Association between blood pressure and retinal arteriolar and venular diameters in Chinese early adolescent children, and whether the association has gender difference: a cross-sectional study

Association between blood pressure and retinal arteriolar and venular diameters in Chinese early... Background: To establish the independent association between blood pressure (BP) and retinal vascular caliber, especially the retinal venular caliber, in a population of 12-year-old Chinese children. Methods: We have examined 1501 students in the 7th grade with mean age of 12.7 years. A non-mydriatic fundus camera (Canon CR-2, Tokyo, Japan) was used to capture 45 fundus images of the right eyes. Retinal vascular caliber was measured using a computer-based program (IVAN). BP was measured using an automated sphygmomanometer (HEM-907, Omron, Kyoto, Japan). Results: The mean retinal arteriolar caliber was 145.3 μm (95% confidence interval [CI], 110.6–189.6 μm) and the mean venular caliber was 212.7 μm (95% CI, 170.6–271.3 μm). After controlling for age, sex, axial length, BMI, waist, spherical equivalent, birth weight, gestational age and fellow retinal vessel caliber, children in the highest quartile of BP had significantly narrower retinal arteriolar caliber than those with lower quartiles (P for trend< 0.05). Each 10-mmHg increase in BP was associated with narrowing of the retinal arterioles by 3.00 μm(multivariable-adjusted P < 0.001), and the results were consist in three BP measurements. The association between BP measures and retinal venular caliber did not persist after adjusting for fellow arteriolar caliber. And there was no significant interaction between BP and sex, age, BMI, and birth status. Conclusions: In a large population of adolescent Chinese children, higher BP was found to be associated with narrower retinal arterioles, but not with retinal venules. Sex and other confounding factors had no effect on the relationship of BP and retinal vessel diameter. Keywords: Hypertension, Adolescents, Retinal arteriolar diameter, Retinal venular diameter, Blood pressure * Correspondence: xiaowwnnll@163.com Beijing Tongren Eye Center, Beijing Tongren Hospital, Beijing Ophthalmology & Visual Science Key Lab, Beijing Institute of Ophthalmology, Capital Medical University, Beijing, China Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. He et al. BMC Ophthalmology (2018) 18:133 Page 2 of 12 Background Methods Major component of the circulatory system is composed Study population of the microcirculation, which plays an important role in The Anyang Childhood Eye Study (ACES) is a maintaining cardiovascular health. There is a widespread school-based cohort study designed to observe the oc- influence of blood pressure (BP) on the structure and currence and development of myopia as well as other function of microcirculation system. Early in the late diseases in school children living in Anyang urban area, nineteenth century, Marcus Gunn had put forward the Henan Province, Central China. Detailed methodology statement that there were associations between micro- of the study has been previously described [12]. In vascular abnormalities and cardiovascular diseases [1]. briefly, 1501 students in 7th grade average aged The retina is a unique structure of the eyes, where the 12.7 years have been examined from October 2011 to in vivo microcirculation can be directly visualized and December 2011. The flowchart of participants included monitored non-invasively. Retinal microcirculation in the present study was shown in Fig. 1. Ethics approval shares the same anatomic architecture and physiological was obtained from the institutional review board of feature with other terminal organs elsewhere in the body Beijing Tongren Hospital, Capital Medical University, [2]. These characteristics increase its utility as a tool to and followed the tenets of the declaration of Helsinki. study the clinical performance of microvascular diseases. Informed written consent was obtained from at least Recently, with the improvement of retinal imaging par- one parent. Verbal assent was obtained from each child. ticularly the computer-assistant analysis techniques from digital retinal images [3], plenty of epidemiological stud- Retinal photography and measurement of retinal vascular ies in adult populations have displayed that abnormal caliber changes in retinal vascular caliber (predominantly retinal The children were examined at health examination sta- arteriolar and venular caliber) are closely associated with tion of the Anyang Eye Hosptial. A non-mydriatic fun- some systemic vascular abnormalities such as cardiovas- dus camera (Canon CR-2, Tokyo, Japan) was used to cular risk factors [4], hypertension [5], coronary heart capture 45 fundus images centering on optic disc and disease [6], risk of diabetes and stroke [7], cerebral in- macular area of children’s right eyes by a well-trained farcts and white matter lesions [8], and renal disease [9], operator [12]. Children with abnormal fundus images independent of other risk factors. would also undergo left eye measurements, and we ana- Despite increasing data on the risk prediction of ret- lyzed one picture for each child. inal vascular caliber measurement in different According to a standardized protocol described previ- population-based studies, there had been still some con- ously [3], the computer-imaging program (IVAN, Uni- troversial opinions on association between retinal vascu- versity of Wisconsin, Madison, WI) was used to measure lar changes and BP, especially for the retinal venular calibers of all retinal arterioles and venules located in changes. Understanding the impacts of BP and changes zone 0.5 to 1 disc diameter from the optic disc margin to the retinal microvasculature in persons with different (zone B). The program automatically combined vessel background is an important aspect of the study on diameters from the six largest arterioles and six largest microcirculation disease. Children are generally free of venules into a pair of indices. The central retinal arteri- many systemic conditions and eye diseases (such as olar and venular equivalents (CRAE and CRVE) repre- glaucoma or diabetic retinopathy, etc.) that could bring sent the average arteriolar and venular caliber for each about confounding effects on observed associations. eye, respectively. One grader masked to children’s iden- High BP in children and adolescents is more and more tity and characteristics performed all measurements. Be- common in western countries [10], and BP levels and fore starting the measurement, 50 randomly selected prevalence of hypertension has increased dramatically retinal images were repeatedly measured by the grader among children and adolescents in China [11]. It is en- with an interval of 2 weeks. The reliability was high with couraging that there are some studies on the association intraclass correlation coefficients of 0.85 for arteriolar of BP and retinal vessel caliber in children recently, but caliber and 0.97 for venular caliber. substantial data on children group are still needed to provide the reference data. Blood pressure measurement In this study, we investigated the independent associ- Blood pressure of children was measured in a seated ation between blood pressure measures and changes to position after 5 min of rest using an automated sphyg- the retinal microvasculature in a relatively large popula- momanometer (HEM-907, Omron, Kyoto, Japan) with tion of 12-year-old Chinese children. This study also appropriate cuff size (bladder length ≈80% and width at assessed the potential modifying influences of age, BMI, least 40% of the arm circumference, covering the upper birth parameters, especially sex, on the associations be- arm but not obscuring the antecubital fossa). Systolic tween BP and retinal vessel caliber. and diastolic blood pressure (SBP and DBP, respectively) He et al. BMC Ophthalmology (2018) 18:133 Page 3 of 12 Fig. 1 The flowchart of participants included in the present study readings were taken. Two readings were taken 5 min quartiles as well as being analyzed as a continuous vari- apart and averaged for analysis. Mean arterial blood able (i.e. each 10 mmHg increase). The retinal arteriolar, pressure (MABP) was computed as 2/3 of the diastolic venular calibers, and arteriolar to venular ratio (AVR) plus 1/3 of the systolic value. were compared across blood pressure quartiles based on three models, Model 1 was analyzed without any adjust- Other measurements ment, Model 2 adjusted for multivariate variables (age, Any abnormality of anterior segment (any abnormalities sex, axial length, BMI, waist, spherical equivalent, birth of the anterior segment of the eye, such as corneal leu- weight, and gestational age) and then Model 3 adjusted koplakia, cataract, pupil abnormalities, iris anterior additionally for fellow retinal vessel diameter. The test of adhesion, etc.) was observed and recorded using a trend was determined by regarding quartiles of BP as slit-lamp (YZ5J, 66 Vision Tech Co, Suzhou, China). continuous ordinal variables. Multiple linear regressions Cycloplegic spherical equivalent refraction was measured were used to estimate the absolute changes in retinal using an autorefractor (HRK7000 A, Huvitz, Gunpo, arteriolar and venular caliber for a 10-mmHg increase in South Korea) with three readings taken and averaged. SBP, DBP, and MABP. Potential modifiers were exam- An optical coherence biometry (IOL-master 1322–734, ined in stratified analyses of age, sex, BMI, and birth Carl Zeiss Meditec AG, Jena, Germany) was applied to parameters. All probabilities quoted are two-sided, and a evaluate the optical axial length (AL) value along the vis- significant P value was defined as < 0.05. ual axis (line connecting the fixation point to the fovea, specifically from the anterior surface of the cornea to Results the retinal pigment epithelium layer of the fovea), with Table 1 shows the study characteristics of the children five repeated measurements taken and averaged. Height included for crosss-sectional analyses. Compared with and weight were measured using an automatic and pro- boys, girls had higher systolic and mean arterial blood fessional integrated set. Body mass index (BMI) was pressure, higher waist and BMI, and had less myopia 2 2 calculated as weight/height (kg/m ). Waist circumfer- and longer axial length. ence was measured with a tape measure and was defined Table 2 shows the mean retinal vascular caliber and as the narrowest part of the student’s trunk. Birth infor- AVR by quartiles of systolic, diastolic and mean arterial mation including gestational weeks, birth weight and blood pressure in three different models. Children with birth length were collected by administrating question- highest quartile of BP were more likely to have narrower naires to the participating students’ parents. retinal arteriolar caliber than those in the lowest quartile after multivariable-adjustment (all P < 0.01), with a mean Statistical analysis difference of 6–7 μm between the highest and lowest SAS (v9.3, SAS Institute Inc., Cary, NC, USA) was used quartiles, and the results were consistent for three BP to perform statistical analysis. BP was categorized into measurements. As for retinal venular diameter, in Model He et al. BMC Ophthalmology (2018) 18:133 Page 4 of 12 Table 1 Basic characteristics of the children included in the study Characteristics Male Female P (n = 792) (n = 709) Age (year) 12.66 (0.50) 12.73 (0.49) 0.004 Spherical equivalent refraction (diopters) −1.78 (2.08) − 1.32 (2.02) < 0.001 Axial length (mm) 23.93 (1.01) 24.35 (1.09) < 0.001 Systolic blood pressure (mm Hg) 104.55 (10.87) 107.36 (10.35) < 0.001 Diastolic blood pressure (mm Hg) 65.35 (7.57) 65.45 (7.21) 0.758 Mean arterial blood pressure (mm Hg) 78.42 (8.23) 79.41 (7.63) 0.005 BMI (kg/m ) 19.32 (3.22) 20.28 (3.91) < 0.001 Waist (cm) 69.04 (7.84) 71.92 (10.14) < 0.001 Data are mean (SD). BMI body mass index; Significant p values are bolded. Significant p values are bolded 1, children with higher BP had significantly narrower each 10-mmHg increase in BP resulted in 2.03–2.68 μm CRVE (P < 0.001 for trend for three BP measurements), (P < 0.05) decrease for boys and 2.15–2.76 μm(P < 0.05) and in Model 2, only children with higher SBP were decrease for girls in model 2, but when CRAE was found to have narrower CRVE than those with lower additionally adjusted in model 2, there is no signifi- SBP (P = 0.038 for trend), however, this association did cant association between BP and CRVE in either boys not persist after adjusting for fellow vessel caliber. In nor girls, which was consistent in three BP measure- Model 1 and Model 2, children with higher BP quartiles ments (Table 5). had consistently and significantly narrower AVR (P < 0.001 for trend), and the results were consistent for Discussion three BP measurements. In this population of 12-year-old Chinese children, we Table 3 shows the multivariable linear regression be- found that increasing blood pressure was significantly tween retinal vascular caliber and BP. In model 1 and associated with narrowing retinal arteriolar caliber and model 2, for each 10-mmHg increase in SBP, DBP and smaller AVR, but not with retinal venular caliber. After MABP, CRAE decreased by 3.07–4.40 μm(P < 0.001) controlling for age, gender, axial length, BMI, waist, and CRVE decreased by 1.47–2.69 μm(P < 0.001). In spherical equivalent, birth parameters and fellow retinal model 3 adjusted for fellow vessel caliber additionally, vessel, each 10-mmHg increase in BP was associated each 10-mmHg increase in BP was associated with 2.34– with an approximate 3~ 4 μm reduction in CRAE, and 3.47 μm decrease in retinal arteriolar caliber (P < 0.001), the changes were consistent of three BP measurements. but no significant change in CRVE (p > 0.42) was ob- The similar pattern and magnitude of change were also served. AVR decreased by 0.010 to 0.014 for every found in the relationship of BP with CRVE prior of tak- 10-mmHg increase in BP in Model 1, Further adjust- ing confounding fellow arteriolar diameter into account, ment for age, gender, axial length, BMI, waist, spherical but after the fellow vessel were further adjusted, the equivalent, birth weight and gestational age had no im- change no longer had significant difference. And there pact on the magnitude of this effect (AVR reduction was no significant interaction between BP and age, sex, 0.007 to 0.012). BMI and birth status. Subgroup analysis stratified by potential effect modi- Both cross-sectional and longitudinal studies had fiers was presented in Tables 4, 5 and 6. Associations provided substantial evidence that there is significant were consistent across subgroups stratified by age, sex, association between elevated blood pressure or BMI, and birth parameters. hypertension and narrower central retinal arteriole It is worth noting that, there were no significant inter- caliber in adult populations [13–19]. However, there actions between sex, and BP on retinal vessel diameters. is conflicting evidence on retinal venular diameter as The impact of BP on the diameters of retinal vessels marker related to hypertension. Some studies [16, 18–22] showed no gender differences between boys and girls. In suggested that retinal venular widening may be independ- model 2, each 10-mmHg increase in BP was associated ently associated with risk of hypertension, others [15, 19, with 3.41–4.91 μm(P < 0.001) and 2.73–3.89 μm(P < 23–25] had found no association, whereas some other re- 0.001) decrease in CRAE for boys and girls respectively, searchers announced that both retinal venular and arteri- and in model 3, the decrease of CRAE reduced to 2.57– olar caliber were inversely related to blood pressure, 3.81 μm(P < 0.001) and 2.12–3.12 μm(P < 0.001) for independent of age, gender, and smoking [26]. boys and girls respectively (Table 4). And for CRVE, He et al. BMC Ophthalmology (2018) 18:133 Page 5 of 12 Table 2 Mean retinal arteriolar diameter, retinal venular diameter, and AVR (mean and standard error) stratified by SBP, DBP and MABP n Range Rentinal Arteriolar Diameter (μm) Rentinal Venular Diameter (μm) AVR (mm Hg) Model 1 Model 2 Model 3 Model 1 Model 2 Model 3 Model 1 Model 2 SBP First quartile 375 79 to 100 149.02 ± 1.31 148.70 ± 0.62 147.91 ± 0.56 214.54 ± 0.63 214.91 ± 0.79 212.96 ± 0.71 0.696 ± 0.004 0.688 ± 0.007 Second quartile 365 101 to 107 146.17 ± 0.62 146.19 ± 0.61 146.20 ± 0.54 213.16 ± 0.30 212.65 ± 0.77 212.12 ± 0.69 0.687 ± 0.002 0.685 ± 0.008 Third quartile 373 107 to 113 144.24 ± 0.54 144.22 ± 0.60 144.36 ± 0.54 212.23 ± 0.20 212.30 ± 0.76 212.89 ± 0.68 0.681 ± 0.002 0.683 ± 0.008 Fourth quartile 388 113 to 142 141.63 ± 1.36 141.99 ± 0.61 142.62 ± 0.55 210.97 ± 0.65 210.91 ± 0.78 212.76 ± 0.70 0.672 ± 0.004 0.680 ± 0.009 P for trend < 0.001 0.001 < 0.001 < 0.001 0.038 0.941 < 0.001 < 0.0001 DBP First quartile 323 49 to 61 147.96 ± 2.50 149.14 ± 0.65 148.15 ± 0.58 214.04 ± 1.21 215.49 ± 0.82 213.29 ± 0.75 0.692 ± 0.007 0.687 ± 0.007 Second quartile 407 61 to 65 145.95 ± 2.18 146.21 ± 0.57 146.19 ± 0.51 213.06 ± 1.05 212.73 ± 0.73 212.19 ± 0.65 0.686 ± 0.007 0.685 ± 0.008 Third quartile 360 66 to 70 144.49 ± 2.20 144.53 ± 0.61 144.92 ± 0.55 212.35 ± 1.06 211.60 ± 0.77 212.01 ± 0.69 0.682 ± 0.007 0.683 ± 0.008 Fourth quartile 411 70 to 90 142.99 ± 2.28 141.84 ± 0.58 142.31 ± 0.52 211.62 ± 1.10 211.36 ± 0.73 213.29 ± 0.66 0.677 ± 0.007 0.682 ± 0.010 P for trend < 0.001 0.005 0.009 < 0.001 0.078 0.970 < 0.001 < 0.0001 MABP First quartile 370 60 to 75 148.62 ± 1.80 149.31 ± 0.61 148.24 ± 0.55 214.36 ± 0.87 215.75 ± 0.78 213.47 ± 0.71 0.695 ± 0.005 0.687 ± 0.007 Second quartile 366 75 to 79 145.96 ± 1.55 145.81 ± 0.60 145.98 ± 0.54 213.07 ± 0.75 212.18 ± 0.77 211.87 ± 0.69 0.686 ± 0.005 0.685 ± 0.008 Third quartile 400 79 to 84 144.28 ± 1.59 144.36 ± 0.58 144.56 ± 0.52 212.25 ± 0.77 212.12 ± 0.73 212.62 ± 0.66 0.681 ± 0.005 0.683 ± 0.008 Fourth quartile 365 84 to 102 142.14 ± 1.84 141.50 ± 0.62 142.21 ± 0.56 211.22 ± 0.89 210.67 ± 0.79 212.78 ± 0.72 0.674 ± 0.005 0.680 ± 0.010 P for trend < 0.001 0.011 0.004 < 0.001 0.086 0.738 < 0.001 < 0.0001 Model 1:unadjusted model; Model 2: adjusted for age, gender, axial length, BMI, waist, spherical equivalent, birth weight and gestational age; Model 3: adjusted for fellow vessel diameter additionally. SBP systolic blood pressure, DBP diastolic blood pressure, MABP mean arterial blood pressure, AVR arteriolar to venular ratio. Significant p values are bolded He et al. BMC Ophthalmology (2018) 18:133 Page 6 of 12 Table 3 Multivariate Linear Regression Models of Retinal Vascular Caliber and Blood Pressure Retinal arteriolar diameter (μm) Retinal venular diameter (μm) AVR Mean (95%CI) P Mean (95%CI) P Mean (95%CI) P SBP Model 1 −3.23(− 3.96 to −2.52) < 0.001 −1.57(− 2.50 to − 0.63) < 0.001 −0.01 (− 0.013 to − 0.007) < 0.001 Model 2 − 3.07 (− 3.79 to − 2.34) < 0.001 − 2.06 (− 2.97 to − 1.15) < 0.001 − 0.007(− 0.010 to − 0.004) < 0.001 Model 3 −2.34 (− 3.00 to − 1.69) < 0.001 − 0.34 (− 1.18 to 0.50) 0.428 –– DBP Model 1 −3.85(− 4.88 to −2.82) < 0.001 − 1.47 (− 2.78 to − 0.15) < 0.001 −0.013 (− 0.017 to − 0.009) < 0.001 Model 2 − 4.02 (− 4.96 to − 3.08) < 0.001 − 2.34 (− 3.53 to − 1.15) < 0.001 − 0.011(− 0.015 to − 0.007) < 0.001 Model 3 −3.20 (− 4.05 to − 2.35) < 0.001 − 0.06 (− 1.16 to 1.03) 0.909 –– MABP Model 1 − 4.37(−5.35 to −3.39) < 0.001 − 1.84 (− 3.11 to − 0.56) < 0.001 −0.014 (− 0.019 to − 0.010) < 0.001 Model 2 − 4.40 (− 5.34 to − 3.47) < 0.001 −2.69 (− 3.88 to − 1.50) < 0.001 − 0.012(− 0.016 to − 0.007) < 0.001 Model 3 −3.47 (− 4.31 to − 2.62) < 0.001 −0.21 (− 1.31 to 0.89) 0.712 –– Model 1:unadjusted model; Model 2: adjusted for age, gender, axial length, BMI, waist, spherical equivalent, birth weight and gestational age; Model 3: adjusted for fellow vessel diameter additionally. SBP systolic blood pressure, DBP diastolic blood pressure, MABP mean arterial blood pressure, AVR arteriolar to venular ratio. Significant p values are bolded In addition, smaller retinal arteriolar caliber was also retinal venules, with each 10-mmHg increase associ- found to be associated with current alcohol consump- ated with 2.00 μm of retinal arteriolar narrowing and tion, greater body mass index and higher levels of total 2.51 μm of retina venular widening. In 2012, Hanssen homocysteine [20], incident clinical stroke, carotid ath- examined 578 school children aged 11.1 ± 0.6 years erosclerosis, incident heart disease and cardiovascular from secondary schools in Germany and found that mortality, as well as metabolic syndrome [13]. Larger diastolic blood pressure was not only independently venular calibers had been shown to be associated with associated with arteriolar narrowing, but also with atherosclerosis [27], inflammation [20–22, 27–30], venular narrowing [39]. Imhof found that systolic and stroke, cardiovascular mortality [13, 31], cigarette smok- diastolic BP were associated with arteriolar narrowing ing [20, 27, 32, 33], and the metabolic syndrome (hyper- in 391 Switzerland children with an average age of glycemia, central obesity, and dyslipidemia) [16, 34]. 7.3 years, but they failed to find the association be- These findings suggested that retinal venular widening tween BP and venular diameter [40]. may has pleiotropic associations with cardiovascular risk According to the results of the above studies, we factors and diseases, and was not a specific biomarker found that just like the roles of retinal venular diameter for hypertension [35]. play on the BP in adults, the relationship between retinal There have been some studies on relationship of blood venular diameter and BP in the childhood population is pressure with retinal vessel calibers in children. Mitchell still in controversy. [36] reported that higher childhood blood pressure was Unlike the SCES [37] (The subjects of this study were associated with retinal arteriolar narrowing but not with comparable in age to our research), we didn’t catch the retinal venular caliber in children aged 6–8 years. They finding that higher BP was associated with wider retinal found that each 10-mmHg increase in systolic blood venules in preadolescent boys. We speculated here that pressure was associated with narrowing of retinal arteri- there are some possible reasons contributing to the dis- oles by 2.08 μm in Sydney children and 1.43 μmin crepancy between the two results. Singapore children. In high school students aged First, at present, there were some epidemiological 12.7 years, they found that elevated blood pressure was studies on adolescent BP, but these studies had not associated with narrower retinal arterioles, and also with reached the uniform conclusion related to the gender wider retinal venules in boys, with each 10-mmHg in- difference. Some studies showed a higher frequency of crease in MABP associated with 2.02-mm decrease in elevated BP in males than in females in children popula- retinal arteriolar caliber, and 2.19 μm increase in CRVE tion based research [41], but these results differed from in boys (the Sydney Childhood Eye Study. SCES) [37]. In those obtained by Rosner B, whose study found that the a later study on Singapore children aged 4~ 5 years, Li prevalence of elevated BP significantly increased among et al. [38] found that higher systolic blood pressure was girls (8.2% versus 12.6%; P = 0.007), but was only of bor- associated with narrower retinal arterioles and wider derline significance among boys (15.8% versus 19.2%; P He et al. BMC Ophthalmology (2018) 18:133 Page 7 of 12 Table 4 Subgroup analysis stratified by potential effect modifiers of retinal Arteriolar Diameter with BP, stratified by potential modifiers Potential Effect Modifiers n Retinal Arteriolar Diameter (μm) Model 1 p Model 2 P Model 3 P SBP Age 10 + 11 70 −1.97 ± 1.66 0.238 −0.60 ± 1.79 0.736 −1.28 ± 1.54 0.411 12 1122 −3.63 ± 0.43 < 0.01 − 3.31 ± 0.42 <.001 − 2.46 ± 0.39 <.001 13 + 14 + 15 309 −2.6 ± 0.82 < 0.01 − 2.60 ± 0.84 0.002 −1.98 ± 0.73 0.007 Sex Male 792 −3.1 ± 0.52 < 0.01 − 3.41 ± 0.52 <.001 −2.57 ± 0.45 <.001 Female 709 −3.05 ± 0.52 < 0.01 − 2.73 ± 0.52 <.001 −2.12 ± 0.49 <.001 BMI Upper 50% 750 −2.37 ± 0.57 < 0.01 −2.39 ± 0.5 <.001 −1.72 ± 0.49 <.001 Lower 50% 751 −4.03 ± 0.55 < 0.01 −3.71 ± 0.52 <.001 −2.89 ± 0.46 <.001 Birth weight Upper 50% 778 −3.69 ± 0.53 < 0.01 −3.09 ± 0.53 <.001 −2.35 ± 0.48 <.001 Lower 50% 723 −2.87 ± 0.51 < 0.01 −2.97 ± 0.52 <.001 −2.28 ± 0.47 <.001 Gestational age Term 1372 −3.27 ± 0.39 < 0.01 − 3.10 ± 0.39 <.001 −2.33 ± 0.35 <.001 Preterm 129 −3.06 ± 1.09 < 0.01 −2.46 ± 1.12 0.03 −2.21 ± 1.02 0.033 DBP Age 10 + 11 70 −1.84 ± 2.04 0.370 −0.78 ± 2.18 0.722 − 1.81 ± 1.88 0.342 12 1122 −4.85 ± 0.62 < 0.01 −4.74 ± 0.56 <.001 −3.76 ± 0.51 <.001 13 + 14 + 15 309 −1.35 ± 1.11 < 0.01 −2.27 ± 1.08 0.037 −1.36 ± 0.95 0.154 Sex Male 792 −4.2 ± 0.74 < 0.01 − 4.65 ± 0.69 <.001 −3.67 ± 0.60 <.001 Female 709 −3.68 ± 0.72 < 0.01 −3.46 ± 0.67 <.001 −2.79 ± 0.62 <.001 BMI Upper 50% 750 −3.33 ± 0.75 < 0.01 −3.73 ± 0.68 <.001 −3.06 ± 0.62 <.001 Lower 50% 751 −4 ± 0.75 < 0.01 −4.30 ± 0.68 <.001 −3.34 ± 0.60 <.001 Birth weight Upper 50% 778 −3.83 ± 0.73 < 0.01 −3.73 ± 0.66 <.001 −3.01 ± 0.59 <.001 Lower 50% 723 −3.92 ± 0.75 < 0.01 −4.31 ± 0.70 <.001 −3.42 ± 0.64 <.001 Gestational age Term 1372 −3.89 ± 0.55 < 0.01 −3.95 ± 0.51 <.001 −3.10 ± 0.46 <.001 Preterm 129 −3.32 ± 1.57 < 0.01 −4.35 ± 1.50 0.005 −3.69 ± 1.39 0.009 MABP Age 10 + 11 70 −2.21 ± 2.03 0.280 −0.81 ± 2.17 0.709 −1.83 ± 1.88 0.334 12 1122 −5.22 ± 0.58 < 0.01 −5.01 ± 0.56 <.001 −3.91 ± 0.51 <.001 13 + 14 + 15 309 −2.41 ± 1.09 < 0.01 −3.00 ± 1.09 0.006 −2.04 ± 0.95 0.034 Sex Male 792 −4.40 ± 0.70 < 0.01 −4.91 ± 0.68 <.001 −3.81 ± 0.59 <.001 Female 709 −4.21 ± 0.70 < 0.01 −3.89 ± 0.68 <.001 −3.12 ± 0.64 <.001 BMI Upper 50% 750 −3.58 ± 0.75 < 0.01 −3.88 ± 0.68 <.001 −3.06 ± 0.63 <.001 Lower 50% 751 −4.90 ± 0.73 < 0.01 − 4.87 ± 0.68 <.001 −3.81 ± 0.60 <.001 Birth weight Upper 50% 778 −4.68 ± 0.71 < 0.01 −4.31 ± 0.68 <.001 −3.40 ± 0.61 <.001 Lower 50% 723 −4.11 ± 0.70 < 0.01 −4.42 ± 0.68 <.001 −3.49 ± 0.62 <.001 Gestational age Term 1372 −4.40 ± 0.53 < 0.01 −4.38 ± 0.51 <.001 −3.39 ± 0.46 <.001 Preterm 129 −3.98 ± 1.49 < 0.01 −4.23 ± 1.47 0.005 −3.66 ± 1.35 0.008 Model 1:unadjusted model; Model 2: adjusted for age, gender, axial length, BMI, waist, spherical equivalent, birth weight and gestational age; Model 3: adjusted for fellow vessel diameter additionally. SBP systolic blood pressure, DBP diastolic blood pressure, MABP mean arterial blood pressure. Term means pregnancy lasts longer than 37 weeks, and preterm represents that the duration of pregnancy is less than 37 weeks. Significant p values are bolded = 0.057), after analyzing a population-based sample of pressure. If the BP of two genders were basically similar, 3248 children in National Health and Nutrition Examin- the difference of the retinal venular caliber maybe asso- ation Survey (NHANES) III (1988–1994) and 8388 chil- ciated with other reasons. dren in continuous NHANES (1999–2008), aged 8 to Second, in the SCES, with regard to the mechanism 17 years [42]. The female subjects in our study were underlying the conclusion that higher blood pressure more frequently shown to have elevated BP compared to was associated with wider retinal venules in boys, the males. The SCES did not present whether there was a author deduced that maybe it was because sex hormones significant difference between girl and boy blood had an protective effect on the retinal circulation, as a He et al. BMC Ophthalmology (2018) 18:133 Page 8 of 12 Table 5 Subgroup analysis stratified by potential effect modifiers of retinal Venular Diameter with BP, stratified by potential modifiers Potential Effect Modifiers n Retinal Venular Diameter (μm) Model 1 p Model 2 P Model 3 P SBP Age 10 + 11 70 0.40 ± 2.16 0.855 1.43 ± 1.99 0.476 1.78 ± 1.71 0.302 12 1122 −2.1 ± 0.55 < 0.001 −2.52 ± 0.54 <.001 −0.73 ± 0.50 0.148 13 + 14 + 15 309 − 0.53 ± 1.08 0.622 −1.61 ± 1.06 0.129 0.02 ± 0.94 0.986 Sex Male 792 −1.12 ± 0.66 0.092 −2.03 ± 0.65 0.002 0.14 ± 0.57 0.809 Female 709 −1.72 ± 0.69 0.013 −2.15 ± 0.68 0.002 −0.85 ± 0.64 0.186 BMI Upper 50% 750 −1.66 ± 0.75 0.028 −2.11 ± 0.69 0.002 −0.84 ± 0.64 0.186 Lower 50% 751 −2.67 ± 0.69 < 0.001 −2.13 ± 0.64 0.001 0.06 ± 0.58 0.923 Birth weight Upper 50% 778 −1.97 ± 0.68 0.004 −2.05 ± 0.67 0.002 −0.27 ± 0.61 0.654 Lower 50% 723 −1.19 ± 0.67 0.074 −2.06 ± 0.66 0.002 −0.43 ± 0.61 0.478 Gestational age Term 1372 −1.61 ± 0.5 0.001 −2.19 ± 0.49 <.001 −0.46 ± 0.45 0.309 Preterm 129 −1.13 ± 1.55 0.467 −0.88 ± 1.64 0.594 0.62 ± 1.53 0.688 DBP Age 10 + 11 70 2.59 ± 2.64 0.330 2.16 ± 2.42 0.376 2.62 ± 2.08 0.213 12 1122 −2.42 ± 0.79 0.002 −2.91 ± 0.72 <.001 −0.31 ± 0.67 0.648 13 + 14 + 15 309 0.3 ± 1.45 0.838 −2.33 ± 1.36 0.089 −0.92 ± 1.20 0.442 Sex Male 792 −1.11 ± 0.94 0.239 −2.38 ± 0.86 0.006 0.60 ± 0.76 0.433 Female 709 −1.96 ± 0.96 0.042 −2.35 ± 0.86 0.007 −0.69 ± 0.82 0.4 BMI Upper 50% 750 −1.42 ± 0.99 0.151 −2.12 ± 0.89 0.017 −0.10 ± 0.82 0.907 Lower 50% 751 −2.11 ± 0.95 0.026 −2.46 ± 0.84 0.004 0.07 ± 0.76 0.93 Birth weight Upper 50% 778 −1.47 ± 0.93 0.112 −1.98 ± 0.84 0.018 0.18 ± 0.76 0.811 Lower 50% 723 −1.48 ± 0.98 0.132 −2.65 ± 0.90 0.003 −0.28 ± 0.83 0.733 Gestational age Term 1372 −1.59 ± 0.71 0.024 −2.37 ± 0.64 <.001 −0.15 ± 0.58 0.798 Preterm 129 −0.02 ± 2.2 0.994 −2.43 ± 2.23 0.278 0.18 ± 2.12 0.931 MABP Age 10 + 11 70 1.92 ± 2.65 0.469 2.13 ± 2.41 0.38 2.61 ± 2.07 0.213 12 1122 −2.75 ± 0.76 < 0.001 −3.32 ± 0.71 <.001 − 0.59 ± 0.67 0.38 13 + 14 + 15 309 − 0.12 ± 1.43 0.933 −2.48 ± 1.37 0.072 −0.62 ± 1.21 0.609 Sex Male 792 −1.34 ± 0.89 0.133 −2.68 ± 0.85 0.002 0.47 ± 0.75 0.535 Female 709 −2.25 ± 0.94 0.017 −2.76 ± 0.88 0.002 −0.90 ± 0.84 0.284 BMI Upper 50% 750 −1.89 ± 0.99 0.056 −2.63 ± 0.89 0.003 −0.55 ± 0.83 0.513 Lower 50% 751 −2.85 ± 0.93 0.002 −2.74 ± 0.83 0.001 0.13 ± 0.76 0.868 Birth weight Upper 50% 778 −2.13 ± 0.91 0.020 −2.52 ± 0.86 0.003 −0.02 ± 0.78 0.978 Lower 50% 723 −1.55 ± 0.92 0.093 −2.80 ± 0.87 0.001 −0.38 ± 0.81 0.643 Gestational age Term 1372 −1.94 ± 0.68 0.004 −2.78 ± 0.64 <.001 −0.33 ± 0.59 0.577 Preterm 129 −0.72 ± 2.13 0.736 −2.07 ± 2.18 0.345 0.49 ± 2.07 0.812 Model 1:unadjusted model; Model 2: adjusted for age, gender, axial length, BMI, waist, spherical equivalent, birth weight and gestational age; Model 3: adjusted for fellow vessel diameter additionally. SBP systolic blood pressure, DBP diastolic blood pressure, MABP mean arterial blood pressure. Term means pregnancy lasts longer than 37 weeks, and preterm represents that the duration of pregnancy is less than 37 weeks.Significant p values are bolded proportion of girls would have commenced puberty. But trials, the women’s health initiative (WHI) [44] and the it was interesting that Zou found that in 76,869 Chinese heart estrogen and progestin replacement study (HERS) girls, the rate of high blood pressure in menstruation [45], found an increase in cardiovascular incidences in group from 11 to 13 years was significant higher than women taking hormone replacement therapy. In some that in the same age group of non-menstruation [43]. adult population based studies, estrogen replacement Similarly, there was conflicting evidence that hormone therapy was found to be associated with narrower retinal treatment could effectively reduce the risk of coronary arteriolar and venular calibers [46], independent of heart disease, data from two large randomized clinical blood pressure and other vascular factors, but other He et al. BMC Ophthalmology (2018) 18:133 Page 9 of 12 Table 6 Subgroup analysis stratified by potential effect modifiers of AVR with BP, stratified by potential modifiers Potential Effect Modifiers n AVR Model 1 p Model 2 P SBP Age 10 + 11 70 −0.010 ± 0.006 0.118 −0.007 ± 0.007 0.37 12 1122 −0.010 ± 0.002 <.001 −0.007 ± 0.002 <.001 13 + 14 + 15 309 −0.010 ± 0.003 0.002 −0.007 ± 0.004 0.05 Sex Male 792 −0.010 ± 0.002 <.001 −0.009 ± 0.002 <.001 Female 709 −0.009 ± 0.006 <.001 −0.006 ± 0.002 0.02 BMI Upper 50% 750 −0.006 ± 0.002 0.020 −0.005 ± 0.002 0.06 Lower 50% 751 −0.010 ± 0.002 <.001 −0.010 ± 0.002 <.001 Birth weight Upper 50% 778 −0.010 ± 0.002 <.001 −0.007 ± 0.002 0.001 Lower 50% 723 −0.010 ± 0.002 <.001 −0.007 ± 0.002 0.002 Gestational age Term 1372 −0.010 ± 0.002 <.001 −0.007 ± 0.001 <.001 Preterm 129 −0.010 ± 0.004 0.035 −0.008 ± 0.007 0.015 DBP Age 10 + 11 70 −0.016 ± 0.008 0.046 −0.009 ± 0.009 0.314 12 1122 −0.015 ± 0.002 <.001 −0.013 ± 0.002 <.001 13 + 14 + 15 309 −0.007 ± 0.005 0.136 −0.003 ± 0.004 0.493 Sex Male 792 −0.016 ± 0.003 <.001 −0.014 ± 0.003 <.001 Female 709 −0.011 ± 0.006 0.003 −0.009 ± 0.003 0.009 BMI Upper 50% 750 −0.011 ± 0.003 <.001 −0.011 ± 0.003 <.001 Lower 50% 751 −0.012 ± 0.003 <.001 −0.012 ± 0.003 <.001 Birth weight Upper 50% 778 −0.013 ± 0.019 <.001 −0.011 ± 0.003 <.001 Lower 50% 723 −0.013 ± 0.003 <.001 −0.012 ± 0.003 <.001 Gestational age Term 1372 −0.013 ± 0.002 <.001 −0.011 ± 0.002 <.001 Preterm 129 −0.015 ± 0.007 0.03 −0.012 ± 0.007 0.137 MABP Age 10 + 11 70 −0.016 ± 0.008 0.048 −0.009 ± 0.009 0.302 12 1122 −0.015 ± 0.002 <.001 −0.013 ± 0.002 <.001 13 + 14 + 15 309 −0.010 ± 0.005 0.02 −0.006 ± 0.005 0.192 Sex Male 792 −0.016 ± 0.002 <.001 −0.014 ± 0.002 <.001 Female 709 −0.013 ± 0.003 <.001 −0.009 ± 0.003 0.005 BMI Upper 50% 750 −0.010 ± 0.003 <.001 −0.010 ± 0.003 0.002 Lower 50% 751 −0.014 ± 0.003 <.001 −0.012 ± 0.003 <.001 Birth weight Upper 50% 778 −0.015 ± 0.003 <.001 −0.012 ± 0.003 <.001 Lower 50% 723 −0.014 ± 0.003 <.001 −0.007 ± 0.007 <.001 Gestational age Term 1372 −0.014 ± 0.002 <.001 −0.012 ± 0.002 <.001 Preterm 129 −0.016 ± 0.006 0.018 −0.012 ± 0.007 0.108 Model 1:unadjusted model; Model 2: adjusted for age, gender, axial length, BMI, waist, spherical equivalent, birth weight and gestational age. SBP systolic blood pressure, DBP diastolic blood pressure, MABP mean arterial blood pressure, AVR arteriolar to venular ratio. Term means pregnancy lasts longer than 37 weeks, and preterm represents that the duration of pregnancy is less than 37 weeks.Significant p values are bolded researchers failed to found relationship between hormo- the result of association of blood pressure and CRVE. nal status in women and retinal vessel caliber [22]. Although a lot of literatures showed that the BMI was Therefore, more and further researches were needed to higher among boys than that of girls [47], Cole TJ acquire a greater depth of understanding on whether the reported that in population of 2–17 years of age, the hormone would have an effect on vessel diameter and prevalence of overweight is 25% in girls and 27% in boys, would produce what kind of impact. and obesity is 7 and 9% in males and females respect- Third, the prevalence of child obesity is increasing rap- ively [48]. In our studies, girls had a significantly higher idly worldwide, and the BMI may play an active role in BMI than boys (P < 0.0001). Obesity might influence the He et al. BMC Ophthalmology (2018) 18:133 Page 10 of 12 change of blood pressure by some mechanisms such as narrowing should be reevaluated by taking into account glomerular and tubular effects, and some of these mech- the separate arteriolar and venular diameters. Therefore, anisms are sex dependent [49]. In the SCES research, many scholars suggested that arteriolar and venular diam- they did not present the particular values of BMI for eters should be examined separately, especially in etiologic boys and girls. If the boys were more likely over- research [23]. In our study, we found that increasing blood weight just like that in other studies, they had a bet- pressure was significantly associated with narrowing ret- ter chance to get wider venule than the same-aged inal arteriolar caliber and smaller AVR, but not with ret- girls. Although the BMI had been adjusted, high BMI inal venular caliber. might accompany by some possible physical abnor- Our results once again stressed the necessity of add- malities such as dyslipidemia, hyperglycemia and in- itional adjustment of concomitant vessels. We found a flammation, which could result in wider retinal relationship between higher SBP and smaller CRVE, venules simultaneously. however, when CRAE was added to the final Forth, lack of regular moderate-to-vigorous intensity multivariate-adjusted model (model 3), the relationship physical activity is a well-known risk factor for cardio- between SBP and CRVE became nonsignificant, and fur- vascular disease, increasingly amount of studies have ther adjustment of the caliber of the CRVE diminished been focusing on the relationship between physical ac- the reduction magnitude of CRAE when BP increased, tivity and retinal microcirculation and cardiovascular suggesting the possibility of a confounding effect of fel- diseases [50]. Physical activity has been shown to be able low vessel caliber on this association. A significant to improve coronary endothelial function, reduce sys- association between narrower venular caliber and hyper- temic blood pressure and improve early markers of ath- tension was initially reported in the Rotterdam Eye erosclerosis in pre-pubertal obese children. The Study [23], but this result was diminished after add- association of higher levels of physical activity with bet- itional adjustment with retinal arteriolar caliber, and the ter retinal vessel health have been demonstrated in same conclusion was obtained by Myers [22]. The differ- adults as well as in children population [39, 51–53]. Be- ence of the results illustrated the importance of correct- fore and during adolescence, girls usually undergo a ing concomitant vessels. lower level of physical exercise and greater decline in ac- Strengths of this study include its random cluster sam- tive physical activity than boys [54], which might explain ple of a large number of representative healthy school- the difference to some extent. Correspondingly, in our children. The samples were free of influences from study, girls had higher waist circumference and BMI, systemic disease processes or eye diseases on retinal ves- which might result from insufficiency of physical activity sel measurements. We also used a previously validated compared with boys. standardized protocol of quantitative retinal imaging In addition to the reasons analyzed above, the asso- program for retinal vessel measurement. However, some ciation between blood pressure and retinal venular potential limitations of our study demand consideration. caliber might be affected by other factors such as First, the study design is cross-sectional and does not smoking status [55], genetic and sex determinants, as provide temporal information on the associations. Sec- well as ethnic differences. In summary, the association ond, the possible selection bias giving rise from the ex- between BP and retinal venular caliber is a result of clusion of students by ineligibility and ungradable retinal the interplay of many complicated reasons, maybe el- photographs may play a part on the real association be- evated blood pressure was associated with wider ret- tween BP and retinal vessel diameters. Finally, we failed inal venules in preadolescent boys, but due to the to acquire further information from our samples such as influence by comprehensive factors, the change was smoking status, family history, blood lipid levels, blood not significantly manifest in our study. glucose, which may have an impact on the results. In the past, researchers had generally attributed a In conclusion, this study shows that in population of lower arteriolar-to-venular ratio (AVR) to generalized ar- 12-year-old Chinese children, increasing blood pressure teriolar narrowing and suggested that this ratio may was significantly associated with narrower retinal arteri- provide information that would predict incident cardio- olar caliber but not with retinal venular caliber, and pos- vascular diseases. But with the advent of semi-automatic sible confounding factors such as sex et al. had no effect examination, it makes it possible to measure arteries and on the relationship between BP and retinal vessel di- veins in retinal fundus separately. Since 2004, Ikram [27] ameters. This finding provided further insight into the and other researchers confirmed that elevated blood relationship of elevated BP on the microcirculation pressures were associated with smaller arteriolar diame- that occurs in early life. The association of wider ret- ters, but larger venular diameters were related to athero- inal venular caliber and hypertension has not yet been sclerosis, inflammation, and cholesterol levels. Hence, consistently found, which should remain one of our the idea that the AVR overall reflects generalized arteriolar highest research priorities. He et al. BMC Ophthalmology (2018) 18:133 Page 11 of 12 Abbreviations stroke: the multi-ethnic study of atherosclerosis (MESA). Stroke. 2012; BMI: Body mass index; BP: Blood pressure; CRAE: Central retinal arteriolar 43(12):3245–51. equivalents; CRVE: Central retinal venular equivalents; DBP: Diastolic blood 8. Hughes AD, Falaschetti E, Witt N, Wijetunge S, Thom SA, Tillin T, Aldington pressure; MABP: Mean arterial blood pressure; SBP: Systolic blood pressure SJ, Chaturvedi N. Association of Retinopathy and Retinal Microvascular Abnormalities with Stroke and cerebrovascular disease. Stroke. 2016;47(11): Acknowledgements 2862–4. The authors thank the support from the Anyang city government for helping 9. Lim LS, Cheung CY, Sabanayagam C, Lim SC, Tai ES, Huang L, Wong TY. to organize the survey. We acknowledge the University of Wisconsin Fundus Structural changes in the retinal microvasculature and renal function. Invest Photograph Reading Center and Nicola Ferrier of the School of Engineering Ophthalmol Vis Sci. 2013;54(4):2970–6. at University of Wisconsin for providing the software of measuring retinal 10. Karatzi K, Protogerou AD, Moschonis G, Tsirimiagou C, Androutsos O, vessels calibers. Chrousos GP, Lionis C, Manios Y. Prevalence of hypertension and hypertension phenotypes by age and gender among schoolchildren in Availability of data and materials Greece: the healthy growth study. Atherosclerosis. 2017;259:128–33. The datasets used and/or analysed during the current study are available 11. Liang YJ, Xi B, Hu YH, Wang C, Liu JT, Yan YK, Xu T, Wang RQ. Trends in from the corresponding author on reasonable request. blood pressure and hypertension among Chinese children and adolescents: China health and nutrition surveys 1991-2004. Blood Press. 2011;20(1):45–53. Authors’ contributions 12. Li SM, Liu LR, Li SY, Ji YZ, Fu J, Wang Y, Li H, Zhu BD, Yang Z, Li L, et al. YH performed all of the retinal vessel pictures and wrote the whole Design, methodology and baseline data of a school-based cohort study in manuscript. S-ML designed the study and supervised the progress of the Central China: the Anyang childhood eye study. Ophthalmic Epidemiol. entire study. M-TK, L-RL and HL participated in the design of the experiment, 2013;20(6):348–59. data collection and analysis. S-FW and A-RR undertook the statistical analysis 13. Henderson AD, Bruce BB, Newman NJ, Biousse V. Hypertension-related eye of sample data. NW designed the study, supervised the progress of the abnormalities and the risk of stroke. Rev Neurol Dis. 2011;8(1–2):1–9. entire study, revised the manuscript and finally agreed to submission. All 14. Wong TY, Hubbard LD, Klein R, Marino EK, Kronmal R, Sharrett AR, Siscovick authors read and approved the final manuscript. DS, Burke G, Tielsch JM. Retinal microvascular abnormalities and blood pressure in older people: the cardiovascular health study. Br J Ophthalmol. Ethics approval and consent to participate 2002;86(9):1007–13. Ethics approval was obtained from the institutional review board of Beijing 15. Sharrett AR, Hubbard LD, Cooper LS, Sorlie PD, Brothers RJ, Nieto FJ, Tongren Hospital, Capital Medical University, and followed the tenets of the Pinsky JL, Klein R. Retinal arteriolar diameters and elevated blood declaration of Helsinki. Informed written consent was obtained from at least pressure: the atherosclerosis risk in communities study. Am J Epidemiol. one parent. Verbal assent was obtained from each child. 1999;150(3):263–70. 16. Jeganathan VS, Sabanayagam C, Tai ES, Lee J, Sun C, Kawasaki R, Nagarajan Competing interests S, Huey-Shi MH, Sandar M, Wong TY. Effect of blood pressure on the retinal All of the authors declare that they have no competing interests. vasculature in a multi-ethnic Asian population. Hypertension research : official journal of the Japanese Society of Hypertension. 2009;32(11):975–82. 17. Sun C, Liew G, Wang JJ, Mitchell P, Saw SM, Aung T, Tai ES, Wong TY. 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Heart and estrogen/progestin replacement study (HERS) research group. Jama. 1998;280(7):605–13. 46. Wong TY, Knudtson MD, Klein BE, Klein R, Hubbard LD. Estrogen replacement therapy and retinal vascular caliber. Ophthalmology. 2005; 112(4):553–8. 47. Kelishadi R, Heshmat R, Motlagh ME, Majdzadeh R, Keramatian K, Qorbani M, Taslimi M, Aminaee T, Ardalan G, Poursafa P, et al. Methodology and early http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Ophthalmology Springer Journals

Association between blood pressure and retinal arteriolar and venular diameters in Chinese early adolescent children, and whether the association has gender difference: a cross-sectional study

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Abstract

Background: To establish the independent association between blood pressure (BP) and retinal vascular caliber, especially the retinal venular caliber, in a population of 12-year-old Chinese children. Methods: We have examined 1501 students in the 7th grade with mean age of 12.7 years. A non-mydriatic fundus camera (Canon CR-2, Tokyo, Japan) was used to capture 45 fundus images of the right eyes. Retinal vascular caliber was measured using a computer-based program (IVAN). BP was measured using an automated sphygmomanometer (HEM-907, Omron, Kyoto, Japan). Results: The mean retinal arteriolar caliber was 145.3 μm (95% confidence interval [CI], 110.6–189.6 μm) and the mean venular caliber was 212.7 μm (95% CI, 170.6–271.3 μm). After controlling for age, sex, axial length, BMI, waist, spherical equivalent, birth weight, gestational age and fellow retinal vessel caliber, children in the highest quartile of BP had significantly narrower retinal arteriolar caliber than those with lower quartiles (P for trend< 0.05). Each 10-mmHg increase in BP was associated with narrowing of the retinal arterioles by 3.00 μm(multivariable-adjusted P < 0.001), and the results were consist in three BP measurements. The association between BP measures and retinal venular caliber did not persist after adjusting for fellow arteriolar caliber. And there was no significant interaction between BP and sex, age, BMI, and birth status. Conclusions: In a large population of adolescent Chinese children, higher BP was found to be associated with narrower retinal arterioles, but not with retinal venules. Sex and other confounding factors had no effect on the relationship of BP and retinal vessel diameter. Keywords: Hypertension, Adolescents, Retinal arteriolar diameter, Retinal venular diameter, Blood pressure * Correspondence: xiaowwnnll@163.com Beijing Tongren Eye Center, Beijing Tongren Hospital, Beijing Ophthalmology & Visual Science Key Lab, Beijing Institute of Ophthalmology, Capital Medical University, Beijing, China Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. He et al. BMC Ophthalmology (2018) 18:133 Page 2 of 12 Background Methods Major component of the circulatory system is composed Study population of the microcirculation, which plays an important role in The Anyang Childhood Eye Study (ACES) is a maintaining cardiovascular health. There is a widespread school-based cohort study designed to observe the oc- influence of blood pressure (BP) on the structure and currence and development of myopia as well as other function of microcirculation system. Early in the late diseases in school children living in Anyang urban area, nineteenth century, Marcus Gunn had put forward the Henan Province, Central China. Detailed methodology statement that there were associations between micro- of the study has been previously described [12]. In vascular abnormalities and cardiovascular diseases [1]. briefly, 1501 students in 7th grade average aged The retina is a unique structure of the eyes, where the 12.7 years have been examined from October 2011 to in vivo microcirculation can be directly visualized and December 2011. The flowchart of participants included monitored non-invasively. Retinal microcirculation in the present study was shown in Fig. 1. Ethics approval shares the same anatomic architecture and physiological was obtained from the institutional review board of feature with other terminal organs elsewhere in the body Beijing Tongren Hospital, Capital Medical University, [2]. These characteristics increase its utility as a tool to and followed the tenets of the declaration of Helsinki. study the clinical performance of microvascular diseases. Informed written consent was obtained from at least Recently, with the improvement of retinal imaging par- one parent. Verbal assent was obtained from each child. ticularly the computer-assistant analysis techniques from digital retinal images [3], plenty of epidemiological stud- Retinal photography and measurement of retinal vascular ies in adult populations have displayed that abnormal caliber changes in retinal vascular caliber (predominantly retinal The children were examined at health examination sta- arteriolar and venular caliber) are closely associated with tion of the Anyang Eye Hosptial. A non-mydriatic fun- some systemic vascular abnormalities such as cardiovas- dus camera (Canon CR-2, Tokyo, Japan) was used to cular risk factors [4], hypertension [5], coronary heart capture 45 fundus images centering on optic disc and disease [6], risk of diabetes and stroke [7], cerebral in- macular area of children’s right eyes by a well-trained farcts and white matter lesions [8], and renal disease [9], operator [12]. Children with abnormal fundus images independent of other risk factors. would also undergo left eye measurements, and we ana- Despite increasing data on the risk prediction of ret- lyzed one picture for each child. inal vascular caliber measurement in different According to a standardized protocol described previ- population-based studies, there had been still some con- ously [3], the computer-imaging program (IVAN, Uni- troversial opinions on association between retinal vascu- versity of Wisconsin, Madison, WI) was used to measure lar changes and BP, especially for the retinal venular calibers of all retinal arterioles and venules located in changes. Understanding the impacts of BP and changes zone 0.5 to 1 disc diameter from the optic disc margin to the retinal microvasculature in persons with different (zone B). The program automatically combined vessel background is an important aspect of the study on diameters from the six largest arterioles and six largest microcirculation disease. Children are generally free of venules into a pair of indices. The central retinal arteri- many systemic conditions and eye diseases (such as olar and venular equivalents (CRAE and CRVE) repre- glaucoma or diabetic retinopathy, etc.) that could bring sent the average arteriolar and venular caliber for each about confounding effects on observed associations. eye, respectively. One grader masked to children’s iden- High BP in children and adolescents is more and more tity and characteristics performed all measurements. Be- common in western countries [10], and BP levels and fore starting the measurement, 50 randomly selected prevalence of hypertension has increased dramatically retinal images were repeatedly measured by the grader among children and adolescents in China [11]. It is en- with an interval of 2 weeks. The reliability was high with couraging that there are some studies on the association intraclass correlation coefficients of 0.85 for arteriolar of BP and retinal vessel caliber in children recently, but caliber and 0.97 for venular caliber. substantial data on children group are still needed to provide the reference data. Blood pressure measurement In this study, we investigated the independent associ- Blood pressure of children was measured in a seated ation between blood pressure measures and changes to position after 5 min of rest using an automated sphyg- the retinal microvasculature in a relatively large popula- momanometer (HEM-907, Omron, Kyoto, Japan) with tion of 12-year-old Chinese children. This study also appropriate cuff size (bladder length ≈80% and width at assessed the potential modifying influences of age, BMI, least 40% of the arm circumference, covering the upper birth parameters, especially sex, on the associations be- arm but not obscuring the antecubital fossa). Systolic tween BP and retinal vessel caliber. and diastolic blood pressure (SBP and DBP, respectively) He et al. BMC Ophthalmology (2018) 18:133 Page 3 of 12 Fig. 1 The flowchart of participants included in the present study readings were taken. Two readings were taken 5 min quartiles as well as being analyzed as a continuous vari- apart and averaged for analysis. Mean arterial blood able (i.e. each 10 mmHg increase). The retinal arteriolar, pressure (MABP) was computed as 2/3 of the diastolic venular calibers, and arteriolar to venular ratio (AVR) plus 1/3 of the systolic value. were compared across blood pressure quartiles based on three models, Model 1 was analyzed without any adjust- Other measurements ment, Model 2 adjusted for multivariate variables (age, Any abnormality of anterior segment (any abnormalities sex, axial length, BMI, waist, spherical equivalent, birth of the anterior segment of the eye, such as corneal leu- weight, and gestational age) and then Model 3 adjusted koplakia, cataract, pupil abnormalities, iris anterior additionally for fellow retinal vessel diameter. The test of adhesion, etc.) was observed and recorded using a trend was determined by regarding quartiles of BP as slit-lamp (YZ5J, 66 Vision Tech Co, Suzhou, China). continuous ordinal variables. Multiple linear regressions Cycloplegic spherical equivalent refraction was measured were used to estimate the absolute changes in retinal using an autorefractor (HRK7000 A, Huvitz, Gunpo, arteriolar and venular caliber for a 10-mmHg increase in South Korea) with three readings taken and averaged. SBP, DBP, and MABP. Potential modifiers were exam- An optical coherence biometry (IOL-master 1322–734, ined in stratified analyses of age, sex, BMI, and birth Carl Zeiss Meditec AG, Jena, Germany) was applied to parameters. All probabilities quoted are two-sided, and a evaluate the optical axial length (AL) value along the vis- significant P value was defined as < 0.05. ual axis (line connecting the fixation point to the fovea, specifically from the anterior surface of the cornea to Results the retinal pigment epithelium layer of the fovea), with Table 1 shows the study characteristics of the children five repeated measurements taken and averaged. Height included for crosss-sectional analyses. Compared with and weight were measured using an automatic and pro- boys, girls had higher systolic and mean arterial blood fessional integrated set. Body mass index (BMI) was pressure, higher waist and BMI, and had less myopia 2 2 calculated as weight/height (kg/m ). Waist circumfer- and longer axial length. ence was measured with a tape measure and was defined Table 2 shows the mean retinal vascular caliber and as the narrowest part of the student’s trunk. Birth infor- AVR by quartiles of systolic, diastolic and mean arterial mation including gestational weeks, birth weight and blood pressure in three different models. Children with birth length were collected by administrating question- highest quartile of BP were more likely to have narrower naires to the participating students’ parents. retinal arteriolar caliber than those in the lowest quartile after multivariable-adjustment (all P < 0.01), with a mean Statistical analysis difference of 6–7 μm between the highest and lowest SAS (v9.3, SAS Institute Inc., Cary, NC, USA) was used quartiles, and the results were consistent for three BP to perform statistical analysis. BP was categorized into measurements. As for retinal venular diameter, in Model He et al. BMC Ophthalmology (2018) 18:133 Page 4 of 12 Table 1 Basic characteristics of the children included in the study Characteristics Male Female P (n = 792) (n = 709) Age (year) 12.66 (0.50) 12.73 (0.49) 0.004 Spherical equivalent refraction (diopters) −1.78 (2.08) − 1.32 (2.02) < 0.001 Axial length (mm) 23.93 (1.01) 24.35 (1.09) < 0.001 Systolic blood pressure (mm Hg) 104.55 (10.87) 107.36 (10.35) < 0.001 Diastolic blood pressure (mm Hg) 65.35 (7.57) 65.45 (7.21) 0.758 Mean arterial blood pressure (mm Hg) 78.42 (8.23) 79.41 (7.63) 0.005 BMI (kg/m ) 19.32 (3.22) 20.28 (3.91) < 0.001 Waist (cm) 69.04 (7.84) 71.92 (10.14) < 0.001 Data are mean (SD). BMI body mass index; Significant p values are bolded. Significant p values are bolded 1, children with higher BP had significantly narrower each 10-mmHg increase in BP resulted in 2.03–2.68 μm CRVE (P < 0.001 for trend for three BP measurements), (P < 0.05) decrease for boys and 2.15–2.76 μm(P < 0.05) and in Model 2, only children with higher SBP were decrease for girls in model 2, but when CRAE was found to have narrower CRVE than those with lower additionally adjusted in model 2, there is no signifi- SBP (P = 0.038 for trend), however, this association did cant association between BP and CRVE in either boys not persist after adjusting for fellow vessel caliber. In nor girls, which was consistent in three BP measure- Model 1 and Model 2, children with higher BP quartiles ments (Table 5). had consistently and significantly narrower AVR (P < 0.001 for trend), and the results were consistent for Discussion three BP measurements. In this population of 12-year-old Chinese children, we Table 3 shows the multivariable linear regression be- found that increasing blood pressure was significantly tween retinal vascular caliber and BP. In model 1 and associated with narrowing retinal arteriolar caliber and model 2, for each 10-mmHg increase in SBP, DBP and smaller AVR, but not with retinal venular caliber. After MABP, CRAE decreased by 3.07–4.40 μm(P < 0.001) controlling for age, gender, axial length, BMI, waist, and CRVE decreased by 1.47–2.69 μm(P < 0.001). In spherical equivalent, birth parameters and fellow retinal model 3 adjusted for fellow vessel caliber additionally, vessel, each 10-mmHg increase in BP was associated each 10-mmHg increase in BP was associated with 2.34– with an approximate 3~ 4 μm reduction in CRAE, and 3.47 μm decrease in retinal arteriolar caliber (P < 0.001), the changes were consistent of three BP measurements. but no significant change in CRVE (p > 0.42) was ob- The similar pattern and magnitude of change were also served. AVR decreased by 0.010 to 0.014 for every found in the relationship of BP with CRVE prior of tak- 10-mmHg increase in BP in Model 1, Further adjust- ing confounding fellow arteriolar diameter into account, ment for age, gender, axial length, BMI, waist, spherical but after the fellow vessel were further adjusted, the equivalent, birth weight and gestational age had no im- change no longer had significant difference. And there pact on the magnitude of this effect (AVR reduction was no significant interaction between BP and age, sex, 0.007 to 0.012). BMI and birth status. Subgroup analysis stratified by potential effect modi- Both cross-sectional and longitudinal studies had fiers was presented in Tables 4, 5 and 6. Associations provided substantial evidence that there is significant were consistent across subgroups stratified by age, sex, association between elevated blood pressure or BMI, and birth parameters. hypertension and narrower central retinal arteriole It is worth noting that, there were no significant inter- caliber in adult populations [13–19]. However, there actions between sex, and BP on retinal vessel diameters. is conflicting evidence on retinal venular diameter as The impact of BP on the diameters of retinal vessels marker related to hypertension. Some studies [16, 18–22] showed no gender differences between boys and girls. In suggested that retinal venular widening may be independ- model 2, each 10-mmHg increase in BP was associated ently associated with risk of hypertension, others [15, 19, with 3.41–4.91 μm(P < 0.001) and 2.73–3.89 μm(P < 23–25] had found no association, whereas some other re- 0.001) decrease in CRAE for boys and girls respectively, searchers announced that both retinal venular and arteri- and in model 3, the decrease of CRAE reduced to 2.57– olar caliber were inversely related to blood pressure, 3.81 μm(P < 0.001) and 2.12–3.12 μm(P < 0.001) for independent of age, gender, and smoking [26]. boys and girls respectively (Table 4). And for CRVE, He et al. BMC Ophthalmology (2018) 18:133 Page 5 of 12 Table 2 Mean retinal arteriolar diameter, retinal venular diameter, and AVR (mean and standard error) stratified by SBP, DBP and MABP n Range Rentinal Arteriolar Diameter (μm) Rentinal Venular Diameter (μm) AVR (mm Hg) Model 1 Model 2 Model 3 Model 1 Model 2 Model 3 Model 1 Model 2 SBP First quartile 375 79 to 100 149.02 ± 1.31 148.70 ± 0.62 147.91 ± 0.56 214.54 ± 0.63 214.91 ± 0.79 212.96 ± 0.71 0.696 ± 0.004 0.688 ± 0.007 Second quartile 365 101 to 107 146.17 ± 0.62 146.19 ± 0.61 146.20 ± 0.54 213.16 ± 0.30 212.65 ± 0.77 212.12 ± 0.69 0.687 ± 0.002 0.685 ± 0.008 Third quartile 373 107 to 113 144.24 ± 0.54 144.22 ± 0.60 144.36 ± 0.54 212.23 ± 0.20 212.30 ± 0.76 212.89 ± 0.68 0.681 ± 0.002 0.683 ± 0.008 Fourth quartile 388 113 to 142 141.63 ± 1.36 141.99 ± 0.61 142.62 ± 0.55 210.97 ± 0.65 210.91 ± 0.78 212.76 ± 0.70 0.672 ± 0.004 0.680 ± 0.009 P for trend < 0.001 0.001 < 0.001 < 0.001 0.038 0.941 < 0.001 < 0.0001 DBP First quartile 323 49 to 61 147.96 ± 2.50 149.14 ± 0.65 148.15 ± 0.58 214.04 ± 1.21 215.49 ± 0.82 213.29 ± 0.75 0.692 ± 0.007 0.687 ± 0.007 Second quartile 407 61 to 65 145.95 ± 2.18 146.21 ± 0.57 146.19 ± 0.51 213.06 ± 1.05 212.73 ± 0.73 212.19 ± 0.65 0.686 ± 0.007 0.685 ± 0.008 Third quartile 360 66 to 70 144.49 ± 2.20 144.53 ± 0.61 144.92 ± 0.55 212.35 ± 1.06 211.60 ± 0.77 212.01 ± 0.69 0.682 ± 0.007 0.683 ± 0.008 Fourth quartile 411 70 to 90 142.99 ± 2.28 141.84 ± 0.58 142.31 ± 0.52 211.62 ± 1.10 211.36 ± 0.73 213.29 ± 0.66 0.677 ± 0.007 0.682 ± 0.010 P for trend < 0.001 0.005 0.009 < 0.001 0.078 0.970 < 0.001 < 0.0001 MABP First quartile 370 60 to 75 148.62 ± 1.80 149.31 ± 0.61 148.24 ± 0.55 214.36 ± 0.87 215.75 ± 0.78 213.47 ± 0.71 0.695 ± 0.005 0.687 ± 0.007 Second quartile 366 75 to 79 145.96 ± 1.55 145.81 ± 0.60 145.98 ± 0.54 213.07 ± 0.75 212.18 ± 0.77 211.87 ± 0.69 0.686 ± 0.005 0.685 ± 0.008 Third quartile 400 79 to 84 144.28 ± 1.59 144.36 ± 0.58 144.56 ± 0.52 212.25 ± 0.77 212.12 ± 0.73 212.62 ± 0.66 0.681 ± 0.005 0.683 ± 0.008 Fourth quartile 365 84 to 102 142.14 ± 1.84 141.50 ± 0.62 142.21 ± 0.56 211.22 ± 0.89 210.67 ± 0.79 212.78 ± 0.72 0.674 ± 0.005 0.680 ± 0.010 P for trend < 0.001 0.011 0.004 < 0.001 0.086 0.738 < 0.001 < 0.0001 Model 1:unadjusted model; Model 2: adjusted for age, gender, axial length, BMI, waist, spherical equivalent, birth weight and gestational age; Model 3: adjusted for fellow vessel diameter additionally. SBP systolic blood pressure, DBP diastolic blood pressure, MABP mean arterial blood pressure, AVR arteriolar to venular ratio. Significant p values are bolded He et al. BMC Ophthalmology (2018) 18:133 Page 6 of 12 Table 3 Multivariate Linear Regression Models of Retinal Vascular Caliber and Blood Pressure Retinal arteriolar diameter (μm) Retinal venular diameter (μm) AVR Mean (95%CI) P Mean (95%CI) P Mean (95%CI) P SBP Model 1 −3.23(− 3.96 to −2.52) < 0.001 −1.57(− 2.50 to − 0.63) < 0.001 −0.01 (− 0.013 to − 0.007) < 0.001 Model 2 − 3.07 (− 3.79 to − 2.34) < 0.001 − 2.06 (− 2.97 to − 1.15) < 0.001 − 0.007(− 0.010 to − 0.004) < 0.001 Model 3 −2.34 (− 3.00 to − 1.69) < 0.001 − 0.34 (− 1.18 to 0.50) 0.428 –– DBP Model 1 −3.85(− 4.88 to −2.82) < 0.001 − 1.47 (− 2.78 to − 0.15) < 0.001 −0.013 (− 0.017 to − 0.009) < 0.001 Model 2 − 4.02 (− 4.96 to − 3.08) < 0.001 − 2.34 (− 3.53 to − 1.15) < 0.001 − 0.011(− 0.015 to − 0.007) < 0.001 Model 3 −3.20 (− 4.05 to − 2.35) < 0.001 − 0.06 (− 1.16 to 1.03) 0.909 –– MABP Model 1 − 4.37(−5.35 to −3.39) < 0.001 − 1.84 (− 3.11 to − 0.56) < 0.001 −0.014 (− 0.019 to − 0.010) < 0.001 Model 2 − 4.40 (− 5.34 to − 3.47) < 0.001 −2.69 (− 3.88 to − 1.50) < 0.001 − 0.012(− 0.016 to − 0.007) < 0.001 Model 3 −3.47 (− 4.31 to − 2.62) < 0.001 −0.21 (− 1.31 to 0.89) 0.712 –– Model 1:unadjusted model; Model 2: adjusted for age, gender, axial length, BMI, waist, spherical equivalent, birth weight and gestational age; Model 3: adjusted for fellow vessel diameter additionally. SBP systolic blood pressure, DBP diastolic blood pressure, MABP mean arterial blood pressure, AVR arteriolar to venular ratio. Significant p values are bolded In addition, smaller retinal arteriolar caliber was also retinal venules, with each 10-mmHg increase associ- found to be associated with current alcohol consump- ated with 2.00 μm of retinal arteriolar narrowing and tion, greater body mass index and higher levels of total 2.51 μm of retina venular widening. In 2012, Hanssen homocysteine [20], incident clinical stroke, carotid ath- examined 578 school children aged 11.1 ± 0.6 years erosclerosis, incident heart disease and cardiovascular from secondary schools in Germany and found that mortality, as well as metabolic syndrome [13]. Larger diastolic blood pressure was not only independently venular calibers had been shown to be associated with associated with arteriolar narrowing, but also with atherosclerosis [27], inflammation [20–22, 27–30], venular narrowing [39]. Imhof found that systolic and stroke, cardiovascular mortality [13, 31], cigarette smok- diastolic BP were associated with arteriolar narrowing ing [20, 27, 32, 33], and the metabolic syndrome (hyper- in 391 Switzerland children with an average age of glycemia, central obesity, and dyslipidemia) [16, 34]. 7.3 years, but they failed to find the association be- These findings suggested that retinal venular widening tween BP and venular diameter [40]. may has pleiotropic associations with cardiovascular risk According to the results of the above studies, we factors and diseases, and was not a specific biomarker found that just like the roles of retinal venular diameter for hypertension [35]. play on the BP in adults, the relationship between retinal There have been some studies on relationship of blood venular diameter and BP in the childhood population is pressure with retinal vessel calibers in children. Mitchell still in controversy. [36] reported that higher childhood blood pressure was Unlike the SCES [37] (The subjects of this study were associated with retinal arteriolar narrowing but not with comparable in age to our research), we didn’t catch the retinal venular caliber in children aged 6–8 years. They finding that higher BP was associated with wider retinal found that each 10-mmHg increase in systolic blood venules in preadolescent boys. We speculated here that pressure was associated with narrowing of retinal arteri- there are some possible reasons contributing to the dis- oles by 2.08 μm in Sydney children and 1.43 μmin crepancy between the two results. Singapore children. In high school students aged First, at present, there were some epidemiological 12.7 years, they found that elevated blood pressure was studies on adolescent BP, but these studies had not associated with narrower retinal arterioles, and also with reached the uniform conclusion related to the gender wider retinal venules in boys, with each 10-mmHg in- difference. Some studies showed a higher frequency of crease in MABP associated with 2.02-mm decrease in elevated BP in males than in females in children popula- retinal arteriolar caliber, and 2.19 μm increase in CRVE tion based research [41], but these results differed from in boys (the Sydney Childhood Eye Study. SCES) [37]. In those obtained by Rosner B, whose study found that the a later study on Singapore children aged 4~ 5 years, Li prevalence of elevated BP significantly increased among et al. [38] found that higher systolic blood pressure was girls (8.2% versus 12.6%; P = 0.007), but was only of bor- associated with narrower retinal arterioles and wider derline significance among boys (15.8% versus 19.2%; P He et al. BMC Ophthalmology (2018) 18:133 Page 7 of 12 Table 4 Subgroup analysis stratified by potential effect modifiers of retinal Arteriolar Diameter with BP, stratified by potential modifiers Potential Effect Modifiers n Retinal Arteriolar Diameter (μm) Model 1 p Model 2 P Model 3 P SBP Age 10 + 11 70 −1.97 ± 1.66 0.238 −0.60 ± 1.79 0.736 −1.28 ± 1.54 0.411 12 1122 −3.63 ± 0.43 < 0.01 − 3.31 ± 0.42 <.001 − 2.46 ± 0.39 <.001 13 + 14 + 15 309 −2.6 ± 0.82 < 0.01 − 2.60 ± 0.84 0.002 −1.98 ± 0.73 0.007 Sex Male 792 −3.1 ± 0.52 < 0.01 − 3.41 ± 0.52 <.001 −2.57 ± 0.45 <.001 Female 709 −3.05 ± 0.52 < 0.01 − 2.73 ± 0.52 <.001 −2.12 ± 0.49 <.001 BMI Upper 50% 750 −2.37 ± 0.57 < 0.01 −2.39 ± 0.5 <.001 −1.72 ± 0.49 <.001 Lower 50% 751 −4.03 ± 0.55 < 0.01 −3.71 ± 0.52 <.001 −2.89 ± 0.46 <.001 Birth weight Upper 50% 778 −3.69 ± 0.53 < 0.01 −3.09 ± 0.53 <.001 −2.35 ± 0.48 <.001 Lower 50% 723 −2.87 ± 0.51 < 0.01 −2.97 ± 0.52 <.001 −2.28 ± 0.47 <.001 Gestational age Term 1372 −3.27 ± 0.39 < 0.01 − 3.10 ± 0.39 <.001 −2.33 ± 0.35 <.001 Preterm 129 −3.06 ± 1.09 < 0.01 −2.46 ± 1.12 0.03 −2.21 ± 1.02 0.033 DBP Age 10 + 11 70 −1.84 ± 2.04 0.370 −0.78 ± 2.18 0.722 − 1.81 ± 1.88 0.342 12 1122 −4.85 ± 0.62 < 0.01 −4.74 ± 0.56 <.001 −3.76 ± 0.51 <.001 13 + 14 + 15 309 −1.35 ± 1.11 < 0.01 −2.27 ± 1.08 0.037 −1.36 ± 0.95 0.154 Sex Male 792 −4.2 ± 0.74 < 0.01 − 4.65 ± 0.69 <.001 −3.67 ± 0.60 <.001 Female 709 −3.68 ± 0.72 < 0.01 −3.46 ± 0.67 <.001 −2.79 ± 0.62 <.001 BMI Upper 50% 750 −3.33 ± 0.75 < 0.01 −3.73 ± 0.68 <.001 −3.06 ± 0.62 <.001 Lower 50% 751 −4 ± 0.75 < 0.01 −4.30 ± 0.68 <.001 −3.34 ± 0.60 <.001 Birth weight Upper 50% 778 −3.83 ± 0.73 < 0.01 −3.73 ± 0.66 <.001 −3.01 ± 0.59 <.001 Lower 50% 723 −3.92 ± 0.75 < 0.01 −4.31 ± 0.70 <.001 −3.42 ± 0.64 <.001 Gestational age Term 1372 −3.89 ± 0.55 < 0.01 −3.95 ± 0.51 <.001 −3.10 ± 0.46 <.001 Preterm 129 −3.32 ± 1.57 < 0.01 −4.35 ± 1.50 0.005 −3.69 ± 1.39 0.009 MABP Age 10 + 11 70 −2.21 ± 2.03 0.280 −0.81 ± 2.17 0.709 −1.83 ± 1.88 0.334 12 1122 −5.22 ± 0.58 < 0.01 −5.01 ± 0.56 <.001 −3.91 ± 0.51 <.001 13 + 14 + 15 309 −2.41 ± 1.09 < 0.01 −3.00 ± 1.09 0.006 −2.04 ± 0.95 0.034 Sex Male 792 −4.40 ± 0.70 < 0.01 −4.91 ± 0.68 <.001 −3.81 ± 0.59 <.001 Female 709 −4.21 ± 0.70 < 0.01 −3.89 ± 0.68 <.001 −3.12 ± 0.64 <.001 BMI Upper 50% 750 −3.58 ± 0.75 < 0.01 −3.88 ± 0.68 <.001 −3.06 ± 0.63 <.001 Lower 50% 751 −4.90 ± 0.73 < 0.01 − 4.87 ± 0.68 <.001 −3.81 ± 0.60 <.001 Birth weight Upper 50% 778 −4.68 ± 0.71 < 0.01 −4.31 ± 0.68 <.001 −3.40 ± 0.61 <.001 Lower 50% 723 −4.11 ± 0.70 < 0.01 −4.42 ± 0.68 <.001 −3.49 ± 0.62 <.001 Gestational age Term 1372 −4.40 ± 0.53 < 0.01 −4.38 ± 0.51 <.001 −3.39 ± 0.46 <.001 Preterm 129 −3.98 ± 1.49 < 0.01 −4.23 ± 1.47 0.005 −3.66 ± 1.35 0.008 Model 1:unadjusted model; Model 2: adjusted for age, gender, axial length, BMI, waist, spherical equivalent, birth weight and gestational age; Model 3: adjusted for fellow vessel diameter additionally. SBP systolic blood pressure, DBP diastolic blood pressure, MABP mean arterial blood pressure. Term means pregnancy lasts longer than 37 weeks, and preterm represents that the duration of pregnancy is less than 37 weeks. Significant p values are bolded = 0.057), after analyzing a population-based sample of pressure. If the BP of two genders were basically similar, 3248 children in National Health and Nutrition Examin- the difference of the retinal venular caliber maybe asso- ation Survey (NHANES) III (1988–1994) and 8388 chil- ciated with other reasons. dren in continuous NHANES (1999–2008), aged 8 to Second, in the SCES, with regard to the mechanism 17 years [42]. The female subjects in our study were underlying the conclusion that higher blood pressure more frequently shown to have elevated BP compared to was associated with wider retinal venules in boys, the males. The SCES did not present whether there was a author deduced that maybe it was because sex hormones significant difference between girl and boy blood had an protective effect on the retinal circulation, as a He et al. BMC Ophthalmology (2018) 18:133 Page 8 of 12 Table 5 Subgroup analysis stratified by potential effect modifiers of retinal Venular Diameter with BP, stratified by potential modifiers Potential Effect Modifiers n Retinal Venular Diameter (μm) Model 1 p Model 2 P Model 3 P SBP Age 10 + 11 70 0.40 ± 2.16 0.855 1.43 ± 1.99 0.476 1.78 ± 1.71 0.302 12 1122 −2.1 ± 0.55 < 0.001 −2.52 ± 0.54 <.001 −0.73 ± 0.50 0.148 13 + 14 + 15 309 − 0.53 ± 1.08 0.622 −1.61 ± 1.06 0.129 0.02 ± 0.94 0.986 Sex Male 792 −1.12 ± 0.66 0.092 −2.03 ± 0.65 0.002 0.14 ± 0.57 0.809 Female 709 −1.72 ± 0.69 0.013 −2.15 ± 0.68 0.002 −0.85 ± 0.64 0.186 BMI Upper 50% 750 −1.66 ± 0.75 0.028 −2.11 ± 0.69 0.002 −0.84 ± 0.64 0.186 Lower 50% 751 −2.67 ± 0.69 < 0.001 −2.13 ± 0.64 0.001 0.06 ± 0.58 0.923 Birth weight Upper 50% 778 −1.97 ± 0.68 0.004 −2.05 ± 0.67 0.002 −0.27 ± 0.61 0.654 Lower 50% 723 −1.19 ± 0.67 0.074 −2.06 ± 0.66 0.002 −0.43 ± 0.61 0.478 Gestational age Term 1372 −1.61 ± 0.5 0.001 −2.19 ± 0.49 <.001 −0.46 ± 0.45 0.309 Preterm 129 −1.13 ± 1.55 0.467 −0.88 ± 1.64 0.594 0.62 ± 1.53 0.688 DBP Age 10 + 11 70 2.59 ± 2.64 0.330 2.16 ± 2.42 0.376 2.62 ± 2.08 0.213 12 1122 −2.42 ± 0.79 0.002 −2.91 ± 0.72 <.001 −0.31 ± 0.67 0.648 13 + 14 + 15 309 0.3 ± 1.45 0.838 −2.33 ± 1.36 0.089 −0.92 ± 1.20 0.442 Sex Male 792 −1.11 ± 0.94 0.239 −2.38 ± 0.86 0.006 0.60 ± 0.76 0.433 Female 709 −1.96 ± 0.96 0.042 −2.35 ± 0.86 0.007 −0.69 ± 0.82 0.4 BMI Upper 50% 750 −1.42 ± 0.99 0.151 −2.12 ± 0.89 0.017 −0.10 ± 0.82 0.907 Lower 50% 751 −2.11 ± 0.95 0.026 −2.46 ± 0.84 0.004 0.07 ± 0.76 0.93 Birth weight Upper 50% 778 −1.47 ± 0.93 0.112 −1.98 ± 0.84 0.018 0.18 ± 0.76 0.811 Lower 50% 723 −1.48 ± 0.98 0.132 −2.65 ± 0.90 0.003 −0.28 ± 0.83 0.733 Gestational age Term 1372 −1.59 ± 0.71 0.024 −2.37 ± 0.64 <.001 −0.15 ± 0.58 0.798 Preterm 129 −0.02 ± 2.2 0.994 −2.43 ± 2.23 0.278 0.18 ± 2.12 0.931 MABP Age 10 + 11 70 1.92 ± 2.65 0.469 2.13 ± 2.41 0.38 2.61 ± 2.07 0.213 12 1122 −2.75 ± 0.76 < 0.001 −3.32 ± 0.71 <.001 − 0.59 ± 0.67 0.38 13 + 14 + 15 309 − 0.12 ± 1.43 0.933 −2.48 ± 1.37 0.072 −0.62 ± 1.21 0.609 Sex Male 792 −1.34 ± 0.89 0.133 −2.68 ± 0.85 0.002 0.47 ± 0.75 0.535 Female 709 −2.25 ± 0.94 0.017 −2.76 ± 0.88 0.002 −0.90 ± 0.84 0.284 BMI Upper 50% 750 −1.89 ± 0.99 0.056 −2.63 ± 0.89 0.003 −0.55 ± 0.83 0.513 Lower 50% 751 −2.85 ± 0.93 0.002 −2.74 ± 0.83 0.001 0.13 ± 0.76 0.868 Birth weight Upper 50% 778 −2.13 ± 0.91 0.020 −2.52 ± 0.86 0.003 −0.02 ± 0.78 0.978 Lower 50% 723 −1.55 ± 0.92 0.093 −2.80 ± 0.87 0.001 −0.38 ± 0.81 0.643 Gestational age Term 1372 −1.94 ± 0.68 0.004 −2.78 ± 0.64 <.001 −0.33 ± 0.59 0.577 Preterm 129 −0.72 ± 2.13 0.736 −2.07 ± 2.18 0.345 0.49 ± 2.07 0.812 Model 1:unadjusted model; Model 2: adjusted for age, gender, axial length, BMI, waist, spherical equivalent, birth weight and gestational age; Model 3: adjusted for fellow vessel diameter additionally. SBP systolic blood pressure, DBP diastolic blood pressure, MABP mean arterial blood pressure. Term means pregnancy lasts longer than 37 weeks, and preterm represents that the duration of pregnancy is less than 37 weeks.Significant p values are bolded proportion of girls would have commenced puberty. But trials, the women’s health initiative (WHI) [44] and the it was interesting that Zou found that in 76,869 Chinese heart estrogen and progestin replacement study (HERS) girls, the rate of high blood pressure in menstruation [45], found an increase in cardiovascular incidences in group from 11 to 13 years was significant higher than women taking hormone replacement therapy. In some that in the same age group of non-menstruation [43]. adult population based studies, estrogen replacement Similarly, there was conflicting evidence that hormone therapy was found to be associated with narrower retinal treatment could effectively reduce the risk of coronary arteriolar and venular calibers [46], independent of heart disease, data from two large randomized clinical blood pressure and other vascular factors, but other He et al. BMC Ophthalmology (2018) 18:133 Page 9 of 12 Table 6 Subgroup analysis stratified by potential effect modifiers of AVR with BP, stratified by potential modifiers Potential Effect Modifiers n AVR Model 1 p Model 2 P SBP Age 10 + 11 70 −0.010 ± 0.006 0.118 −0.007 ± 0.007 0.37 12 1122 −0.010 ± 0.002 <.001 −0.007 ± 0.002 <.001 13 + 14 + 15 309 −0.010 ± 0.003 0.002 −0.007 ± 0.004 0.05 Sex Male 792 −0.010 ± 0.002 <.001 −0.009 ± 0.002 <.001 Female 709 −0.009 ± 0.006 <.001 −0.006 ± 0.002 0.02 BMI Upper 50% 750 −0.006 ± 0.002 0.020 −0.005 ± 0.002 0.06 Lower 50% 751 −0.010 ± 0.002 <.001 −0.010 ± 0.002 <.001 Birth weight Upper 50% 778 −0.010 ± 0.002 <.001 −0.007 ± 0.002 0.001 Lower 50% 723 −0.010 ± 0.002 <.001 −0.007 ± 0.002 0.002 Gestational age Term 1372 −0.010 ± 0.002 <.001 −0.007 ± 0.001 <.001 Preterm 129 −0.010 ± 0.004 0.035 −0.008 ± 0.007 0.015 DBP Age 10 + 11 70 −0.016 ± 0.008 0.046 −0.009 ± 0.009 0.314 12 1122 −0.015 ± 0.002 <.001 −0.013 ± 0.002 <.001 13 + 14 + 15 309 −0.007 ± 0.005 0.136 −0.003 ± 0.004 0.493 Sex Male 792 −0.016 ± 0.003 <.001 −0.014 ± 0.003 <.001 Female 709 −0.011 ± 0.006 0.003 −0.009 ± 0.003 0.009 BMI Upper 50% 750 −0.011 ± 0.003 <.001 −0.011 ± 0.003 <.001 Lower 50% 751 −0.012 ± 0.003 <.001 −0.012 ± 0.003 <.001 Birth weight Upper 50% 778 −0.013 ± 0.019 <.001 −0.011 ± 0.003 <.001 Lower 50% 723 −0.013 ± 0.003 <.001 −0.012 ± 0.003 <.001 Gestational age Term 1372 −0.013 ± 0.002 <.001 −0.011 ± 0.002 <.001 Preterm 129 −0.015 ± 0.007 0.03 −0.012 ± 0.007 0.137 MABP Age 10 + 11 70 −0.016 ± 0.008 0.048 −0.009 ± 0.009 0.302 12 1122 −0.015 ± 0.002 <.001 −0.013 ± 0.002 <.001 13 + 14 + 15 309 −0.010 ± 0.005 0.02 −0.006 ± 0.005 0.192 Sex Male 792 −0.016 ± 0.002 <.001 −0.014 ± 0.002 <.001 Female 709 −0.013 ± 0.003 <.001 −0.009 ± 0.003 0.005 BMI Upper 50% 750 −0.010 ± 0.003 <.001 −0.010 ± 0.003 0.002 Lower 50% 751 −0.014 ± 0.003 <.001 −0.012 ± 0.003 <.001 Birth weight Upper 50% 778 −0.015 ± 0.003 <.001 −0.012 ± 0.003 <.001 Lower 50% 723 −0.014 ± 0.003 <.001 −0.007 ± 0.007 <.001 Gestational age Term 1372 −0.014 ± 0.002 <.001 −0.012 ± 0.002 <.001 Preterm 129 −0.016 ± 0.006 0.018 −0.012 ± 0.007 0.108 Model 1:unadjusted model; Model 2: adjusted for age, gender, axial length, BMI, waist, spherical equivalent, birth weight and gestational age. SBP systolic blood pressure, DBP diastolic blood pressure, MABP mean arterial blood pressure, AVR arteriolar to venular ratio. Term means pregnancy lasts longer than 37 weeks, and preterm represents that the duration of pregnancy is less than 37 weeks.Significant p values are bolded researchers failed to found relationship between hormo- the result of association of blood pressure and CRVE. nal status in women and retinal vessel caliber [22]. Although a lot of literatures showed that the BMI was Therefore, more and further researches were needed to higher among boys than that of girls [47], Cole TJ acquire a greater depth of understanding on whether the reported that in population of 2–17 years of age, the hormone would have an effect on vessel diameter and prevalence of overweight is 25% in girls and 27% in boys, would produce what kind of impact. and obesity is 7 and 9% in males and females respect- Third, the prevalence of child obesity is increasing rap- ively [48]. In our studies, girls had a significantly higher idly worldwide, and the BMI may play an active role in BMI than boys (P < 0.0001). Obesity might influence the He et al. BMC Ophthalmology (2018) 18:133 Page 10 of 12 change of blood pressure by some mechanisms such as narrowing should be reevaluated by taking into account glomerular and tubular effects, and some of these mech- the separate arteriolar and venular diameters. Therefore, anisms are sex dependent [49]. In the SCES research, many scholars suggested that arteriolar and venular diam- they did not present the particular values of BMI for eters should be examined separately, especially in etiologic boys and girls. If the boys were more likely over- research [23]. In our study, we found that increasing blood weight just like that in other studies, they had a bet- pressure was significantly associated with narrowing ret- ter chance to get wider venule than the same-aged inal arteriolar caliber and smaller AVR, but not with ret- girls. Although the BMI had been adjusted, high BMI inal venular caliber. might accompany by some possible physical abnor- Our results once again stressed the necessity of add- malities such as dyslipidemia, hyperglycemia and in- itional adjustment of concomitant vessels. We found a flammation, which could result in wider retinal relationship between higher SBP and smaller CRVE, venules simultaneously. however, when CRAE was added to the final Forth, lack of regular moderate-to-vigorous intensity multivariate-adjusted model (model 3), the relationship physical activity is a well-known risk factor for cardio- between SBP and CRVE became nonsignificant, and fur- vascular disease, increasingly amount of studies have ther adjustment of the caliber of the CRVE diminished been focusing on the relationship between physical ac- the reduction magnitude of CRAE when BP increased, tivity and retinal microcirculation and cardiovascular suggesting the possibility of a confounding effect of fel- diseases [50]. Physical activity has been shown to be able low vessel caliber on this association. A significant to improve coronary endothelial function, reduce sys- association between narrower venular caliber and hyper- temic blood pressure and improve early markers of ath- tension was initially reported in the Rotterdam Eye erosclerosis in pre-pubertal obese children. The Study [23], but this result was diminished after add- association of higher levels of physical activity with bet- itional adjustment with retinal arteriolar caliber, and the ter retinal vessel health have been demonstrated in same conclusion was obtained by Myers [22]. The differ- adults as well as in children population [39, 51–53]. Be- ence of the results illustrated the importance of correct- fore and during adolescence, girls usually undergo a ing concomitant vessels. lower level of physical exercise and greater decline in ac- Strengths of this study include its random cluster sam- tive physical activity than boys [54], which might explain ple of a large number of representative healthy school- the difference to some extent. Correspondingly, in our children. The samples were free of influences from study, girls had higher waist circumference and BMI, systemic disease processes or eye diseases on retinal ves- which might result from insufficiency of physical activity sel measurements. We also used a previously validated compared with boys. standardized protocol of quantitative retinal imaging In addition to the reasons analyzed above, the asso- program for retinal vessel measurement. However, some ciation between blood pressure and retinal venular potential limitations of our study demand consideration. caliber might be affected by other factors such as First, the study design is cross-sectional and does not smoking status [55], genetic and sex determinants, as provide temporal information on the associations. Sec- well as ethnic differences. In summary, the association ond, the possible selection bias giving rise from the ex- between BP and retinal venular caliber is a result of clusion of students by ineligibility and ungradable retinal the interplay of many complicated reasons, maybe el- photographs may play a part on the real association be- evated blood pressure was associated with wider ret- tween BP and retinal vessel diameters. Finally, we failed inal venules in preadolescent boys, but due to the to acquire further information from our samples such as influence by comprehensive factors, the change was smoking status, family history, blood lipid levels, blood not significantly manifest in our study. glucose, which may have an impact on the results. In the past, researchers had generally attributed a In conclusion, this study shows that in population of lower arteriolar-to-venular ratio (AVR) to generalized ar- 12-year-old Chinese children, increasing blood pressure teriolar narrowing and suggested that this ratio may was significantly associated with narrower retinal arteri- provide information that would predict incident cardio- olar caliber but not with retinal venular caliber, and pos- vascular diseases. But with the advent of semi-automatic sible confounding factors such as sex et al. had no effect examination, it makes it possible to measure arteries and on the relationship between BP and retinal vessel di- veins in retinal fundus separately. Since 2004, Ikram [27] ameters. This finding provided further insight into the and other researchers confirmed that elevated blood relationship of elevated BP on the microcirculation pressures were associated with smaller arteriolar diame- that occurs in early life. The association of wider ret- ters, but larger venular diameters were related to athero- inal venular caliber and hypertension has not yet been sclerosis, inflammation, and cholesterol levels. Hence, consistently found, which should remain one of our the idea that the AVR overall reflects generalized arteriolar highest research priorities. He et al. BMC Ophthalmology (2018) 18:133 Page 11 of 12 Abbreviations stroke: the multi-ethnic study of atherosclerosis (MESA). Stroke. 2012; BMI: Body mass index; BP: Blood pressure; CRAE: Central retinal arteriolar 43(12):3245–51. equivalents; CRVE: Central retinal venular equivalents; DBP: Diastolic blood 8. Hughes AD, Falaschetti E, Witt N, Wijetunge S, Thom SA, Tillin T, Aldington pressure; MABP: Mean arterial blood pressure; SBP: Systolic blood pressure SJ, Chaturvedi N. Association of Retinopathy and Retinal Microvascular Abnormalities with Stroke and cerebrovascular disease. Stroke. 2016;47(11): Acknowledgements 2862–4. The authors thank the support from the Anyang city government for helping 9. Lim LS, Cheung CY, Sabanayagam C, Lim SC, Tai ES, Huang L, Wong TY. to organize the survey. We acknowledge the University of Wisconsin Fundus Structural changes in the retinal microvasculature and renal function. Invest Photograph Reading Center and Nicola Ferrier of the School of Engineering Ophthalmol Vis Sci. 2013;54(4):2970–6. at University of Wisconsin for providing the software of measuring retinal 10. Karatzi K, Protogerou AD, Moschonis G, Tsirimiagou C, Androutsos O, vessels calibers. Chrousos GP, Lionis C, Manios Y. Prevalence of hypertension and hypertension phenotypes by age and gender among schoolchildren in Availability of data and materials Greece: the healthy growth study. Atherosclerosis. 2017;259:128–33. The datasets used and/or analysed during the current study are available 11. Liang YJ, Xi B, Hu YH, Wang C, Liu JT, Yan YK, Xu T, Wang RQ. Trends in from the corresponding author on reasonable request. blood pressure and hypertension among Chinese children and adolescents: China health and nutrition surveys 1991-2004. Blood Press. 2011;20(1):45–53. Authors’ contributions 12. Li SM, Liu LR, Li SY, Ji YZ, Fu J, Wang Y, Li H, Zhu BD, Yang Z, Li L, et al. YH performed all of the retinal vessel pictures and wrote the whole Design, methodology and baseline data of a school-based cohort study in manuscript. S-ML designed the study and supervised the progress of the Central China: the Anyang childhood eye study. Ophthalmic Epidemiol. entire study. M-TK, L-RL and HL participated in the design of the experiment, 2013;20(6):348–59. data collection and analysis. S-FW and A-RR undertook the statistical analysis 13. Henderson AD, Bruce BB, Newman NJ, Biousse V. Hypertension-related eye of sample data. NW designed the study, supervised the progress of the abnormalities and the risk of stroke. Rev Neurol Dis. 2011;8(1–2):1–9. entire study, revised the manuscript and finally agreed to submission. All 14. Wong TY, Hubbard LD, Klein R, Marino EK, Kronmal R, Sharrett AR, Siscovick authors read and approved the final manuscript. DS, Burke G, Tielsch JM. Retinal microvascular abnormalities and blood pressure in older people: the cardiovascular health study. Br J Ophthalmol. Ethics approval and consent to participate 2002;86(9):1007–13. Ethics approval was obtained from the institutional review board of Beijing 15. Sharrett AR, Hubbard LD, Cooper LS, Sorlie PD, Brothers RJ, Nieto FJ, Tongren Hospital, Capital Medical University, and followed the tenets of the Pinsky JL, Klein R. Retinal arteriolar diameters and elevated blood declaration of Helsinki. Informed written consent was obtained from at least pressure: the atherosclerosis risk in communities study. Am J Epidemiol. one parent. Verbal assent was obtained from each child. 1999;150(3):263–70. 16. Jeganathan VS, Sabanayagam C, Tai ES, Lee J, Sun C, Kawasaki R, Nagarajan Competing interests S, Huey-Shi MH, Sandar M, Wong TY. Effect of blood pressure on the retinal All of the authors declare that they have no competing interests. vasculature in a multi-ethnic Asian population. Hypertension research : official journal of the Japanese Society of Hypertension. 2009;32(11):975–82. 17. Sun C, Liew G, Wang JJ, Mitchell P, Saw SM, Aung T, Tai ES, Wong TY. Publisher’sNote Retinal vascular caliber, blood pressure, and cardiovascular risk factors in an Springer Nature remains neutral with regard to jurisdictional claims in Asian population: the Singapore Malay eye study. Invest Ophthalmol Vis Sci. published maps and institutional affiliations. 2008;49(5):1784–90. 18. Kawasaki R, Cheung N, Wang JJ, Klein R, Klein BE, Cotch MF, Sharrett AR, Shea Author details 1 S, Islam FA, Wong TY. Retinal vessel diameters and risk of hypertension: the Beijing Tongren Eye Center, Beijing Tongren Hospital, Beijing multiethnic study of atherosclerosis. J Hypertens. 2009;27(12):2386–93. Ophthalmology & Visual Science Key Lab, Beijing Institute of Ophthalmology, 19. Wong TY, Klein R, Klein BE, Meuer SM, Hubbard LD. Retinal vessel diameters Capital Medical University, Beijing, China. Anyang Eye Hospital, Anyang, and their associations with age and blood pressure. Invest Ophthalmol Vis Henan, China. Sci. 2003;44(11):4644–50. 20. 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BMC OphthalmologySpringer Journals

Published: Jun 4, 2018

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