ORIGINAL STUDY
Childhood Vascular Risk Factors and Retinal Vessel Caliber Ning Cheung, MBBS,*Þþ Seang M. Saw, PhD,Þ§ Gerald Liew, PhD,¶ Erica Y. Liu, BSc,Þ Lauren Hodgson, BSc,* Paul Mitchell, MD, PhD,¶ and Tien Y. Wong, MD, PhD*Þ
Purpose: Variations in retinal vessel caliber have been associated with risk of ocular and systemic vascular diseases in adults. In this study, we examined the relationships between childhood vascular risk factors and retinal vessel caliber in young healthy adolescents. Design: This was a cross-sectional study of 1225 adolescents recruited from 3 community-based schools in Singapore. Methods: Blood pressure and anthropometry measurements were obtained through standardized examinations. Birth weight was ascertained from health records completed by medical personnel soon after birth. Retinal vessel caliber was measured from retinal photographs using a semiautomated computer-based program following a validated standardized protocol. Results: After adjusting for age, sex, and other relevant factors, each SD increase in blood pressure levels (systolic or diastolic) was associated with narrower arteriolar caliber (1.61 Km; P G 0.001); each SD increase in body mass index was associated with narrower arteriolar caliber (1.49 Km; P G 0.001) and wider venular caliber (2.68 Km; P G 0.001), and each SD decrease in birth weight was associated with narrower arteriolar caliber (1.31 Km; P = 0.001). Conclusions: Young adolescents with elevated blood pressure, obesity, or low birth weight have changes in retinal vessel caliber that are associated with ocular and systemic vascular diseases in adulthood. These findings provide evidence of possible adverse effects of childhood vascular risk factors on the retinal microvasculature early in life. Key Words: retinal vessel caliber, blood pressure, body mass index, birth weight, cardiovascular disease (Asia-Pacific Journal of Ophthalmology 2012;1: 193Y197)
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pidemiologic studies in middle-aged and elderly populations have indicated that specific variations in retinal vessel caliber, such as narrowed arterioles and widened venules, are associated with common eye diseases (eg, diabetic retinopathy1Y6 and glaucoma7Y9),10Y12 and with systemic subclinical13Y16 and clinical cardiovascular diseases (eg, stroke, coronary heart disease).17Y19
From the *Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Victoria, Australia; †Singapore Eye Research Institute, National University of Singapore, Singapore; ‡Department of Ophthalmology and Visual Sciences, Chinese University of Hong Kong, Hong Kong, People’s Republic of China; §Department of Community, Occupational and Family Medicine, National University of Singapore, Singapore; and ¶Centre for Vision Research, the University of Sydney, New South Wales, Australia. Received for publication February 16, 2012; accepted May 8, 2012. This research is supported by the National Medical Research Council, Singapore, NMRC/0975/2005 (S.M.S.), NMRC/STaR/0003/2008, and the SingHealth Foundation SHF/FG227P/2005, Singapore BioImaging Consortium C-011/2006 (T.Y.W.). The authors have no conflicts of interest to declare. Reprints: Ning Cheung, MBBS, Centre for Eye Research Australia, University of Melbourne, 32 Gisborne St, East Melbourne, Victoria 3002, Australia. E-mail: [email protected]. Copyright * 2012 by Asia Pacific Academy of Ophthalmology ISSN: 2162-0989 DOI: 10.1097/APO.0b013e31825e4d79
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Moreover, these retinal vessel changes have also been implicated in ocular therapeutics. Intravitreal antiYvascular-endothelial growth factor therapy, for example, has been shown to induce constriction of retinal arterioles,20 whereas larger retinal venules have recently been associated with poorer treatment response among patients with neovascular age-related macular degeneration.21 However, less is known about the systemic determinants of retinal vessel caliber in children. Such knowledge is of interest because it might uncover important insights into the genesis of microvascular disease not only in the eyes but also throughout the human body. In this study, we examined the associations of retinal vessel caliber with 3 major childhood vascular risk factors: blood pressure, body mass index (BMI), and birth weight in young healthy adolescents.
MATERIALS AND METHODS Study Population The Singapore Cohort Study of Risk Factors for Myopia is a study of 1979 schoolchildren, aged 7 to 9 years at baseline, in Singapore. Details of the study population have been described elsewhere.22 In brief, 2913 children were initially recruited from 3 community-based schools with a participation rate of 67.9% (1979 participants) during 1999 to 2001. Children with medical conditions (n = 94), such as heart disorders, syndrome-associated myopia, or eye disorders, such as cataract, were excluded from the study. Retinal photography was performed for all the participants who returned for the follow-up examination in 2006. Of these, we excluded those with ungradable retinal photographs or incomplete anthropometry or blood pressure measurements, leaving 1225 participants for the current analyses. The Ethics Committee of the Singapore Eye Research Institute approved the study, and the conduct of the study followed the tenets of the Declaration of Helsinki. Written informed consent was obtained from all parents after the nature of the study was explained.
Retinal Photography and Retinal Vessel Caliber Measurements All participants were examined on the school premises by a team of ophthalmologists, optometrists, and research assistants at the 2006 visit. After pupil dilatation with cyclopentolate 1%, digital retinal photographs centered on the optic disc were taken of both eyes using standardized settings.22 Methods used to measure and summarize retinal vessel caliber from retinal photographs followed a previously validated standardized protocol.23,24 In brief, we used a computer-based program to measure the caliber of all retinal vessels coursing through the region half to 1 optic disc diameter away from the optic disc margin in the retinal images. Individual retinal vessel caliber measurements from an eye were summarized as an average index according to formulas described elsewhere.23,24 These indices, the central retinal arteriolar and venular equivalents, represented the average arteriolar and venular caliber of
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that eye. Trained graders, masked to participant identity and characteristics, performed all the retinal measurements. Retinal vessel caliber in the right eye was measured, and left eye measurements were performed when photographs of the right eye were ungradable. Remeasurement of 50 retinal images 2 weeks apart showed high reproducibility, with intraclass correlation coefficients of 0.853 for arteriolar caliber and 0.973 for venular caliber.
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were analyzed as either continuous (eg, per SD change) or categorical (eg, quartiles, weight status) variables. All models included adjustments for age, sex, ethnicity, axial length, spherical equivalent refraction, and other relevant factors. All statistical analyses were undertaken using SPSS version 12.0.1 (SPSS Inc, Chicago, Ill).
RESULTS
Assessment of Vascular Risk Factors We examined participants for 3 major childhood risk factors of cardiovascular disease: blood pressure levels, anthropometry measurements, and birth parameters. Blood pressure was measured in a seated position after 5 minutes of rest using an automated sphygmomanometer.25 The average of 3 separate measurements was used for analysis. Height and weight were measured, with participants standing and without shoes, on the school premises in adherence to a standardized protocol.26 Body mass index was calculated as the weight divided by the square of the height (kg/m2). Childhood obesity was defined according to ageand sex-specific BMI cutoff points.27 Birth history, including birth weight, birth length, head circumference, and gestational age, was obtained from a health booklet completed by medical personnel soon after birth.
Collection of Other Information The parents completed a number of questionnaires, written in English or Chinese, at the baseline visit. Questions have covered topics including demographic information, parental smoking status, and indicators of socioeconomic status, such as parental education level. Measurements of cycloplegic spherical equivalent refraction and ocular biometric parameters have been described elsewhere.22
Statistical Analysis We initially compared characteristics of adolescents in different ethnic groups. Results were reported as means or proportions with differences tested using analysis of variance or W2 test, respectively. Analyses of covariance and linear regression models were used to determine the associations of vascular risk factors with retinal arteriolar and venular calibers. The vascular risk factors
Table 1 shows the characteristics of our study population. The mean age of the participants was 11.9 years, and 60.5% were males. Chinese adolescents had slightly lower BMI; higher birth weight, blood pressure levels, axial length, and myopic refraction; and narrower arteriolar and venular calibers compared with other ethnic groups. In this population, the mean (SD) retinal arteriolar caliber was 149.3 (12.3) Km, and venular caliber was 224.6 (17.8) Km. Table 2 shows that, after adjusting for age, sex, ethnicity, axial length, spherical equivalent refraction, birth weight, and BMI, increasing quartiles of systolic, diastolic, and mean arterial blood pressure were associated with narrower retinal arteriolar caliber (P for trend G0.001). Each SD increase in systolic or diastolic blood pressure was associated with a 1.61-Km narrower retinal arteriolar caliber (P G 0.001). Blood pressure levels were not significantly associated with retinal venular caliber. Table 3 shows that, after adjusting for age, sex, ethnicity, axial length, spherical equivalent refraction, birth weight, and mean arterial blood pressure, increasing quartiles of BMI and weight were associated with narrower retinal arteriolar caliber (P for trend G0.001 for BMI and 0.012 for weight) and wider retinal venular caliber (P for trend G0.001). Each SD increase in BMI was associated with a mean 1.49-Km narrower retinal arteriolar caliber (P G 0.001) and 2.68-Km wider retinal venular caliber (P G 0.001). Obese adolescents on average had 4.0-Km narrower retinal arteriolar caliber and 7.6-Km wider retinal venular caliber (P G 0.001) compared with adolescents of normal weight. Table 4 shows that, after adjusting for age, sex, ethnicity, axial length, spherical equivalent refraction, BMI, and mean arterial blood pressure, lower birth weight was associated with
TABLE 1. Characteristics of the Study Population
Characteristic
Total (n = 1225)
Chinese (n = 871)
Malay (n = 256)
Indian (n = 84)
Mean
SD
Mean
SD
Mean
SD
Mean
SD
P*
49.4 1.0 12.9 9.5 4.0 1.8 481.8 13.9 8.8 15.6 11.4 1.2 3.6 12.3 17.8
438 11.9 49.7 159.3 19.4 38.6 3175.7 111.0 63.9 84.0 91.9 24.5 j2.3 148.4 222.3
50.3 1.0 11.9 9.4 3.8 1.7 454.2 13.8 8.8 15.4 11.4 1.2 3.6 12.0 16.9
121 12.0 51.0 158.3 20.1 38.4 3153.2 110.8 65.2 83.9 93.2 23.9 j0.5 151.8 232.2
47.3 1.0 14.5 10.0 4.4 2.1 549.1 14.1 8.6 16.0 11.6 1.1 2.9 12.4 19.1
38.0 12.1 52.6 158.7 20.6 38.2 2991.3 104.8 62.4 80.2 89.1 23.8 j1.1 151.1 226.0
45.2 1.1 16.4 8.8 5.4 2.2 505.7 13.4 9.5 16.2 11.9 1.1 3.1 13.6 16.9
0.640 0.110 0.093 0.055 0.029 0.315 0.015 0.002 0.094 0.118 0.055 0.000 0.000 0.001 0.000
Sex, male 605 Age, y 11.9 Weight, kg 50.2 Height, cm 159.1 BMI, kg/m2 19.7 Gestational age, wk 38.5 Birth weight, g 3157.7 Systolic blood pressure, mm Hg 110.6 Diastolic blood pressure, mm Hg 64.1 Pulse pressure, mm Hg 83.7 Mean arterial blood pressure, mm Hg 92.0 Axial length, mm 24.3 Spherical equivalent refraction, diopter j1.8 Retinal arteriolar caliber, Km 149.3 Retinal venular caliber, Km 224.6
Data are presented as numbers and proportions or means and SDs. *P value based on W2 (categorical) and independent-samples t test (continuous).
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Vascular Risk Factors and Retinal Vessel Caliber
TABLE 2. Relationship Between Blood Pressure and Retinal Vessel Caliber Arteriolar Caliber, Km Systolic blood pressure, mm Hg 1st Quartile, G101 2nd Quartile, 101Y110 3rd Quartile, 111Y120 4th Quartile, Q120 Per SD increase Diastolic blood pressure, mm Hg 1st Quartile, G58 2nd Quartile, 58Y63 3rd Quartile, 64Y70 4th Quartile, Q70 Per SD increase
n
Mean (95% CI)*
301 306 305 293
151.5 (148.7Y154.4) 150.3 (147.4Y153.1) 149.0 (146.2Y151.8) 148.0 (145.1Y150.9) j1.61 (j2.30 to j0.93)
309 283 305 308
151.2 (148.4Y154.1) 150.6 (147.8Y152.0) 149.2 (146.5Y152.0) 147.3 (144.4Y150.2) j1.61 (j2.23 to j0.99)
Venular Caliber, Km P
Mean (95% CI)*
P
G0.001† G0.001
222.1 (218.1Y226.2) 222.0 (218.0Y226.0) 220.3 (216.4Y224.2) 221.3 (217.2Y225.5) j0.39 (j1.37 to 0.58)
0.358† 0.429
G0.001† G0.001
221.1 (217.1Y225.1) 220.3 (216.3Y224.3) 221.7 (217.8Y225.6) 222.3 (218.2Y226.4) 0.49 (j0.40 to 1.38)
0.208† 0.279
*Mean (or mean difference) adjusted for age, sex, ethnicity, axial length, spherical equivalent refraction, birth weight and BMI, and arteriolar caliber. †P for trend across quartiles. CI indicates confidence interval.
narrower retinal arteriolar caliber (P for trend G0.001 across categories and a mean 1.31-Km narrower retinal arteriolar caliber for each SD decrease in birth weight). Birth weight was not associated with retinal venular caliber. Gestational status and other birth parameters (birth length, head circumference; data not shown) were not significantly associated with either retinal arteriolar or venular caliber.
DISCUSSION Advances in retinal image analysis have allowed reliable and precise measurement of retinal vessel caliber from retinal photographs. Using this approach, studies of middle-aged and elderly populations have associated narrowed retinal arteriolar caliber and widened retinal venular caliber with risk of ocular1Y5,7Y12 and systemic vascular diseases.13Y19 Our current study extends
from our previous pilot study28 and represents one of the few studies that have examined retinal vessel caliber in young adolescents. Our data have shown that narrower retinal arterioles are associated with elevated blood pressure, obesity, and low birth weight, whereas wider retinal venules are associated with only measures of obesity. Our findings are supported by the Sydney Childhood Eye Study of predominantly white 6-year-old children in Australia, and the Strabismus, Amblyopia and Refractive Error Study of a much smaller sample of Singaporean Chinese preschoolers.25,29Y31 In these studies, higher blood pressure was significantly and monotonically associated with retinal arteriolar narrowing, a vascular feature associated with glaucoma7Y9 and predictive of systemic hypertension and diabetes in middle-aged and older populations.32,33 Higher BMI has similarly been reported to be associated with not only retinal arteriolar narrowing,29 but also
TABLE 3. Relationship Between Obesity Measures and Retinal Vessel Caliber Arteriolar Caliber, Km BMI, kg/m2 1st Quartile, G16.9 2nd Quartile, 16.9Y18.9 3rd Quartile, 19.0Y21.7 4th Quartile, 921.7 Per SD increase Weight status‡ Normal Overweight Obese
n
Mean (95% CI)*
300 302 301 302
150.8 (148.0Y153.6) 150.4 (147.6Y153.2) 150.4 (147.6Y153.2) 147.2 (144.4Y150.0) j1.49 (j2.10 to j0.87)
882 223 97
150.6 (147.9Y153.2) 147.6 (144.7Y150.5) 146.6 (143.3Y149.8)
Venular Caliber, Km P
Mean (95% CI)*
P
G0.001† G0.001
219.5 (215.5Y223.5) 219.7 (215.7Y223.7) 220.7 (216.7Y224.7) 225.4 (221.4Y229.4) 2.68 (1.81Y3.54)
G0.001† G0.001
G0.001†
220.0 (216.3Y223.8) 223.6 (219.5Y227.7) 227.6 (222.9Y232.2)
G0.001†
*Mean (or mean difference) adjusted for age, sex, ethnicity, axial length, spherical equivalent refraction, birth weight, and mean arterial blood pressure. †P for trend across quartiles. ‡Defined in methods. CI indicates confidence interval.
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TABLE 4. Relationship Between Birth Factors and Retinal Vessel Caliber Arteriolar Caliber, Km Birth weight, g G2500 2500Y3000 3001Y3500 3501Y4000 Per SD decrease Gestational age, wk Very preterm, G32 Preterm, 32Y37 Term, 937 Per week decrease
n
Mean (95% CI)*
78 248 393 151
147.6 (143.7Y151.5) 148.5 (145.2Y151.8) 150.2 (147.0Y153.4) 150.7 (147.2Y154.2) j1.31 (j2.06 to j0.56)
16 147 707
146.3 (140.5Y152.0) 149.0 (145.5Y152.4) 149.8 (146.6Y152.9) j0.65 (j1.31 to 0.01)
Venular Caliber, Km P
Mean (95% CI)*
P
0.021† 0.001
224.1 (218.7Y229.5) 223.4 (218.8Y228.1) 221.2 (216.8Y225.7) 222.2 (217.3Y227.0) 0.69 (j0.36 to 1.74)
0.244† 0.197
0.166† 0.052
227.8 (219.8Y235.9) 223.1 (218.3Y227.9) 221.9 (217.6Y226.3) 0.64 (j0.28 to 1.56)
0.091† 0.171
*Mean (or mean difference) adjusted for age, sex, ethnicity, axial length, spherical equivalent refraction, BMI, mean arterial blood pressure, and gestational age (or birth weight). †P for trend across categories. CI indicates confidence interval.
retinal venular widening,26,29 a vascular feature associated with diabetic retinopathy1Y6 and predictive of obesity and cardiovascular mortality in adults.17Y19,34 Furthermore, although we observed no significant associations between birth factors and retinal vessel caliber in our previous smaller pilot study,28 subsequent studies have linked impaired fetal growth, reflected as low birth weight or other indices of small birth size (eg, birth length, head circumference), with retinal arteriolar narrowing in young children and middle-aged adults without clinical cardiovascular disease.35Y37 The lack of significant association in our smaller pilot study could be related to power concerns as we examined only a subset (50%) of the Singapore Cohort Study of Risk Factors for Myopia cohort at that visit. In the current study with a larger sample, we found that retinal arteriolar narrowing is indeed associated with lower birth weight. It is also interesting to note that we did not find any significant associations of retinal vessel caliber with birth parameters other than birth weight. This pattern is consistent with the fact that placental insufficiency, a major cause of fetal growth restriction, is known to affect birth weight more markedly than other birth parameters.38 Although our findings may support the long-standing theory that cardiovascular disease has an etiologic origin in early life,39 the exact pathophysiological mechanisms remain to be determined. Hypoxia, inflammation, and endothelial dysfunction have all been implicated in the pathogenesis of retinal arteriolar narrowing and retinal venular dilatation.40 Therefore, it is plausible that our findings might reflect these pathological processes taking place in early microvascular disease. On the contrary, it is also possible that our findings could be a result of normal physiological adaptive response of the microcirculatory system to the examined vascular risk factors. Strengths of our study include its large sample of adolescents, standardized assessment of vascular risk factors and birth factors, and the use of computer-based measurement of retinal vessel caliber according to a validated standardized protocol. Potential limitations should also be noted. First, the crosssectional design of our study limited causal inference for the observed associations. Second, our study was not designed to determine whether the retinal vessel caliber changes in adoles-
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cents with vascular risk factors predict a higher risk of cardiovascular events later in life. Nevertheless, our findings highlight this important area for future research that would require longterm follow-up of this or other cohorts. Third, residual confounding from measured and unmeasured factors could have influenced our results. This is less likely given our sample of generally healthy adolescents without clinical cardiovascular or eye diseases that are known to be associated with vascular risk factors and retinal vessel caliber. Finally, camera and ocular magnification effects might be an inherent potential source of measurement errors for retinal vessel caliber. Nonetheless, our findings are unlikely due to such random errors, which would more likely bias the results to the null. In summary, our data show that 3 common childhood vascular risk factors, elevated blood pressure, obesity, and low birth weight, are associated with retinal arteriolar narrowing and venular widening. These findings suggest that adverse microvascular effects of vascular risk factors may manifest early in life. Furthermore, our data may offer new insights into the genesis of microangiopathy associated with ocular (eg, diabetic retinopathy, glaucoma) and systemic (eg, hypertension) diseases in older people. REFERENCES 1. Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet. 2010; 376:124Y136. 2. Cheung N, Rogers SL, Donaghue KC, et al. Retinal arteriolar dilation predicts retinopathy in adolescents with type 1 diabetes. Diabetes Care. 2008:31:1842Y1846. 3. Rogers S, Tikellis G, Cheung N, et al. Retinal arteriolar caliber predicts incident retinopathy: the Australia Diabetes, Obesity and Lifestyle (AusDiab) Study. Diabetes Care. 2008;31:761Y763. 4. Cheung N, Wong TY. Predicting risk of diabetic retinopathy from retinal vessel analysis: personalized medicine in transition. Arch Ophthalmol. 2012;130:783Y784. 5. Tsai AS, Wong TY, Lavanya R, et al. Differential association of retinal arteriolar and venular caliber with diabetes and retinopathy. Diabetes Res Clin Pract. 2011;94:291Y298.
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6. Klein R, Myers CE, Lee KE, et al. Changes in retinal vessel diameter and incidence and progression of diabetic retinopathy. Arch Ophthalmol. 2012;130:749Y755. 7. Amerasinghe N, Aung T, Cheung N, et al. Evidence of retinal vascular narrowing in glaucomatous eyes in an Asian population. Invest Ophthalmol Vis Sci. 2008;49:5397Y5402. 8. Zheng Y, Cheung N, Aung T, et al. Relationship of retinal vascular caliber with retinal nerve fiber layer thickness: the Singapore Malay Eye Study. Invest Ophthalmol Vis Sci. 2009;50:4091Y4096. 9. Mitchell P, Leung H, Wang JJ, et al. Retinal vessel diameter and open-angle glaucoma: the Blue Mountains Eye Study. Ophthalmology. 2005;112:245Y250. 10. Youm DJ, Ha MM, Chang Y, et al. Retinal vessel caliber and risk factors for branch retinal vein occlusion. Curr Eye Res. 2012;37:334Y338. 11. Li LJ, Cheung CY, Gazzard G, et al. Relationship of ocular biometry and retinal vascular caliber in preschoolers. Invest Ophthalmol Vis Sci. 2011;52:9561Y9566. 12. Yang K, Zhan SY, Liang YB, et al. Association of dilated retinal arteriolar caliber with early age-related macular degeneration: the Handan Eye Study. Graefes Arch Clin Exp Ophthalmol. 2012;250:741Y749. 13. Cheung N, Bluemke DA, Klein R, et al. Retinal arteriolar narrowing and left ventricular remodeling: the multi-ethnic study of atherosclerosis. J Am Coll Cardiol. 2007;50:48Y55. 14. Cheung N, Islam AFM, Jacobs DR, et al. Arterial compliance and retinal vascular caliber in cerebrovascular disease. Ann Neurol. 2007;62: 618Y624. 15. Cheung N, Sharret AR, Klein R, et al. Aortic distensibility and retinal arteriolar narrowing: the Multi-ethnic Study of Atherosclerosis. Hypertension. 2007;50:617Y622. 16. Cheung CY, Tay WT, Mitchell P, et al. Quantitative and qualitative retinal microvascular characteristics and blood pressure. J Hypertens. 2011;29:1380Y1391. 17. McGeechan K, Liew G, Macaskill P, et al. Prediction of incident stroke events based on retinal vessel caliber: a systematic review and individual-participant meta-analysis. Am J Epidemiol. 2009;170: 1323Y1332. 18. McGeechan K, Liew G, Macaskill P, et al. Meta-analysis: retinal vessel caliber and risk for coronary heart disease. Ann Intern Med. 2009;151:404Y413. 19. Cheung N, Wong TY. Diabetic retinopathy and systemic vascular complications. Prog Retin Eye Res. 2008;27:161Y176. 20. Papadopoulou DN, Mendrinos E, Mangioris G, et al. Intravitreal ranibizumab may induce retinal arteriolar vasoconstriction in patients with neovascular age-related macular degeneration. Ophthalmology. 2009;116:1755Y1761. 21. Wickremasinghe SS, Busija L, Guymer RH, et al. Retinal venular caliber predicts visual outcome after intravitreal ranibizumab injection treatments for neovascular AMD. Invest Ophthalmol Vis Sci. 2012;53:37Y41. 22. Saw SM, Chua WH, Hong CY, et al. Nearwork in early-onset myopia. Invest Ophthalmol Vis Sci. 2002;43:332Y339.
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23. Hubbard LD, Brothers RJ, King WN, et al. Methods for evaluation of retinal microvascular abnormalities associated with hypertension/ sclerosis in the Atherosclerosis Risk in Communities Study. Ophthalmology. 1999;106:2269Y2280. 24. Wong TY, Knudtson MD, Klein R, et al. Computer-assisted measurement of retinal vessel diameters in the Beaver Dam Eye Study: methodology, correlation between eyes, and effect of refractive errors. Ophthalmology. 2004;111:1183Y1190. 25. Mitchell P, Cheung N, de Haseth K, et al. Blood pressure and retinal arteriolar narrowing in children. Hypertension. 2007;49: 1156Y1162. 26. Cheung N, Saw SM, Islam FM, et al. BMI and retinal vascular caliber in children. Obesity (Silver Spring). 2007;15:209Y215. 27. Cole TJ, Bellizzi MC, Flegal KM, et al. Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ. 2000;320:1240Y1243. 28. Cheung N, Islam FM, Saw SM, et al. Distribution and associations of retinal vascular caliber with ethnicity, gender, and birth parameters in young children. Invest Ophthalmol Vis Sci. 2007;48:1018Y1024. 29. Taylor B, Rochtchina E, Wang JJ, et al. Body mass index and its effects on retinal vessel diameter in 6-year-old children. Int J Obes (Lond). 2007;31:1527Y1533. 30. Li LJ, Cheung CY, Chia A, et al. The relationship of body fatness indices and retinal vascular caliber in children. Int J Pediatr Obes. 2011;6: 267Y274. 31. Li LJ, Cheung CY, Liu Y, et al. Influence of blood pressure on retinal vascular caliber in young children. Ophthalmology. 2011;118: 1459Y1465. 32. Wong TY, Klein R, Sharrett AR, et al. Retinal arteriolar narrowing and risk of diabetes mellitus in middle-aged persons. JAMA. 2002; 287:2528Y2533. 33. Wong TY, Shankar A, Klein R, et al. Prospective cohort study of retinal vessel diameters and risk of hypertension. BMJ. 2004;329:79. 34. Wang JJ, Taylor B, Wong TY, et al. Retinal vessel diameters and obesity: a population-based study in older persons. Obesity. 2006;14: 206Y214. 35. Mitchell P, Liew G, Rochtchina E, et al. Evidence of arteriolar narrowing in low-birth-weight children. Circulation. 2008;118:518Y524. 36. Liew G, Wang JJ, Duncan BB, et al. Low birthweight is associated with narrower arterioles in adults. Hypertension. 2008;51:933Y938. 37. Sun C, Ponsonby AL, Wong TY, et al. Effect of birth parameters on retinal vascular caliber. The Twins Eye Study in Tasmania. Hypertension. 2009;53:487Y493. 38. Cheung N. Birth factors and retinal vascular caliber in a twin study. Hypertension. 2009;53:e28. 39. Ingelfinger JR. Pediatric antecedents of adult cardiovascular diseaseVawareness and intervention. N Engl J Med. 2004;350: 2123Y2126. 40. Nguyen TT, Wang JJ, Wong TY. Retinal vascular changes in pre-diabetes and pre-hypertensionVnew findings and their research and clinical implications. Diabetes Care. 2007;30:2708Y2715.
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Childhood Vascular Risk Factors and Retinal Vessel Caliber Ning Cheung, MBBS,*Þþ Seang M. Saw, PhD,Þ§ Gerald Liew, PhD,¶ Erica Y. Liu, BSc,Þ Lauren Hodgson, BSc,* Paul Mitchell, MD, PhD,¶ and Tien Y. Wong, MD, PhD*Þ
Purpose: Variations in retinal vessel caliber have been associated with risk of ocular and systemic vascular diseases in adults. In this study, we examined the relationships between childhood vascular risk factors and retinal vessel caliber in young healthy adolescents. Design: This was a cross-sectional study of 1225 adolescents recruited from 3 community-based schools in Singapore. Methods: Blood pressure and anthropometry measurements were obtained through standardized examinations. Birth weight was ascertained from health records completed by medical personnel soon after birth. Retinal vessel caliber was measured from retinal photographs using a semiautomated computer-based program following a validated standardized protocol. Results: After adjusting for age, sex, and other relevant factors, each SD increase in blood pressure levels (systolic or diastolic) was associated with narrower arteriolar caliber (1.61 Km; P G 0.001); each SD increase in body mass index was associated with narrower arteriolar caliber (1.49 Km; P G 0.001) and wider venular caliber (2.68 Km; P G 0.001), and each SD decrease in birth weight was associated with narrower arteriolar caliber (1.31 Km; P = 0.001). Conclusions: Young adolescents with elevated blood pressure, obesity, or low birth weight have changes in retinal vessel caliber that are associated with ocular and systemic vascular diseases in adulthood. These findings provide evidence of possible adverse effects of childhood vascular risk factors on the retinal microvasculature early in life. Key Words: retinal vessel caliber, blood pressure, body mass index, birth weight, cardiovascular disease (Asia-Pacific Journal of Ophthalmology 2012;1: 193Y197)
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pidemiologic studies in middle-aged and elderly populations have indicated that specific variations in retinal vessel caliber, such as narrowed arterioles and widened venules, are associated with common eye diseases (eg, diabetic retinopathy1Y6 and glaucoma7Y9),10Y12 and with systemic subclinical13Y16 and clinical cardiovascular diseases (eg, stroke, coronary heart disease).17Y19
From the *Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Victoria, Australia; †Singapore Eye Research Institute, National University of Singapore, Singapore; ‡Department of Ophthalmology and Visual Sciences, Chinese University of Hong Kong, Hong Kong, People’s Republic of China; §Department of Community, Occupational and Family Medicine, National University of Singapore, Singapore; and ¶Centre for Vision Research, the University of Sydney, New South Wales, Australia. Received for publication February 16, 2012; accepted May 8, 2012. This research is supported by the National Medical Research Council, Singapore, NMRC/0975/2005 (S.M.S.), NMRC/STaR/0003/2008, and the SingHealth Foundation SHF/FG227P/2005, Singapore BioImaging Consortium C-011/2006 (T.Y.W.). The authors have no conflicts of interest to declare. Reprints: Ning Cheung, MBBS, Centre for Eye Research Australia, University of Melbourne, 32 Gisborne St, East Melbourne, Victoria 3002, Australia. E-mail: [email protected]. Copyright * 2012 by Asia Pacific Academy of Ophthalmology ISSN: 2162-0989 DOI: 10.1097/APO.0b013e31825e4d79
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Moreover, these retinal vessel changes have also been implicated in ocular therapeutics. Intravitreal antiYvascular-endothelial growth factor therapy, for example, has been shown to induce constriction of retinal arterioles,20 whereas larger retinal venules have recently been associated with poorer treatment response among patients with neovascular age-related macular degeneration.21 However, less is known about the systemic determinants of retinal vessel caliber in children. Such knowledge is of interest because it might uncover important insights into the genesis of microvascular disease not only in the eyes but also throughout the human body. In this study, we examined the associations of retinal vessel caliber with 3 major childhood vascular risk factors: blood pressure, body mass index (BMI), and birth weight in young healthy adolescents.
MATERIALS AND METHODS Study Population The Singapore Cohort Study of Risk Factors for Myopia is a study of 1979 schoolchildren, aged 7 to 9 years at baseline, in Singapore. Details of the study population have been described elsewhere.22 In brief, 2913 children were initially recruited from 3 community-based schools with a participation rate of 67.9% (1979 participants) during 1999 to 2001. Children with medical conditions (n = 94), such as heart disorders, syndrome-associated myopia, or eye disorders, such as cataract, were excluded from the study. Retinal photography was performed for all the participants who returned for the follow-up examination in 2006. Of these, we excluded those with ungradable retinal photographs or incomplete anthropometry or blood pressure measurements, leaving 1225 participants for the current analyses. The Ethics Committee of the Singapore Eye Research Institute approved the study, and the conduct of the study followed the tenets of the Declaration of Helsinki. Written informed consent was obtained from all parents after the nature of the study was explained.
Retinal Photography and Retinal Vessel Caliber Measurements All participants were examined on the school premises by a team of ophthalmologists, optometrists, and research assistants at the 2006 visit. After pupil dilatation with cyclopentolate 1%, digital retinal photographs centered on the optic disc were taken of both eyes using standardized settings.22 Methods used to measure and summarize retinal vessel caliber from retinal photographs followed a previously validated standardized protocol.23,24 In brief, we used a computer-based program to measure the caliber of all retinal vessels coursing through the region half to 1 optic disc diameter away from the optic disc margin in the retinal images. Individual retinal vessel caliber measurements from an eye were summarized as an average index according to formulas described elsewhere.23,24 These indices, the central retinal arteriolar and venular equivalents, represented the average arteriolar and venular caliber of
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that eye. Trained graders, masked to participant identity and characteristics, performed all the retinal measurements. Retinal vessel caliber in the right eye was measured, and left eye measurements were performed when photographs of the right eye were ungradable. Remeasurement of 50 retinal images 2 weeks apart showed high reproducibility, with intraclass correlation coefficients of 0.853 for arteriolar caliber and 0.973 for venular caliber.
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were analyzed as either continuous (eg, per SD change) or categorical (eg, quartiles, weight status) variables. All models included adjustments for age, sex, ethnicity, axial length, spherical equivalent refraction, and other relevant factors. All statistical analyses were undertaken using SPSS version 12.0.1 (SPSS Inc, Chicago, Ill).
RESULTS
Assessment of Vascular Risk Factors We examined participants for 3 major childhood risk factors of cardiovascular disease: blood pressure levels, anthropometry measurements, and birth parameters. Blood pressure was measured in a seated position after 5 minutes of rest using an automated sphygmomanometer.25 The average of 3 separate measurements was used for analysis. Height and weight were measured, with participants standing and without shoes, on the school premises in adherence to a standardized protocol.26 Body mass index was calculated as the weight divided by the square of the height (kg/m2). Childhood obesity was defined according to ageand sex-specific BMI cutoff points.27 Birth history, including birth weight, birth length, head circumference, and gestational age, was obtained from a health booklet completed by medical personnel soon after birth.
Collection of Other Information The parents completed a number of questionnaires, written in English or Chinese, at the baseline visit. Questions have covered topics including demographic information, parental smoking status, and indicators of socioeconomic status, such as parental education level. Measurements of cycloplegic spherical equivalent refraction and ocular biometric parameters have been described elsewhere.22
Statistical Analysis We initially compared characteristics of adolescents in different ethnic groups. Results were reported as means or proportions with differences tested using analysis of variance or W2 test, respectively. Analyses of covariance and linear regression models were used to determine the associations of vascular risk factors with retinal arteriolar and venular calibers. The vascular risk factors
Table 1 shows the characteristics of our study population. The mean age of the participants was 11.9 years, and 60.5% were males. Chinese adolescents had slightly lower BMI; higher birth weight, blood pressure levels, axial length, and myopic refraction; and narrower arteriolar and venular calibers compared with other ethnic groups. In this population, the mean (SD) retinal arteriolar caliber was 149.3 (12.3) Km, and venular caliber was 224.6 (17.8) Km. Table 2 shows that, after adjusting for age, sex, ethnicity, axial length, spherical equivalent refraction, birth weight, and BMI, increasing quartiles of systolic, diastolic, and mean arterial blood pressure were associated with narrower retinal arteriolar caliber (P for trend G0.001). Each SD increase in systolic or diastolic blood pressure was associated with a 1.61-Km narrower retinal arteriolar caliber (P G 0.001). Blood pressure levels were not significantly associated with retinal venular caliber. Table 3 shows that, after adjusting for age, sex, ethnicity, axial length, spherical equivalent refraction, birth weight, and mean arterial blood pressure, increasing quartiles of BMI and weight were associated with narrower retinal arteriolar caliber (P for trend G0.001 for BMI and 0.012 for weight) and wider retinal venular caliber (P for trend G0.001). Each SD increase in BMI was associated with a mean 1.49-Km narrower retinal arteriolar caliber (P G 0.001) and 2.68-Km wider retinal venular caliber (P G 0.001). Obese adolescents on average had 4.0-Km narrower retinal arteriolar caliber and 7.6-Km wider retinal venular caliber (P G 0.001) compared with adolescents of normal weight. Table 4 shows that, after adjusting for age, sex, ethnicity, axial length, spherical equivalent refraction, BMI, and mean arterial blood pressure, lower birth weight was associated with
TABLE 1. Characteristics of the Study Population
Characteristic
Total (n = 1225)
Chinese (n = 871)
Malay (n = 256)
Indian (n = 84)
Mean
SD
Mean
SD
Mean
SD
Mean
SD
P*
49.4 1.0 12.9 9.5 4.0 1.8 481.8 13.9 8.8 15.6 11.4 1.2 3.6 12.3 17.8
438 11.9 49.7 159.3 19.4 38.6 3175.7 111.0 63.9 84.0 91.9 24.5 j2.3 148.4 222.3
50.3 1.0 11.9 9.4 3.8 1.7 454.2 13.8 8.8 15.4 11.4 1.2 3.6 12.0 16.9
121 12.0 51.0 158.3 20.1 38.4 3153.2 110.8 65.2 83.9 93.2 23.9 j0.5 151.8 232.2
47.3 1.0 14.5 10.0 4.4 2.1 549.1 14.1 8.6 16.0 11.6 1.1 2.9 12.4 19.1
38.0 12.1 52.6 158.7 20.6 38.2 2991.3 104.8 62.4 80.2 89.1 23.8 j1.1 151.1 226.0
45.2 1.1 16.4 8.8 5.4 2.2 505.7 13.4 9.5 16.2 11.9 1.1 3.1 13.6 16.9
0.640 0.110 0.093 0.055 0.029 0.315 0.015 0.002 0.094 0.118 0.055 0.000 0.000 0.001 0.000
Sex, male 605 Age, y 11.9 Weight, kg 50.2 Height, cm 159.1 BMI, kg/m2 19.7 Gestational age, wk 38.5 Birth weight, g 3157.7 Systolic blood pressure, mm Hg 110.6 Diastolic blood pressure, mm Hg 64.1 Pulse pressure, mm Hg 83.7 Mean arterial blood pressure, mm Hg 92.0 Axial length, mm 24.3 Spherical equivalent refraction, diopter j1.8 Retinal arteriolar caliber, Km 149.3 Retinal venular caliber, Km 224.6
Data are presented as numbers and proportions or means and SDs. *P value based on W2 (categorical) and independent-samples t test (continuous).
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Vascular Risk Factors and Retinal Vessel Caliber
TABLE 2. Relationship Between Blood Pressure and Retinal Vessel Caliber Arteriolar Caliber, Km Systolic blood pressure, mm Hg 1st Quartile, G101 2nd Quartile, 101Y110 3rd Quartile, 111Y120 4th Quartile, Q120 Per SD increase Diastolic blood pressure, mm Hg 1st Quartile, G58 2nd Quartile, 58Y63 3rd Quartile, 64Y70 4th Quartile, Q70 Per SD increase
n
Mean (95% CI)*
301 306 305 293
151.5 (148.7Y154.4) 150.3 (147.4Y153.1) 149.0 (146.2Y151.8) 148.0 (145.1Y150.9) j1.61 (j2.30 to j0.93)
309 283 305 308
151.2 (148.4Y154.1) 150.6 (147.8Y152.0) 149.2 (146.5Y152.0) 147.3 (144.4Y150.2) j1.61 (j2.23 to j0.99)
Venular Caliber, Km P
Mean (95% CI)*
P
G0.001† G0.001
222.1 (218.1Y226.2) 222.0 (218.0Y226.0) 220.3 (216.4Y224.2) 221.3 (217.2Y225.5) j0.39 (j1.37 to 0.58)
0.358† 0.429
G0.001† G0.001
221.1 (217.1Y225.1) 220.3 (216.3Y224.3) 221.7 (217.8Y225.6) 222.3 (218.2Y226.4) 0.49 (j0.40 to 1.38)
0.208† 0.279
*Mean (or mean difference) adjusted for age, sex, ethnicity, axial length, spherical equivalent refraction, birth weight and BMI, and arteriolar caliber. †P for trend across quartiles. CI indicates confidence interval.
narrower retinal arteriolar caliber (P for trend G0.001 across categories and a mean 1.31-Km narrower retinal arteriolar caliber for each SD decrease in birth weight). Birth weight was not associated with retinal venular caliber. Gestational status and other birth parameters (birth length, head circumference; data not shown) were not significantly associated with either retinal arteriolar or venular caliber.
DISCUSSION Advances in retinal image analysis have allowed reliable and precise measurement of retinal vessel caliber from retinal photographs. Using this approach, studies of middle-aged and elderly populations have associated narrowed retinal arteriolar caliber and widened retinal venular caliber with risk of ocular1Y5,7Y12 and systemic vascular diseases.13Y19 Our current study extends
from our previous pilot study28 and represents one of the few studies that have examined retinal vessel caliber in young adolescents. Our data have shown that narrower retinal arterioles are associated with elevated blood pressure, obesity, and low birth weight, whereas wider retinal venules are associated with only measures of obesity. Our findings are supported by the Sydney Childhood Eye Study of predominantly white 6-year-old children in Australia, and the Strabismus, Amblyopia and Refractive Error Study of a much smaller sample of Singaporean Chinese preschoolers.25,29Y31 In these studies, higher blood pressure was significantly and monotonically associated with retinal arteriolar narrowing, a vascular feature associated with glaucoma7Y9 and predictive of systemic hypertension and diabetes in middle-aged and older populations.32,33 Higher BMI has similarly been reported to be associated with not only retinal arteriolar narrowing,29 but also
TABLE 3. Relationship Between Obesity Measures and Retinal Vessel Caliber Arteriolar Caliber, Km BMI, kg/m2 1st Quartile, G16.9 2nd Quartile, 16.9Y18.9 3rd Quartile, 19.0Y21.7 4th Quartile, 921.7 Per SD increase Weight status‡ Normal Overweight Obese
n
Mean (95% CI)*
300 302 301 302
150.8 (148.0Y153.6) 150.4 (147.6Y153.2) 150.4 (147.6Y153.2) 147.2 (144.4Y150.0) j1.49 (j2.10 to j0.87)
882 223 97
150.6 (147.9Y153.2) 147.6 (144.7Y150.5) 146.6 (143.3Y149.8)
Venular Caliber, Km P
Mean (95% CI)*
P
G0.001† G0.001
219.5 (215.5Y223.5) 219.7 (215.7Y223.7) 220.7 (216.7Y224.7) 225.4 (221.4Y229.4) 2.68 (1.81Y3.54)
G0.001† G0.001
G0.001†
220.0 (216.3Y223.8) 223.6 (219.5Y227.7) 227.6 (222.9Y232.2)
G0.001†
*Mean (or mean difference) adjusted for age, sex, ethnicity, axial length, spherical equivalent refraction, birth weight, and mean arterial blood pressure. †P for trend across quartiles. ‡Defined in methods. CI indicates confidence interval.
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TABLE 4. Relationship Between Birth Factors and Retinal Vessel Caliber Arteriolar Caliber, Km Birth weight, g G2500 2500Y3000 3001Y3500 3501Y4000 Per SD decrease Gestational age, wk Very preterm, G32 Preterm, 32Y37 Term, 937 Per week decrease
n
Mean (95% CI)*
78 248 393 151
147.6 (143.7Y151.5) 148.5 (145.2Y151.8) 150.2 (147.0Y153.4) 150.7 (147.2Y154.2) j1.31 (j2.06 to j0.56)
16 147 707
146.3 (140.5Y152.0) 149.0 (145.5Y152.4) 149.8 (146.6Y152.9) j0.65 (j1.31 to 0.01)
Venular Caliber, Km P
Mean (95% CI)*
P
0.021† 0.001
224.1 (218.7Y229.5) 223.4 (218.8Y228.1) 221.2 (216.8Y225.7) 222.2 (217.3Y227.0) 0.69 (j0.36 to 1.74)
0.244† 0.197
0.166† 0.052
227.8 (219.8Y235.9) 223.1 (218.3Y227.9) 221.9 (217.6Y226.3) 0.64 (j0.28 to 1.56)
0.091† 0.171
*Mean (or mean difference) adjusted for age, sex, ethnicity, axial length, spherical equivalent refraction, BMI, mean arterial blood pressure, and gestational age (or birth weight). †P for trend across categories. CI indicates confidence interval.
retinal venular widening,26,29 a vascular feature associated with diabetic retinopathy1Y6 and predictive of obesity and cardiovascular mortality in adults.17Y19,34 Furthermore, although we observed no significant associations between birth factors and retinal vessel caliber in our previous smaller pilot study,28 subsequent studies have linked impaired fetal growth, reflected as low birth weight or other indices of small birth size (eg, birth length, head circumference), with retinal arteriolar narrowing in young children and middle-aged adults without clinical cardiovascular disease.35Y37 The lack of significant association in our smaller pilot study could be related to power concerns as we examined only a subset (50%) of the Singapore Cohort Study of Risk Factors for Myopia cohort at that visit. In the current study with a larger sample, we found that retinal arteriolar narrowing is indeed associated with lower birth weight. It is also interesting to note that we did not find any significant associations of retinal vessel caliber with birth parameters other than birth weight. This pattern is consistent with the fact that placental insufficiency, a major cause of fetal growth restriction, is known to affect birth weight more markedly than other birth parameters.38 Although our findings may support the long-standing theory that cardiovascular disease has an etiologic origin in early life,39 the exact pathophysiological mechanisms remain to be determined. Hypoxia, inflammation, and endothelial dysfunction have all been implicated in the pathogenesis of retinal arteriolar narrowing and retinal venular dilatation.40 Therefore, it is plausible that our findings might reflect these pathological processes taking place in early microvascular disease. On the contrary, it is also possible that our findings could be a result of normal physiological adaptive response of the microcirculatory system to the examined vascular risk factors. Strengths of our study include its large sample of adolescents, standardized assessment of vascular risk factors and birth factors, and the use of computer-based measurement of retinal vessel caliber according to a validated standardized protocol. Potential limitations should also be noted. First, the crosssectional design of our study limited causal inference for the observed associations. Second, our study was not designed to determine whether the retinal vessel caliber changes in adoles-
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cents with vascular risk factors predict a higher risk of cardiovascular events later in life. Nevertheless, our findings highlight this important area for future research that would require longterm follow-up of this or other cohorts. Third, residual confounding from measured and unmeasured factors could have influenced our results. This is less likely given our sample of generally healthy adolescents without clinical cardiovascular or eye diseases that are known to be associated with vascular risk factors and retinal vessel caliber. Finally, camera and ocular magnification effects might be an inherent potential source of measurement errors for retinal vessel caliber. Nonetheless, our findings are unlikely due to such random errors, which would more likely bias the results to the null. In summary, our data show that 3 common childhood vascular risk factors, elevated blood pressure, obesity, and low birth weight, are associated with retinal arteriolar narrowing and venular widening. These findings suggest that adverse microvascular effects of vascular risk factors may manifest early in life. Furthermore, our data may offer new insights into the genesis of microangiopathy associated with ocular (eg, diabetic retinopathy, glaucoma) and systemic (eg, hypertension) diseases in older people. REFERENCES 1. Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet. 2010; 376:124Y136. 2. Cheung N, Rogers SL, Donaghue KC, et al. Retinal arteriolar dilation predicts retinopathy in adolescents with type 1 diabetes. Diabetes Care. 2008:31:1842Y1846. 3. Rogers S, Tikellis G, Cheung N, et al. Retinal arteriolar caliber predicts incident retinopathy: the Australia Diabetes, Obesity and Lifestyle (AusDiab) Study. Diabetes Care. 2008;31:761Y763. 4. Cheung N, Wong TY. Predicting risk of diabetic retinopathy from retinal vessel analysis: personalized medicine in transition. Arch Ophthalmol. 2012;130:783Y784. 5. Tsai AS, Wong TY, Lavanya R, et al. Differential association of retinal arteriolar and venular caliber with diabetes and retinopathy. Diabetes Res Clin Pract. 2011;94:291Y298.
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6. Klein R, Myers CE, Lee KE, et al. Changes in retinal vessel diameter and incidence and progression of diabetic retinopathy. Arch Ophthalmol. 2012;130:749Y755. 7. Amerasinghe N, Aung T, Cheung N, et al. Evidence of retinal vascular narrowing in glaucomatous eyes in an Asian population. Invest Ophthalmol Vis Sci. 2008;49:5397Y5402. 8. Zheng Y, Cheung N, Aung T, et al. Relationship of retinal vascular caliber with retinal nerve fiber layer thickness: the Singapore Malay Eye Study. Invest Ophthalmol Vis Sci. 2009;50:4091Y4096. 9. Mitchell P, Leung H, Wang JJ, et al. Retinal vessel diameter and open-angle glaucoma: the Blue Mountains Eye Study. Ophthalmology. 2005;112:245Y250. 10. Youm DJ, Ha MM, Chang Y, et al. Retinal vessel caliber and risk factors for branch retinal vein occlusion. Curr Eye Res. 2012;37:334Y338. 11. Li LJ, Cheung CY, Gazzard G, et al. Relationship of ocular biometry and retinal vascular caliber in preschoolers. Invest Ophthalmol Vis Sci. 2011;52:9561Y9566. 12. Yang K, Zhan SY, Liang YB, et al. Association of dilated retinal arteriolar caliber with early age-related macular degeneration: the Handan Eye Study. Graefes Arch Clin Exp Ophthalmol. 2012;250:741Y749. 13. Cheung N, Bluemke DA, Klein R, et al. Retinal arteriolar narrowing and left ventricular remodeling: the multi-ethnic study of atherosclerosis. J Am Coll Cardiol. 2007;50:48Y55. 14. Cheung N, Islam AFM, Jacobs DR, et al. Arterial compliance and retinal vascular caliber in cerebrovascular disease. Ann Neurol. 2007;62: 618Y624. 15. Cheung N, Sharret AR, Klein R, et al. Aortic distensibility and retinal arteriolar narrowing: the Multi-ethnic Study of Atherosclerosis. Hypertension. 2007;50:617Y622. 16. Cheung CY, Tay WT, Mitchell P, et al. Quantitative and qualitative retinal microvascular characteristics and blood pressure. J Hypertens. 2011;29:1380Y1391. 17. McGeechan K, Liew G, Macaskill P, et al. Prediction of incident stroke events based on retinal vessel caliber: a systematic review and individual-participant meta-analysis. Am J Epidemiol. 2009;170: 1323Y1332. 18. McGeechan K, Liew G, Macaskill P, et al. Meta-analysis: retinal vessel caliber and risk for coronary heart disease. Ann Intern Med. 2009;151:404Y413. 19. Cheung N, Wong TY. Diabetic retinopathy and systemic vascular complications. Prog Retin Eye Res. 2008;27:161Y176. 20. Papadopoulou DN, Mendrinos E, Mangioris G, et al. Intravitreal ranibizumab may induce retinal arteriolar vasoconstriction in patients with neovascular age-related macular degeneration. Ophthalmology. 2009;116:1755Y1761. 21. Wickremasinghe SS, Busija L, Guymer RH, et al. Retinal venular caliber predicts visual outcome after intravitreal ranibizumab injection treatments for neovascular AMD. Invest Ophthalmol Vis Sci. 2012;53:37Y41. 22. Saw SM, Chua WH, Hong CY, et al. Nearwork in early-onset myopia. Invest Ophthalmol Vis Sci. 2002;43:332Y339.
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23. Hubbard LD, Brothers RJ, King WN, et al. Methods for evaluation of retinal microvascular abnormalities associated with hypertension/ sclerosis in the Atherosclerosis Risk in Communities Study. Ophthalmology. 1999;106:2269Y2280. 24. Wong TY, Knudtson MD, Klein R, et al. Computer-assisted measurement of retinal vessel diameters in the Beaver Dam Eye Study: methodology, correlation between eyes, and effect of refractive errors. Ophthalmology. 2004;111:1183Y1190. 25. Mitchell P, Cheung N, de Haseth K, et al. Blood pressure and retinal arteriolar narrowing in children. Hypertension. 2007;49: 1156Y1162. 26. Cheung N, Saw SM, Islam FM, et al. BMI and retinal vascular caliber in children. Obesity (Silver Spring). 2007;15:209Y215. 27. Cole TJ, Bellizzi MC, Flegal KM, et al. Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ. 2000;320:1240Y1243. 28. Cheung N, Islam FM, Saw SM, et al. Distribution and associations of retinal vascular caliber with ethnicity, gender, and birth parameters in young children. Invest Ophthalmol Vis Sci. 2007;48:1018Y1024. 29. Taylor B, Rochtchina E, Wang JJ, et al. Body mass index and its effects on retinal vessel diameter in 6-year-old children. Int J Obes (Lond). 2007;31:1527Y1533. 30. Li LJ, Cheung CY, Chia A, et al. The relationship of body fatness indices and retinal vascular caliber in children. Int J Pediatr Obes. 2011;6: 267Y274. 31. Li LJ, Cheung CY, Liu Y, et al. Influence of blood pressure on retinal vascular caliber in young children. Ophthalmology. 2011;118: 1459Y1465. 32. Wong TY, Klein R, Sharrett AR, et al. Retinal arteriolar narrowing and risk of diabetes mellitus in middle-aged persons. JAMA. 2002; 287:2528Y2533. 33. Wong TY, Shankar A, Klein R, et al. Prospective cohort study of retinal vessel diameters and risk of hypertension. BMJ. 2004;329:79. 34. Wang JJ, Taylor B, Wong TY, et al. Retinal vessel diameters and obesity: a population-based study in older persons. Obesity. 2006;14: 206Y214. 35. Mitchell P, Liew G, Rochtchina E, et al. Evidence of arteriolar narrowing in low-birth-weight children. Circulation. 2008;118:518Y524. 36. Liew G, Wang JJ, Duncan BB, et al. Low birthweight is associated with narrower arterioles in adults. Hypertension. 2008;51:933Y938. 37. Sun C, Ponsonby AL, Wong TY, et al. Effect of birth parameters on retinal vascular caliber. The Twins Eye Study in Tasmania. Hypertension. 2009;53:487Y493. 38. Cheung N. Birth factors and retinal vascular caliber in a twin study. Hypertension. 2009;53:e28. 39. Ingelfinger JR. Pediatric antecedents of adult cardiovascular diseaseVawareness and intervention. N Engl J Med. 2004;350: 2123Y2126. 40. Nguyen TT, Wang JJ, Wong TY. Retinal vascular changes in pre-diabetes and pre-hypertensionVnew findings and their research and clinical implications. Diabetes Care. 2007;30:2708Y2715.
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