Dietary Antioxidants and Peripheral Arterial Disease

The Rotterdam Study

Kerstin Klipstein-Grobusch1,2, Johanna H. den Breeijen3, Diederick E. Grobbee3, Heiner Boeing2, Albert Hofman1 and Jacqueline C. M. Witteman1

1 Department of Epidemiology and Biostatistics, Erasmus University Medical School, Rotterdam, the Netherlands.
2 Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbrücke, Germany.
3 Julius Center for Patient Oriented Research, Utrecht University Hospital, Utrecht, the Netherlands.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
This study examined cross-sectionally the association of dietary ß-carotene, vitamin C, and vitamin E with peripheral arterial disease in Rotterdam, the Netherlands (1990–1993). The 4,367 subjects from the Rotterdam Study were aged 55–94 years and had no previous cardiovascular disease at baseline. Diet was assessed with a food frequency questionnaire. Peripheral arterial disease was defined as an ankle-arm systolic blood pressure index (AAI) of <=0.9 and was present in 204 men and 370 women. In multivariate-adjusted logistic regression analyses, vitamin C intake was significantly inversely associated with peripheral arterial disease in women (highest vs. lowest quartile: relative risk = 0.64, 95% confidence interval (CI): 0.48, 0.89; ptrend = 0.006), and a 100-mg increase in intake was associated with a 0.013 AAI increase (95% CI: 0.001, 0.025). In men, vitamin E intake was inversely associated with peripheral arterial disease (relative risk = 0.67, 95% CI: 0.44, 1.03; ptrend = 0.067); a 10-mg increase in intake was associated with a 0.015 AAI increase (95% CI: 0.001, 0.031). Whether these differences in antioxidant intake and the risk of a low AAI and of peripheral arterial disease between sexes are attributable to a different food pattern for men compared with women remains to be elucidated.

antioxidants; arterial occlusive diseases; ascorbic acid; beta carotene; cardiovascular diseases; cross-sectional studies; diet; vitamin E

Abbreviations: AAI, ankle-arm systolic blood pressure index; CI, confidence interval


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Observational studies indicate that dietary antioxidants may exert a protective effect on incidence of and mortality from cardiovascular disease (1GoGoGoGoGoGoGoGoGo–10Go), suggesting an inverse association with atherosclerosis (11GoGoGoGoGo–16Go). Peripheral arte-rial disease, reflecting the presence of atherosclerotic vessel wall abnormalities of the arteries of the lower extremities, is considered to indicate generalized atherosclerosis (17Go, 18Go). This disease is common in the elderly (17Go, 19Go, 20Go) and is a strong predictor of subsequent morbidity and mortality (19Go, 21Go, 22Go). The present study aimed to investigate whether dietary antioxidants are associated with the presence of peripheral arterial disease.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Study population
The Rotterdam Study is a community-based, prospective cohort study of 7,983 persons in Rotterdam, the Netherlands (response rate, 78 percent) aged 55 years or more. The study investigates the incidence of and risk factors for chronic and disabling diseases (23Go). Dietary assessment was conducted for 5,646 participants. Subjects (n = 212) who did not fully cooperate during the dietary interview, resulting in unreliable reported diets, were excluded. Blood pressure of the lower extremities was measured in 4,879 subjects for whom dietary data were available. Thirty subjects with an ankle-arm systolic blood pressure index (AAI) of >1.5 were excluded, because this index usually reflects arterial rigidity that prevents arterial compression. Subjects with self-reports of myocardial infarction, cerebrovascular accident, bypass surgery, percutaneous transluminal coronary angioplasty, or intermittent claudication (n = 482) were also excluded from analysis because they might intentionally have changed their diet after experiencing a cardiovascular event. These exclusions resulted in 4,367 subjects for analysis.

Measurements
All subjects were first visited at their home, and then they participated in two research center visits for detailed medical examinations (23Go). Height and weight were measured, and body mass index (weight in kilograms/height in meters2) was calculated. Sitting blood pressure was measured at the upper arm by using a random-zero sphygmomanometer. Systolic blood pressure at both ankles (posterior tibial artery) was measured in the supine position with an 8-MHz Doppler transducer (24Go). The AAI is the ratio of systolic blood pressure at the ankle to systolic blood pressure at the arm. Peripheral arterial disease was defined as a right or left AAI of <=0.9 (25Go).

Dietary assessment
Habitual diet during the past year was assessed by using a semiquantitative food frequency questionnaire that included 170 food items in 13 food groups and questions about dietary habits, supplementation, and prescribed diets (26Go). Nutrient intake from supplements was not considered because of insufficient accuracy in the recording of dose and duration. The relative validity of the questionnaire was assessed by comparison with the estimated nutrient intake from a food diary, which covered 15 days of food recording over a 1-year period (27Go).

Data analysis
Dietary ß-carotene, vitamin C, and vitamin E from food sources were adjusted for energy intake by regressing the antioxidant intake on total energy and adding the residuals to the median intakes (28Go). Analysis of variance and chi-square statistics for categorical variables were applied to test for age-adjusted differences in mean levels of dietary antioxidants and risk factors for peripheral arterial disease between subjects with and without peripheral arterial disease. The association between antioxidant intake and disease was examined primarily by logistic regression. Dietary antioxidant intake was categorized into quartiles, and risk of peripheral arterial disease was assessed by comparing the upper quartiles with the lowest quartile. The initial analysis examined associations adjusted for age. The analysis was subsequently adjusted for body mass index, number of cigarette pack-years smoked, equivalent household income (five categories), highest level of education attained (five categories), and alcohol intake (five categories). The models were fit separately for both sexes. Associations were expressed as relative risks with 95 percent confidence intervals. Linear regression analyses were performed with the AAI as the dependent variable. Regression coefficients (ß) were reported with 95 percent confidence intervals and two-tailed p values. Results were considered statistically different at the two-tailed 0.05 alpha level. Statistical analysis was performed by using SAS software (release 6.11; SAS Institute, Inc., Cary, North Carolina).


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The mean ages of the 1,673 men and 2,694 women were 66.6 years (standard deviation, 7.2) and 67.4 years (standard deviation, 7.9), respectively. Vitamin supplements containing ß-carotene, vitamin C, or vitamin E were used by 9.0 percent of the male and 13.8 percent of the female subjects. Peripheral arterial disease was present in 12.2 percent of the male and 3.7 percent of the female subjects. Those with peripheral arterial disease were significantly older. Analyses were thus adjusted for age. Risk factors were significantly more frequent in subjects with peripheral arterial disease (table 1).


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TABLE 1. Age-adjusted means and distributions of baseline characteristics* for 1,673 men and 2,694 women with and without peripheral arterial disease, the Rotterdam Study, Rotterdam, the Netherlands, 1990–1993{dagger}

 
Beta-carotene was inversely associated with age (men: r = -0.13, p < 0.001; women: r = -0.11, p < 0.001). Vitamin C and ß-carotene were correlated for both sexes (men: r = 0.39, p < 0.001; women: r = 0.36, p < 0.001); correlations between ß-carotene and vitamin E and between vitamin C and vitamin E were rather modest (range, 0.11–0.20; p < 0.001). Dietary fat and cholesterol were inversely associated with antioxidants, but total fat and polyunsaturated fatty acids correlated with vitamin E. Antioxidative vitamins were weakly correlated with measures of body composition, blood pressure, and serum cholesterol. Current smokers had a lower dietary antioxidant intake than never or former smokers.

In women, dietary vitamin C was inversely associated with risk of peripheral arterial disease (table 2). The age-adjusted relative risk for the highest versus the lowest quartile of intake was 0.61 (95 percent confidence interval (CI): 0.44, 0.84, ptrend = 0.002). Multivariate adjustment did not change the risk estimates. Further adjustment by ß-carotene, vitamin E, and use of antioxidative vitamin supplements only slightly altered the risk estimates (data not shown). Table 3 delineates the relations of antioxidant vitamin intake with AAI. An increase of 10 mg in vitamin C intake was associated with a 0.0016 AAI increase (95 percent CI: 0.0004, 0.0028) in an age-adjusted model (p = 0.010). Dietary intake of ß-carotene and vitamin E was not associated with risk of peripheral arterial disease and AAI.


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TABLE 2. Relative risk and 95% confidence interval for peripheral arterial disease, according to quartile of energy-adjusted dietary antioxidants, for 1,673 men and 2,694 women in the Rotterdam Study, Rotterdam, the Netherlands, 1990–1993*

 

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TABLE 3. Linear regression of energy-adjusted dietary antioxidant intake on the ankle-arm systolic blood pressure index for 1,673 men and 2,694 women in the Rotterdam Study, Rotterdam, the Netherlands, 1990–1993*

 
In men, dietary vitamin E was inversely associated with age-adjusted risk of peripheral arterial disease. The relative risk for the highest versus the lowest quartile of intake was 0.62 (95 percent CI: 0.41, 0.95, ptrend = 0.026). Multivariate adjustment slightly decreased the point estimates (table 2). In age-adjusted regression analysis, the AAI increased by 0.020 (95 percent CI: 0.0004, 0.0036) with every 10-mg increase in vitamin E (p = 0.020) (table 3). Beta-carotene and vitamin C were not associated with risk of peripheral arterial disease and AAI.

The risk of peripheral arterial disease increased significantly in subjects reporting a prescribed diet. The multivariate-adjusted relative risks were 1.76 (95 percent CI: 1.10, 2.75, p = 0.016) for men and 1.57 (95 percent CI: 1.17, 2.09, p < 0.001) for women. Exclusion of subjects reporting a diet (n = 526) strengthened the association between vitamin C intake and peripheral arterial disease in women (relative risk for the highest vs. the lowest quartile = 0.55, 95 percent CI: 0.38, 0.79; ptrend = 0.001). For men, however, the association of vitamin E intake with peripheral arterial disease decreased (relative risk for the highest vs. the lowest quartile = 0.72, 95 percent CI: 0.46, 1.21; ptrend = 0.139).


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In the present study, we investigated the association of dietary antioxidants with peripheral arterial disease and AAI in an elderly cohort. In women, vitamin C intake was significantly inversely associated with risk of peripheral arterial disease and AAI; in men, inverse associations of peripheral arterial disease and AAI with vitamin E were observed.

Interpretation of our findings should be preceded by methodological considerations. Our results were based on a cross-sectional analysis, inherently limiting the basis for causal inference. Timing of dietary intake with respect to development of peripheral arterial disease is not known, but one might expect that recent dietary changes would not reflect the dietary milieu in which the disease developed. For most subjects, peripheral arterial disease is asymptomatic; therefore, we do not expect that changes occurred differentially in subjects with and without the disease. We excluded subjects with symptomatic disease, assuming that they might have changed their diets because of cardiovascular symptoms or a cardiovascular event. We further evaluated whether exclusion of subjects reporting a prescribed diet modified risk estimates. For women, the inverse association of vitamin C intake with peripheral arterial disease was strengthened; for men, the association of vitamin E intake with peripheral arterial disease was diminished. Depending on the type of diet, nutrient intake may be affected differently (26Go). Most subjects were assigned to a diet low in energy, cholesterol, and fat. Considering the intercorrelation of total fat with vitamin E, exclusion of subjects reporting a diet may have considerably altered the observed association of vitamin E with peripheral arterial disease in men.

Few other studies have focused on the association of dietary antioxidants with peripheral arterial disease. In cross-sectional analyses from the Atherosclerosis Risk in Communities study (29Go), lower dietary intakes of vitamins E, C, and A were significantly associated with a lower AAI in men only. Cross-sectional data from the Edinburgh Artery Study associated lower vitamin E intake with a decreased AAI (30Go), whereas case-control data from the same study showed no association of {alpha}-tocopherol and ß-carotene with intermittent claudication. However, among cases with intermittent claudication, a lower intake of vitamin C was observed (31Go). In the current study, we found dietary vitamin C to be significantly inversely associated with peripheral arterial disease and AAI in women and vitamin E to be inversely associated with peripheral arterial disease and AAI in men. Whether relations between antioxidant intake and peripheral arterial disease and AAI indeed differ between men and women, or whether our findings are in part attributable to a different food pattern for men compared with women, remains to be elucidated.


    ACKNOWLEDGMENTS
 
The study was supported by a grant from the NESTOR program for research in the elderly (supported by the Netherlands Ministry of Health and Education).

The authors thank all field workers and dietitians in the Ommoord research center for their enthusiasm and skillful contributions to data collection and the participating general practitioners and research physicians of the Rotterdam Study for their commitment in collecting follow-up information.


    NOTES
 
Correspondence to Dr. Jacqueline C. M. Witteman, Department of Epidemiology and Biostatistics, Erasmus University Medical School, P.O. Box 1738, 3000 DR Rotterdam, the Netherlands (e-mail: witteman{at}epib.fgg.eur.nl).


    REFERENCES
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication April 26, 1999. Accepted for publication December 20, 2000.