Purpose
To determine whether retinal arteriolar wall signs are associated with early age-related macular degeneration (AMD).
Design
Population-based cross-sectional study.
Methods
The Singapore Malay Eye Study (SiMES) is a population-based eye survey including 3280 (78.7% response) persons aged 40 to 80 years. Retinal arteriolar wall signs and AMD were assessed from photographs by trained technicians, according to standardized protocols. Data on major cardiovascular risk factors and blood pressure were collected.
Results
Of the 3280 participants, 2541 had photographs that were gradable for both AMD and retinal arteriolar wall signs. Early AMD was present in 76 subjects. There were no significant associations of any retinal arteriolar wall signs with early AMD. For specific AMD signs, retinal arteriolar wall opacification was associated with presence of soft distinct drusen (odds ratio [OR] 1.58, 95% confidence interval [CI]: 1.06, 2.35). This association was most significant among non-statin users (OR 1.90, 95% CI: 1.23, 2.93). Focal arteriolar narrowing was associated with retinal hypopigmentation (OR 1.67, 95% CI: 1.02, 2.73). Arteriovenous nicking was not associated with soft drusen (OR 0.89, 95% CI: 0.51, 1.57), hyperpigmentation (OR 0.49, 95% CI: 0.22, 1.08), or hypopigmentation (OR 0.86, 95% CI: 0.46, 1.61).
Conclusions
Retinal arteriolar wall signs are not consistently associated with early AMD. We report a new association of retinal arteriolar wall opacification and the presence of soft drusen. This finding could support the hypothesis of a link between lipids and drusen formation.
Age-related macular degeneration (AMD) is the leading cause of blindness in many countries. AMD is believed to have a multifactorial pathogenesis that includes both genetic and environmental factors. There is now an increasing body of evidence suggesting that AMD and cardiovascular disease have common risk factors, such as hypertension, cigarette smoking, dyslipidemia, and atherosclerosis. These associations have led to a “common soil” theory, which contends that common pathogenic pathways such as vascular disease and inflammation are shared by AMD and cardiovascular disease. Recently several genome-wide association studies have reported association between hepatic lipase gene and AMD. The hepatic lipase gene encodes the hepatic lipase enzyme and affects serum high-density lipoprotein (HDL) cholesterol levels. These novel gene discoveries have once again sparked interest in studying of the relationship of AMD and plasma cholesterol levels. Studies in this area have so far yielded inconclusive results.
Studying characteristics of the retinal vasculature may offer an opportunity to examine early arteriolosclerotic changes in eyes with AMD. The Blue Mountains Eye Study (BMES) investigated whether retinal vessel signs were independent predictors of AMD progression, and reported that arteriovenous nicking (AVN) was associated with an increased long-term risk of AMD progression over 10 years, independent of traditional vascular risk factors. The Beaver Dam Eye Study (BDES), however, reported that generalized arteriolar narrowing was not associated with AMD cross-sectionally, but was associated with incident retinal pigment epithelial changes over a 10-year study period. The BDES concluded that there is weak and inconsistent association between hypertensive retinal arteriolar characteristics and the incidence of AMD. The ARIC study found only an association between focal arteriolar narrowing (FAN) and retinal pigment epithelium (RPE) depigmentation, but not for other AMD signs. No studies in Asians have examined this relationship.
In the Singapore Malay Eye Study (SiMES), we previously reported that wider retinal venular caliber was significantly associated with retinal pigmentary abnormalities and early AMD after controlling for age, gender, smoking, hypertension, diabetes, and body mass index. In this study, we aimed to determine whether retinal arteriolar wall signs were independently associated with early AMD and specific early AMD lesion.
Methods
The SiMES is a population-based cross-sectional survey of eye diseases in urban Malay adults ranging from 40 to 80 years of age, residing in 15 districts in southwestern Singapore. Subjects were selected from a computer-generated list provided by the Singapore Ministry of Home Affairs, using an age-stratified (by 10-year age groups) random sampling method. Of 4168 eligible participants, 3280 (78.7%) participated in the study, conducted from August 1, 2004 through June 30, 2006.
All participants had an interview, systemic examination, and laboratory investigations to determine cardiovascular risk factors. A structured interviewer-administered questionnaire was used to collect relevant socio-demographic and medical information. Demographic variables included age, gender, marital status, level of education, occupation, income, and family history of diabetes and hypertension. Age was defined as the age at the time of examination. Questions on lifestyle included smoking habits and alcohol consumption. Smoking history was used to determine whether participants were current smokers, ex-smokers, or nonsmokers. Blood pressure (BP) was taken with the participant seated and after 5 minutes of rest. Systolic and diastolic BP and pulse rate were measured with a digital automatic BP monitor (Dinamap model Pro Series DP110X-RW 100V2; GE Medical Systems Information Technologies Inc, Milwaukee, Wisconsin, USA) following methods used in the Multi-Ethnic Study of Atherosclerosis (ME-SA). BP was measured on 2 occasions 5 minutes apart. If the BP differed by more than 10 mm Hg systolic and 5 mm Hg diastolic, a third measurement was made.
The BP of each individual was then taken as the mean between the 2 closest readings. Hypertension was defined as a recorded systolic blood pressure (SBP) ≥140 mm Hg, diastolic blood pressure (DBP) ≥90 mm Hg at examination, or a previous physician diagnosis, self-reported by the subject. Documentation of antihypertensive medication was not included in the hypertension definition.
A 40-mL nonfasting sample of venous blood was collected to determine serum lipid levels including total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides. All serum biochemistry tests were sent to the National University Hospital Reference Laboratory for measurement on the same day. Hyperlipidemia was defined as total cholesterol ≥6.2 mmol/L or use of lipid-lowering drugs.
Age-Related Macular Degeneration Grading
A digital fundus camera (Canon CR-DGi with 10D SLR digital camera back; Canon, Tokyo, Japan) was used to capture fundus photographs after pupil dilation. Of the 3280 participants, 2871 had fundus photographs of at least 1 eye of sufficient quality for assessment of retinal vascular parameters and AMD status.
AMD grading was performed at the Centre for Vision Research, University of Sydney, using a modification of the Wisconsin Age-Related Maculopathy Grading System as used in the BMES, adopting nomenclature for describing AMD signs from the international classification. Details of the definition of AMD signs were described elsewhere. In brief, early AMD lesions, including soft distinct, indistinct, or reticular drusen or retinal pigmentary abnormalities (hypopigmentation or hyperpigmentation), were determined. Early AMD was defined following the definition as either soft indistinct or reticular drusen, or soft distinct drusen plus RPE abnormalities. Neovascular AMD lesions were defined as the presence of RPE detachment, neurosensory detachment, subretinal or sub-RPE hemorrhages, or intraretinal, subretinal, or sub-RPE scar tissue. Subretinal hemorrhages within the macular area also were considered to be signs of neovascular AMD if other causes were ruled out. Geographic atrophy was defined by the presence of visible choroidal vessels and a discrete atrophic area with a sharp border with 175 μm in diameter or more. Measurements from right eyes were used, unless the parameter studied was ungradable, in which case left eye measurements were used.
Assessment Of Retinal Arteriolar Wall Signs
Assessment of retinal arteriolar wall signs was performed at Centre for Eye Research Australia, University of Melbourne. Retinal arteriolar wall signs including FAN, AVN, and opacification of arteriolar wall (OAW) were assessed by trained graders based on a standardized protocol and compared to a standard set of reference images. Adjudication was provided by a senior researcher (J.J.W.). FAN, AVN, and OAW were defined as present if graded as definite.
Statistical Analysis
Statistical analyses were performed using the statistical package for the social sciences (SPSS software version 17.0; SPSS Inc, Chicago, Illinois, USA). Binary logistic models were used to examine the association of retinal vascular changes with early AMD and component lesions. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated while controlling for age in model 1 and additionally controlling for gender, current smoking status, mean arterial blood pressure, body mass index, glucose level, total cholesterol, and HDL cholesterol. Logistic regression analyses by subgroup stratified by smoking status, hypertension, hyperlipidemia, and statin status were also conducted. The power of subgroup analysis (determined by using software version 3.0, SPSS Inc) is 60% for nonsmokers and 20% for smokers; 30% for subjects without hypertension and 60% for those with hypertension; 40% for both strata with and without hyperlipidemia; 60% for subjects not taking statin and 20% for those taking statin.
Results
A total of 3280 participants were recruited in the study. Seven hundred thirty-nine subjects were excluded from analyses for the following reasons: 575 had unreadable photographs for OAW status, 150 had coexisting glaucoma, and 14 had late AMD. The remaining 2541 subjects were included for analysis; early AMD was present in 76 (3.0%). Table 1 shows the demographic characteristics, subcategorized by the presence or absence of early AMD. Subjects with early AMD were significantly older and were more likely to have either hypertension or higher mean arterial blood pressure. None of the studied arteriolar wall signs were significantly associated with early AMD ( Table 1 ).
| Mean (Standard Deviation) | ||||
|---|---|---|---|---|
| All (n = 2541) | No AMD (n = 2465) | Early AMD (n = 76) | P a | |
| Age (years) | 56.5 (10.21) | 56.2 (10.13) | 65.5 (8.76) | <.001 |
| Body mass index (kg/m 2 ) | 26.5 (5.04) | 26.5 (5.02) | 26.1 (5.59) | .463 |
| Glucose level (mmol/L) | 6.7 (3.69) | 6.7 (3.68) | 6.9 (3.96) | .678 |
| Mean arterial blood pressure, (mm Hg) | 101.5 (13.81) | 101.4 (13.76) | 105.9 (14.90) | .004 |
| Total cholesterol (mmol/L) | 5.6 (1.14) | 5.6 (1.14) | 5.5 (1.24) | .513 |
| HDL cholesterol (mmol/L) | 1.35 (0.33) | 1.35 (0.33) | 1.35 (0.32) | .846 |
| Number (%) | ||||
|---|---|---|---|---|
| Male gender | 1228 (48.3) | 1186 (48.1) | 42 (55.3) | .219 |
| Hypertension | 1655 (65.2) | 1592 (64.6) | 63 (82.9) | .001 |
| Diabetes | 562 (22.1) | 543 (22.0) | 19 (25.0) | .539 |
| Smoking status | 549 (21.6) | 536 (21.8) | 13 (17.3) | .358 |
| Focal arteriolar narrowing (FAN) | 245 (9.6) | 234 (10.5) | 11 (16.9) | .147 |
| Arteriovenous nicking (AVN) | 212 (8.3) | 204 (8.3) | 8 (10.5) | .485 |
| Opacification (OAW) | 434 (17.1) | 415 (16.8) | 19 (25.0) | .062 |
a P value based on χ 2 (categorical) and independent sample t test (continuous).
Significant associations of retinal vascular wall signs with individual AMD signs are summarized in Table 2 . Opacification of arteriolar wall was associated with the presence of soft distinct drusen (OR 1.58, 95% CI: 1.08, 2.31). This association remained significant (OR 1.58, 95% CI: 1.06, 2.35) after adjusting for age, gender, current smoking status, mean arterial blood pressure, total cholesterol, HDL cholesterol, and triglyceride levels. Further subgroup analysis showed that this association was most significant in non-statin users, followed by nonsmokers and subjects with hypertension ( Table 3 ). In a separate analysis, there was a trend towards lower HDL cholesterol (1.30 vs 1.33, P = .074) and higher triglyceride (1.77 vs 1.65, P = .070) in subjects with OAW ( Table 4 ). FAN was associated with retinal hypopigmentation (OR 1.67, 95% CI: 1.02, 2.73) ( Table 2 ).
| Retinal Arteriolar Wall Opacification (OAW) | Focal Arteriolar Narrowing (FAN) | Arteriovenous Nicking (AVN) | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No. at Risk | No. of Cases (%) | Unadjusted OR (95% CI) | P | Age-Adjusted OR (95% CI) | P | Multivariate-Adjusted OR a (95% CI) | P | Unadjusted OR (95% CI) | P | Age-Adjusted OR (95% CI) | P | Multivariate-Adjusted OR a (95% CI) | P | Unadjusted OR (95% CI) | P | Age-Adjusted OR (95% CI) | P | Multivariate-Adjusted OR a (95% CI) | P | |
| Soft distinct drusen | 1831 | 192 (10.5) | 2.00 (1.40, 2.85) | <.001 | 1.58 (1.08, 2.31) | .02 | 1.58 (1.06, 2.35) | .02 | 1.87 (1.20, 2.91) | .006 | 1.35 (0.85, 2.16) | .21 | 1.23 (0.75, 2.01) | .42 | 1.35 (0.80, 2.27) | 1.35 | 0.92 (0.54, 1.60) | .78 | 0.89 (0.51, 1.57) | .70 |
| Hyperpigmentation | 2478 | 137 (5.5) | 1.19 (0.77, 1.83) | .438 | 1.04 (0.67, 1.61) | .88 | 1.21 (0.77,1.90) | .41 | 1.77 (1.09, 2.88) | .021 | 1.54 (0.94, 2.52) | .09 | 1.54 (0.93, 2.58) | .09 | 0.68 (0.33, 1.40) | .68 | 0.56 (0.27, 1.18) | .13 | 0.49 (0.22, 1.08) | .08 |
| Hypopigmentation | 2487 | 146 (5.9) | 0.89 (0.54, 1.37) | .52 | 0.78 (0.49, 1.25) | .30 | 0.92 (0.57, 1.49) | .75 | 1.83 (1.15, 2.92) | .011 | 1.71 (1.06, 2.76) | .03 | 1.67 (1.02, 2.73) | .04 | 0.93 (0.53, 1.79) | .93 | 0.90 (0.48, 1.66) | .73 | 0.86 (0.46, 1.61) | .63 |
a Adjusted for age, gender, current smoking, c, glucose level, body mass index, total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride.
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