Published online before print June 24, 2004, doi: 10.1161/01.ATV.0000136648.62973.c8
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© 2004 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Effects of Long-Term Daily Low-Dose Supplementation With Antioxidant Vitamins and Minerals on Structure and Function of Large Arteries
From the National Institute of Health and Medical Research (INSERM) (M.Z., P.D., J.B.) Unit 258, Villejuif; Unit 508 INSERM (M.Z.), Lille; Unit 557 INSERM/INRA/CNAM, Institut Scientifique et Technique de la Nutrition et de l’Alimentation, ISTNA/CNAM (P.G., S.B., L.M., S.C., S.H.), Paris; and Centre de Diagnostic, Hôtel Dieu Hospital (J.B., S.C.) Paris, France.
Correspondence to Dr Mahmoud Zureik, INSERM U508, Institut Pasteur de Lille, 1 rue Calmette, BP 245-59019 LILLE cedex France. E-mail mahmoud.zureik{at}pasteur-lille.fr
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Abstract |
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Objective— Limited data exist from randomized trials evaluating, noninvasively, the impact of antioxidant supplementation on vascular structure and function.
Methods and Results— This is a substudy of the SU.VI.MAX Study, which is a randomized, double-blind, placebo-controlled, cardiovascular and cancer primary prevention trial. Eligible participants (free of symptomatic chronic diseases and apparently healthy) were randomly allocated to daily receive either a combination of antioxidants (120 mg vitamin C, 30 mg vitamin E, 6 mg beta carotene, 100 µg selenium, and 20 mg zinc) or placebo and followed-up over an average of 7.2±0.3 years. At the end-trial examination, the carotid ultrasound examination and carotid–femoral pulse-wave velocity (PWV) measurement were performed blindly in 1162 subjects aged older than 50 years and living in the Paris area. The percentage of subjects with carotid plaques was higher in the intervention group compared with the placebo group (35.2% versus 29.5%, P=0.04). Common carotid intima-media thickness (mean±SD) was not different between the 2 groups (0.70±0.08 versus 0.70±0.08 mm, P=0.38). Mean PWV tended to be lower (indicating less stiff aortic arteries) in the intervention group but the difference did not reach statistical significance (P=0.13).
Conclusion— These results suggest no beneficial effects of long-term daily low-dose supplementation of antioxidant vitamins and minerals on carotid atherosclerosis and arterial stiffness.
Limited data exist from randomized trials evaluating, noninvasively, the impact of antioxidant supplementation on vascular structure and function. The results of this large-scale study suggest no beneficial effects of long-term supplementation of antioxidant vitamins and minerals on carotid atherosclerosis and arterial stiffness in 1162 apparently healthy individuals (at baseline) in France.
Key Words: atherosclerosis • nutrition • oxidant stress • remodeling • developmental biology
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Introduction |
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The results of several animal experimental and population-based epidemiological studies have suggested that enhanced lipid peroxidation is associated with atherogenesis and cardiovascular diseases.1 Many observational studies show that a high dietary intake or high blood concentration of antioxidant vitamins are associated with reduced risk of cardiovascular diseases.2 Dietary antioxidants are recognized to protect against lipid peroxidation. However, randomized controlled studies investigating the clinical use of antioxidant supplementation to prevent cardiovascular disease have provided conflicting, even disappointing, results.3–8
Plausible explanations of discrepancies include the types of the populations recruited, the timing of the intervention relative to the atherosclerotic process, the duration of the intervention, the supplementation levels used (nutritional doses versus higher doses), the number of antioxidants tested, and the type of administration used (alone versus in combination with other nutrients).9
To understand the mechanisms linking antioxidants to cardiovascular disease, it is necessary to assess the potential effects of antioxidant supplementation on vascular structure and function on humans. Few randomized studies have investigated this issue, and most of them were limited by the use of carotid intima-media thickness (IMT) as the only marker of vascular alterations.10–13
B-mode ultrasound of carotid arteries is a noninvasive, valid, and reproducible method for directly visualizing and assessing carotid structure (IMT, lumen diameter, and focal atherosclerosis [plaques]).14–16 Noninvasive measurement of carotid–femoral pulse-wave velocity (PWV) is an easy and reproducible method of assessing aortic arterial stiffness,17 a major component of vascular function.
In this study of 1162 subjects aged older than 50 years and living in the Paris area, we report the effects of long-term daily nutritional dose supplementation with antioxidant vitamins and minerals on carotid IMT, lumen diameter, and plaques and aortic stiffness assessed by B-mode ultrasound and carotid-femoral PWV.
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Methods |
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This is a substudy of the SU.VI.MAX (SUpplémentation en VItamines et Minéraux AntioXydants) Study, which is a randomized, double-blind, placebo-controlled, primary prevention trial undertaken to determine whether supplementation with antioxidant vitamins and minerals at nutritional doses can reduce the incidence of cancers and cardiovascular diseases. The rationale, design, and methods of the study as well as characteristics of the participants have been described in detail elsewhere.18,19 In brief, in March through July 1994, information on the objectives and outline of the study was presented in various public media, along with a call for volunteers (women aged 35 to 60, or men aged 45 to 60, living in France). Eligible individuals free of symptomatic chronic diseases and apparently healthy at baseline (judged by clinical examination) were invited to an enrollment visit during which they received a manual, along with software or paper forms, to be completed during follow-up, and were randomly allocated to receive either a combination of antioxidants (120 mg vitamin C, 30 mg vitamin E, 6 mg beta carotene, 100 µg selenium (as selenium-enriched yeast) and 20 mg zinc (as gluconate) or a matching placebo, in a single daily capsule. The rationale of using this combination and doses has been previously provided.18 Capsules were prepared in 52 weekly packages of 7 capsules provided in a yearly box, labeled with the subjects participant number and a 10-digit lot number. Random treatment allocation was performed by block-sequence generation, stratified by gender and age-group; 13 017 eligible subjects were included to be followed-up for 7.5 years. Participants visited local SU.VI.MAX facilities each year. These visits involved the collection of blood and/or an extensive clinical examination.
At the end of follow-up, 74% of the participants reported having taken at least two-thirds of the capsules. There were no differences in capsule consumption between the groups (mean percentage of capsules taken: 79% in each). Compliance was confirmed for the intervention group by statistically significant increases in all biochemical markers of supplementation after 2 years, and after 7 years for beta carotene, vitamin C, and selenium in a subgroup of subjects (Table I, available online at http://atvb.ahajournals.org).
All subjects gave their informed written consent to the study, which was approved by the ad hoc ethical committees, ie, the "Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale" (CCPPRB no 706 Paris-Cochin Hospital, France) and the "Commission Nationale de l’Informatique et des Libertés" (CNIL no 334641).
Eligible subjects for this specific substudy were participants living in the Paris area, aged older than 50 years in 2002, whose end-trial visit should take place in 1 facility (CNAM center). These subjects were blindly examined between January and July 2002. The ultrasound examination and PWV measurement of this side protocol were added to the standard measures performed during the end-trial visit.
Carotid Ultrasound Examination
Ultrasound examinations were performed with the use of the Aloka SSD-650, with a transducer frequency of 7.5 MHz. Acquisition, processing, and storage of B-mode images were computer-assisted with the new version of a software previously described (M’ATHS).20
Ultrasound examinations were performed by 2 trained technicians and the protocol, which was similar to that applied in the Aging Vascular Study (EVA Study).21,22 Please see online Methods, available at http://atvb.ahajournals.org
PWV
This parameter is inversely proportional to the square root of the voluminal distensibility of the aorta. Carotid–femoral PWV was evaluated using 2 pressure probes. This method using an automatic device (Complior, Colson) has been extensively analyzed.23 Please see online Methods, available at http://atvb.ahajournals.org.
Reproducibility Study
Please see online Methods, available at http://atvb.ahajournals.org
Baseline and End-Trial Risk Factors Assessment
Please see online Methods, available at http://atvb.ahajournals.org.
Data Analysis
All analyses comparing the placebo group to the intervention group were performed by intention-to-treat and standard procedures from the Statistical Analysis System (SAS, Cary, NC) were used for statistical analyses. Outcomes considered in the analyses were carotid plaques (qualitative variable), common carotid artery (CCA)–IMT, CCA–lumen diameter, and PWV (quantitative variables). Baseline and end-trial characteristics according to intervention and placebo groups were compared by t test, 
2 test, and Fisher exact test as appropriate (results were expressed as percentages or means±SD). Multivariate adjustments for potential baseline cardiovascular risk factors and serum vitamins and minerals were performed by analyses of covariance (ANCOVA) for continuous variables and multiple logistic regression models for qualitative variables. Potential baseline cardiovascular risk factors considered in the analyses were age, sex, body mass index, hypertension (or hypertension treatment), total cholesterol, diabetes, and smoking habits. All multivariate analyses were repeated after substitution of end-trial cardiovascular risk factors for baseline cardiovascular risk factors. All reported P values are 2-tailed and P<0.05 was considered significant.
We have planned to include 
1200 subjects. This provides, at the 0.05 significance level, at least 90% power to detect 0.03-mm differences between the 2 groups for CCA-IMT, 0.4 m/s for PWV, and 7% differences in carotid plaque prevalence.
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Results |
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Of 1302 eligible individuals, 1162 (89.2%) have undergone complete vascular measurements (563 in the placebo group and 599 in the intervention group) (Figure). Reasons for dropout included technical problems and time constraint caused mainly by the high number of examined subjects on certain days. At baseline, there were no statistical significant differences between eligible included subjects and eligible excluded subjects concerning classical cardiovascular risk factors and serum vitamins and minerals.
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The duration of follow-up was 7.2±0.3 years. The main characteristics of the 1162 study population subjects at the baseline are presented in Table 1. At baseline, there were no significant differences between treatment groups in age or any demographic, biochemical nutritional, or clinical characteristics. At the end-trial visit (Table 2), only the frequency of hypertension treatment tended to be lower in the intervention group compared with the placebo group (P=0.11).
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The mean CCA–IMT was 0.71±0.08 mm for men and 0.69±0.07 mm for women (P<0.001), mean PWV was, respectively, 11.90±2.32 and 10.77±1.93 m/sec (P<0.0001), and the percentages of subjects with plaques were, respectively, 41.8% and 23.0% (P<0.0001). CCA–IMT, PWV, and carotid plaque were positively associated with baseline and end-trial values of age, body mass index, systolic blood pressure, hypertension treatment, and hypertension status. Carotid plaque was negatively associated with serum beta carotene measured at baseline. The means of baseline beta carotene in subjects without plaques and in those with plaques were, respectively, 0.60±0.39 and 0.49±0.31 µmol/L (P<0.0001). Subjects with carotid plaques also had a higher mean of CCA–IMT (0.72±0.08 mm versus 0.69±0.07 mm, P<0.0001) and a higher mean of PWV (11.67±2.36 m/s versus 11.18±2.11 m/s, P<0.001) than subjects without plaques.
Association of Carotid Plaques With Antioxidant Supplementation
The percentage of subjects with plaques was higher in the intervention group compared with the placebo group (35.2% versus 29.5%, P=0.04) (Table 3). Multivariate analyses (multiple logistic regression model) showed that this association was independent of sex, baseline age, and the baseline other potential risk factors including serum vitamins and minerals. The multivariate odds ratio of carotid plaques in the intervention group compared with the placebo group was 1.24 (95% CI, 1.01 to 1.52, P=0.03). In the multivariate model, the substitution of end-trial cardiovascular risk factors for baseline cardiovascular risk factors did not modify the results (odds ratio=1.22, 95% CI, 1.01 to 1.50, P=0.04). This was also the case when further adjustment for CCA–IMT and/or PWV was performed.
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Analyses separately repeated in subgroups according to sex, baseline age (younger than 50 years, 50 years and older), hypertension status, smoking habits, serum vitamins, and minerals yielded similar patterns of results, and no interaction term was statistically significant (Table II, available online at http://atvb.ahajournals.org).
Associations of CCA–IMT and CCA–Lumen Diameter With Antioxidant Supplementation
Neither CCA–IMT nor CCA–lumen diameter was associated with antioxidant supplementation (Table 4). Multivariate analyses (ANCOVA) and/or analyses separately performed in each subgroup did not modify these results.
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Association of PWV With Antioxidant Supplementation
Mean PWV tended to be lower in the intervention group compared with the placebo group, but the difference did not reach statistical significance (Table 4). However, women in the intervention group had significantly lower mean PWV than women who received placebo (Table 4). In men, the lack of association between PWV and antioxidant supplementation was confirmed in the multivariate analyses (ANCOVA).
In women, when multivariate analyses were performed, the adjusted mean PWV was 10.53±1.83 m/s in the intervention group and 11.05±1.91 m/s in the placebo group (P=0.02). When PWV values were divided into tertile categories, the multivariate odds ratio of having higher values of PWV (tertile 3) in the intervention group compared with the placebo group (provided from multiple logistic regression model) was 0.48 (95% CI, 0.26 to 0.92, P=0.01). Substitution of end-trial cardiovascular risk factors for baseline cardiovascular risk factors did not modify the results.
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Discussion |
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The main findings of this large-scale study of the effects of vitamins and minerals supplementation on vascular structure and function of large arteries were as follows. First, carotid atherosclerotic plaques tend to be more frequent in the group that received antioxidants, independently of conventional cardiovascular risk factors and serum antioxidants. Second, PWV tends to be lower in the intervention group, and the differences between groups were more pronounced and statistically significant in women. Third, neither CCA–IMT nor CCA–lumen diameter seemed to be modified by antioxidant supplementation.
Our present study is a substudy of the SU.VI.MAX Study, a randomized, double-blind, placebo-controlled, primary prevention trial designed to test the efficacy of daily supplementation with antioxidant vitamins and minerals. Compared with the other randomized trials, several particularities of this study could be noted. Three vitamins (C, E, and beta carotene) and 2 minerals (selenium and zinc) were combined at nutrition-like doses (1 to 3 times the daily recommended dietary allowances) and were supplemented in subjects not selected because of cardiovascular risk factors. The rates of cardiovascular clinical events after a median follow-up of 7.5 years were not different between the intervention and placebo groups.24 These results were in agreement with those of several trials suggesting a lack of beneficial effects of vitamins supplementation (especially vitamin E and beta carotene) in cardiovascular primary and secondary preventions.3–8
Few randomized studies using noninvasive cardiovascular parameters like IMT have been previously published and their results were controversial. In the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study, which was a randomized trial of the effect of vitamin E (272 IU per day) and slow-release vitamin C (500 mg per day) on 3-year and 6-year progressions of carotid atherosclerosis in 520 hypercholesterolemic patients, the supplementation with combination of vitamin E and vitamin C slowed carotid IMT progression in men but not in women.10,11 The rate of progression of IMT was unaffected by the use of either antioxidant alone in men. In the Study to Evaluate Carotid Ultrasound Changes in patients treated with ramipril and vitamin E (SECURE), 400 IU of vitamin E daily had no detectable effect on carotid IMT progression after 4.5 years (on average) of follow-up in a randomized study of 637 high-risk men and women aged 55 years or older at baseline.12 In the Vitamin E Atherosclerosis Prevention Study (VEAPS), the supplementation of vitamin E (400 IU per day) over a 3-year period in 162 healthy men and women at low risk for cardiovascular disease increased (with borderline statistical significance) the progression of carotid IMT compared with 170 subjects randomized to placebo.13
Carotid IMT is commonly used as a surrogate marker of atherosclerosis. However, B-mode ultrasonography is unable to differentiate the intimal from the medial layer, so the anatomic structure involved in the arterial wall thickening cannot be determined.22 Carotid intima-media thickening may result from an atherosclerosis process affecting intima and from hypertension- and arterial stiffness-associated medial vascular hypertrophy.25 In our study, the modest deleterious effects of supplementation on confirmed atherosclerosis end-point (plaque) would lead to increasing intima thickness, and the trend for beneficial effects on arterial stiffness may lead to decreasing media thickness. These opposite effects on arterial thickness may explain, in part, the lack of association between supplementation and CCA–IMT.
In the present report, subjects with vitamin and mineral supplementation had higher carotid plaques. One hypothesis is that the associations of vitamin supplementation with carotid plaques might be mediated by the pro-oxidant effects of vitamin E promoting intimal lipid peroxidation and atherosclerosis.26,27 In fact, vitamin E can have antioxidant, neutral, or pro-oxidant activity, and this more complex function may be then reflected in the inconclusive results of vitamin E intervention studies of atherosclerosis in animals and in humans.26 Nevertheless, further studies are needed to confirm our results and to better-understand the reasons for the possible increased risk of atherosclerotic plaque with vitamin supplementation.
In the literature, many different ultrasound protocols have been used, and there is no consensus on carotid examination in epidemiological studies and clinical trials. In the present study, we used a methodological approach for carotid imaging that clearly differentiates between plaque and diffuse intima-media thickening. We have previously reported that the 2 types of lesions were interrelated,22 but some factors could be specifically associated with increased IMT alone or with plaques alone.25,28 Other investigators have measured maximum (or mean of maximum) of carotid IMT from one and/or several segments including sites with plaques in their measurements.14,15,29 When we constructed, a posteriori, a variable allowing maximum CCA–IMT values for subjects without plaques and maximum plaque thickness for those with plaques at common carotids, this variable tended to be higher in the intervention group compared with the placebo group (0.84±0.14 mm versus 0.79±0.15 mm, P=0.12). In our protocol, an optimal transverse image (one for each side: left and right) at the position of the thickest part (far or near wall) of the intima-media complex (visually judged) was also captured and IMT was measured off-line. The maximum carotid thickness was higher in the intervention group compared with the placebo group (1.06±0.20 mm versus 0.98±0.20 mm, P<0.03) and the percentages of subjects with maximum IMT 
1 mm were, respectively, 41.6% and 34.5% (P<0.02). Although these results support our main results concerning the association between carotid plaques and supplementation groups, direct comparisons with other studies are not easy and the interpretation of results provided by different studies may be dependent on the methodology used to assess the IMT, especially on the site of measurement and the inclusion or not of atherosclerotic plaques in the measurement interval.
To our knowledge, this is the first study that reports the effects of long-term daily antioxidant supplementation on arterial stiffness. It has been previously shown that short-term supplementation (8 weeks) of vitamin E (400 IU daily) improved arterial compliance in 28 volunteer middle-aged men and women.30 In 30 patients with type 2 diabetes, supplementation of 500 mg/d of vitamin C for 1 month also improved arterial stiffness.31 In our study, the PWV values were lower in the intervention group compared with the placebo group in women, indicating better arterial compliance and function. This result should be interpreted with caution because it was obtained from a subgroup analysis. The explanations of the differential association of antioxidant supplementation with PWV in men and women are unclear and the mechanisms linking antioxidants to arterial function are largely unknown. Age and blood pressures (or hypertension) are the strongest determinants of arterial stiffness.25 At the end-trial visit, the frequency of hypertension treatment tended to be lower in the intervention group. However, adjustment for hypertension status at baseline visit or at end-trial visit (or hypertension treatment) did not modify our results, suggesting that the observed associations were largely independent of blood pressure. It was speculated that the potential beneficial vitamins effects on arterial stiffness might be the results of improved endothelial vasodilator function or perhaps an effect on vascular smooth muscle cell proliferation.32,33
Although carotid plaques and PWV were positively associated, differential relationships of the parameters with antioxidant supplementation were observed. Atherosclerosis and arterial stiffness are to some extent related, but they are 2 distinct physiopathological processes affecting arterial structure. Our results may indicate that the potential mechanisms linking antioxidants to plaques are not mediated by arterial stiffness (and vice versa).
Several limits to our study should be noted. Carotid ultrasound and PWV examinations were not performed at baseline; therefore, progression rates of vascular parameters could not be determined. We do not think that this fact would have markedly modified our results and conclusions. Baseline cardiovascular risk factors were very well-balanced between intervention and placebo groups. In addition, even if the study may be considered as an observational investigation, the major advantage, compared with classical epidemiological studies on this issue, is that supplementation of antioxidants was randomly assigned and our results cannot then be confounded by indication bias. The classical epidemiological studies on this issue have been criticized by the fact that the use of diets rich in antioxidants and/or the use of vitamin supplements may be just markers that identify populations with higher health awareness and with healthy lifestyle behaviors, possibly entirely independent of antioxidant intake.34 Nevertheless, the possibility that our results could have been obtained by chance and/or might at least partially reflect differences between the 2 groups in carotid plaques and/or in PWV at baseline cannot be completely excluded.
One could argue that the compliance, which was similar to those reported in other comparable vitamins trials,11,12 was relatively low. However, the adherence rate can be considered as acceptable because our study is a very long-term primary prevention trial conducted in apparently healthy subjects. In addition, an increase in biological markers of vitamins and minerals, except vitamin E and zinc, in the intervention group were observed over time. We could not completely exclude that the doses of vitamin E and zinc were not sufficient to induce arterial modifications. Selection bias to undergo the final examination (because of the presence of coronary heart disease) might have been occurred. However, the number of subjects with coronary heart disease was low and not different between the 2 groups, and the exclusion of these subjects from statistical analyses yielded very similar results to those conducted in the whole population (data available from authors). In addition, the percentage of carotid plaques and the distributions of CCA–IMT and PWV in the placebo group were comparable to those reported in other French populations at similar age.21,25,35 The definition of carotid plaques may be difficult by B-mode ultrasound and varies considerably across studies. When we defined, a posteriori, the plaques as a localized protrusion of the vessel wall into the lumen with a thickness of 1.2 mm instead of 1 mm, the prevalences of plaques were 32.6% in the intervention group and 28.1% in the placebo group (P=0.08). For a thickness of 1.4 mm, they were, respectively, 30.7% and 26.0% (P=0.07). Only common carotid IMT was systematically measured in our study. However, there are large variations in IMT according to the arterial site. The internal carotid artery and the bifurcation show greater IMT and more pronounced right skewness than the CCA.36 However, assessing and quantification of the IMT in the internal carotid artery and the bifurcation are more difficult for various technical and methodological reasons (tortuosity, proximity to the mandible, reproducibility, etc).37 Good-quality images of the far wall of the straight part of the CCA are easy to obtain and IMT can be reliably measured in nearly all subjects.
In conclusion, the results of this large-scale study suggest no marked beneficial effects of long-term daily low-dose supplementation of antioxidant vitamins and minerals on carotid structure and arterial stiffness.
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Acknowledgments |
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Acknowledgments
The SU.VI.MAX project was supported by a grant from the National Institute of Health and Medical Research. It received also support from public and private sectors. Special acknowledgments are addressed to Fruit d’Or Recherche, Lipton, Candia, Kellogg’s, CERIN, LU/Danone, Sodexho, Céréal, L’Oréal, Estée Lauder, Peugeot, Jet Service, RPScherer, France Telecom, Becton Dickinson, Fould Springer, Boehringer diagnostic, Deppie Givaudan Lavirotte, Le Grand Canal, Air Liquide, Carboxique, Klocké, Trophy Radio, Carlo Erba, Jouan, and Perkin Elmer.
Received April 16, 2004; accepted May 19, 2004.
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