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(Hypertension. 2003;42:534.)
© 2003 American Heart Association, Inc.

Scientific Contributions

Hypertensive Retinal Vessel Wall Signs in a General Older Population

The Blue Mountains Eye Study

Jie Jin Wang; Paul Mitchell; Harry Leung; Elena Rochtchina; Tien Yin Wong; Ronald Klein

From the Centre for Vision Research, Department of Ophthalmology and the Westmead Millennium and Save Sight Institutes, the University of Sydney (J.J.W., P.M., H.L., E.R.), Australia; Singapore National Eye Center and National University of Singapore (T.Y.W.), Singapore; and the Department of Ophthalmology and Visual Science, University of Wisconsin-Madison (R.K.), Wis.

Correspondence to Jie Jin Wang, MMed, PhD, Centre for Vision Research, Department of Ophthalmology, University of Sydney, Westmead Hospital, Hawkesbury Road, Westmead, NSW Australia, 2145. E-mail jiejin_wang{at}wmi.usyd.edu.au

	Abstract

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To describe cross-sectional relations between hypertension and retinal vessel wall signs in an older white population. These signs were defined from fundus photographs in 3654 Blue Mountains Eye Study participants 49 years of age. Focal arteriolar narrowing and arteriovenous nicking were graded through the use of standard protocol. Photographs were digitized to measure retinal vessel diameters. Average arteriolar diameter, summarized as central retinal arteriolar equivalent and arteriole-to-venule ratio, were used as indexes of generalized arteriolar narrowing. Blood pressure was measured with the use of a mercury sphygmomanometer. Hypertension was defined through the use of antihypertensive medications, systolic blood pressure 160 mm Hg, or diastolic blood pressure 95 mm Hg. Hypertension was categorized as controlled (using medication, normal blood pressure), uncontrolled (using medication, high blood pressure), or untreated (not using medication). Hypertensive subjects had higher prevalence of all retinal microvascular signs. After adjusting for age, gender, body mass index, and smoking, persons with controlled (18.2%), uncontrolled (13.8%), or untreated hypertension (13.8%) were significantly more likely than normotensive subjects (54.2%) to have (a) lower central retinal arteriolar equivalent: adjusted odds ratios 1.5, (95% CI, 1.1 to 1.9), 2.1 (1.6 to 2.7), and 2.1 (1.6 to 2.7), respectively, and lower arteriole-to-venule ratio: 1.3 (1.0 to 1.6), 1.4 (1.1 to 1.8), and 1.7 (1.3 to 2.2), respectively; (b) focal arteriolar narrowing: 1.3 (0.9 to 1.9), 2.2 (1.5 to 3.2), and 2.5 (1.8 to 3.6), respectively; and (c) arteriovenous nicking: 1.3 (0.9 to 1.8), 2.3 (1.6 to 3.2), and 1.9 (1.3 to 2.7), respectively. Our findings demonstrate a strong relation between presence and severity of hypertension and retinal microvascular structural changes.

Key Words: age • antihypertensive therapy • arterioles • blood pressure • microcirculation • cross-sectional studies

	Introduction

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Hypertensive retinal microvascular signs include a spectrum of lesions, such as generalized¹ and focal retinal arteriolar narrowing,^1,2 arteriovenous (AV) nicking,³ and retinopathy.^4,5 These signs are important markers of microvascular damage from elevated blood pressure. Previous studies on hypertensive retinal microvascular disease have been mainly conducted on highly selected, clinic-based patients and have used clinical ophthalmoscopy to define vessel wall changes, a method that has poor reproducibility. Recent developments in grading these structural changes from photographs have allowed a more precise documentation of hypertensive retinal microvascular signs in the general population.^3–7

In the Beaver Dam Eye Study (4926 participants, 43 to 86 years of age), nondiabetic subjects with uncontrolled hypertension despite use of antihypertensive medications were more frequently found to have nondiabetic retinopathy lesions, focal arteriolar narrowing, or AV nicking at baseline than those who were normotensive or hypertensive but controlled.³ Incident focal arteriolar narrowing or retinopathy was more likely to develop in these subjects over a 5-year period.⁸

In the Atherosclerosis Risk in Communities (ARIC) Study population (11 114 participants, 48 to 73 years of age at the third examination round), mean arterial blood pressure was significantly associated with focal arteriolar narrowing, AV nicking, and retinopathy, independent of age, gender, race, and smoking.⁶

However, the assessment of early signs of hypertensive retinopathy such as generalized retinal arteriolar narrowing has remained problematic because of limited precision in these largely qualitative grading methods. In the ARIC study, a semiautomated, computer-based technique was developed to measure retinal vessel diameters from digitized photographs. Using this technique, the ARIC Study reported that generalized arteriolar narrowing was strongly associated not only with current blood pressure but also with blood pressure measured 3 years and 6 years before the retinal assessment.⁷ Similar findings were observed in the Cardiovascular Health Study (CHS) population (2056 nondiabetic participants, 69 to 97 years of age).⁹ These data therefore suggest that generalized retinal arteriolar narrowing reflect previously elevated blood pressure and may be a useful indicator of hypertensive severity and control.

In the Blue Mountains Eye Study (BMES), a population-based survey of older white Australians, we previously reported the association of more severe retinopathy lesions (microaneurysms and hemorrhages) and the presence and severity of hypertension in persons without diabetes.⁵ We have now applied the quantitative methods used in the ARIC Study to measure retinal vessel diameters in the BMES.¹⁰ In the current study, we examined the association between hypertension control and presence of retinal vessel wall signs (structural microvascular changes), including generalized retinal arteriolar narrowing, focal arteriolar narrowing, and AV nicking.

	Methods

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The Blue Mountains Eye study is a population-based cohort study of vision, common eye diseases, and other health outcomes in an urban population 49 years of age. Baseline participants (n=3654) represented 82.4% of those eligible living in two postcodes of the Blue Mountains, west of Sydney, Australia. The study was approved by the Western Sydney Area Human Ethics Committee, and written informed consent was obtained from all participants.¹¹

At the baseline examinations (1992 to 1994), blood pressure (BP) was measured once, using a single mercury sphygmomanometer with an appropriate cuff size, after participants had been seated for at least 10 minutes. Systolic and diastolic blood pressures (SBP and DBP) were recorded from the first and fifth Korotkoff sounds. Mean arterial blood pressure (MABP) was calculated as 0.33 (SBP)+0.67 (DBP). Because this is an older population, we defined hypertension as present in persons who were currently using antihypertensive medications or were found to have SBP 160 mm Hg or DBP 95 mm Hg at the time of the examination. Hypertensive subjects were divided into 3 groups: controlled (using medication, normal BP at examination), uncontrolled (using medication, elevated BP at examination), and untreated (elevated BP at examination but not using medication). Isolated systolic hypertension was defined as present in persons with normal diastolic BP (<95 mm Hg) but with elevated systolic BP (160 mm Hg). Diabetes was diagnosed by either medical history or fasting blood glucose 7.0 mmol/L at the baseline examination. Body weight and height were measured and body mass index (BMI) was calculated as weight (kg)/height (m)².

Dilated 30° stereoscopic retinal photographs of the macula, optic disc, and other retinal fields of both eyes were taken with the use of a Zeiss FF3 fundus camera (Carl Zeiss). Retinal photographs of both eyes were taken in 98% of study participants. Focal arteriolar narrowing and arteriovenous (AV) nicking were graded from 35-mm slides of both eyes by one grader, using a light box (Kelvin rating 6200°) and a Donaldson stereo-viewer with x5 magnification. Only arterioles located at least one half-disc diameter away from the optic disc margin were assessed for focal arteriolar narrowing. Standard photographs for retinal microvascular signs were selected by a retinal specialist from the standard photographic set developed for the Modified Airlie House Classification of Diabetic Retinopathy¹² and the Wisconsin Age-related Maculopathy Grading System.¹³ Focal arteriolar narrowing was graded as absent/questionable (none/less severe than the standard photograph) or present (equal to or more severe than the standard). AV nicking (nipping) was defined as a decrease in venular width on both sides of the venule where crossed by an arteriole and was graded as absent/questionable, mild (less than the standard), or moderate to severe (equal to or greater than the standard). The intragrader reliability for detecting focal arteriolar narrowing and AV nicking were ( statistic) 0.80 and 0.87, respectively. Lesions in the worse eye were chosen to classify the person.

A computer-assisted grading method with high reproducibility was used to measure retinal vessel width. Details of this method have been described previously.^10,14,15 Average retinal arteriolar or venular width (diameter) was calculated by means of the Parr-Hubbard formula^6,16 and is presented as the central retinal arteriolar equivalent (CRAE) or central retinal venular equivalent (CRVE). Arteriovenous ratio (AVR) was calculated from CRAE and CRVE. Generalized retinal arteriolar narrowing was defined as CRAE or AVR within the lowest quintile in the population. Intragrader and intergrader reliability of this method was high,¹⁴ with quadratic weighted values of 0.85 (CRAE) and 0.90 (CRVE) found for intergrader reliability and between 0.80 to 0.93 and 0.80 to 0.92 for intragrader reliability of graders 1 and 2, respectively. Since good correlation in the measurements between right and left eyes was found in our study population previously,¹⁵ we believe that measurement of vessel diameters from one eye is adequate.

Statistical Methods
The Statistical Analysis System (SAS, SAS Institute) was used for statistical analysis. Study variables included MABP (in quintiles) and presence of hypertension. Subjects with controlled, uncontrolled, or untreated hypertension were compared with the normotensive group. Subjects with isolated systolic hypertension were compared with normotensive subjects, after excluding those using antihypertensive medications or with elevated diastolic BP. Logistic regression analysis was performed to assess associations between the hypertension status, MABP, and each of the retinal vessel outcome variables, adjusting for age, gender, BMI, and smoking. Similar analyses were also performed separately for subjects with and without diabetes. Adjusted means of the CRAE and AVR were obtained by covariance analysis (general linear model). Odds ratios, 95% confidence intervals, and adjusted P values for trend are presented.

	Results

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Of the 3654 BMES baseline participants, 3541 (96.9%) had photographs gradable in at least one eye for focal arteriolar narrowing and AV nicking by means of the manual grading method and 3355 (91.8%) had photographs of at least one eye (mainly the right eye) gradable for generalized arteriolar narrowing by means of the computer-assisted method. There were 40 participants with missing or incomplete blood pressure or hypertension data. Of the 3614 remaining participants, 1858 (54.2%) were normotensive, 659 (18.2%) had controlled hypertension, 498 (13.8%) had uncontrolled hypertension, and 499 (13.8%) had untreated hypertension. Of the 3541 participants with gradable photographs, focal retinal arteriolar narrowing was detected in 280 (7.9%). Mild and moderate to severe AV nicking (nipping) was found in 1415 (40.0%) and 316 (8.9%) of participants, respectively. Diabetes was diagnosed in 281 participants (7.8%). Table 1 shows the proportion of the population with hypertension and retinal vessel wall signs by age group. Prevalence of both uncontrolled and untreated hypertension increased with age. All retinal microvascular signs also demonstrated significant age-related trends except for AVR.

View this table: [in this window] [in a new window]   TABLE 1. Frequency Distribution (%) of Hypertension and Retinal Vessel Wall Signs by Age in the Blue Mountains Eye Study Population

Tables 2 and 3 show the relation between MABP and retinal vessel wall signs in persons with and those without diabetes. After adjusting for age, gender, BMI and smoking, MABP was strongly associated with the presence of all retinal vascular wall signs in persons without diabetes. Compared with subjects with the lowest quintile of MABP, nondiabetic subjects with each higher quintile of MABP had an increasing likelihood of presenting with each of the retinal vessel wall signs. The increasing likelihood (odds ratios) showed a dose-response pattern corresponding to increasing MABP quintiles (P values for trend <0.0001) for all retinal vessel wall signs in subjects without diabetes. Among persons with diabetes, however, only the highest quintile of MABP was significantly associated with the narrowest quintile of central retinal arteriolar equivalent.

View this table: [in this window] [in a new window]   TABLE 2. Retinal Vessel Wall Signs by Quintiles of MAP in the Blue Mountains Eye Study Population, Stratified by Diabetes

View this table: [in this window] [in a new window]   TABLE 3. Generalized Retinal Arteriolar Narrowing by Quintiles of MAP in the Blue Mountains Eye Study Population, Stratified by Diabetes

Tables 4 and 5 show the relations between hypertension and retinal vessel wall signs in persons with and without diabetes. The age- and gender-adjusted mean central retinal arteriolar equivalent was 189, 186, 184, and 183 µm, respectively, among persons with normal blood pressure and controlled, uncontrolled, and untreated hypertension. The age- and gender-adjusted mean arteriole-to-venule ratio was 0.84, 0.83, 0.83, and 0.82, respectively, in the same groups.

View this table: [in this window] [in a new window]   TABLE 4. Retinal Vessel Wall Signs by Hypertension Group in the Blue Mountains Eye Study Population, Stratified by Diabetes

View this table: [in this window] [in a new window]   TABLE 5. Generalized Retinal Arteriolar Narrowing by Hypertension Group in the Blue Mountains Eye Study Population, Stratified by Diabetes

After further adjustment for BMI, smoking, and blood glucose level, the decreasing pattern in mean CRAE, CRVE, and AVR associated with hypertension remained and was similar for women and men (Figures 1, 2, and 3). Table 4 shows that after adjusting for age, gender, BMI, and smoking, nondiabetic subjects with uncontrolled or untreated hypertension were significantly more likely than normotensive subjects to have focal arteriolar narrowing and AV nicking. Table 5 shows that nondiabetic subjects with controlled, uncontrolled, and untreated hypertension were all significantly more likely than normotensive subjects to have generalized arteriolar narrowing. Tables 4 and 5 also demonstrate that nondiabetic persons with isolated systolic hypertension had a similar increased likelihood of having focal or generalized arteriolar narrowing and AV nicking. Among diabetic subjects, only persons with untreated hypertension were significantly more likely to have generalized arteriolar narrowing, as shown in Table 5.

View larger version (17K): [in this window] [in a new window]   Figure 1. Mean (±SE) CRAE by hypertension status and gender after adjusting for age, BMI, smoking, and blood glucose level.

View larger version (18K): [in this window] [in a new window]   Figure 2. Mean (±SE) CRVE by hypertension status and gender after adjusting for age, BMI, smoking, and blood glucose level.

View larger version (18K): [in this window] [in a new window]   Figure 3. Mean (±SE) AVR by hypertension status and gender after adjusting for age, BMI, smoking, and blood glucose level.

	Discussion

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We previously reported an association between retinopathy lesions and hypertension in persons without diabetes.⁵ In the current report, we investigate retinal vessel wall signs, including focal arteriolar narrowing and AV nicking (assessed using manual grading) and generalized arteriolar narrowing (assessed using a quantitative computer-based method).¹⁴ We have also explored the dose-relation between MABP levels and the likelihood of finding these retinal microvascular signs in persons with and without diabetes, after adjusting for age, gender, smoking, and BMI.

We demonstrated a strong association in this population between elevated blood pressure and the presence of each retinal microvascular sign, as previously reported in participants of the Beaver Dam Eye Study,^3,8 the ARIC study,^6,7 and the CHS.⁹ As in the CHS population, we found a dose-response relation between quintiles of blood pressure and the magnitude of association with each retinal microvascular sign.

In the Beaver Dam Eye Study, persons with uncontrolled or untreated hypertension were more likely to have focal arteriolar narrowing, and persons with untreated hypertension were significantly more likely to have AV nicking.³ Among persons without diabetes in the CHS population, those with uncontrolled or untreated hypertension were more likely to have focal arteriolar narrowing, whereas persons with uncontrolled hypertension were significantly more likely to have AV nicking or retinopathy.⁹ Our data support the findings from both of these studies, with a similar magnitude, a 2-fold higher prevalence of retinal microvascular signs among persons with uncontrolled or untreated hypertension compared with those without hypertension. Furthermore, our study indicates consistent associations across the whole spectrum of retinal microvascular signs for persons with either untreated or uncontrolled hypertension. Although controlled hypertension was not significantly associated with focal arteriolar narrowing or AV nicking, it was significantly associated with generalized arteriolar narrowing in our study. A recent report from the ARIC study documented that blacks have a higher prevalence of hypertensive retinopathy than whites and that the excess prevalence in blacks was partially explained by blood pressure and the severity of hypertension.¹⁷ Since retinal microvascular lesions are correlated with end-organ damage elsewhere^18–25 and independently predict stroke,^26,27 these data further support the importance of adequate control of elevated blood pressure in reducing the morbidity from hypertension.

Our data suggest that the association is strongest among persons without diabetes. The findings are very much in line with the recent report from the CHS.⁹ Among persons with diabetes, both our study and the CHS found weaker associations between blood pressure and most retinal microvascular signs. Both studies, however, had relatively low study power to investigate these associations in persons with diabetes. It is possible that slightly different processes masked the occurrence of retinal microvascular signs in persons with diabetes. For example, retinopathy in persons with diabetes may be more strongly related to blood glucose level and to the duration of diabetes, whereas retinopathy in persons without diabetes appears principally related to blood pressure level.⁵

Although we used standard photographs to grade focal arteriolar narrowing and AV nicking, the methodology in assessing these retinal microvascular signs is relatively subjective, with greater interobserver and intraobserver variability compared with the semiobjective assessment of generalized arteriolar narrowing.⁶ Despite this limitation, however, findings from our study (data not provided) and from the earlier ARIC report indicate that assessment of focal arteriolar narrowing and AV nicking can provide stroke risk information independent of other microvascular risk factors.²⁶

Although our data are cross-sectional, there are a number of biologically plausible mechanisms for the relation between elevated blood pressure or hypertension and retinal arteriolar caliber changes. In response to elevated BP, retinal arteriolar tone can increase through the process of autoregulation, leading to generalized arteriolar narrowing.¹ Persistent BP elevation can lead to hyperplasia, intimal thickening, and hyalinization of the tunica media, thereby reducing the lumen or internal diameter of retinal vessels.²⁸

Recently published longitudinal findings from the ARIC study^22,24–27 and a clinical cohort study²⁹ indicate that retinal microvascular signs carry prognostic information not only for subsequent strokes^26,27 but also for subsequent development of coronary heart disease^22,29 and diabetes.²⁴ In the ARIC study population, a positive association between retinal microvascular signs and cognitive impairment was also documented.²⁵ Retinal microvascular signs may thus predict subsequent development of these end-organ diseases, independent of other vascular risk factors. This is probably due to the unique value of retinal vessel images in providing information on microvascular structural change resulting from elevated blood pressure and other vascular risk factors.²⁰

Perspectives
Data from the Australian Blue Mountains Eye Study support and strengthen recent findings from older US populations (the Beaver Dam Eye Study, ARIC, and CHS) that retinal microvascular signs are strongly related to blood pressure levels or hypertension. The consistency of the findings from population-based studies, including the dose-response relations reported herein, suggest that elevated blood pressure may be involved in the pathogenesis of these lesions. Adequate control of elevated blood pressure in hypertensive subjects is needed to minimize such microvascular damage. The usefulness of careful fundus examination and the potential for quantitative digital imaging of retinal vessels as an independent measure of microvascular damage as well as risk of cerebrovascular, cardiovascular, and other important systemic outcomes merits further exploration.

	Acknowledgments

 
This study was supported by the Australian National Health and Medical Research Council, Canberra Australia (grant No. 153948] and US grants to Klein and coworkers, NIH-EY06594 and HL-59259.

Received June 16, 2003; first decision July 2, 2003; accepted July 28, 2003.

	References

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