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American Journal of Epidemiology Advance Access originally published online on March 22, 2007
American Journal of Epidemiology 2007 165(11):1305-1313; doi:10.1093/aje/kwm016
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American Journal of Epidemiology Copyright © 2007 by the Johns Hopkins Bloomberg School of Public Health All rights reserved; printed in U.S.A.

ORIGINAL CONTRIBUTIONS

Dietary Intakes of Flavonols and Flavones and Coronary Heart Disease in US Women

Jennifer Lin1, Kathy M. Rexrode1, Frank Hu2,3, Christine M. Albert1,4, Claudia U. Chae1,5, Eric B. Rimm2,6, Meir J. Stampfer2,6 and JoAnn E. Manson1,2,6

1 Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
2 Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
3 Department of Nutrition, Harvard School of Public Health, Boston, MA
4 Division of Cardiovascular Disease, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
5 Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA
6 Department of Epidemiology, Harvard School of Public Health, Boston, MA

Correspondence to Dr. Jennifer Lin, Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, 900 Commonwealth Avenue East, Boston, MA 02215 (e-mail: jhlin{at}rics.bwh.harvard.edu).

Received for publication September 1, 2006. Accepted for publication November 17, 2006.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Dietary flavonols and flavones are subgroups of flavonoids that have been suggested to decrease the risk of coronary heart disease (CHD). The authors prospectively evaluated intakes of flavonols and flavones in relation to risk of nonfatal myocardial infarction and fatal CHD in the Nurses' Health Study. They assessed dietary information from the study's 1990, 1994, and 1998 food frequency questionnaires and computed cumulative average intakes of flavonols and flavones. Cox proportional hazards regression with time-varying variables was used for analysis. During 12 years of follow-up (1990–2002), the authors documented 938 nonfatal myocardial infarctions and 324 CHD deaths among 66,360 women. They observed no association between flavonol or flavone intake and risk of nonfatal myocardial infarction or fatal CHD. However, a weak risk reduction for CHD death was found among women with a higher intake of kaempferol, an individual flavonol found primarily in broccoli and tea. Women in the highest quintile of kaempferol intake relative to those in the lowest had a multivariate relative risk of 0.66 (95% confidence interval: 0.48, 0.93; p for trend = 0.04). The lower risk associated with kaempferol intake was probably attributable to broccoli consumption. These prospective data do not support an inverse association between flavonol or flavone intake and CHD risk.

coronary disease; diet; flavones; flavonols; myocardial infarction; women

Abbreviations: CHD, coronary heart disease; CI, confidence interval; FFQ, food frequency questionnaire; SD, standard deviation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Flavonoids are polyphenol derivatives of 2-phenyl-1-benzopyran-4-1 that are present in foods and beverages of plant origin, such as fruits, vegetables, tea, and wine (1). Depending on their structural features, flavonoids can be further divided into subgroups such as flavonols and flavones. Flavonols include compounds such as quercetin, myricetin, and kaempferol, and they are present in many plant foods, such as fruits, leaves, vegetables, and tea. Flavones, such as apigenin and luteolin, are found in leafy vegetables and herbs. These polyphenol compounds have been suggested to decrease the risk of coronary heart disease (CHD) by preventing the oxidation of low density lipoprotein cholesterol, inhibiting platelet aggregation, and improving endothelial function (2–7).

Observational studies that have examined the relation of dietary flavonoid intake to risk of CHD have provided mixed results. Several studies (8–14), but not all (15–17), have found an inverse association between flavonoid intake and risk of death from CHD. A few studies (11, 12, 14, 16, 18) have evaluated the association between flavonoid intake and nonfatal coronary events, with some showing no risk reduction (12, 16, 18). Because most of these studies were not large enough to reliably address the associations, we decided to evaluate whether dietary intakes of flavonols and flavones were associated with risk of nonfatal myocardial infarction or fatal CHD in a large cohort of women from the Nurses' Health Study.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study population
The Nurses' Health Study was established in 1976, when 121,700 female registered nurses aged 30–55 years from 11 US states were enrolled. Every 2 years, participants completed a mailed questionnaire requesting information on various risk factors and occurrence of disease, including CHD.

At baseline in 1990, 78,861 women returned the study's food frequency questionnaire (FFQ) with sufficient data on dietary and daily energy intakes within the plausible range of 600–3,500 kcal/day. Among these women, we excluded those who had been previously diagnosed with cancer (n = 6,908) or cardiovascular disease, including myocardial infarction, angina, coronary revascularization, or stroke (n = 5,593). These exclusions left a total of 66,360 women for the present analysis.

Dietary assessment
Dietary intake data were collected from the participants using the 1990, 1994, and 1998 FFQs. These FFQs collected more detailed information (e.g., onion intake) than previous versions of the questionnaire, to allow for the measurement of flavonols. For each food item on the FFQ, participants chose from nine answers ranging from never or less than one serving per month to six or more servings per day. Individual nutrient intakes were calculated by multiplying the frequency of consumption of each food by the nutrient content of the specified portion size (obtained from the US Department of Agriculture and supplemented by the food manufacturers).

Our database for flavonols and flavones has been described in great detail elsewhere (19). Briefly, the flavonol and flavone contents of foods were determined on the basis of composition analysis conducted by Hertog et al. (15) and supplemented with values for an additional 15 US foods (19, 20). Intakes of individual flavonols, including quercetin, kaempferol, and myricetin, and of individual flavones, including apigenin and luteolin, were calculated as the sum of the consumption frequency of each food multiplied by the flavonol or flavone content for the specified serving size. Total flavonol and flavone intake was the sum of intakes of the five compounds. Intakes of nutrients including flavonols and flavones and their subclasses were adjusted for total energy using the residual method (21).

The reproducibility and validity of the dietary questionnaire were assessed previously by comparing responses from the FFQ with those from two 1-week dietary records completed by 127 subjects from a male cohort (22, 23). Although the reproducibility and validity of values for flavonol and flavone intake could not be directly tested, we examined correlations between the questionnaire and the dietary records for the major food sources of flavonols and flavones. The Pearson correlation coefficients were 0.77 for tea, 0.70 for apples, and 0.46 for broccoli (23).

Case ascertainment
The endpoint for this study was nonfatal myocardial infarction or fatal CHD that occurred after the return of the 1990 questionnaire and before June 2002. We sought permission to obtain the medical records of women who reported having a nonfatal myocardial infarction on a follow-up questionnaire. Study physicians who were blinded to exposure data reviewed the records. Nonfatal myocardial infarction was confirmed if data in the medical records met World Health Organization criteria, based on symptoms plus either diagnostic electrocardiographic changes or elevated cardiac enzyme concentrations (24). Myocardial infarctions that required hospital admission and for which confirmatory information was obtained by interview or letter but for which no medical records were available were designated probable infarctions (21 percent of all reported nonfatal infarctions).

Deaths were reported by family members or the US Postal Service or were ascertained from the National Death Index. We estimate that follow-up for mortality was more than 98 percent complete (25). Fatal CHD was defined as International Classification of Diseases, Ninth Revision, codes 410–414 and was confirmed by hospital records, next of kin, or autopsy, or by review of the death certificate if CHD was the cause of death and evidence of previous CHD was available.

Data analysis
We grouped intakes of flavonols and flavones and their subclasses into quintiles. We did not analyze intakes of two individual flavones, luteolin and apigenin, which contributed only minor amounts to the total (<0.5 percent of the total). Major food sources, including tea, onions, apples, tomatoes, broccoli, raisins or grapes, and red wine, were grouped into five intake categories. Onion intake included consumption of onions either as a garnish or as a vegetable. Apple sources included apple juice, apple cider, and fresh apples. Tomato sources included tomato juice, tomato sauce, and tomatoes. To examine the long-term intakes of flavonols and flavones, individual flavonols, and major food items, we utilized dietary information from the 1990, 1994, and 1998 FFQs and computed cumulative average intakes of flavonols and flavones (26). Specifically, dietary information collected in the 1990 FFQ was used to predict CHD incidence between 1990 and 1994. The average of the 1990 and 1994 nutrient intakes was used to predict CHD between 1994 and 1998, and the average of the 1990, 1994, and 1998 nutrient intakes was used to predict CHD between 1998 and 2002.

We calculated person-years of observation for each participant from the return date of the 1990 questionnaire to the date of an incident coronary event, death from any cause, or June 1, 2002, whichever occurred first. Cox proportional hazards models with time-varying variables were used to model relative risks and 95 percent confidence intervals for CHD, comparing higher quintiles or categories with the lowest (the referent). Analyzed models were first adjusted for age (in 5-year categories). The multivariate models were additionally adjusted for potential risk factors for CHD, including body mass index (weight (kg)/height (m)2; <23, 23–<25, 25–<30, or ≥30), physical activity (metabolic equivalents/week, in quintiles), smoking status (never, past, or current), alcohol consumption (never, <10, 10–<20, or ≥20 g/day), energy intake (kcal/day, in quintiles), use of multivitamin supplements (yes, no), use of aspirin (yes, no), use of vitamin E supplements (yes, no), menopausal status (premenopausal or postmenopausal), postmenopausal hormone use (never, past, or current), history of diabetes mellitus (yes, no), history of hypercholesterolemia (yes, no), history of hypertension (yes, no), and parental history of myocardial infarction before the age of 60 years (yes, no). Data on most of these covariates were updated every 2 years during follow-up, except that questions on history of diabetes, hypercholesterolemia, and hypertension were asked in 1990 and information on parental history of myocardial infarction before age 60 was obtained in 1976. Tests for trend were performed by using median intake values to form a continuous variable. All p values were two-sided.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
In this cohort of women, the baseline mean intake of flavonol and flavone combined was 21.2 mg/day (standard deviation (SD), 16.0). Of the individual flavonols, quercetin (15.4 mg/day (SD, 10.9)) was the major contributor to the total amounts, followed by kaempferol (4.7 mg/day (SD, 5.6)) and myricetin (1.0 mg/day (SD, 1.1)). Contributions of flavones were minor (0.03 mg/day (SD, 1.06)). Six major food items accounted for 83.4 percent of the total food sources of flavonols and flavones: tea (35 percent), onions (23.3 percent), apples (9.2 percent), broccoli (8.3 percent), tomatoes (5.9 percent), and grape products, including raisins or grapes and red wine (1.7 percent).

Table 1 presents the baseline distribution of risk factors for total CHD according to intake quintiles of flavonols and flavones. Women who consumed greater amounts of flavonols and flavones were older, were less likely to be current smokers, and had a higher prevalence of reported hypertension and diabetes than those who consumed less. Women reporting higher intake were also more likely to use multivitamin and vitamin E supplements and to be more physically active, but were less likely to consume alcohol. Body mass index and parental history of myocardial infarction did not appear to differ substantially across the quintiles of intake.


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  		TABLE 1. Age-adjusted data on risk factors for coronary heart disease according to quintiles of energy-adjusted intake of total flavonols and flavones among participants in the Nurses' Health Study at baseline (i.e., 1990)

 
During 12 years of follow-up from 1990 to 2002, we documented 938 nonfatal myocardial infarctions and 324 CHD deaths. Higher intakes of flavonols and flavones were not associated with a lower risk of nonfatal or fatal CHD in the age-adjusted model (table 2). The association was not appreciably changed when the model was additionally adjusted for other risk factors for CHD. Compared with women in the lowest quintile of flavonol and flavone intake, women in the highest quintile of intake had relative risks of 1.05 (95 percent confidence interval (CI): 0.85, 1.29) for nonfatal myocardial infarction (p for trend = 0.55) and 0.81 (95 percent CI: 0.57, 1.16) for CHD death (p for trend = 0.29). Additional adjustment for intakes of saturated fat, dietary fiber, vitamin C, ß-carotene, lycopene, and lutein/zeaxanthin did not materially alter the association.


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  		TABLE 2. Relative risks of nonfatal myocardial infarction and fatal coronary heart disease according to quintiles of energy-adjusted intake of total flavonols and flavones, updated cumulatively, during 12 years of follow-up in the Nurses' Health Study, 1990–2002

 
The association between flavonol and flavone intake and risk of nonfatal and fatal CHD was not appreciably modified by use of vitamin E supplements or by history of hypertension, diabetes, or hypercholesterolemia (data not shown). There was also no inverse association with risk of nonfatal or fatal CHD among never, past, or current smokers.

Because previous studies suggested that the inverse association between flavonoid intake and risk of death from coronary disease was limited to participants who had prevalent CHD (8, 12), we also assessed the relative risk of CHD death by including women who had a history of CHD. In 1990, 835 women in our cohort had received a confirmed diagnosis of nonfatal myocardial infarction between 1976 and 1990. As of 2002, we documented 355 deaths from CHD in these women. No association was observed for risk of CHD death; relative risks in the higher four quintiles were 0.93, 1.02, 0.91, and 0.89, respectively (p for trend = 0.47).

We then examined the association between the individual classes of flavonols and CHD. In the multivariate analyses of individual flavonols, higher intakes of quercetin, kaempferol, and myricetin were not significantly associated with a lower risk of nonfatal myocardial infarction (table 3). However, higher intake of kaempferol was associated with a lower risk of CHD death; the multivariate relative risk among women in the highest quintile compared with those in the lowest was 0.66 (95 percent CI: 0.48, 0.93; p for trend = 0.04). Intake of quercetin or myricetin was not significantly associated with CHD death (table 3).


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  		TABLE 3. Multivariate-adjusted relative risks of nonfatal myocardial infarction and fatal coronary heart disease according to quintiles of energy-adjusted intake of subclasses of flavonols, updated cumulatively, during 12 years of follow-up in the Nurses' Health Study, 1990–2002

 
We next carried out analyses of the food sources of flavonols and flavones: tea, onions, apples, broccoli, tomatoes, raisins or grapes, red wine, and coffee. Of these food items, tea and broccoli were two major sources of kaempferol. We observed a trend toward lower risk of coronary events with higher intake of broccoli (table 4). Compared with women who consumed half a serving of broccoli per week or less, women who consumed five or more servings of broccoli every week had relative risks of 0.76 (95 percent CI: 0.49, 1.17) for nonfatal myocardial infarction (p for trend = 0.11) and 0.65 (95 percent CI: 0.30, 1.44) for CHD death (p for trend = 0.05). Higher consumption of red wine was weakly inversely associated with lower incidence of coronary disease; however, additional adjustment for total alcohol consumption eliminated the inverse association (table 4). Intakes of other food sources, including tea, onions, apples, and raisins or grapes, were not significantly associated with the risk of coronary events (table 4).


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  		TABLE 4. Multivariate-adjusted relative risks of nonfatal myocardial infarction and fatal coronary heart disease according to categories of intake of major food sources of flavonols and flavones, updated cumulatively, during 12 years of follow-up in the Nurses' Health Study, 1990–2002

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
In this prospective study of women, higher intakes of dietary flavonols and flavones were not associated with a lower risk of nonfatal myocardial infarction or CHD death. However, there was a reduction in the risk of CHD death with higher intake of one individual flavonol, kaempferol, which was probably attributable to broccoli consumption. Other major food sources of flavonols and flavones were not significantly associated with risk of CHD.

Flavonoids are antioxidants that have been shown to possess several cardioprotective properties. In vitro and in vivo studies have suggested that flavonoids decrease the susceptibility of low density lipoprotein cholesterol to oxidation by scavenging free radicals, chelating metal ions, or inhibiting enzymatic systems responsible for the generation of free radicals (3, 7), which in turn reduces atherosclerotic complications. Flavonoids have also been found to significantly inhibit ex vivo platelet activity and experimental coronary thrombosis in animals (27). The antiplatelet effects of flavonoids may be attributable to inhibition of thromboxane formation (28), blunting hydrogen peroxide production, or inhibition of phospholipase C (5). Moreover, mounting evidence from human trials suggests that flavonoid-rich beverages such as red wine and purple grape juice are vasodilators and improve endothelial function, probably because of a nitric oxide-dependent mechanism (4, 29–32).

Observational studies on the association between flavonoid intake and risk of nonfatal coronary disease are sparse (11, 12, 14, 16). Our study and two other cohort studies (12, 16) observed no association with nonfatal coronary disease. In a Dutch cohort study, Geleijnse et al. (11) observed possible risk reduction for nonfatal coronary disease among participants in higher tertiles of intake, but the linear trend did not reach significance. To our knowledge, only Hirvonen et al. (14), in a Finnish cohort study, observed an inverse association between flavonoid intake and nonfatal myocardial infarction; the relative risks among persons in the higher four quintiles of intake relative to those in the lowest were 0.84, 0.89, 0.77, and 0.77, respectively. It is notable that all of the men in the Finnish cohort were smokers. In our cohort, the association between flavonoid intake and coronary disease incidence did not differ according to smoking status.

Although our data did not confirm an association between total intakes of flavonols and flavones and CHD death, most other observational studies have suggested a potential reduction in the risk of coronary death with higher intake of flavonoids (8–10, 12–14). In the Zutphen Elderly Study, comprising 805 men, a higher intake of flavonoids was strongly associated with a lower risk of death from coronary disease; for the highest tertile versus the lowest, the relative risk was 0.32 (95 percent CI: 0.15, 0.71) (8). These results were confirmed in the same cohort after an additional 5 years of follow-up (9) and in four other cohort studies (10, 12–14). In a meta-analysis of results from seven cohort studies, Huxley et al. (33) observed a 20 percent reduction in risk of CHD death among persons in the upper tertile of flavonol intake relative to those in the lowest (relative risk = 0.80, 95 percent CI: 0.69, 0.93), suggesting that flavonoids may play a role in preventing coronary death.

The various chemical structures in the flavonoid subclasses have been suggested to have different biologic impacts on human health (34). However, few investigators have reported on associations between intake of individual flavonoids and CHD incidence. We observed a lower risk of CHD death with a higher kaempferol intake, which has also been observed in two other cohort studies (10, 17). The antioxidant properties of kaempferol have been suggested to have protective cardiovascular effects (35). It was further suggested that the cardioprotective effect of kaempferol may be mediated by the inhibition of platelet-derived growth factor ß-receptor phosphorylation (36), resulting in retardation of the progression of atherosclerotic lesions (37). Our finding of an inverse association between kaempferol and CHD death warrants additional study.

The inverse association we observed between kaempferol intake and CHD death in this cohort was probably attributable to broccoli consumption, which was also associated with a lower risk of CHD death. Our finding is consistent with that of another female cohort study which observed a relative risk of coronary death of 0.52 in the highest quartile of broccoli intake (10). Nevertheless, broccoli is also rich in other nutrients (e.g., vitamin C and folate) that may be associated with a reduction in the risk of CHD (38, 39). Therefore, we cannot rule out the possibility that the inverse association we observed here reflects constituents of broccoli other than kaempferol. Intake of tea, the major food source of kaempferol, was not inversely associated with CHD incidence. In a meta-analysis comprising seven observational studies, Peters et al. (40) obtained a relative risk of myocardial infarction of 0.89 (95 percent CI: 0.79, 1.01) for an increase in tea consumption of 3 cups per day. The quantity of tea consumption was low in this cohort (average intake = 0.7 cups/day), which may have contributed to the null finding.

The strengths of this study include the use of prospective data with a large sample size and long-term follow-up. Dietary intakes of total flavonols and flavones as well as their food sources were measured multiple times, and analyses of these nutrients using cumulative intake not only took into account changes in eating habits but also reduced measurement errors due to within-person variation (41). In addition, we had information on potential confounders for CHD for which data were also updated over time.

Nevertheless, our study had several limitations. Despite controlling for several potentially confounding variables in our multivariate analyses, we cannot exclude the possibility of residual confounding from these factors. In addition, our FFQ may be subject to incomplete assessment of dietary flavonoids. Because the flavonoid content of foods varies with numerous factors, such as processing, storage, and species variety (34), different types of foods such as apples and tomatoes, as well as different classes of beverages such as red wine and tea, are likely to contain different levels of flavonoids. However, the Nurses' Health Study FFQ offers no such specific information on types or classes of most foods. Finally, data on other primary subclasses of flavonoids, such as flavan-3-ols (e.g., epicatechin, epicatechin 3-gallate, and epigallocatechin 3-gallate), were not available in the present study for examination of their effects on CHD risk. Apples and tea are two major food sources of flavan-3-ols (42, 43), and we observed no association between apple or tea intake and CHD incidence.

In this large cohort of women, we observed little evidence that total intakes of flavonols and flavones prevent CHD. However, our data suggest that higher kaempferol intake, partially attributed to a higher intake of broccoli, may be associated with a lower risk of CHD death.


   ACKNOWLEDGMENTS
 
This research was supported by grants (HL34594 and CA40356) from the National Institutes of Health.

The authors thank Dr. Walter Willett for his valuable comments and suggestions on the manuscript and Laura Sampson for her assistance in database interpretation.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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