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INTRODUCTION

Myopic retinopathy is characterized by degenera-tion of chorioretinal tissues resulting from excessive axial elongation of the eye, and includes the signs of posterior staphyloma, lacquer cracks, choroidal neo-vascularization (CNV), and chorioretinal atrophy.1–3 Myopic retinopathy has been reported to be an important cause of visual impairment and a leading cause of legal blindness in many population-based studies.3–5

Retinal structural and functional changes in eyes with high myopia (refraction greater than −6.00 diopter (D)) were evaluated by previous studies.6–14 Compared to more frequent milder degrees of myopia, eyes with high myopia were

found to have thinner macular and retinal nerve fiber layer thickness in the peripapillary area, with reduced visual function as assessed using multifo-cal electroretinograms.6,7 Using color Doppler imag-ing, a significant reduction in choroidal and retinal blood flow has been observed in highly myopic eyes.8–10 The blood flow resistance index in the pos-terior ciliary artery was also increased in myopic eyes with CNV compared to fellow eyes without CNV.11 Using fluorescein angiography, Avetisov et al. reported a delay in fluorescein transit times in eyes with myopic retinopathy compared to eyes with low to moderate levels of myopia without retinopathy.12 However, findings from a popula-tion-based study did not show significant changes in retinal vessel caliber in high myopic eyes after

Ophthalmic Epidemiology, 18(6), 275–280, 2011Copyright © 2011 Informa Healthcare USA, Inc.ISSN: 0928-6586 print/ 1744-5086 onlineDOI: 10.3109/09286586.2011.602508

Received 13 March 2011; revised 29 April 2011; accepted 23 June 2011

Correspondence: Jie Jin Wang, Centre for Vision Research, University of Sydney, Westmead Hospital, Hawkesbury Road, Westmead, NSW 2145, Australia. Tel: +61 2 9845 5006. Fax: +61 2 9845 8345. E-mail: jiejin_wang@wmi.usyd.edu.au

13 March 2011

29 April 2011

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ORIGINAL ARTICLE

Retinal Vessel Caliber and Myopic Retinopathy: The Blue Mountains Eye Study

Haitao Li1, Paul Mitchell1, Elena Rochtchina1, George Burlutsky1, Tien Y. Wong2,3, and Jie Jin Wang1,2

1Centre for Vision Research, Department of Ophthalmology &Westmead Millennium Institute, University of Sydney, Australia, 2Centre for Eye Research Australia, Department of Ophthalmology,

University of Melbourne, Australia, and 3Singapore Eye Research Institute, National University of Singapore, Singapore

ABSTRACT

Purpose: To evaluate changes in the retinal vasculature in eyes with myopic retinopathy.

Methods: Population-based, cross-sectional study. Emmetropic and myopic participants from the Blue Mountains Eye Study baseline survey were included in this study. Myopia was defined as a refractive error of less than −1.00 diopter. Myopic retinopathy was defined if either staphyloma, lacquer crack, Fuchs’ spot or chorioretinal atrophy were present in myopic eyes. Retinal vascular caliber was measured from fundus photographs using standardized methods. The association of retinal vascular caliber with myopic retinopathy was assessed using generalized estimating equation models.

Results: A total of 2598 eyes of 1409 subjects were selected from 3654 baseline participants, with 2076 emme-tropic eyes (normal controls), 486 myopic eyes without myopic retinopathy (myopic controls) and 36 myopic eyes with myopic retinopathy (cases). After adjusting for age, gender, height, body mass index and blood pressure, eyes with myopic retinopathy had significantly narrower mean arteriolar (166.6μm) and venular caliber (213.3μm), compared to normal (188.1μm and 226.9μm, respectively) or myopic control eyes (190.4μm and 227.0μm, respectively) (all P < 0.001). These retinal vessel caliber differences between myopic retinopathy and the two control groups remained significant after additional adjustment for refraction (all P < 0.001).

Conclusions: Our findings suggest that myopic retinopathy is associated with attenuation of retinal vessels.

Keywords: Myopic retinopathy, Myopia, Retinal vascular caliber, Refractive error, Retinal microvasculature

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correcting for refractive magnification.13 Instead, a significant reduction in vascular geometric complex-ity was documented in myopic eyes with a refractive error greater than −6D.14

In this study, we compared the mean retinal vascu-lar caliber between eyes with myopic retinopathy and eyes that were emmetropic or myopic but which did not have myopic retinopathy signs, after adjusting for pos-sible confounding co-variables, in a well-characterized older population in Australia.

METHODS

Study Population

The Blue Mountains Eye Study (BMES) is a cohort study of older Australians (aged 49–97 years) living in a suburban area west of Sydney (baseline survey conducted during 1992–1994). Detailed study meth-ods were described previously.15 Retinal photographs and other data from the baseline examinations were used in this study. All participants underwent detailed systemic and ocular examinations. The study was conducted according to recommendations of the Declaration of Helsinki and approved by the Sydney West Area Health Service Human Research Ethics Committee. Written, informed consent was obtained from all participants.

Measurement of Refraction and Definitions of Subgroup

Refraction was measured using a standard protocol described previously.16 Following objective refraction with an autorefractor (Model 530, Humphrey, San Leandro, CA), subjective refraction was performed according to a modification of the Early Treatment Diabetic Retinopathy Study protocol using a logMAR chart. Baseline refraction data were converted to spheri-cal equivalent refractive power (SER), calculated as the sum of the best-corrected spherical plus half the cylin-der power. Emmetropia was defined as SER between -1.00 D and +1.00 D inclusive. Myopia was defined as SER less than−1.00 D.

Only emmetropic (both eyes having emmetropic refraction) and myopic subjects (at least one eye hav-ing a myopic refraction) were included in this study. In myopic subjects, only myopic eyes were included. Eyes with missing or ungradable retinal photographs, or with glaucoma, aphakia or pseudophakia, or that had been enucleated were excluded from the study. Eyes that had β-peripapillary atrophy (β-PPA) alone were also excluded, as β-PPA is not specific to myopia-related changes but a degenerative change associated with many other ocular disorders, such as glaucoma and aging.3,17,18

Grading of Myopic Retinopathy

At the baseline examination, 30-degree retinal photo-graphs of the optic disc, macula, and other retinal fields of both eyes were taken after pupil dilation using a Zeiss FF3 fundus camera (Carl Zeiss, Oberkochen, Germany). The 35-mm retinal slides were mounted in clear plastic sleeves and examined using a Donaldson stereoviewer and fluorescent viewing box, and then graded for signs of myopic retinopathy.

β-PPA was defined according to the descriptions by Jonas et al.17 Myopic retinopathy was diagnosed in myopic eyes that had any of the following signs: staphy-loma, lacquer cracks, Fuchs’ spot, myopic chorioretinal thinning or atrophy.3 Staphyloma was diagnosed when the border of an ectasia was visualized.19 Care was taken to distinguish staphyloma from coloboma; lacquer cracks from angioid streaks or age-related maculopa-thy (ARM); Fuchs’ spot from central pigmented lesions caused by ARM, toxoplasmosis or other conditions; myopic chorioretinal atrophy from the atrophic signs of ARM, toxoplasmosis, or laser scars. All signs were adju-dicated and confirmed by a retinal specialist (PM).

Measurement of Retinal Vascular Caliber

Optic disc-centered photographs were digitized in monochrome and graded for retinal vascular caliber. Retinal arteriolar and venular calibers were measured using a computer-assisted program (Howard pro-gram, University of Wisconsin, described elsewhere).20 Vessels passing through a pre-specified zone between 0.5 to 1.0 disc diameter away from the optic disc mar-gin were measured. Individual vessel caliber mea-sures were summarized using formulae developed by Parr and Hubbard.21 The summarized indices, central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE), represent the estimated mean retinal arteriolar and venular caliber of an eye. A cor-rection factor (1–0.017SER) described by Bengtsson was used to account for magnification effects resulting from refraction.13,22

Measurement Relevant Systemic Factors

Systolic and diastolic blood pressure (BP) measure-ments were taken at the baseline visit, using a mercury sphygmomanometer with appropriate adult cuff size on each participant, after being seated for at least 10 minutes. Mean arterial BP was calculated as (0.33 × sys-tolic BP + 0.67 × diastolic BP).13 Diabetes was defined as a physician diagnosis of diabetes or a fasting blood glucose level of ≥7.0 mmol/L.23 Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared.24 Smoking history was collected for all participants using an interviewer-administered

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questionnaire and smoking status was defined as cur-rent smoking or non-current smoking (never smoked and past smoking).25

Statistical Analysis

The eyes included in this study were divided into three groups: normal controls (emmetropia without retinal pathology), myopic controls (myopia without myopic retinopathy), and myopic retinopathy cases. Eye-specific data were analyzed using SAS (version 9.1; SAS Institute, Cary, NC.). Generalized estimating equa-tion (GEE) models were used to assess the relationship between myopic retinopathy, CRAE and CRVE, while taking into account the correlation between the two eyes. Given 36 myopic eyes, our study is able to detect a minimum difference of 7.7μm in mean CRAE between any two groups, with 80% power and 5% two-sided significance level. Model 1 adjusted for age, gender, height, BMI and mean arterial BP; Model 2 included all variables in Model 1 plus refraction, to assess whether vascular changes associated with myopic retinopathy were independent of refraction. Model 3 included all variables in Model 2 plus diabetes and smoking status, to exclude the influence of systemic factors on vascular caliber measurement. Model 4 included all variables in Model 1 plus CRVE in model for CRAE and vice visa, to assess if their associations with myopic retinopathy were independent of the fellow vessel caliber, given the relatively high correlation between the two (r = 0.59).26 As myopic retinopathy is strongly associated with the level of myopic refraction,3 and retinal vessel caliber was documented to be associated with image magnification associated with refraction,13 we attempted to separate the associations of CRAE with myopic retinopathy from the association of CRAE with image magnification due to refraction, and therefore performed subgroup analy-ses on the associations of CRAE with refraction levels in the three stratified subgroups (normal control, myopic control and myopic retinopathy groups). The intercepts, or the starting points of the linear regression lines at the same refractive level of zero diopter, and the slopes

(β coefficients) of the regression lines, were compared among the three groups. P values less than 0.05 were considered to be statistically significant.

RESULTS

We included 2878 eyes from 1549 BMES participants initially, and further excluded 280 eyes with either glau-coma or β-PPA without any other myopic retinopathy changes. Of the 2598 eyes included (1409 subjects), 2076 were emmetropic without any retinal pathology (normal controls), 486 were myopic without myopic retinopathy (myopic controls) and 36 were myopic with signs of myopic retinopathy (cases) (Table 1). Eyes with myopic retinopathy had considerably more myopic refraction (mean −7.66 D, 95% confidence interval (CI): −9.13 D, −6.20 D, range: −17.88D to −1.13D) than myopic controls (mean −2.76 D, 95% CI: −2.92 D, −2.61 D, range: −11.13 D to −1.10D) (P < 0.0001) (Table 1). Except for a slightly older mean age and lower frequency of current smok-ers in participants with myopic retinopathy compared with the two control groups (P < 0.05), there were no significant differences in gender, mean height, BMI, BP, or in the frequency of diabetes among the three groups (all P > 0.05).

Table 2 shows the associations of covariables with CRAE or CRVE, assessed in Model 3 where all the vari-ables were included in the same GEE model. Age, gen-der and current smoking were significantly associated with both CRAE and CRVE. High blood pressure was associated with narrower CRAE and higher BMI was associated with wider CRVE. No significant association was found between refractive error and retinal vascular calibers.

Retinal Vascular Caliber

There were no significant differences for all vascu-lar parameters examined between the emmetropic and myopic control groups, whereas the mean ves-sel caliber was significantly narrower in eyes with

TABLE 1. Characteristics of subjects with emmetropia and with myopia with or without myopic retinopathy.Parameter Emmetropia Myopia without retinopathy Myopic retinopathyEyes (n) 2076 486 36Refraction (diopter) 0.19 (0.17, 0.21) −2.76 (−2.92, −2.61)* −7.66 (−9.13, −6.20)*†

Age (years) 61.6 (61.3, 62.0) 63.4 (62.4, 64.36)* 68.8 (65.9, 71.6)*Sex (male %) 47.2 43.8 33.3Height (cm) 166.1 (165.7, 166.5) 166.4 (165.5, 167.2) 165.6 (162.3, 168.9)Body mass index (kg/m2) 26.5 (26.3, 26.7) 25.9 (25.5, 26.3) 27.3 (25.5, 29.0)Mean arterial BP (mmHg) 103.5 (103.0, 104.0) 103.8 (102.7, 104.9) 104.6 (101.1, 108.0)Diabetes (%) 7.7 5.1 11.8Current tobacco smoker (%) 16.5 19.4 3.0*†

All data are expressed as frequency (%) or means with 95% confidence intervals. BP, blood pressure*P < 0.05 results comparing myopia (with or without myopic retinopathy) to emmetropia.†P < 0.05 results comparing myopic retinopathy to myopia without myopic retinopathy.

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myopic retinopathy compared to both control groups (Table 3). After adjusting for age, gender, height, BMI and BP (Model 1), the mean CRAE was more than 20μm narrower in eyes with myopic retinopathy than the mean CRAE for the two control groups (P < 0.001). The mean CRVE was also substantially narrower in the myopic retinopathy group (P < 0.001). Additional adjustments for refraction level (Model 2) and dia-betes and current smoking status (Model 3) did not alter the associations of CRAE and CRVE with myopic retinopathy. Further adjustment for the fellow vessel caliber (Model 4) did not alter the differences in mean CRAE, but the differences in mean CRVE became non-significant (P > 0.05) (Table 3).

Figure 1 shows homogeneity in the β coefficients (the slope of the linear pattern in the associations) between CRAE and refraction level across the three subgroups (P ≥ 0.158). However, differences in mean values of arteriolar caliber were consistent across all levels of

TABLE 3 Comparisons of retinal vascular caliber between myopic retinopathy and emmetropia and myopia without myopic retinopathy

Vascular parameters Emmetropia (2076 eyes) Myopia without retinopathy (486 eyes)

Myopic retinopathy (36 eyes) P* P†

CRAE (μm) Model 1 188.1 (187.2, 189.0) 190.4 (188.5, 192.2) 166.6 (158.8, 174.4) <0.001 <0.001Model 2 188.3 (187.3, 189.4) 189.4 (186.8, 191.9) 163.7 (154.8, 172.6) <0.001 <0.001Model 3 187.9 (187.0, 189.2) 189.5 (186.8, 192.1) 164.4 (155.5, 173.9) <0.001 <0.001Model 4 188.1 (187.3, 188.8) 190.3 (188.8, 191.8) 172.4 (165.8, 178.9) <0.001 <0.001CRVE (μm) Model 1 226.9 (225.9, 228.0) 227.0 (224.8, 229.2) 213.3 (205.5, 221.1) <0.001 <0.001Model 2 227.6 (226.5, 228.7) 224.4 (221.4, 227.3) 205.2 (195.1, 215.3) <0.001 <0.001Model 3 227.5 (226.3, 228.6) 224.6 (221.7, 227.6) 204.3 (193.7, 214.9) <0.001 <0.001Model 4 227.0 (226.1, 227.9) 226.0 (224.2, 227.8) 224.1 (217.4, 230.9) 0.408 0.598All data are expressed as means with 95% confidence intervals.CRAE, central retinal artery equivalent; CRVE, central retinal vein equivalent;Model 1: Generalized estimating equation model adjusting for age, gender, height, body mass index, blood pressure.Model 2: Included all variables in Model 1, plus refractive error.Mode 3: Included all variables in Model 2, plus presence of diabetes and current smoking status.Model 4: Included all variables in Model 1, plus CRVE in the model for CRAE or CRAE in the model for CRVE.*P value comparing myopic retinopathy to emmetropia.†P value comparing myopic retinopathy to myopia without retinopathy.

FIGURE 1 Associations of central retinal arteriolar equivalent (CRAE) with refraction by three subgroups of emmetropia (nor-mal control, dotted line), myopia only (myopic control, solid line) and myopic retinopathy (broken line).

TABLE 2. Association (β coefficients*) of covariables with retinal vascular caliber using generalized estimating equation models (N = 2598 eyes) CRAE CRVECovariables β coefficients P β coefficients PAge (years) −0.25 <0.0001 −0.31 <0.0001Sex (male %) −3.49 0.004 2.90 0.044Height (cm) −4.11 0.536 −7.98 0.325Body mass index (kg/m2) −0.12 0.235 0.33 0.006Mean arterial BP (mmHg) −0.24 <0.0001 −0.06 0.147Diabetes 3.11 0.090 1.10 0.590Current tobacco smoking 5.75 <0.0001 9.93 <0.0001Refraction (diopter) 0.14 0.678 −0.18 0.540CRAE, central retinal artery equivalent; CRVE, central retinal vein equivalent*Age, sex, height, body mass index, blood pressure, diabetes, smoking and refraction were simultaneously adjusted in the same model.

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refraction (from −15 D to −1 D) between the myopic retinopathy group and the myopic control group. The stating points of the linear pattern (the intercept val-ues) at the same refractive level of zero diopter were heterogeneous (P < 0.0001). The intercept of the linear association in the myopic retinopathy group (161.9μm) was significantly lower than the intercepts of the two control groups (188.4μm for the normal control and 188.7μm for the myopic control) (P < 0.0001).

DISCUSSION

In this older population, we showed that eyes with signs of myopic retinopathy had narrower retinal arterioles and venules than either emmetropic eyes or myopic eyes without retinopathy. The reduction in vascular caliber in eyes with myopic retinopathy was independent of its association with refraction, although high myopia and myopic retinopathy are closely related.3

In the analyses of the associations between refraction and retinal arteriolar caliber stratified by myopia and myopic retinopathy status, we observed differences in mean values of arteriolar caliber across all levels of refraction from −15 D to −1 D between the myo-pic retinopathy group and the myopic control group, but no significant differences in the magnitude of the associations between CRAE and refraction level (i.e. the β coefficients of the linear associations) across the three groups (Fig. 1). In other words, eyes with myopic retinopathy had substantially narrower retinal vascular caliber compared to myopic eyes without retinopathy, and the difference was consistent across all levels of myopic refraction from −15 D to −1 D. These findings suggest that the degenerative changes that comprise myopic retinopathy may include an attenuation of the retinal arterioles and venules, independent of the myo-pic refraction level.

Our finding that the significant association between narrower retinal venular caliber and myopic retinopa-thy became non-significant after adjusting for arteriolar caliber, could be explained by the likely confounding effect of arteriolar caliber on the association of myo-pic retinopathy with venular caliber. Retinal arteriolar and venular caliber are highly correlated, and retinal arteriolar caliber is strongly associated with myopic retinopathy.

Other mechanisms are also possible, in addition to eye ball elongation, to explain the demonstrated changes in the retinal microvasculature in eyes with myopic retinopathy. It is known that retinal vessels have no autonomic innervation and are regulated by vascular endothelial cells that respond to variation in perfusion pressure, as well as by the neural retinal tis-sue responses to changes in retinal activity.27 Possible explanations for the association between myopic retin-opathy and alterations in the retinal vasculature may

include two mutually related pathways: first, neural retinal atrophy in myopic retinopathy may lead to a decrease in oxygen demand and consequent decrease in blood flow and secondary narrowing of the lumen of small vessels; second, reduced retinal blood supply (narrowing of retinal vascular caliber) may induce retina ischemia and thus lead to myopic degenerative changes in the chorioretinal tissues. Our data, however, cannot determine whether the retinal vascular caliber narrow-ing antecedes or is consequential to the occurrence of myopic retinopathy, so that further longitudinal studies are needed.

Strengths of our study include its population-based sampling, standardized assessment of myopic retinopa-thy, and quantitative measurements of vascular caliber from digitized fundus photographs using validated computer-assisted programs. Limitations should also be noted. The number of eyes with myopic retinopathy was relative small (n = 36). The reasons for this are two-fold: first, the prevalence of retinal retinopathy in this older population was only 1.2%.3 Second, a large pro-portion of the eyes with myopic retinopathy either had relatively dense cataract with ungradable photographs, or had undergone cataract surgery, so that their base-line refractive status was unknown. Although potential measurement errors may exist for measures of retinal vascular caliber,13 these errors are likely to be random and should only lead to an underestimate of the associa-tions observed.

In summary, we found that myopic retinopathy was associated with narrower retinal arterioles, and that this association was independent of the level of myo-pic refraction. Our findings suggest that degenerative changes typically associated with myopic retinopathy involve an attenuation of the retinal vessels.

ACKNOWLEDGMENTS

Source of Funding: Australian National Health & Medical Research Council (NHMRC, Project grant IDs: 153948, 211069 & 302068), Singapore Bioimaging Consortium (SBIC RP C-011/2006) and Biomedical Research Council (Grant No 501/1/25-5), and Pfizer Australia (Cardiovascular Lipid Grant 2007). JJW is funded by a National Health & Medical Research Council Senior Research Fellowship (2005–2014).

Declaration of interest: The authors report no conflict of interest. The authors alone are responsible for the content and writing of the article.

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