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(Stroke. 2000;31:2301.)
© 2000 American Heart Association, Inc.
Original Contributions |
Intake of Flavonoids, Carotenoids, Vitamins C and E, and Risk of Stroke in Male Smokers
From the Department of Nutrition, National Public Health Institute, Helsinki, Finland (T.H., J.V., P.K., P.P.), and Division of Clinical Sciences, National Cancer Institute, Bethesda, Md (D.A.).
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Abstract |
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Background and Purpose—Antioxidants may protect against atherosclerosis and thus prevent cerebrovascular disease. We studied the association between dietary antioxidants and subtypes of stroke.
Methods—The study cohort consisted of 26 593 male smokers, aged 50 to 69 years, without a history of stroke. They were participants of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study in Finland. The men completed a validated dietary questionnaire at baseline. Incident cases were identified through national registers.
Results—During a 6.1-year follow-up, 736 cerebral infarctions, 83 subarachnoid hemorrhages, and 95 intracerebral hemorrhages occurred. Neither dietary flavonols and flavones nor vitamin E were associated with risk for stroke. The dietary intake of ß-carotene was inversely associated with the risk for cerebral infarction (relative risk [RR] of highest versus lowest quartile 0.74, 95% CI 0.60 to 0.91), lutein plus zeaxanthin with risk for subarachnoid hemorrhage (RR 0.47, 95% CI 0.24 to 0.93), and lycopene with risks of cerebral infarction (RR 0.74, 95% CI 0.59 to 0.92) and intracerebral hemorrhage (RR 0.45, 95% CI 0.24 to 0.86). Vitamin C intake was inversely associated with the risk for intracerebral hemorrhage (RR 0.39, 95% CI 0.21 to 0.74). After simultaneous modeling of the antioxidants, a significant association remained only between ß-carotene intake and risk for cerebral infarction (RR 0.77, 95% CI 0.61 to 0.99).
Conclusions—Dietary intake of ß-carotene was inversely associated with the risk for cerebral infarction. No association was detected between other dietary antioxidants and risk for stroke.
Key Words: antioxidants • diet • epidemiology • stroke
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Consumption of fruits and vegetables has been shown to be associated with a lowered risk for stroke.1 2 This may result from fruits and vegetables being rich in several antioxidants, which are known to be effective scavengers of free radicals.3 Antioxidants could, therefore, protect low-density lipoproteins from oxidation and slow the formation of atherosclerotic plaques.4 Other mechanisms by which antioxidants could protect from stroke are reduction of platelet aggregation (especially flavonoids5 and vitamin E)6 and lowering of blood pressure (especially vitamin C).7 However, results on specific antioxidants in fruits and vegetables have been inconsistent. Inverse associations with the risk for stroke have been observed for flavonols and flavones,8 carotenoids,9 and vitamin C.10 11 In contrast, studies also exist in which no clear associations with dietary antioxidants were found.12 13 One reason for the inconsistent results may be that these studies have examined only the associations with total stroke. Different subtypes of stroke, however, have different etiopathologies14 and thus most likely also have different associations with dietary antioxidants.
The aim of this study was to examine the relation of intakes of flavonols and flavones, vitamin C, vitamin E, and carotenoids to the risk for subtypes of stroke among male smokers.
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Subjects and Methods |
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Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study
The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study was a double-blind, placebo-controlled, primary prevention trial undertaken to determine whether supplementation with
-tocopherol, ß-carotene, or both would reduce the
incidence of lung cancer in male smokers. The rationale, design, and
methods of the study as well as the characteristics of the participants
have been described in detail.15 The participants of the ATBC study were recruited from the total male population aged 50 to 69 years in southwestern Finland (n=290 406). To be eligible, subjects had to be smokers of least 5 cigarettes per day at entry and to give written informed consent. The exclusion criteria included a history of cancer or other serious disease limiting long-term participation; use of vitamin E, vitamin A, or ß-carotene supplements in excess of predefined doses; and treatment with anticoagulant agents.
The eligible men (n=29 133) were randomized into 1 of 4
supplementation regimens: -tocopherol alone (daily dose
50 mg), ß-carotene alone (20 mg), -tocopherol and
ß-carotene, or placebo. Trial follow-up continued for 5 to 8 years
(median 6.1 years).
Baseline Measurements
To establish baseline, the men completed a questionnaire on
general background characteristics and medical and smoking histories.
Height, weight, and blood pressure were measured, and serum samples
were stored at -70°C. Serum total cholesterol and
high-density lipoprotein (HDL) cholesterol levels were
determined enzymatically (CHOD-PAP method, Boehringer
Mannheim).
Dietary Assessment
Diet was assessed at baseline using a self-administered,
modified diet history method.16 The diet questionnaire
included 276 food items and mixed dishes. It was used with a
portion-size picture booklet of 122 photographs of foods, each with 3
to 5 different portion sizes. The subject was asked to report the usual
frequency of consumption and the usual portion size of foods during the
previous 12 months. Frequencies were reported as the number of times
per month, week, or day. At the first baseline visit, the
questionnaire, along with the picture booklet, was given to the subject
to be completed at home. At the second baseline visit 2 weeks later,
the questionnaire was returned, reviewed, and completed with a study
nurse. The questionnaire was satisfactorily completed by 27 111
participants (93%).
The food consumption data were used to compute daily nutrient intake values based on the food composition database and related software at the National Public Health Institute. Flavonol and flavone content of foods are based mainly on composition analyses done by Hertog and colleagues.17 18 The flavonol content of berries is, however, based on Finnish analysis.19 Total flavonol and flavone intake was calculated as the sum of intakes of quercetin, kaempherol, myricetin, luteolin, and apigenin. Carotenoid and vitamin E contents of foods are based on Finnish analyses.20 21
The dietary method was validated in a pilot study carried out among 190 men before the ATBC study.16 The men completed the questionnaire first and then kept a food record for 24 days, spread over 6 months, as the reference method. They filled in the questionnaire again at the end of the study. The energy-adjusted Pearson correlations between the first dietary questionnaire and the food records were the following: flavonols and flavones 0.59, vitamin C 0.58, vitamin E 0.66, ß-carotene 0.63, lutein and zeaxanthin 0.44, and lycopene 0.54.
Ascertainment of End Points
The end points of this study were cerebral infarction (CI),
subarachnoid hemorrhage (SAH), and
intracerebral hemorrhage (ICH). Only the first
stroke event after randomization was registered as an end point. End
points were identified from national registers by using the unique
personal identification number. In Finland, all hospitalizations are
registered in the Hospital Discharge Register and all deaths in the
Register of Causes of Death. Both registers use the codes of the
International Classification of Diseases (ICD), the eighth
edition of which was in use until the end of 1986 and the ninth edition
thereafter. The study end points comprised ICD-8 codes 430–434 and
ICD-9 codes 430–431 and 433–434, excluding ICD-8 codes 431.01 and
431.91 denoting subdural hemorrhage and ICD-9 codes 4330X,
4331X, 4339X, and 4349X denoting cerebral or precerebral artery
stenosis or occlusion without cerebral infarction. Utilization
of the national registers also enabled identification of stroke events
among study dropouts.
The validity of the stroke diagnoses in the registers has been evaluated: in a random sample (n=546), 90% of the stroke cases in the Hospital Discharge Register and 97% in the Register of Causes of Death retained the diagnosis of stroke in a review of clinical and autopsy data according to the criteria of the National Survey of Stroke and WHO MONICA Study.22
Statistical Analysis
After excluding participants who at baseline reported history of
stroke (n=614) and those who did not completely fill in the dietary
questionnaire (n=1926), 26 497 individuals remained. The participants
contributed follow-up time from the date of randomization until an end
point, death, or the end of the trial (April 30, 1993). All nutrients
and other antioxidants were log transformed and then energy adjusted by
the regression residual method.23 Alcohol intake was not
energy adjusted. Men were grouped into quartiles of energy-adjusted
intakes of nutrients and other antioxidants. Proportional hazards
models were used to estimate relative risks (RRs, with 95% CIs) of
stroke associated with different intake levels of the antioxidants,
with simultaneous adjustment for age, supplementation
group, and cardiovascular risk factors
(systolic and diastolic blood pressures, serum
total cholesterol, serum HDL cholesterol, body
mass index, number of smoking years, number of cigarettes daily,
history of diabetes or coronary heart disease, alcohol intake,
and education). Tests for linearity of the trend were obtained from the
Wald test by treating median values of each quartile as continuous
variables in the proportional hazards model. Interactions between
antioxidant and any baseline variable were calculated by dividing
the baseline values into 2 groups according to median values and using
these indicators and their interaction as covariates in the
proportional hazards model. The main analyses were repeated for
cerebral infarction in the placebo group of the trial cohort, whereas
the number of hemorrhagic strokes were too small for meaningful
analyses in the placebo group only.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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During the 6.1-year follow-up, 736 cerebral infarctions, 83 subarachnoid hemorrhages, and 95 intracerebral hemorrhages were identified. Table 1
shows the baseline levels of
selected characteristics among participants with different subtypes of
stroke. Both systolic and diastolic blood pressures
were higher in participants (cases) with all subtypes of stroke
compared with noncases. In addition, cases of cerebral infarction were
older and drank more alcohol than noncases; cases of
subarachnoid hemorrhage had higher intake of energy,
fat, and alcohol; and cases of intracerebral
hemorrhage were older and had lower serum total
cholesterol.
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The median daily intakes of antioxidants were the following: flavonols and flavones 8.0 mg, vitamin C 96 mg, vitamin E 11 mg, ß-carotene 1.7 mg, lutein and zeaxanthin 1.4 mg, and lycopene 0.59 mg. The highest correlation coefficients among energy-adjusted antioxidants were those between ß-carotene and vitamin C (r=0.55), ß-carotene and lutein plus zeaxanthin (r=0.54), flavonols/flavones and vitamin C (r=0.50), and vitamin C and lutein/zeaxanthin (r=0.47).
In the multivariate model, dietary flavonols and
flavones, and vitamin E were not associated with any subtype of stroke
(Table 2). Dietary vitamin C was
inversely associated with risk for intracerebral
hemorrhage, whereas no association was found between intake of
vitamin C and risks for cerebral infarction and subarachnoid
hemorrhage. ß-Carotene intake was inversely associated only
with the risk for cerebral infarction. Intake of lutein plus zeaxanthin
was inversely associated with the risk for subarachnoid
hemorrhage, and intake of lycopene inversely with the risks for
cerebral infarction and intracerebral
hemorrhage. Neither smoking (numbers of cigarettes per day and
smoking years) nor serum total cholesterol level modified
the association between intake of ß-carotene and the risk for
cerebral infarction.
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When the multivariate models were simultaneously adjusted for other dietary antioxidants, the inverse association between ß-carotene intake and cerebral infarction remained essentially unchanged (RR between the highest and lowest quartile of intake 0.77, 95% CI 0.61 to 0.99, P for trend=0.02). All other associations were attenuated such that the RR between the highest and the lowest quartile was no longer significant.
In food group analysis, higher consumption of fruits was
associated with reduced risk for intracerebral
hemorrhage (Table 3). When
further adjusted for vitamin C intake, the association became
nonsignificant (RR of highest versus lowest quartile of consumption
0.57, 95% CI 0.27 to 1.21, P for trend=0.42). Higher
consumption of vegetables was associated with lower risk for cerebral
infarction. However, adjustment for ß-carotene intake attenuated the
association (RR 0.81, 95% CI 0.61 to 1.09, P for
trend=0.18). In a multivariate model that
simultaneously included all foods (fruits, berries,
vegetables, tea, and wine), RRs for different subtypes of stroke were
similar to those when the foods were included one at a time in the
model.
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The analyses were repeated for cerebral infarction in the placebo group of the trial cohort, and they showed similar results except for vitamin C intake and fruit consumption. The RR of the highest versus the lowest quartile for vitamin C intake was 0.66 (95% CI 0.49 to 0.99, P for trend=0.02) and for fruit consumption 0.59 (95% CI 0.39 to 0.89, P for trend=0.01). When these variables were added simultaneously to the multivariate model, their association attenuated and became nonsignificant: RRs of the highest versus the lowest quartile 0.81 (95% CI 0.49 to 1.34) and 0.67 (95% CI 0.40 to 1.11) for vitamin C intake and fruit consumption, respectively.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Dietary ß-carotene proved to be inversely associated with the risk for cerebral infarction. In addition, evidence was found for lowered risk for stroke subtypes with high intake of other carotenoids and vitamin C, but these associations lost their significance after adjustment for other dietary antioxidants. Neither flavonols nor flavones or vitamin E appeared to be related to risk.
This investigation has many strengths compared with previous studies. The validity of both the diagnoses of stroke and the dietary assessment method have been established. The end point database used permitted analysis of stroke subtypes separately. This is important, given the known differences in their etiologies.14 Nevertheless, our numbers of subarachnoid and intracerebral hemorrhages are rather small and thus more vulnerable to chance findings.
The association between the intake of vitamin E and the risk for stroke has been investigated in 3 published studies.8 9 24 No associations were found in any of these studies. In randomized controlled trials, vitamin E supplementation has either had no effect on stroke in patients with high risk for cardiovascular events25 26 or has decreased the risk for cerebral infarction while concomitantly increasing the risk for fatal hemorrhagic stroke.27 Thus, more studies are needed to conclusively determine the effects of vitamin E on different stroke subtypes.
The association between the intake of flavonoids and the risk for stroke has been investigated in only 2 epidemiologic studies.8 28 In the former study,8 intake of flavonols and flavones was inversely associated with the risk for stroke (RR 0.27, 95% CI 0.11 to 0.70). However, the cohort was small (872 persons), and the number of stroke cases was limited (42). In the other cohort study,28 no association was observed between the intake of flavonols and flavones and stroke risk (RR 1.18, 95% CI 0.70 to 2.00).
Few studies have investigated the relationship between vitamin C intake and risk for stroke. In a cohort of 730 elderly British persons (aged >65 years), vitamin C intake was inversely associated with risk (RR for the highest versus the lowest tertile of intake 0.5, 95% CI 0.3 to 0.8).11 In a small Norwegian study10 that included 99 cases, intake of vitamin C was also inversely related to the risk for hemorrhagic but not ischemic stroke. Vitamin C intake was not, however, related to the risk for stroke in most of these studies.8 9 13 Ness and coworkers7 have suggested in their recent systematic review that an apparent inverse association exists between vitamin C and blood pressure. In our study, both systolic and diastolic blood pressures were similar at all levels of vitamin C intake, and our multivariate models were adjusted for blood pressure (data not shown). Therefore, blood pressure cannot explain the inverse association we observed between the intake of vitamin C and the risk for intracerebral stroke in our study.
In the Health Professionals’ Follow-Up Study, intake of ß-carotene was inversely associated with the risk for both ischemic and hemorrhagic strokes, but the associations were not significant.9 In 3 other cohort studies,8 12 13 intake of ß-carotene was unrelated to risk for stroke. Furthermore, in large-scale intervention trials ß-carotene supplementation either had no effect on risk for stroke29 or had no effect on the risk for cerebral infarction but increased risk for intracerebral hemorrhage.27 Thus, our finding of an inverse association between ß-carotene intake and cerebral infarction receives little support from other studies and may be a chance finding. Alternatively, dietary ß-carotene may be a surrogate for some other dietary or lifestyle factors that are the true protectors against stroke. This is partly contradicted by the finding that after adding all dietary antioxidants to the multivariate model, only ß-carotene remained significantly associated with the risk for cerebral infarction. However, since some antioxidant intakes are moderately correlated, it is difficult to conclude their independent associations with the risk for stroke.
The present study involved male smokers. In the Health Professionals’ Study,9 the RR for stroke in the highest quintile of ß-carotene intake compared with the lowest quintile was 0.29 among current smokers, whereas the respective RR was 1.20 among never-smokers, but neither group showed a significant trend. Whether dietary ß-carotene is inversely associated with the risk for stroke only among smokers needs further confirmation. However, null effects in controlled trials contradicts this possibility.27 29 The generalizability of our results applies, of course, also to other antioxidants. It is possible that the effects of antioxidants in general are different in smokers compared with nonsmokers. Therefore, our results cannot be generalized to nonsmokers.
Epidemiologic data for other carotenoids are scant. Lutein intake was inversely associated with the risk for ischemic but not hemorrhagic stroke in one cohort study.9 The intake of lycopene was not associated with the risk for either ischemic stroke or hemorrhagic stroke.9
The majority of epidemiological studies on consumption of fruits and vegetables and stroke risk have reported an inverse association. We found that consumption of vegetables was inversely associated with the risk for cerebral infarction, and the consumption of fruits was inversely associated with the risk for intracerebral hemorrhage. When intake of ß-carotene and vitamin C, respectively, were added to the multivariate models, both associations attenuated but a moderate nonsignificant association still remained. This suggests that in addition to ß-carotene in vegetables and vitamin C in fruit, other dietary factors in these foods provide protection against stroke.
In conclusion, high intake of ß-carotene was associated with decreased risk for cerebral infarction in male smokers. This finding is, however, not supported by other studies and must therefore be interpreted cautiously. In addition, no consistent associations were found between other dietary antioxidants and stroke subtypes. The protective association between fruit and vegetable consumption and risk for stroke was confirmed.
Received May 12, 2000; revision received July 12, 2000; accepted July 21, 2000.
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H. D Sesso, J M. Gaziano, S. Liu, and J. E Buring Flavonoid intake and the risk of cardiovascular disease in women Am. J. Clinical Nutrition, June 1, 2003; 77(6): 1400 - 1408. [Abstract] [Full Text] [PDF]
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 T. Rissanen, S. Voutilainen, K. Nyyssonen, and J. T. Salonen Lycopene, Atherosclerosis, and Coronary Heart Disease Experimental Biology and Medicine, November 1, 2002; 227(10): 900 - 907. [Abstract] [Full Text] [PDF]
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E. S Ford, C. Gillespie, C. Ballew, A. Sowell, and D. M Mannino Serum carotenoid concentrations in US children and adolescents Am. J. Clinical Nutrition, October 1, 2002; 76(4): 818 - 827. [Abstract] [Full Text] [PDF]
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P. Knekt, J. Kumpulainen, R. Jarvinen, H. Rissanen, M. Heliovaara, A. Reunanen, T. Hakulinen, and A. Aromaa Flavonoid intake and risk of chronic diseases Am. J. Clinical Nutrition, September 1, 2002; 76(3): 560 - 568. [Abstract] [Full Text] [PDF]
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 U. Peters, C. Poole, and L. Arab THE AUTHORS REPLY Am. J. Epidemiol., September 1, 2002; 156(5): 490 - 491. [Full Text] [PDF]
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 P. G. A. Van Hoydonck, E. H. M. Temme, and E. G. Schouten A Dietary Oxidative Balance Score of Vitamin C, {beta}-Carotene and Iron Intakes and Mortality Risk in Male Smoking Belgians J. Nutr., April 1, 2002; 132(4): 756 - 761. [Abstract] [Full Text] [PDF]
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U. Peters, C. Poole, and L. Arab Does Tea Affect Cardiovascular Disease? A Meta-Analysis Am. J. Epidemiol., September 15, 2001; 154(6): 495 - 503. [Abstract] [Full Text] [PDF]
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 M. O. McCarron, J. A.R. Nicoll, M. J. O'Leary, R. J.L. Waugh, A. I. Qureshi, and D. F. Hanley Spontaneous Intracerebral Hemorrhage N. Engl. J. Med., September 6, 2001; 345(10): 769 - 770. [Full Text] [PDF]
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