australia, n=2182), and the Multi-Ethnic Study of Atherosclerosis (MESA, USA, n=6079). Retinopathy was diagnosed from multiple retinal photographs of each eye, and graded according to the modified Airlie House Classification system. Plasma glucose concentrations were measured from fasting venous blood samples. FINDINGS The overall prevalence of retinopathy was 11.5% in BMES (95% CI 10.4-12.6%), 9.6% in AusDiab (8.4-10.9), and 15.8% in MESA (14.9-16.7). However, we found inconsistent evidence of a uniform glycaemic threshold for prevalent and incident retinopathy, with analyses suggesting a continuous relation. The widely used diabetes FPG cutoff of 7.0 mmol/L or higher had sensitivity less than 40% (range 14.8-39.1) for detecting retinopathy, with specificity between 80.8% and 95.8%. The area under receiver operating characteristic curves for FPG and retinopathy was low and ranged from 0.56 to 0.61. INTERPRETATION We saw no evidence of a clear and consistent glycaemic threshold for the presence or incidence of retinopathy across different populations. The current FPG cutoff of 7.0 mmol/L used to diagnose diabetes did not accurately identify people with and without retinopathy. These findings suggest that the criteria for diagnosing diabetes could need reassessment.

Assessing New Biomarkers and Predictive Models for Use in Clinical Practice: A Clinician's Guide

The caliber of the retinal vessels has been shown to be associated with stroke events. However, the consistency and magnitude of association, and the changes in predicted risk independent of traditional risk factors, are unclear. To determine the association between retinal vessel caliber and the risk of stroke events, the investigators combined individual data from 20,798 people, who were free of stroke at baseline, in 6 cohort studies identified from a search of the Medline (National Library of Medicine, Bethesda, Maryland) and EMBASE (Elsevier B.V., Amsterdam, the Netherlands) databases. During follow-up of 5-12 years, 945 (4.5%) incident stroke events were recorded. Wider retinal venular caliber predicted stroke (pooled hazard ratio = 1.15, 95% confidence interval: 1.05, 1.25 per 20-micron increase in caliber), but the caliber of retinal arterioles was not associated with stroke (pooled hazard ratio = 1.00, 95% confidence interval: 0.92, 1.08). There was weak evidence of heterogeneity in the hazard ratio for retinal venular caliber, which may be attributable to differences in follow-up strategies across studies. Inclusion of retinal venular caliber in prediction models containing traditional stroke risk factors reassigned 10.1% of people at intermediate risk into different, mostly lower, risk categories.

The Retinal Vasculature as a Fractal: Methodology, Reliability, and Relationship to Blood Pressure

Objective: To examine whether retinal vascular calibre independently predicts risk of coronary heart disease (CHD) -related death. Methods: In a population-based cohort study of 3654 Australians aged ⩾ 49 years, retinal arteriolar and venular calibres were measured from baseline retinal photographs and the arteriole to venule ratio (AVR) was calculated. CHD-related death was confirmed from the Australian National Death Index. Results: Over nine years, 78 women (4.1%) and 114 men (7.8%) had incident CHD-related deaths. In people aged 49–75 years, wider venules were associated with CHD death, with relative risk (RR) 1.8 (95% confidence interval (CI) 1.1 to 2.7) and RR 2.0 (95% CI 1.1 to 3.6) per standard deviation (SD) increase in venular calibre for men and women, respectively, after adjustment for traditional risk factors. Additionally, in women aged 49–75 years, smaller AVR and narrower arterioles were associated with CHD death (RR 1.5, 95% CI 1.1 to 2.2, and RR 1.9, 95% CI 1.0 to 3.5 per SD decrease in AVR and arteriolar calibre, respectively, after adjustment). These associations were not observed in people aged > 75 years. Conclusions: These findings suggest that microvascular disease processes may have a role in CHD development in middle-aged people, particularly in women. Retinal photography may be useful in cardiovascular risk prediction.