Relationship of Retinal Vascular Caliber With Diabetes and Retinopathy: The Multi-Ethnic Study of Atherosclerosis (MESA)

THANH TAN NGUYEN MBBS JIE JIN WANG PHD A. RICHEY SHARRETT DRPH F.M. AMIRUL ISLAM PHD RONALD KLEIN BARBARA E.K. KLEIN MARY FRANCES COTCH PHD TIEN YIN WONG PHD OBJECTIVE To examine the relationship of retinal vascular caliber with diabetes, glycemia, and diabetic retinopathy. RESEARCH DESIGN AND METHODS Population-based study using data from the Multi-Ethnic Study of Atherosclerosis (MESA), comprising 5,976 individuals (whites, blacks, Hispanics, and Chinese) residing in six U.S. communities who were free of clinical cardiovascular disease at baseline. Retinal vascular caliber was measured from digital retinal photographs. RESULTS There were 4,585 individuals with normal fasting glucose (NFG), 499 with impaired fasting glucose (IFG), 165 with diabetes with retinopathy signs, and 727 with diabetes without retinopathy signs. After multivariate analysis, retinal arteriolar caliber increased from 143.8 m in subjects with NFG to 144.5 m in IFG and 146.1 m in diabetes (P 0.001 for trend). Retinal venular caliber increased from 214.4 m in NFG to 216.7 m in IFG and 218.0 m in diabetes (P 0.001 for trend). Retinal venular caliber was significantly larger with increasing levels of fasting glucose and A1C. In a subgroup analysis by ethnicity, the association between wider arteriolar caliber and diabetes was evident in whites only, whereas wider venular caliber and diabetes was evident in Hispanics and Chinese only. In people with diabetes, eyes with retinopathy had larger retinal venular but not arteriolar caliber. CONCLUSIONS Retinal arteriolar and venular calibers are larger in individuals with diabetes, but the pattern of associations appears to vary by ethnicity. Retinal venular caliber is additionally associated with retinopathy signs. These findings add further to the concept that variations in retinal vascular caliber may reflect early diabetic microvascular damage. - T ble to direct noninvasive visualizahe retinal blood vessels are accessition. There is increasing evidence that changes in retinal vascular caliber may be markers of early microvascular dysfunction associated with diabetes, prediabetes, and diabetes complications (1,2). However, although there have been a number of studies reporting various associations of retinal vascular caliber, the specific changes in arteriolar and venular caliber size with glycemic levels remain unclear. Early studies, for example, evaluated associations with the ratio of the retinal arteriolar to venular caliber (AV ratio), initially thought to reflect smaller arteriolar caliber. These studies showed that a smaller AV ratio was related to the development of type 2 diabetes (3,4). However, other studies subsequently found that these associations are driven by venular caliber, and one study demonstrated that larger retinal venular caliber was associated with the incidence of impaired fasting glucose and possibly diabetes (5). Associations of retinal arteriolar and venular caliber with diabetic microvascular complications, such as retinopathy, have also been inconsistent (6,7). Furthermore, it is now recognized that because arteriolar and venular calibers are highly correlated, statistical analysis of retinal vascular caliber should account for this correlation (8). To address these issues, we assessed the associations of retinal arteriolar and venular caliber with the full spectrum of glycemic-related disorders and complications, ranging from impaired fasting glucose and clinically diagnosed diabetes to the presence of diabetic retinopathy in a multiethnic population-based cohort. RESEARCH DESIGN AND METHODS The Multi-Ethnic Study of Atherosclerosis (MESA) is a prospective cohort study of men and women aged 45 84 years comprising four racial/ethnic groups (whites, blacks, Hispanics, and Chinese). Participants have no history of clinical cardiovascular disease at baseline and are residents of six U.S. communities (9). Tenets of the Declaration of Helsinki were followed, and institutional review board approval was granted at each study site. Written informed consent was obtained from each participant. At the first examination, there were 6,814 participants. Retinal photography was done at the second examination, which immediately followed the baseline examination, from August 2002 to January 2004 (10). At the second examination, 6,237 returned, 6,147 had retinal photographs for grading retinopathy, and 5,976 (97.3%) had photographs that Table 1Characteristics of participants in MESA Glucose status (n No retinopathy were suitable for measurement of retinal vascular caliber. Measurement of retinal vascular caliber Retinal photography was performed using a standardized protocol (11). Both eyes of each participant were photographed using a 45-degree 6.3-megapixel digital nonmydriatic camera. Two photographic fields (optic disc and macula) were taken of each eye. Images were sent from the six field centers to the University of Wisconsin, Madison, for measurement of retinal vascular caliber and assessment of other retinal pathology. Retinal vascular caliber was measured using a computer-based program by trained graders who were masked to participant characteristics, based on a detailed protocol (11). Photographs in the right eye were selected for measurement; the left eye was chosen if measurements could not be performed in the right eye. For each image, all arterioles and venules coursing through an area one-half to onedisc diameter from the optic disc margin were measured and summarized as the central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE) (10,11). These equivalents are projected calibers for the central retinal vessels, measured away from the optic disc. Reproducibility of these measurements has been reported, with intra- and intergrader intraclass correlation coefficients ranging from 0.78 to 0.99 (10). Definition of diabetic retinopathy Diabetic retinopathy assessment has been previously published. For each eye, a retinopathy severity score was assigned based on modification of the Airlie House Classification system (12). Levels 14 20 were defined as minimal retinopathy, and levels 20 (levels 31 80) were defined as early to severe diabetic retinopathy. A persons retinopathy level was based on the scores in the right eye, as most of the retinal vascular caliber measurements were obtained from this eye. Six eyes with proliferative retinopathy were excluded from analysis because of previous laser treatment, which may have an effect on vascular calibers (6,7). Assessment of diabetes Diabetes was defined as fasting glucose 7.0 mmol/l (126 mg/dl) or use of insulin or oral hypoglycemic medication (13). No distinction was made between type 1 and type 2 diabetes. Impaired fasting glucose (IFG) was defined as a fasting glucose level of 6.1 6.9 mmol/l (110 125 mg/ dl). All other participants were defined as having normal fasting glucose (NFG). A (...truncated)