Experimental studies have demonstrated that oxidation of

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1 Serum Antioxidant Vitamins and Blood Pressure in the United States Population Jing Chen, Jiang He, Lee Hamm, Vecihi Batuman, Paul K. Whelton Abstract Serum vitamin C has been inversely associated with blood pressure in several epidemiologic studies, but little is known about effect of other antioxidant vitamins. We examined the relation between serum vitamins A, C, and E, and -carotene levels and blood pressure among men and women 20 years of age who participated in the Third National Health and Nutrition Examination Survey. Blood pressure was characterized as the average of 6 measurements obtained over 2 visits by trained observers and hypertension was defined as blood pressure 140/ 90 mm Hg and/or taking antihypertensive medications. In multivariate models, a1sddifference in vitamin A (16.2 g/dl) and vitamin E (20.4 g/dl) was associated with a 43% (OR, 1.43; 95% CI, 1.34 to 1.53) and 18% (OR, 1.18; 95% CI, 1.09 to 1.27) higher odds of hypertension, respectively. A1SDdifference in -carotene (0.47 g/dl) and -carotene (496 g/dl) was associated with a 16% (OR, 0.84; 95% CI, 0.76 to 0.94) and 11% (OR, 0.89; 95% CI, 0.82 to 0.97) lower odds of hypertension, respectively. In addition, serum vitamins A and E were positively and significantly associated with both systolic and diastolic blood pressure, whereas -carotene and -carotene were inversely and significantly associated with systolic and vitamin C associated with diastolic blood pressure in multivariate linear regression analyses. These findings indicate that antioxidant vitamins may be important in the underlying cause and prevention of hypertension. Further studies in this important area are warranted. (Hypertension. 2002;40: ) Key Words: blood pressure vitamins epidemiology antioxidants Experimental studies have demonstrated that oxidation of LDL plays an important role in the development and progression of atherosclerosis in animal models. 1 3 Observational epidemiologic studies have also documented an inverse association between increased intake of antioxidant vitamins such as vitamin E, and vitamin C and reduced morbidity and mortality rates from coronary heart disease. 1 6 However, results from several recently published, large, randomized, controlled clinical trials, which provide the best evidence for a causal relation, do not support the hypothesis that vitamin E or -carotene supplementation has a protective effect on coronary heart disease or cardiovascular disease as whole. 7 9 Given the wide use of antioxidant vitamins in the US general population, it is important to examine the beneficial as well as potential adverse effects of vitamin supplementation in this context. Observational epidemiologic studies have suggested an inverse association between dietary intake or serum level of vitamin C and blood pressure (BP) Several small and short-term clinical trials in which the effect of vitamin C supplements on BP was examined have yielded inconsistent findings There are sparse data on the relation between other antioxidant vitamins and BP in human populations We took advantage of a large representative sample of the US general population to examine the relation of serum antioxidant vitamins, including vitamins A, C, and E, and -carotene to BP. We hypothesized that serum levels of antioxidant vitamins might be inversely related to BP levels as well as risk of hypertension. Methods Study Participants The Third National Health and Nutrition Examination Survey (NHANES III) was conducted by the National Center for Health Statistics between 1988 and The details of study participants and study methods have been published elsewhere. 23 In brief, a stratified multistage probability design was used to obtain a representative sample of the civilian noninstitutionalized US general population. 23 The design included oversampling of the very young, the elderly, non-hispanic blacks, and Mexican-Americans to improve the precision of estimates in these groups. A total of persons 20 years of age participated in NHANES III. For the current analysis, participants were excluded if their self-reported race/ethnicity was not non-hispanic white, non-hispanic black, or Mexican-American (n 715). Participants were also excluded from the analysis if there was a lack of data on BP (n 348) or serum antioxidant vitamin levels (n 2445). A total of 6755 non-hispanic whites, 4250 non-hispanic blacks, and 4312 Mexican-Americans 20 years of age met the inclusion criteria and were included in the current analysis. In addition, 2544 participants who were currently taking antihypertensive medications were further excluded from the Received April 8, 2002; first decision May 2, 2002; revision accepted July 2, From the Department of Medicine, Tulane University School of Medicine (J.C., J.H., L.H., V.B., P.K.W), and the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine (J.H., P.K.W.), New Orleans, La. Correspondence to Dr Jiang He, Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, 1430 Tulane Ave, SL 18, New Orleans, LA jhe@tulane.edu 2002 American Heart Association, Inc. Hypertension is available at DOI: /01.HYP

2 Chen et al Antioxidant Vitamins and Blood Pressure 811 TABLE 1. Characteristics of the Study Participants by Hypertensive Status Variables Normotensives (n ) Hypertensives (n 4860) P Age, y Male gender, % Non-Hispanic white, % Non-Hispanic black, % High school graduate, % Weekly alcohol drinking, % Self-reported diabetes, % Body mass index, kg/m Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Total energy intake, kcal/24 hr Dietary saturated fat intake, % kcal Dietary sodium intake, mg/1000 kcal Dietary potassium intake, mg/1000 kcal Serum vitamin A, g/dl Serum g/dl Serum g/dl Serum vitamin C, mg/dl Serum vitamin E, g/dl Values are mean SE or percentage. linear regression analysis in which BP was used as a dependent variable. Measurements The NHANES III data collection included a standardized home interview followed by a detailed physical examination in a mobile examination center or the participant s home. Information on a wide variety of sociodemographic, medical history, nutritional history, and family history questions, such as self-reported age, race/ethnicity, gender, years of education completed, history of smoking, diabetes, and hypertension, use of antihypertensive medication, alcohol consumption, use of vitamin supplements, and 24-hour dietary recall, were obtained during the home interview. 23 BP was measured 3 times during the home interview and during the subsequent evaluation at the mobile examination center by trained observers using a standard protocol. 23 BP for individual participants was calculated as the average of all available systolic and diastolic readings. Hypertension was defined as the presence of a mean systolic BP 140 mm Hg and/or diastolic BP 90 mm Hg and/or use of antihypertensive medication. Body weight and height were measured according to a standard protocol, and body mass index was calculated as an index for obesity. A blood sample was collected at the second visit. Serum levels of antioxidant vitamins, including vitamin A, vitamin C, and vitamin E were measured at the National Center for Environmental Health of the Centers for Disease Control and Prevention (Atlanta, Ga) by isocratic high-performance liquid chromatography. 24 Statistical Analyses Mean values for age, BP, body mass index, dietary nutrient intake, serum antioxidant vitamins, and other continuous variables, as well as percentages for gender, race/ethnicity, and other categoric variables, were calculated by hypertension status. The statistical significance of differences was examined by means of Student t test (continuous variables) and the 2 test (categoric variables). The agreement between serum level of vitamins and supplement use or dietary intake was assessed by Pearson correlation coefficients (r). Bivariate relations were explored by plotting each serum antioxidant vitamin versus BP, which does not impose any statistical modeling assumptions on the associations. The linearity of the association was tested by means of correlation analysis. Linear regression analysis was used to assess the association between serum antioxidant vitamin levels and BP. Logistic regression analysis was used to explore the relation between serum antioxidant vitamin levels and odds of hypertension. Estimated regression coefficients or odds ratios are reported as the difference in BP (mm Hg) or odds of hypertension associated with a 1 SD increment in serum antioxidant vitamin levels. Confounding of the association between BP and antioxidant vitamin levels was evaluated by adding possible confounders to the models. Two final models, age-, gender-, and race-adjusted model and multivariate-adjusted model (additional adjustment for education, alcohol consumption, and body mass index, dietary intake of sodium, potassium, saturated fat, and total energy) are presented. All statistical analyses were performed with the use of Stata software, which included functions for the analysis of complex survey data. 25 Results The general characteristics of study participants by hypertension status are presented in Table 1. On average, normotensives were 20 years younger than hypertensives. The percentages of male and non-hispanic whites were similar between the two groups, whereas normotensives had a lower proportion of non-hispanic blacks and a higher proportion of high school graduates and participants who consumed alcohol at least once per week. The prevalence of self-reported history of diabetes was significantly higher in hypertensives than in normotensives. As expected, normotensives had a lower mean body mass index and systolic and diastolic BP than their hypertensive counterparts. Normotensives reported a higher intake of dietary saturated fat and a lower intake of sodium and potassium compared with hypertensives. Mean

3 812 Hypertension December 2002 TABLE 2. Odds Ratio (95% CI) of Hypertension Associated With Serum Antioxidant Vitamins: Multivariate Logistic Regression Analysis* Age-, Gender-, and Race-Adjusted Multivariate-Adjusted Serum Vitamins, 1 SD OR (95% CI) P OR (95% CI) P Vitamin A, 16.2 g/dl 1.40 (1.31, 1.49) (1.34, 1.53) g/dl 0.76 (0.68, 0.85) (0.76, 0.94) g/dl 0.81 (0.73, 0.89) (0.82, 0.97) 0.01 Vitamin C, 0.47 mg/dl 0.91 (0.84, 0.99) (0.91, 1.07) 0.7 Vitamin E, 496 g/dl 1.18 (1.09, 1.27) (1.09, 1.27) SD indicates standard deviation. *n for age-, gender-, and race-adjusted analyses and n for multivariate-adjusted analyses. Adjusted for age, gender, race/ethnicity, education, alcohol consumption, body mass index, history of diabetes, dietary intake of sodium, potassium, saturated fat, and total energy. serum levels of antioxidant vitamins, including vitamins A, C, and E, and were significantly lower in normotensives compared with hypertensives. The self-reported vitamin supplement use during the past month was significantly correlated with serum levels of vitamin A (r 0.13), vitamin C (r 0.31), vitamin E (r 0.32), -carotene (r 0.15), and -carotene (r 0.18) among study participants. Dietary intake of vitamins from 24-hour recall was also significantly associated with serum levels of vitamin A (r 0.09), vitamin C (r 0.23), vitamin E (r 0.04), -carotene (r 0.19), and -carotene (r 0.16). Antioxidant Vitamins and Hypertension Table 2 depicts the odds ratios and 95% CIs for hypertension associated with 1 SD difference in level of serum vitamin A (16.2 g/dl), -carotene (4.8 g/dl), -carotene (20.4 g/dl), vitamin C (0.47 mg/dl), and vitamin E (496 g/dl). After adjustment for age, gender, and race/ethnicity, serum vitamins A and E were significantly associated with a higher odds of hypertension, whereas serum and vitamin C were significantly associated with a lower odds of hypertension. After additional adjustment for education, alcohol consumption, body mass index, history of diabetes, dietary intake of sodium, potassium, saturated fat, and total energy, the relation between level of serum antioxidant vitamins and odds of hypertension remained significant, except for serum vitamin C. The odds ratio of hypertension associated with serum vitamin C was diminished and became nonsignificant in the multivariate-adjusted model. The relation between serum antioxidant vitamins and hypertension was consistent among subgroups defined by age, gender, and race/ethnicity (Table 3). Antioxidant Vitamins and Blood Pressure Table 4 shows differences in systolic and diastolic BP associated with a 1 SD difference in levels of serum antioxidant vitamins. After adjustment for age, gender, and race/ ethnicity, vitamins A and E were positively and significantly associated with both systolic and diastolic BP, whereas and vitamin C were inversely and significantly associated with both systolic and diastolic BP. After additional adjustment for education, alcohol consump- TABLE 3. Odds Ratios (95% CI) for Hypertension Associated with Serum Level of Antioxidant Vitamins Among Age, Gender, and Race/Ethnicity Groups: Multivariate Logistic Regression Analysis Subgroups n Vitamin A, 16.2 g/dl 4.8 g/dl 20.4 g/dl Vitamin C, 0.47 mg/dl Vitamin E, 496 g/dl Age, y (1.29, 1.57) 0.79 (0.67, 0.92) 0.72 (0.61, 0.85) 0.93 (0.83, 1.03) 1.20 (1.05, 1.35) (1.25, 1.54) 0.89 (0.80, 0.99)* 0.99 (0.90, 1.08) 1.04 (0.96, 1.13) 1.09 (1.01, 1.18)* Gender Men (1.24, 1.53) 0.90 (0.77, 1.05) 0.92 (0.82, 1.03) 1.00 (0.88, 1.15) 1.14 (1.02, 1.29)* Women (1.30, 1.59) 0.79 (0.71, 0.87) 0.85 (0.77, 0.93) 0.94 (0.86, 1.02) 1.16 (1.05, 1.29) Race/ethnicity Non-Hispanic whites (1.32, 1.55) 0.82 (0.73, 0.92) 0.88 (0.79, 0.97) 1.00 (0.92, 1.10) 1.17 (1.07, 1.28) Non-Hispanic blacks (1.37, 1.59) 0.94 (0.84, 1.04) 0.98 (0.90, 1.07) 0.88 (0.77, 1.02) 1.33 (1.15, 1.54) Mexican-Americans (1.01, 1.32)* 0.82 (0.67, 1.01) 0.83 (0.71, 0.98)* 0.85 (0.72, 1.01) 1.12 (1.02, 1.23)* Values are adjusted for age, gender, race/ethnicity, education, alcohol consumption, history of diabetes, body mass index, dietary intake of sodium, potassium, saturated fat, and total energy, except for gender in men and women subgroups, and race in white, black, and Mexican-American subgroups. *P 0.05; P 0.01; and P

4 Chen et al Antioxidant Vitamins and Blood Pressure 813 TABLE 4. Effect of Serum Antioxidant Vitamins on SBP and DBP Levels: Multiple Linear Regression Analysis SBP, mm Hg DBP, mm Hg Serum Vitamins, 1 SD Effect (95% CI) P Effect (95% CI) P Vitamin A, 16.2 g/dl Age-, gender-, and race-adjusted 1.56 (1.15, 1.97) (1.13, 1.68) Multivariate-adjusted* 1.44 (1.01, 1.86) (1.03, 1.54) g/dl Age-, gender-, and race-adjusted 1.40 ( 1.83, 0.97) ( 0.58, 0.08) 0.01 Multivariate-adjusted* 0.86 ( 1.25, 0.47) ( 0.20, 0.22) g/dl Age-, gender-, and race-adjusted 1.47 ( 1.93, 1.00) ( 0.83, 0.35) Multivariate-adjusted* 0.92 ( 1.39, 0.45) ( 0.41, 0.01) 0.06 Vitamin C, 0.47 mg/dl Age-, gender-, and race-adjusted 0.69 ( 1.14, 0.24) ( 0.85, 0.32) Multivariate-adjusted* 0.10 ( 0.52, 0.32) ( 0.62, 0.13) Vitamin E, 496 g/dl Age-, gender-, and race-adjusted 0.70 (0.26, 1.14) (0.77, 1.26) Multivariate-adjusted* 0.66 (0.22, 1.11) (0.59, 1.08) Participants on antihypertensive medications were excluded. n for age-, gender-, and race-adjusted analyses and n for multivariate-adjusted analyses. *Adjusted for age, gender, education, alcohol consumption, body mass index, history of diabetes, dietary intake of sodium, potassium, saturated fat, and total energy. tion, body mass index, history of diabetes, dietary intake of sodium, potassium, saturated fat, and total energy, vitamins A and E remained positively and significantly associated with systolic and diastolic BP. In addition, -carotene and -carotene were inversely and significantly associated with systolic BP, whereas vitamin C was inversely and significantly associated with diastolic BP in multivariate-adjusted models. Table 5 shows multivariate-adjusted differences in systolic and diastolic BP associated with a1sddifference in level of serum antioxidant vitamins among specified subgroups by age, gender, race/ethnicity, and hypertension status. Serum vitamin A was positively and significantly associated with both systolic and diastolic BP in each subgroup, except in participants with hypertension. Serum -carotene was inversely and significantly related to systolic BP among most of the subgroups. Serum -carotene was inversely related to both systolic and diastolic BP in participants who were younger than 60 years, in women and in whites, and was related to systolic BP in men and in normotensives. Serum vitamin C was inversely associated with diastolic BP in participants who were younger than 60 years, in men and women, and in hypertensives and normotensives. In addition, serum vitamin C was inversely and significantly associated with both systolic and diastolic BP among blacks. Serum vitamin E was positively associated with both systolic and diastolic BP among most of the subgroups. Discussion Our study is one of the first to identify a significant and inverse relation between serum levels of -carotene and -carotene and risk of hypertension. It is also one of the first to recognize a significant and positive relation between serum levels of vitamin A and E and risk of hypertension in a human population. These relations were independent of age, gender, race, and other important risk factors for hypertension. In addition, our study identified a significant inverse relation between serum vitamin C and diastolic BP. These results suggest that antioxidant vitamins may play an important role in the underlying cause and prevention of hypertension. As such, they have important public health and clinical implications. Hypertension, a major risk factor for coronary heart disease, stroke, congestive heart failure, end-stage renal disease, and peripheral vascular disease, affects as many as 50 million adult Americans. 26 More than $34.4 billion is spent annually for medications, office visits, and laboratory tests related to treatment of hypertension in the US population. 27 Epidemiologic studies and clinical trials have demonstrated that nutritional factors play an important role in the underlying cause and prevention of hypertension. 28 The findings from our study provide new insights regarding the potential role of various antioxidant vitamins in modulating BP. Experimental studies in animal models suggest that oxidative stress may be important in the pathogenesis of hypertension or in the underlying cause of arterial damage related to hypertension. 29,30 However, there are scarce data in the relation between oxidative stress or antioxidants and BP in human populations. In cross-sectional studies, higher serum levels or dietary intake of vitamin C have been consistently and significantly related to lower systolic and diastolic BP among middle-aged or elderly populations However, there was insufficient attention to confounding effects by other dietary factors in most of these studies. 31 Several small

5 814 Hypertension December 2002 TABLE 5. Effect (95% CI) of Serum Antioxidant Vitamins on SBP and DBP Levels Among Age, Gender, and Race/Ethnicity Groups: Multiple Linear Regression Analysis Subgroups Vitamin A, 16.2 g/dl 4.8 g/dl 20.4 g/dl Vitamin C, 0.47 mg/dl Vitamin E, 496 g/dl Age, y (n 9092) SDP 1.49 (1.04, 1.94) 0.77 ( 1.17, 0.37) 1.36 ( 1.82, 0.90) 0.24 ( 0.68, 0.20) 0.60 (0.18, 1.02) DBP 1.48 (1.15, 1.80) 0.18 ( 0.43, 0.06) 0.42 ( 0.64, 0.20) 0.28 ( 0.54, 0.02)* 0.96 (0.62, 1.30) 60 (n 3010) SBP 0.81 (0.00, 1.62)* 0.60 ( 1.40, 0.20) 0.04 ( 0.63, 0.71) 0.00 ( 0.92, 0.93) 0.72 ( 0.09, 1.53) DBP 0.47 (0.06, 0.88)* 0.02 ( 0.48, 0.43) 0.11 ( 0.48, 0.25) 0.34 ( 0.74, 0.07) 0.18 ( 0.19, 0.54) Gender Men (n 5819) SBP 0.88 (0.30, 1.47) 0.82 ( 1.47, 0.18) 1.17 ( 1.83, 0.51) 0.36 ( 0.94, 0.21) 0.43 ( 0.11, 0.98) DBP 1.58 (1.17, 2.00) 0.12 ( 0.23, 0.46) 0.16 ( 0.53, 0.21) 0.45 ( 0.83, 0.07)* 1.20 (0.82, 1.59) Women (n 6283) SBP 1.77 (1.26, 2.28) 1.03 ( 1.42, 0.65) 1.01 ( 1.49, 0.54) 0.06 ( 0.55, 0.42) 0.57 ( 0.17, 1.31) DBP 0.98 (0.65, 1.31) 0.10 ( 0.30, 0.11) 0.29 ( 0.52, 0.07) 0.36 ( 0.63, 0.10) 0.37 ( 0.01, 0.74) Race Whites (n 6273) SBP 1.72 (1.27, 2.16) 1.25 ( 1.64, 0.86) 1.15 ( 1.70, 0.61) 0.11 ( 0.29, 0.52) 0.86 (0.44, 1.28) DBP 1.23 (0.93, 1.52) 0.04 ( 0.21, 0.29) 0.22 ( 0.44, 0.00)* 0.20 ( 0.43, 0.03) 0.89 (0.64, Blacks (n 4050) SBP 1.72 (0.87, 2.56) 0.12 ( 0.51, 0.28) 0.06 ( 0.64, 0.75) 1.38 ( 2.28, 0.48) 1.70 (0.77, 2.62) DBP 1.01 (0.34, 1.67) 0.11 ( 0.37, 0.14) 0.22 ( 0.62, 0.18) 1.01 ( 1.45, 0.57) 0.67 (0.06, 1.28)* Mexican-Americans (n 4195) SBP 1.32 (0.64, 2.00) 0.83 ( 1.70, 0.04) 0.36 ( 1.22, 0.50) 0.42 ( 1.05, 0.21) 0.43 ( 0.24, 1.09) DBP 1.01 (0.55, 1.47) 0.04 ( 0.54, 0.47) 0.32 ( 0.69, 0.04) 0.31 ( 0.74, 0.12) 1.23 (0.70, 1.75) Hypertensives (n 2119) SBP 0.33 ( 1.10, 0.44) 0.28 ( 1.02, 0.47) 0.11 ( 0.58, 0.80) 0.42 ( 1.07, 0.23) 0.39 ( 1.15, 0.36) DBP 0.22 ( 0.28, 0.73) 0.35 ( 0.24, 0.94) 0.08 ( 0.57, 0.72) 0.67 ( 1.14, 0.20) 0.13 ( 0.40, 0.66) Normotensives (n 9983) SBP 1.19 (0.83, 1.56) 0.48 ( 0.77, 0.18) 0.65 ( 1.02, 0.28) 0.05 ( 0.42, 0.32) 0.55 (0.25, 0.85) DBP 1.24 (0.95, 1.53) 0.07 ( 0.14, 0.28) 0.06 ( 0.24, 0.13) 0.23 ( 0.46, 0.01)* 0.80 (0.53, 1.06) Adjusted for age, gender, race/ethnicity, education, alcohol consumption, body mass index, history of diabetes, dietary intake of sodium, potassium, saturated fat, and total energy, except for gender in men and women subgroups, and race in white, black, and Mexican-American subgroups. Participants on antihypertensive medications were excluded. *P 0.05; P 0.01; P clinical trials that have tested the effect of vitamin C supplementation on BP have yielded inconsistent findings For example, Fotherby and colleagues 17 found that BP was not reduced after supplementation with 500 mg vitamin C per day for 3 months in a double-blind, randomized, placebo-controlled crossover study. However, daytime levels of ambulatory systolic BP was slightly but significantly reduced, by 2.0 mm Hg (95% CI, 0 to 3.9 mm Hg), in the vitamin C supplementation phase compared with the placebo control phase. Our study identified an inverse association between serum vitamin C level and risk of hypertension and BP in age, gender, and race-adjusted analyses. After further adjustment for other risk factors including dietary nutrients, serum vitamin C level was only significantly related to diastolic BP. Furthermore, our study indicated that serum vitamin C level was significantly related to both systolic and diastolic BP in blacks who had a lower mean level of serum vitamin C. These findings might imply that low intake of dietary vitamin C related to increased risk of hypertension. To the best our knowledge, the present study is the first to have examined the relation between serum carotene levels and BP in a human population. Our study identified an inverse relation between serum levels of -carotene and -carotene and risk of hypertension and systolic BP. In a randomized crossover trial conducted in 21 hypertensive patients, a combination of antioxidants consisting of 200 mg of zinc sulfate, 500 mg of vitamin C, 600 mg of -tocopherol, and 30 mg of -carotene per day significantly lowered systolic BP. 32 However, in a larger randomized controlled

6 Chen et al Antioxidant Vitamins and Blood Pressure 815 trial conducted in 297 participants, combined antioxidant vitamin capsules providing 400 IU vitamin E, 500 mg vitamin C, and 6 mg -carotene per day did not reduce BP during a 2- to 4-month period of intervention. 33 Future studies are required to confirm our findings and to examine the independent effect of carotene on BP. Our study is one of the first to report a strong, independent, and positive association between higher serum vitamin A level and increased risk of hypertension and BP in a large population sample. The association was consistent across age, gender, and race groups. This finding is in conflict with the results from two previous reports. In the First National Health and Nutrition Examination Survey population, a significant decrease in dietary intake of vitamin A was identified in hypertensives compared with normotensives. 34 In addition, a significant decrease in plasma vitamin A level was reported in 105 hypertensive patients compared with 100 normotensive controls. 29 In the NHANES III study population, we have also identified a positive and significant association between serum vitamin A level and risk of chronic kidney disease. 35 Serum level of vitamin E was significantly and positively related with both systolic and diastolic BP in our study. Experimental studies have shown that vitamin E decreases BP in animal models. 36,37 However, data from human populations are more inconsistent. For example, epidemiologic studies have reported that serum level of vitamin E is reduced 29 or is no different 38 in hypertensive patients compared with normotensive control subjects. Palumbo et al 20 found that vitamin E supplementation had no effect on BP in treated hypertensive patients in a randomized, controlled, open trial. Our findings of a positive and independent relation between serum vitamin E and BP call for further investigation in this important area. Several large clinical trials, which examined the effect of -carotene or vitamin E supplements on risk of cardiovascular disease, have reported negative results. 7 9 For example, Yusuf and colleagues 9 summarized 4 major clinical trials of vitamin E supplementation with a total of participants in the treatment group and participants in the placebo control group. The relative risk of cardiovascular disease associated with vitamin E supplementation was 0.97, with a 95% CI from 0.92 to 1.02 (P 0.27). The recently completed Heart Protection Study indicates that antioxidant vitamin supplementation (650 mg vitamin E, 250 mg vitamin C, and 20 mg -carotene) does not reduce risk of cardiovascular disease among participants during 5 years of followup. 39,40 Our study raises new concerns on vitamin A and E supplement use in the general population. Our findings are noteworthy because they are based on experience in a large, representative sample of the US general population, where careful measurement of BP and serum vitamin levels allowed for more reliable assessment of the association, and it was possible to adjust for consumption of dietary nutrient and other important covariables. However, the cross-sectional study design used in NHANES III hinders making inferences regarding causality between antioxidant vitamins and BP. For instance, we cannot establish the temporal relation between serum levels of antioxidant vitamins and BP. In addition, oversampling some subgroups and imperfect response rates may affect the representation of the sample. Furthermore, serum level of antioxidant vitamins may be a marker for other confounding factors. If the relation between antioxidant vitamins and risk of hypertension is confirmed in large cohort studies, then randomized, controlled trials with sufficient sample size and intervention duration will be needed to test for causality. Perspectives Our study findings indicate that vitamin C, and -carotene are inversely associated with BP, whereas vitamins A and E are positively associated with BP. These relations are stronger in normotensive and younger participants. These findings suggest that antioxidant vitamins may play an important role in the underlying cause and prevention of hypertension. With increased recognition of oxidative stress in the pathogenesis of hypertension and wide use of antioxidant vitamins in the general population, further investigations are warranted in this important area. Acknowledgments This study was supported in part by grant R01HL60300 from the National Heart, Lung, and Blood Institute of the National Institutes of Health. References 1. Diaz MN, Frei B, Vita JA, Keaney JF Jr. Antioxidants and atherosclerotic heart disease. N Engl J Med. 1997;337: Tribble DL. AHA Science Advisory. Antioxidant consumption and risk of coronary heart disease: emphasis on vitamin C, vitamin E, and betacarotene: a statement for healthcare professionals from the American Heart Association. Circulation. 1999;99: Spencer AP. Carson DS. Crouch MA. Vitamin E and coronary artery disease. Arch Intern Med. 1999;159: Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett WC. Vitamin E consumption and the risk of coronary disease in women. 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