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1From the Departments of Epidemiology and Biostatistics and 2Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands; 3The Netherlands Ophthalmic Research Institute, Royal Academy of Arts and Sciences (KNAW), Amsterdam, The Netherlands; and 4Department of Ophthalmology, Academic Medical Center, Amsterdam, The Netherlands.
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Abstract |
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METHODS. The study was performed within the Rotterdam Study, a population-based, prospective cohort study in Rotterdam, The Netherlands. A total of 4822 subjects who at baseline were aged 55 years more, were free of ARM, and participated in at least one of two follow-up examinations after a mean of 2 and 6.5 years, were included in the study. At baseline, blood pressure and the presence of atherosclerosis were determined. ARM was assessed according to the International Classification and Grading System and defined as large, soft drusen with pigmentary changes; indistinct drusen; or atrophic or neovascular age-related macular degeneration.
RESULTS. After a mean follow-up of 5.2 years, incident ARM was diagnosed in 417 subjects. Increased systolic blood pressure or pulse pressure was associated with a higher risk of ARM. Adjusted for age, gender, smoking, total and high-density lipoprotein cholesterol, body mass index, and diabetes mellitus, odds ratios (OR) per 10-mm Hg increase were 1.08 (95% confidence interval [CI]: 1.03–1.14) and 1.11 (95% CI: 1.04–1.18), respectively. Moreover, different measures of atherosclerosis were associated with the risk of ARM. An increase in carotid wall thickness (OR per 1 SD, 1.15; 95% CI: 1.03–1.28) increased the risk of ARM. The lowest compared with the highest tertile of ankle–arm index had an OR of 1.32 (95% CI: 1.00–1.75). A weak association was found between aortic calcifications and the risk of ARM.
CONCLUSIONS. Elevated systolic blood or pulse pressure or the presence of atherosclerosis may increase the risk of development of ARM.
Decades ago, in 1937, Verhoeff and Grossman postulated that systemic vascular factors may be involved in the pathogenesis of AMD.7 More recently, interest in this potential relationship has grown,8 and a vascular model has been proposed in which a process that resembles atherosclerosis causes an accumulation of lipids and subsequently an increase in choroidal vascular resistance.9 This process would interfere with the high metabolic rate of the retinal pigment epithelium and lead to the development of subretinal deposits (drusen), pigment abnormalities, and, finally, the blinding late stages of atrophic or neovascular AMD. Collectively, these early and late fundus signs are called age-related maculopathy (ARM), according to an international consensus.10
Most epidemiologic studies have addressed the vascular hypothesis by studying the classic risk factors for cardiovascular disease, such as blood pressure, serum cholesterol, and smoking, as well as clinical manifestations of atherosclerosis, such as myocardial infarction. Except for smoking, the results have been inconclusive.11 12 13 14 15 16 17 18 19 20 However, very few of these studies were population based and prospective in design. Only two prevalence studies, including a cross-sectional analysis of the Rotterdam Study, used direct measurements of atherosclerosis.21 22
To explore further the vascular hypothesis, we studied, in a population-based cohort, the association of systemic blood pressure and subclinical atherosclerosis with the risk of ARM. We used noninvasive techniques for the measurement of atherosclerotic changes and prospectively studied the development of ARM.
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Methods |
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Diagnosis of Age-Related Maculopathy
A detailed description of the diagnostic procedures has been presented elsewhere.23 Participants underwent a full eye examination, including stereo 35° fundus photography (TRV-50VT fundus camera; Topcon Optical Corp., Tokyo, Japan) centered on field 2 (the fovea) after pharmacologic mydriasis. The resultant transparencies were graded with 12.5x magnification, according to the International Classification and Grading System for ARM and AMD.10 In this system, all ARM fundus signs within a standard circular area (diameter 6000 µm) around the fovea are recorded. Two graders, trained according to the Wisconsin ARM grading system and having 8 years experience, first graded the follow-up transparencies, after which the grades were compared with grades of those taken at baseline. The grading procedures and definitions, as well as the graders, were identical at baseline and at follow-up. Consensus sessions were conducted, and between-grader comparisons were performed regularly. Weighted 
statistics were 0.72 for soft distinct drusen, 0.80 for hyperpigmentation, and 0.58 for hypopigmentation.
ARM was defined as the presence of large (
63 µm), soft, distinct drusen with pigmentary irregularities, or indistinct (125 µm) or reticular drusen, or atrophic or neovascular AMD. Atrophic AMD was defined as any sharply demarcated round or oval area of apparent absence of the RPE, larger than 175 µm, irrespective of distance from the foveola but within the grid, with visible choroidal vessels and no neovascular AMD. Neovascular AMD was defined as the presence of a serous or hemorrhagic neuroretinal or RPE detachment, and/or a subretinal neovascular membrane, and/or a subretinal hemorrhage, and/or a periretinal fibrous scar. Lesions that were considered to be the result of generalized disease, such as diabetic retinopathy, chorioretinitis, high myopia, trauma, congenital diseases, or photocoagulation for reasons other than for neovascular AMD, were excluded from ARM diagnosis.
Exposure Measurement
Information on smoking habits and current use of medication was derived from the baseline interview. Smoking was categorized as never, former, or current. At the research center, height and weight were determined, and nonfasting blood samples were obtained. Serum total cholesterol and HDL-cholesterol levels were measured by an automated enzymatic procedure. Diabetes mellitus was considered to be present when subjects currently used oral blood-glucose-lowering medication or insulin, or had a nonfasting or postload glucose level above 11.0 mM.
Blood pressure was measured with a random-zero sphygmomanometer at the right brachial artery with the subject in a sitting position, and two consecutive measurements were averaged. Pulse pressure was calculated by taking the difference between systolic and diastolic blood pressure. The systolic blood pressure level of the posterior tibial artery was measured at both sides using an 8-MHz continuous-wave Doppler probe (500 D; Huntleigh, Sussex, UK) and a random-zero sphygmomanometer. The ankle-arm index was calculated by taking the ratio of the systolic blood pressure at the ankle to the systolic pressure at the arm. The ratio was calculated for each leg, and the lowest index was used in the analyses. An ankle-arm index < 0.90 was considered to indicate peripheral atherosclerosis.
The wall thickness of the carotid artery was assessed by ultrasonography using a 7.5-MHz linear-array transducer (Ultra-Mark IV; ATL, Bethel, West Australia), in accordance with the Rotterdam Study ultrasound protocol.25 Briefly, the intima-media thickness was measured on a longitudinal, two-dimensional ultrasound image of the common carotid artery, the carotid bifurcation, and the internal carotid artery at both the left and right side. When an optimal image of the interface of the anterior (near) and posterior (far) walls was obtained, it was frozen on the R-wave of the electrocardiogram (ECG), stored on videotape, and digitized by additional dedicated software. Next, the interfaces of the common carotid artery, the carotid bifurcation, and the internal carotid artery were marked across a length of 10 mm. The computer calculated the mean and maximum intima-media thickness for both near and far walls. For the analyses, the wall thickness was determined as the mean of the maximum intima-media thickness of near- and far-wall measurements of both the left- and right-side arteries. The thicknesses of each of the three arterial segments were combined after standardization. The ultrasonographers and readers of the images were masked to the case status of the subject.
The common carotid artery, bifurcation, and internal carotid artery were also examined for the presence of atherosclerotic plaques. Plaques were defined as focal thickening of the vessel wall relative to adjacent segments, composed of calcified or noncalcified components. The plaque score reflected the total number of locations where plaques were found, and it ranged from zero to six (left- and right-side common carotid artery, bifurcation, and internal carotid artery).
Aortic atherosclerosis was diagnosed by detecting calcified deposits in the abdominal aorta on lateral radiographic films of the lumbar spine, as described previously.26 Calcification was considered present when linear densities were seen in an area parallel and anterior to the lumbar spine (L1–L4). The extent of calcification was classified according to the length of the involved area (0, 0.5 to <1, 1 to <2.5, 2.5 to <5, 5 to <10, and 10 cm). We considered the first classification to be the reference; the second and third to be mild to moderate; and the fourth, fifth, and sixth to be severe calcification.
Finally, a composite score of atherosclerosis was constructed with both the continuous (ankle-arm index and carotid wall thickness) and categorical measurements (number of carotid plaques and aortic calcifications). To do so, we transformed all variables to a 10-point scale. For the continuous variables, deciles were created, and subjects received 1 point per decile. For the categorical variables, we determined what percentage of the study population was in a less-severe category, and this percentage was converted to points. For example, a person with an ankle-arm index of 1.1 (6th decile), a carotid wall thickness of 0.8 mm (6th decile), carotid plaques at two locations (57% of the population had less than two locations), and 1 cm to less than 2.5 cm of aortic calcifications (43% had less than this), had a score of 6 + 6 + 5.7 + 4.3 = 22.
Study Sample
Of the 6780 participants in the ophthalmic part of the baseline study, 6477 (95.5%) persons underwent fundus photography and 6418 (94.7%) persons had gradable fundus transparencies in at least one eye. Prevalent ARM was diagnosed in 582 (9.1%) subjects, including 106 cases of AMD. This resulted in a cohort of 5836 subjects at risk who were free of ARM (i.e., subjects with no drusen, only hard or distinct drusen, or pigmentary abnormalities only). Of this cohort, 283 (4.8%) subjects died before the first follow-up examination and another 789 (13.5%) subjects died before the second follow-up. Of those alive at the first screening (n = 5553), 46 subjects were lost to follow-up, 905 refused to participate, and 13 had ungradable photographs. Of those alive at the second follow-up (n = 4764), 15 subjects were lost to follow-up, 1267 refused to participate, and 47 had ungradable photographs. In total, 4822 subjects (83% of those at risk) participated in at least one follow-up examination. Among them, blood pressure measurements were missing in 50 participants, ankle-arm index in 394 participants, carotid wall thickness in 770 participants, plaques in carotid artery in 1572 participants, and aortic calcifications in 497participants. The main cause of missing data on ultrasonography was restricted availability of technicians, which was irrespective of a subject’s exposure and disease status.
Incidence of ARM was defined as absence of ARM in either eye at baseline and presence of ARM in at least one eye at follow-up.
Data Analysis
Analysis of variance, adjusted for age and gender, was used to compare baseline characteristics of eligible subjects participating in at least one follow-up examination with those who were alive at the time of examination but did not participate.
We studied the associations of baseline blood pressure and atherosclerosis with incident ARM in subjects with no ARM at baseline. Logistic regression analysis was used with time of follow-up included in every model. Systolic blood pressure, diastolic blood pressure, and pulse pressure were entered in the model, as either a continuous or categorical variable. In the first case, the regression coefficient was expressed per 10-mm Hg increase. In the second case, three dummy variables were defined based on absolute blood pressures with predefined cutoff points. To detect a J-shaped relationship, the second category of diastolic blood pressure (65–74 mm Hg) was used as the reference. Ankle-arm index was analyzed with the predefined cutoff point of 0.9, as well as in tertiles. We studied wall thickness of the carotid artery both as a continuous variable (per SD) and as a categorical variable (tertiles). Plaques in the carotid artery were analyzed both continuously (in number of plaques) and in categories. Aortic calcifications were studied in categories only, and the atherosclerosis composite score was analyzed in quartiles.
Initially, the regression analysis was adjusted for age and gender (model 1). In model 2, additional adjustment was made for smoking (current, former, or never), diabetes mellitus (yes/no), total cholesterol and HDL-cholesterol (per mM), and body mass index (kilograms per square meter). In model 3, we also adjusted for the composite score of atherosclerosis in the blood pressure analyses, and for systolic and diastolic blood pressure in the atherosclerosis analyses. The associations are presented as odds ratios (ORs), which can be interpreted as relative risks, with 95% confidence intervals (CIs). All analyses were performed on computer (SPSS, ver. 11; SPSS Inc., Chicago, IL).
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Results |
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In Table 2 , the odds ratios (OR) of incident ARM associated with baseline blood pressure are shown. When adjusted for age and gender, elevated systolic blood pressure was associated with an increased risk of ARM (OR per 10-mm Hg increase: 1.06, 95% CI: 1.01–1.12). When additional adjustments were made for smoking, total and HDL cholesterol, body mass index, diabetes mellitus, and the composite score of atherosclerosis, the association remained statistically significant. Diastolic blood pressure was also associated with ARM, but this did not reach statistical significance (OR per 10-mm Hg increase: 1.05, 95% CI: 0.96–1.15, adjusted for age and gender). Additional adjustment did not change this relationship. Also, taking the lowest category as reference instead of the second did not change the risk estimates. Pulse pressure was positively associated with the risk of ARM, both as a continuous and as a categorical variable. Adjustment for the composite score of atherosclerosis, however, attenuated the association with categories of pulse pressure to nonsignificant levels. Excluding subjects who used blood pressure-lowering medication at baseline did not substantially alter the results (data not shown).
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Discussion |
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In this study, we used the combination of early and late signs of ARM as incident outcome. Because subjects with early stages at baseline were excluded, AMD developed in very few (n = 14) within the 5-year follow-up period and the large majority (97%) of incident cases were of early ARM. When participants with incident AMD were excluded from the analysis, the same results were obtained (data not shown). We may therefore conclude that blood pressure and atherosclerosis promote the development of drusen and other signs of early ARM and not (only) the progression of early ARM to neovascular AMD, as has been suggested by some investigators.27 A separate analysis of those cases of only neovascular AMD as an outcome was not possible because of the small sample. Given the well-documented risk of early ARM to progress to the blinding stage of AMD, it seems justified to assume that risk factors of early ARM also increase the risk of AMD.28 29
A concern in this as well as other follow-up studies is selective nonresponse. Because the international standard for the diagnosis of ARM in epidemiologic studies relies on fundus photography,10 follow-up depends on a subject’s participation in the eye examination. According to the analysis of baseline characteristics, subjects who did not participate in the follow-up examinations had more cardiovascular risk factors and more atherosclerosis. Therefore, subjects with severe atherosclerosis were underrepresented in the studied sample. This reduction in the range of atherosclerosis severity made it more difficult to find an association.
Sixteen percent of participants had missing data on carotid wall thickness and plaques, which was mainly due to logistic problems and to technical difficulties in visualization of the carotid artery. Because these reasons were not related to carotid wall thickness, we do not think that this biased our results. Still, it is possible that some error occurred in the measurement of atherosclerosis. Such a measurement error would have led to an underestimation of the true relationship with ARM, provided that the error occurred to the same extent among subjects with ARM and those without. Another question to be discussed is whether ankle–arm index and ultrasonographic measurement of carotid wall thickness are true indicators of atherosclerosis. The relation between ankle–arm index and atherosclerosis seems well established.30 Increase in the carotid intima-media thickness may also reflect hypertrophy of the vessel wall as a response to hypertensive stress. Because many studies have shown that increased carotid wall thickness is associated independently of hypertension with both cardiovascular risk factors and cardiovascular events, it can be regarded as a valid indicator of atherosclerosis.25 31
An association between blood pressure or hypertension and prevalent AMD was reported earlier in three case–control studies: the Eye Disease Case–Control Study,12 the AMD Risk Factors Study,15 and the Age-Related Eye Disease Study.14 Also, the Framingham Eye Study found an association between prevalent ARM and hypertension diagnosed 25 years before.11 On the contrary, no association between blood pressure and prevalence of ARM was found in several population-based studies.16 17 18 19 20 21 The only prospective, population-based study of this association so far, the Beaver Dam Eye Study, found that both systolic blood pressure and hypertension were significantly related to the incidence of retinal pigment epithelial depigmentation, but not of drusen.13 Loss of power may be the explanation, because the number of incident cases of early ARM in their cohort was about half that in our study.
The association between ultrasonographically determined atherosclerosis, and the incidence of ARM has not yet been studied, as far as we know. Klein et al.21 have studied the prevalence of ARM in the population-based Atherosclerosis Risk in Communities (ARIC) study, in which data on carotid intima-media wall thickness and carotid plaques were available. They found a statistically significant association between carotid plaques and retinal depigmentation, but, referring to the large number of associations studied, they concluded that atherosclerosis was unrelated to ARM overall. Also, they used nonstereoscopic 45° fundus photographs taken through a nonpharmacologically dilated pupil of only one eye, which may have resulted in a decreased detection of ARM.32 In an earlier cross-sectional analysis of data from the Rotterdam Study, we found that subjects with plaques in the carotid bifurcation were 4.5 times more likely to have AMD.22 Also, an ankle-arm index below 0.9 was significantly (OR: 2.0; 95% CI: 1.2–3.2) associated with the presence of AMD. However, in the latter study, the early signs of ARM were not included, and the number of AMD cases were low with corresponding wide confidence intervals. Moreover, given the cross-sectional design no causal inferences could be made.
Not all measures of atherosclerosis yielded the same results. The strongest association with ARM was observed for carotid wall thickness and carotid plaques, whereas no association was found for calcifications in the abdominal aorta and peripheral arterial disease. Considering this difference, one might hypothesize that atherosclerosis of the cerebral circulation is more important for the risk of ARM than atherosclerosis of the aorta or peripheral arteries.
There are several ways in which atherosclerosis may be related to ARM. Carotid atherosclerosis may lead to stenosis and, in the end, to a diminished blood flow to the ophthalmic artery and in the choroidal and retinal circulation. Considering the low prevalence of carotid stenosis in our cohort, this explanation seems implausible. It is more likely that the atherosclerosis we measured reflects a similar process in the choroidal vessels under the retina. Thickening and stiffening of the vessel wall results in a decreased lumen diameter, an increased blood flow resistance, and a decreased tissue perfusion. This process may then either directly impair the functioning of the retinal pigment epithelium, which is responsible for the metabolism of rod and cone outer segments, or may lead to leakage and deposition of proteins and lipids due to elevated hydrostatic pressure, as was proposed by Friedman.9 A decreased choriocapillary density was demonstrated in aging human eyes, especially in those with ARM.33 Moreover, in patients with ARM, reduced choroidal perfusion was shown by direct measurement of the choroidal blood flow.34 35 36 37 In summary, multiple lines of evidence suggest a role for atherosclerosis in the pathophysiology of ARM.
The question should be answered of whether high blood pressure is a risk factor for ARM in itself or high blood pressure is a risk factor for ARM only through its association with atherosclerosis. To disentangle this relationship, we put both determinants in the same model. Adjustment for the composite score of atherosclerosis did not change the association between systolic or diastolic blood pressure and ARM. The association with pulse pressure was somewhat attenuated, possibly indicating that pulse pressure has more overlap with atherosclerosis. Additional adjustment for systolic and diastolic blood pressure altered only to a slight degree the risk estimates for the association of atherosclerosis with ARM. The interpretation of these analyses may be that high blood pressure and atherosclerosis, independent of each other, increase the risk of ARM. However, because both determinants are strongly linked and both were measured at the same time, the previous analyses are not sufficient to determine the exact order of the pathophysiological pathway.
The level of oxidative defense could disturb the association between atherosclerosis and ARM. Because oxidative stress is implicated both in the etiology of ARM38 and in the pathogenesis of atherosclerosis,39 antioxidants may act as a confounder in the observed association. However, this confounder is less likely to explain the relationship between blood pressure and ARM, which was independent of atherosclerosis.
In conclusion, in this large prospective cohort study we showed that high systolic blood pressure, high pulse pressure, or the presence of subclinical atherosclerosis increases the risk of ARM. The magnitude of the risk estimates varied, with a maximum OR of 2.1. Because of the high prevalence of hypertension and atherosclerosis in the population, the impact of these factors on the total incidence of ARM may still be large. Our results suggest that a reduction in the occurrence of hypertension and atherosclerosis may add to the prevention of this blinding disease.
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Acknowledgements |
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Footnotes |
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Supported by Optimix Foundation, Amsterdam; Netherlands Organization for Scientific Research (NWO), The Hague; The Netherlands Society for the Prevention of Blindness, Doorn; Blindenhulp Foundation, The Hague; Rotterdamse Blindenbelangen Foundation, Rotterdam; OOG Foundation, The Hague; Topcon Europe BV, Capelle aan de IJssel; and The Edward and Marianne Blaauw Foundation, Amsterdam, The Netherlands.
Submitted for publication February 5, 2003; revised May 19, 2003; accepted May 29, 2003.
Disclosure: R. van Leeuwen, None; M.K. Ikram, None; J.R. Vingerling, None; J.C.M. Witteman, None; A. Hofman, None; P.T.V.M. de Jong, None
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. 
1734 solely to indicate this fact.
Corresponding author: Paulus T. V. M. de Jong, The Netherlands Ophthalmic Research Institute, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands; p.dejong{at}ioi.knaw.nl.
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