To examine the association of corneal arcus to cardiovascular disease (CVD) in an adult, ethnic Indian population.
Population-based cross-sectional study.
Population-based study of ethnic South Asian Indians 40 to 80 years of age in Singapore from June 2007 through March 2009. We obtained a 75.5% response rate (3397/4497). All participants underwent standardized interview and systemic and ocular examinations, followed by nonfasting blood sampling. Corneal arcus was detected using a standardized slit-lamp examination. The main outcome measure was CVD, defined from a self-reported history of previous myocardial infarction, angina, or stroke.
Corneal arcus, found in 1701 (50.1%) of 3397 participants, was associated with older age (odds ratio [OR], 3.07; 95% CI, 2.78 to 3.40; P < .001), male gender (OR, 2.17; 95% CI, 1.81 to 2.62; P < .001), higher levels of total cholesterol (OR, 1.14; 95% CI, 1.05 to 1.24; P = .002), hypertension (OR, 1.14; 95% CI, 1.05 to 1.24; P = .013), and cigarette smoking (OR, 1.59; 95% CI, 1.25 to 2.03; P < .001). Corneal arcus was associated with CVD (OR, 1.31; 95% CI, 1.02 to 1.7; P = .0038) independent of the above-named cardiovascular risk factors. Participants with low-risk Framingham scores were more likely to be associated with CVD if they had corneal arcus (men: OR, 2.02; 95% CI, 1.20 to 3.40; P = .008; women: OR, 2.78; 95% CI, 1.36 to 3.01; P < .001). Corneal arcus was associated with CVD independent of the Framingham score (men: Akaike information criterion, 1524.39 for Framingham Score and corneal arcus vs 1527.38 for Framingham Score alone; women: 1000.14 vs 1003.54, respectively).
Corneal arcus is associated with CVD, independent of risk factors in ethnic Indian adults, even in those at low risk for vascular disease.
Corneal arcus consists of lipid deposits within the corneal stroma, seen clinically as grey-white arcs in the inferior, then superior poles of the peripheral cornea, before joining to form a peripheral corneal annulus with a clear perilimbic zone. The prevalence of corneal arcus increases with age, up to a reported prevalence of more than 80% in persons older than 60 years. The evidence of lipid infiltration from the limbic vasculature into the corneal stroma, without any underlying degenerative changes, suggests that arcus is more than just a sign of age. Architectural changes to the collagen fibrils in the peripheral cornea and increased permeability of limbal vessels seen in arcus formation have been linked to mechanisms similar to atherosclerosis.
Corneal arcus long has been recognized as a clinical sign of hyperlipidemia and is associated with other vascular risk factors such as hypertension, higher body mass index, diabetes mellitus, and cigarette smoking. Corneal arcus also has been linked to cardiovascular disease (CVD), including myocardial infarction and stroke. However, previous studies have not shown if the relationship with CVD is independent of hyperlipidemia and other vascular risk factors, or if knowledge of corneal arcus status improves the ability to predict CVD beyond traditional risk factors, such as those included in the Framingham risk equation. In our current study, we examined the association of corneal arcus to CVD and associated vascular risk factors in a population-based study of South Asian ethnic Indians.
The Singapore Indian Eye Study is a population-based study of ethnic South Asian Indians in Singapore described elsewhere. In brief, we used age-stratified random sampling to select ethnic Indians 40 to 80 years of age from the entire population of Singapore during the study period. Of the 4497 eligible adult ethnic Indians, 3397 participated in our study (75.5% response rate). The study was conducted from June 2007 through March 2009 at the Singapore Eye Research Institute.
Details of our study design and methodology have been described. We conducted standardized systemic and ocular examinations, administered interviewer-administered questionnaires, and carried out standard blood investigations for all participants.
Standardized slit-lamp examinations were performed by study ophthalmologists to determine the presence or absence of corneal arcus in our participants. As defined in our study protocol, corneal arcus was defined as absent or present if the arc of the involved cornea was more than 180 degrees.
A detailed interviewer-administered questionnaire was used to collect relevant sociodemographic data and medical history from all participants. Our main outcome measure was CVD, which was collected using an interview-based, standardized questionnaire on this outcome. CVD was defined as a self-reported history of previously recognized myocardial infarction, stable and unstable angina pectoris, stroke, or transient ischemic attack that was diagnosed by a doctor or required treatment, similar to epidemiologic cross-sectional studies. We also collected data such as country and state of birth with ancestral origin (India), marital status, education, occupation, current housing status, participants’ lifestyle factors, current medications, lifestyle risk factors (e.g., smoking and alcohol intake), systemic medical and surgical history, and family history of eye diseases. Being overweight was defined as body mass index of more than 25 kg/m 2 . Blood pressure was measured with a digital automatic blood pressure monitor (Dinamap model Pro Series DP110X-RW, 100V2; GE Medical Systems Information Technologies Inc, Milwaukee, Wisconsin, USA) after the participants were seated for at least 5 minutes. Hypertension was defined as systolic blood pressure of 140 mm Hg or more, diastolic blood pressure of 90 mm Hg or more, or use of anti-hypertensive medication.
We also collected nonfasting venous blood samples for biochemistry tests including serum lipids (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol), glycosylated hemoglobin A1c), creatinine, and random glucose. All cholesterol levels were analyzed in participants on a continuous scale. Where applicable, hypercholesterolemia was defined as total cholesterol of 6.2 mmol/L or more or use of lipid-lowering drugs. A high level of low-density lipoprotein (LDL) cholesterol was defined as LDL cholesterol of 4.1 mmol/L or more and a low level of high-density lipoprotein (HDL) cholesterol was defined as HDL cholesterol of less than 1.0 mmol/L. Diabetes mellitus was defined as random glucose of 11.1 mmol/L or more, use of diabetic medication, or a physician diagnosis of diabetes mellitus. We calculated the Framingham score for all study subjects using recognized criteria. The risk factors used in the Framingham score were age, total cholesterol, HDL cholesterol, blood pressure, and cigarette smoking. In brief, risk status was determined by a 2-step procedure: the number of risk factors was assessed first, which then was used to determine the 10-year risk assessment using Framingham scoring. Persons were divided into 3 groups of low, medium, and high risk, based on these combinations.
Statistical analysis included descriptive statistics, where the mean and standard deviation were calculated for the continuous variables, whereas frequency distribution and percentages were used for categorical variables. Differences between participants with and without corneal arcus initially were assessed using the t test or chi-square test, as appropriate. Multivariate logistic regression analysis was performed to evaluate the association between prevalence of corneal arcus and CVD while adjusting for potential confounders by using a backward selection method, considering all risk factors initially in the logistic regression. The estimate of odds ratio (OR) and its relative 95% confidence interval (CI) were calculated. We estimated the Akaike information criterion (AIC) to determine the likelihood of CVD using the Framingham score, corneal arcus, and a combination of both. AIC is used as a tool for model selection, with the model having the lowest AIC being the best. All reported P values were compared to a significance level of 5%. All analyses were performed using STATA software version 11 (StataCorp LP, College Station, Texas, USA).
In our study cohort of 3397 ethnic Indian adults, we found the overall prevalence of corneal arcus to be 50.1% (n = 1701). The overall mean age of our study cohort was 57.8 ± 10.1 years (standard deviation) with an equal sex ratio (1704 males; 50.2%). The overall characteristics of our study population and the differences between participants with and without arcus are depicted in Table 1 . We found that the prevalence of corneal arcus in our study cohort increased with age ( P < .001, test for trend) and was significantly higher in men than in women in all age groups ( P < .001; Figure 1 ). Participants with corneal arcus were older, male, cigarette smokers, and more likely to be hypertensive and diabetic at the time of our study ( Table 1 ). There were significantly more participants with corneal arcus who had CVD, such as previous myocardial infarction, angina, and stroke, as compared with those who did not in the overall study cohort (20.2% vs 11.3%; P < .001). Although the participants with corneal arcus had lower cholesterol levels (total and LDL) and were less overweight in the crude (unadjusted) analysis, we performed a multivariate analysis to account for other possible factors that could influence these observations, such as lipid-lowering medications ( Table 2 ).
|Characteristics||Total (n = 3397)||Corneal Arcus Status|
|Present (n = 1701)||Absent (n = 1696)||P Value a|
|Age (y), mean (SD)||57.8 (10.1)||62.8 (9.7)||52.8 (7.6)||<.001|
|HbA 1c (%), mean (SD)||6.4 (1.4)||6.5 (1.4)||6.4 (1.4)||.004|
|Blood glucose (mmol/L), mean (SD)||7.2 (3.6)||7.4 (3.6)||7.0 (3.6)||.002|
|Systolic blood pressure (mm Hg), mean (SD)||135.4 (19.6)||139.1 (19.8)||131.7 (18.7)||<.001|
|Diastolic blood pressure (mm Hg), mean (SD)||77.4 (10.1)||77.1 (10.2)||77.7 (10.1)||.109|
|Total cholesterol (mmol/L), mean (SD)||5.2 (1.1)||5.1 (1.2)||5.3 (1.1)||<.001|
|LDL cholesterol (mmol/L), mean (SD)||3.3 (0.9)||3.2 (1.0)||3.4 (0.9)||<.001|
|HDL cholesterol (mmol/L), mean (SD)||1.1 (0.3)||1.1 (0.3)||1.1 (0.3)||.050|
|Male gender, no. (%)||1704 (50.2)||990 (58.2)||714 (42.1)||<.001|
|Overweight (BMI ≥ 25 kg/m 2 ), no. (%)||1908 (56.5)||893 (52.9)||1015 (60.0)||<.001|
|Hypertension, no. (%)||2044 (60.2)||1218 (71.6)||826 (48.7)||<.001|
|Diabetes mellitus, no. (%)||1128 (34.2)||664 (40.3)||464 (28.1)||<.001|
|Current cigarette smoking, no. (%)||498 (14.7)||288 (17.0)||210 (12.4)||<.001|
|Alcohol consumption, no. (%)||429 (12.7)||237 (14.0)||192 (11.3)||.021|
|Lipid-lowering medication use, no. (%)||1034 (30.4)||654 (38.4)||380 (22.4)||<.001|
|Cardiovascular disease, no. (%) b||483 (14.3)||342 (20.2)||141 (8.3)||<.001|