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Nutritional Epidemiology

Both - and β-Carotene, but Not Tocopherols and Vitamin C, Are Inversely Related to 15-Year Cardiovascular Mortality in Dutch Elderly Men^1,2

³ Division of Human Nutrition, Wageningen University, Wageningen, 6700 EV The Netherlands; ⁴ National Institute for Public Health and the Environment, (RIVM), Bilthoven, 3720 BA The Netherlands; ⁵ German Institute for Human Nutrition (DIfE), Department of Epidemiology, Nuthetal, 14558 Germany; and ⁶ Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN 55454

^* To whom correspondence should be addressed. E-mail: daan.kromhout{at}wur.nl.

	ABSTRACT

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 
The role of β-carotene, -tocopherol, and vitamin C in the prevention of cardiovascular diseases (CVD) is controversial. Prospective studies on -tocopherol and carotenoids other than β-carotene are sparse. We assessed relations between the intake of different carotenoids, - and -tocopherol, and vitamin C with 15-y CVD mortality in elderly men who participated in the Zutphen Elderly Study. Information on diet and potential confounding factors was collected in 1985, 1990, and 1995. In 1985, 559 men (mean age 72 y) free of chronic diseases were included in the current analysis. After 15 y of follow-up, comprising 5744 person-years, 197 men had died from CVD. After adjustment for age, smoking, and other potential lifestyle and dietary confounders, relative risks (RR) (95% CI) of CVD death for a 1-SD increase in intake were 0.81 (0.66–0.99) for -carotene and 0.80 (0.66–0.97) for β-carotene. Carrots were the primary source of - and β-carotene and their consumption was related to a lower risk of death from CVD (adjusted RR, 0.83; 95% CI = 0.68–1.00). Intakes of carotenoids other than - and β-carotene were not associated with CVD mortality, nor were vitamin C and - and tocopherol. In conclusion, dietary intakes of -carotene and β-carotene are inversely associated with CVD mortality in elderly men. This study does not indicate an important role for other carotenoids, tocopherols, or vitamin C in lowering the risk of CVD death.

	Introduction

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

Findings from in vitro studies indicate that these antioxidants directly scavenge reactive oxygen and nitrogen species (3). In addition, depletion of vitamin E in humans leads to increased susceptibility of LDL to in vitro oxidation (4) and a reduction of LDL in vitro oxidation is observed after supplementation of -tocopherol (5–8,9). Although there are indications that support a similar role for vitamin C (10), the evidence is equivocal (8). One intervention study, however, suggests that this antioxidant improves endothelial function (11) and a cross-sectional observational study in persons free of CVD found inverse associations of vitamin C with circulating markers of inflammation and endothelial function (12). Finally, in addition to their role as scavengers of free oxygen and nitrogen species, observational studies on carotenoids suggest that they also may have antiinflammatory properties (13,14) and may improve endothelial function (14).

Early reports of prospective cohort studies have suggested that a high intake of vitamin E (15–17), carotene (15), fruit and vegetables rich in carotene (18), or carotenoids (17) lowers the risk of coronary heart disease. In sharp contrast, large-scale trials conducted in high-risk populations have not shown protective effects of these antioxidants against CVD (19,20). Likewise, intervention studies on the progression of atherosclerosis have in general not shown an effect of antioxidant supplementation either (21). Meanwhile, findings from observational studies continue to show inverse associations of dietary intake (22,23) or tissue levels (24,25) of especially β-carotene with CVD risk.

The precise reason for the contradictory results between observational studies and large-scale intervention trials is yet unclear. One of the possibilities is that other carotenoids and tocopherols account for the inverse associations of β-carotene and -tocopherol with CVD in observational studies. Prospective studies on dietary carotenoids other than β-carotene have only been published sparingly (22) and those on specifically dietary -tocopherol are lacking. Therefore, we evaluated whether dietary intakes of 6 different carotenoids, - and -tocopherol, and also vitamin C were related to CVD mortality in elderly men living in the town of Zutphen, the Netherlands.

	Materials and Methods

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 
    Study population. The Zutphen Elderly Study is a prospective population-based cohort study and is a continuation of the Zutphen Study, the Dutch contribution to the Seven Countries Study (26). Baseline data were collected between March and June in 1985 and repeated measurements were carried out in the same months in 1990 and 1995 (27). In 1985, 555 men of the original cohort who were still alive and a random sample of 711 other men of the same age and also living in Zutphen were selected. Of these 1266 men aged 65–84 y, 939 participated (response 74%) in the study. Information on dietary intake in 1985 was collected from 876 men. Because men with known CVD, diabetes, and cancer may have changed their dietary habits, we excluded prevalent disease cases at baseline, yielding a study population of 559 men. In 1985 and 1990, the study was approved by the Medical Ethics Committee of Leiden University Medical Centre, the Netherlands, and in 1995 and 2000 by the Medical Ethics Committee of the Netherlands Organization for Applied Scientific Research.

    Dietary assessment. Information on habitual food consumption was collected in 1985, 1990, and 1995 by using a cross-check dietary history method adapted to Dutch conditions (28). All subjects were interviewed about their dietary habits during the month preceding the interview. Experienced dieticians conducted the interviews, which took place at the subjects' homes in the presence of the person who usually prepared the hot meal. The habitual consumption of foods per day was estimated with a checklist and verified by estimating the quantities of foods bought per week for the whole family. In case this verification raised uncertainties about the consumption of a particular food, the participant was asked for more details.

Based on the information of the dietary histories in 1985, 1990, and 1995, the intake of nutrients and energy was calculated using the Netherlands food composition table from 1987–1988, 1989–1990, and 1996, respectively. The 2001 version of this table includes detailed information on the content of carotenoids, tocopherols, and folate⁸ in foods (29). Therefore, this release was used to calculate the intake of these nutrients in each survey year. Apart from the individual tocopherol levels, this food composition table also provides -tocopherol equivalents (-TE) in foods according to the formula -tocopherol intake x 1.00 + β-tocopherol x 0.40 + -tocopherol x 0.10 + -tocopherol x 0.01 (29) [this conversion to -TE differs from the conversion that was commonly used in the US, i.e. -TE = mg -tocopherol x 1.0 + mg β-tocopherol x 0.5 + mg -tocopherol x 0.1 + mg -tocopherol x 0.03 + mg -tocotrienol x 0.3 + mg β-tocotrienol 0.05 (30).] The intake of trans fatty acids in every survey year was calculated by using previously collected information on the content of these fatty acids in foods consumed by the Zutphen elderly (31).

    Collection of risk factor and morbidity data. During a medical exam, weight and height were measured while subjects wore light underwear. BMI was calculated by dividing weight by height squared (kg/m²). Information on cigarette smoking, socioeconomic status, prescribed diet by a physician, and the use of aspirin, antihypertensive medication, and anticoagulants was collected using a questionnaire. All subjects were also asked whether they used (yes or no) multivitamin supplements or vitamin C or E supplements. Physical activity of walking, cycling, hobbies, sports, and gardening was estimated in min/wk by using a validated questionnaire originally designed for retired men (32). In addition, socioeconomic status was assessed based on longest occupation. The highest occupational status included professionals, managers, and teachers.

The history of previous myocardial infarction, stroke, and cancer was ascertained using a questionnaire and was verified with information from general practitioners or hospital discharge information. Information on the history of diabetes mellitus was obtained from a standardized questionnaire.

    Ascertainment of follow-up events. Municipal registries provided information on vital status and were checked at 5-y intervals. Two men were lost to follow-up during the study. Their time to follow-up was censored after their last physical exam. Information on the cause of death during 15 y of follow-up was obtained from hospital discharge data, cancer registries, and/or general practitioners. One clinical epidemiologist ascertained the final causes of death. The underlying causes of death were coded according to the Ninth Revision of the International Classification of Diseases (ICD-9). CVD cover ICD-9 codes 390–459. This included ischemic heart disease (ICD-9 codes 410–414) and stroke (codes 430–438) as main causes and also other diseases of the circulatory system. The first, 2nd, and 3rd cause of death was used to identify mortality from CVD. Information on the cause of death was lacking for 2 men and their follow-up was censored after they had died.

    Data analysis. Relative risks (RR) and 95% CI were calculated for a 1-SD increase of antioxidants from diet only by using Cox regression models. To check the assumption on linearity, we also performed analyses for tertiles of antioxidant intake. Because this yielded similar findings, we report only RR based upon continuous analysis. In time-dependent analysis, we analyzed the cumulative mean intake of antioxidants using methods for repeated measurements (33). Specifically, mortality between 1985 and 1990 was related to the intake reported in 1985; mortality between 1990 and 1995 was related to the mean intake of 1985 and 1990 and mortality from the period 1995 to 2000 was related to the mean intake of 1985, 1990, and 1995. The intake of antioxidants and other dietary variables was adjusted for total energy intake by using the residual method (34).

We also investigated the total intake of vitamin C and -tocopherol from diet and vitamin supplements. Because the information on dosage of vitamin supplements was not collected, we performed analyses in tertiles of intake, in which users of vitamin C were forced into the highest tertile of vitamin C, users of vitamin E in the highest tertile of -tocopherol, and users of multivitamin supplements in the highest tertile of vitamin C and -tocopherol. In these analyses, the lowest tertile served as the reference category.

Finally, we assessed whether a diet rich in 3 major antioxidants was related to CVD mortality by constructing a dietary antioxidant score, i.e. the sum of carotenoids, the sum of -tocopherol and -tocopherol, and vitamin C. First, tertiles of intake (1 to 3) were computed for each of the 3 antioxidants. These 3 tertile variables were then summed, yielding a score that ranged from 3 (indicating a diet poor in antioxidants) to 9 (indicating a diet rich in antioxidants). Tertiles of the antioxidant score were computed and entered in the Cox regression models, in which the lowest tertile served as the reference. At baseline, the antioxidant score in the lowest tertile ranged from 3 to 5, the middle tertile consisted of men with a score of 6, and the score in the highest tertile ranged from 7 to 9.

All analyses were adjusted for age and total energy intake. We then adjusted additionally for current and former cigarette smoking. This model was extended with nondietary covariates, including BMI (kg/m²), physical activity (min/wk), alcohol consumption (yes or no), diet prescription (yes or no), vitamin supplement use (yes or no), socioeconomic status (high vs. low), and the use of antihypertensive medication (yes or no), aspirin (yes or no), and anticoagulants (yes or no). The final model included additional adjustments for the intake of dietary fiber, folate, saturated fat, polyunsaturated fat, and trans fatty acids. Physical activity and nutrient intakes were entered in the models as cumulative means. Effect modification by smoking, alcohol consumption, physical activity, BMI, and socioeconomic status was evaluated by including product terms into the multivariable model B and were considered significant at P < 0.05. All analyses were performed with SAS version 9.1 (SAS Institute) and reported P-values are 2-sided.

	Results

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 
    Characteristics of the study population. Characteristics of the study population in 1985, 1990, and 1995 are shown in Table 1. At baseline, the mean age of the men was 72 y. During the study, the proportion of smokers decreased from one-third at baseline to one-fifth 10 y later. The use of vitamin supplements was 15% throughout the study. The mean intake of most nutrients remained stable throughout the study, although the intake of lycopene increased and the intake of trans fatty acids decreased substantially during 10 y.

Intakes of several dietary antioxidants were associated (P < 0.05) with each other. Examples are -carotene and β-carotene (Spearman r = 0.74), β-cryptoxanthin and zeaxanthin (r = 0.65), -tocopherol and -tocopherol (r = 0.56), vitamin C with β-cryptoxanthin (r = 0.64), and zeaxanthin (r = 0.60).

    Dietary antioxidants and CVD mortality. After 15 y of follow-up, comprising 5744 person-years, 383 men had died (68.5%). CVD were the cause of death in 197 men. Major cardiovascular causes of death were ischemic heart disease (n = 89) and stroke (n = 52). In time-dependent analysis and after adjustment for age and total energy intake, -carotene and β-cryptoxanthin were significantly related to a lower CVD mortality (Table 2). After further adjustment for smoking, BMI, physical activity, alcohol use, socioeconomic status, the use of medications, vitamin supplements, and dietary factors, a 1-SD increase in intake of - and β-carotene was associated with 20% lower RR of death from CVD. An association of similar strength was observed for the consumption of carrots, the major source of - and β-carotene, in relation to 15-y CVD mortality (multivariate-adjusted RR = 0.83; 95% CI = 0.68–1.00). Intakes of carotenoids other than - and β-carotene were not significantly associated with CVD mortality, nor were intakes of vitamin C and vitamin E analyzed as -TE, -tocopherol, or -tocopherol.

To avoid bias from change in diet and lifestyle due to nonfatal cardiovascular events, analyses were performed in which we stopped updating the information on diet and physical activity if subjects reported a nonfatal myocardial infarction or stroke (whichever came first) during the follow-up of the study, comprising 136 men. This, however, did not change our findings. We also analyzed the associations in nonusers of vitamin supplements (n = 504) and found virtually the same results. We finally performed analyses without possible subclinical CVD cases at baseline by excluding men who died within the first 2 y of follow-up (n = 15). This strengthened the multivariate-adjusted RR for a 1-SD increase to 0.72 (95% CI = 0.57–0.90) for -carotene and 0.74 (0.60–0.91) for β-carotene.

    Total intake of vitamins C and E, and CVD mortality. The total intake of vitamin C and vitamin E, i.e. from diet and vitamin supplements together, was studied in tertiles. After adjustment for age, energy intake, and lifestyle not including dietary factors (Model A), total vitamin E intake was significantly and total vitamin C intake borderline significantly associated with CVD mortality, indicating 30% lower CVD mortality risk in the highest tertile compared with the lowest (Table 3). Further adjustment for dietary factors (Model B), especially trans fatty acids, attenuated these relations to yield nonsignificant findings (P for trend > 0.10 for both).

	Discussion

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

The strengths of this study include its prospective design, the nearly complete mortality follow-up, and the relatively high CVD mortality rate. Also, the use of cumulative means of repeated measurements of diet and physical activity better reflect long-term exposure and reduce within-person variation (33). This study also has limitations. First, the credibility of observational studies is often criticized because of the potential of residual confounding due to measurement error and unmeasured variables (35). In this study, men with higher intakes of - and β-carotene were less likely to smoke, more often used multivitamin supplements, and had a higher socioeconomic status. Although the relation of - and β-carotene with CVD mortality did not differ between levels of these variables, we cannot exclude the possibility of residual confounding by these or other factors. Second, as many dietary carotenoids, especially - and β-carotene, were correlated with each other, their independent association with CVD mortality was difficult to establish. Third, the sample size of the study population limited the power to detect small effects of antioxidants and their dietary sources. Finally, information about the dose and frequency of vitamin supplement use was not collected in this study. Although we forced users of vitamin supplements in the highest tertile of antioxidant intake, this may have resulted in some misclassification.

Several prospective cohort studies on dietary carotenoids showed an inverse relation between the intake of β-carotene or total carotenoids and the risk of coronary heart disease (22,36), although sometimes only in subgroups (15). This is in line with the inverse relation between the intake of β-carotene and CVD mortality in the current study. The Nurses' Health Study also confirmed the inverse relation for -carotene (22).

Findings from observational studies that addressed relations between circulating carotenoids and intermediaries for CVD and clinical CVD are inconsistent. Subjects with high blood concentrations of - or β-carotene had less atherosclerosis compared with subjects with low concentrations (37,38), although this finding is not consistent in all studies (39,40). Yet, circulating levels of either - or β-carotene, or both, are inversely associated with future CVD in some (24,41) but not all studies (13,42).

In this study, we constructed an antioxidant score combining 6 carotenoids, 2 tocopherols, and vitamin C, in which each of these 3 antioxidants was given the same weight. Such an approach may be preferable to studying 1 antioxidant at a time, as single antioxidants are less likely to lower CVD risk (19–21), whereas a diet rich in multiple antioxidants may do so. However, the weak inverse association between the antioxidant score and CVD mortality in this study was driven by - or β-carotene and did not clearly support the hypothesis that a diet rich in multiple antioxidants lowers CVD risk. To our knowledge, only 1 other study has applied a score in which dietary antioxidants were included (43). In that study population, which consisted of male smokers, an oxidative balance score based on the dietary intake of β-carotene, vitamin C, and iron was not related to CVD mortality (43).

- and β-carotene are considered to be important antioxidants. It has been hypothesized that lipoprotein oxidation induced by reactive nitrogen species within the arterial wall preferably depletes these carotenes compared with other fat-soluble antioxidants (44). When the diet no longer provides sufficient amounts of these carotenes, their concentrations in LDL and plasma will decrease and lipoproteins will become more prone to oxidation. However, although it has been shown that in vitro lipoprotein oxidation induced by reactive nitrogen species depletes - and β-carotene (44), it is yet not clear whether reactive nitrogen species are an important cause of in vivo lipoprotein oxidation. Also, recently it was shown that circulating carotenoids, including - and β-carotene, are inversely associated with inflammation and oxidative stress and positively associated with markers of endothelial function (14), which suggests that they may influence CVD risk through different pathways. Alternatively, it may also be that other nutrients and dietary bioactive compounds, correlated with dietary - and β-carotene, may account for the observed inverse association of these 2 carotenoids with cardiovascular mortality.

Research on vitamin E has been mainly focused on -tocopherol, whereas scientific interest in -tocopherol was raised only recently (45). -Tocopherol constitutes 70% of the vitamin E in the typical American diet (46) and 50% in the diet consumed by the population in this study. Our findings do not support a role of vitamin E in lowering mortality from CVD. Observational studies on vitamin E and CVD have yielded conflicting results, whereas large-scale trials with vitamin E largely produced null results (19). The most conspicuous study is the Alpha-Tocopherol Beta-Carotene trial, in which 50 mg/d synthetic vitamin E did not affect primary and secondary prevention of CVD in male Finnish smokers (47,48), but baseline serum levels of -tocopherol were, paradoxically, inversely related to CVD mortality (49).

Despite the possibility that vitamin C may exert antiinflammatory effects (11) and may improve endothelial function (12), dietary vitamin C intake was not related with CVD mortality in this study or in large prospective cohort studies on dietary vitamin C intake and cardiovascular events (15,50–53). Although in a recent meta-analysis of large prospective cohort studies vitamin C from foods and supplements was related to a lower risk of coronary heart disease (54), the few trials that have investigated the efficacy of vitamin C supplementation on mortality do not support a role for this antioxidant in reducing overall mortality (55).

In summary, intakes of - and β-carotene, especially from carrots, were inversely related to a CVD death in elderly men. More observational studies on the intake of individual carotenoids and their specific sources, as well as foods correlated with their intake, in relation to CVD are warranted. Our findings on dietary vitamin C and - and -tocopherol do not support a role for these antioxidants in lowering CVD mortality.

	FOOTNOTES

 
¹ The Zutphen Elderly Study was supported by grants of the Netherlands Prevention Foundation.

² Author disclosures: B. Buijsse, E. J. M. Feskens, L. Kwape, F. J. Kok, and D. Kromhout, no conflict of interest.

⁷ Abbreviations used: CVD, cardiovascular disease; ICD-9, International Classification of Diseases, Ninth Revision; IQR, inter quartile range; RR, relative risk; -TE, -tocopherol equivalent.

⁸ During this study, legislation in the Netherlands did not allow fortification of foods with folic acid.

Manuscript received 2 July 2007. Initial review completed 6 August 2007. Revision accepted 29 October 2007.

	LITERATURE CITED

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