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American Journal of Epidemiology

Copyright 1999 by The John s Hopkins University School of Hygiene and Public Health

All rights reserved

Vol.149, No. 10

rinted inUSA

Dietary Flavonoid Intake and Risk of Cardiovascular Disease in

Postmenopausal Women

Laura Yochum,

1

Lawrence H. Kushi,

1

Katie Meyer,

2

and Aaron R. Folsom

1

Flavonoids, a group of phenolic compounds found in fruits and vegetables, are known to have antioxidant

prope rties. They p revent low density lipopro tein oxidation in vitro and thus may play a role in the preven tion of

coronary heart disease (CHD). In 1986, in a prospective study of 34,492 postmenopausal women in Iowa, the

authors exam ined the association of flavonoid intake with C HD and stroke m ortality. Over 10 years of follow-up,

438 deaths from CH D and 131 deaths from stroke were docum ented. Total flavonoid intake was associated w ith

a decreased risk of CHD death after adjusting for age and energy intake (p for trend = 0.04). This association

was attenuated after multivariate adjustment. However, decreased risk was seen in each category of intake

compared with the lowest. Relative risks and 95 confidence intervals of CHD death from lowest to highest

intake category were 1.0, 0.67 (95 confidence interval (Cl) 0.49 -0.92 ), 0.56 (95 Cl 0.39-0 .79), 0.86 (95

Cl 0.63-1.18 ), and 0.62 (95 Cl 0.44-0 .87).T here was no association between total flavonoid intake and stroke

mortality (p for trend = 0.83). Of the foods that contributed the most to flavonoid intake in this cohort, only

broccoli was strongly associated w ith reduced risk of CHD death. The data of this study suggest that flavonoid

intake may reduce risk of death from CHD in postmenopausal women. Am J E pidemiol 1999; 149:94 3-9.

antioxidants; coronary heart disease; diet; flavonoids; postmenopau sal women

Oxidation of low density lipoproteins is believed to

play an important role in the development of athero-

sclerosis (1,2). Oxidized low density lipoprotein cho-

lesterol (LDL cholesterol) is taken up more readily by

macrophages, which leads to the formation of foam

cells and atherosclerotic plaques (1, 3). Mechanisms

that slow or prevent this chain of events may decrease

risk of coronary heart disease (CHD) and stroke (4).

Flavonoids are a group of phenolic compounds that

are found in fruits and vegetables and are known to

have antioxidant properties (5). They have been

reported to be scavengers of free radicals, including

superoxide anions (6), singlet oxygen (7), and

lipi

peroxy-radicals (8). In addition, flavonoids have been

shown to prevent LDL cholesterol oxidation and cytb-

toxicity in vitro (9).

Epidemiologic studies investigating the relation

between flavonoid intake, CHD , and stroke have pro-

duced inconsistent results. Some studies have found an

Received for publication January 21 ,19 98 , and accepted for pub-

lication September 25, 1998 .

Abbreviations: CHD, coronary heart disease ; Cl, confidence inter-

val;LDL cholesterol, low density lipoprotein cholesterol; RR, relative

risk.

1

Division of Epidemiology, University of Minnesota, Minneapolis,

MN.

2

Harvard School of Public Health, Department of Epidemiology,

Boston,MA.

Reprint requests to Dr. Aaron R. Folsom, Division of

Epidemiology, University of Minnesota, 1300 S. 2nd Street, Suite

300,

Minneapolis, MN 55105.

inverse association between intake and CHD mortality

(10-12) and stroke (13), while others have not (14).

Another suggested that the potential benefit of

flavonoids is limited to men with prevalent CH D (15).

To further evaluate the potential effect of dietary

flavonoids, we investigated the relation between

flavonoid intake, CHD, and stroke mortality in a

prospective cohort study of postmenopausal wom en in

Iowa.

MATERIALS AND METHODS

Study population

In January 1986, a 16-page questionnaire was

mailed to a random sample of 99,826 women aged

55-69 years who had valid Iowa drivers licenses in

1985. The 41,836 women who responded to the ques-

tionnaire were enrolled in the Iowa W omen s Health

Study. Questions related to demographic characteris-

tics,

health habits, medical history, and gynecologic

history were included in the baseline questionnaire. In

addition, diet was assessed through a semiquantitative

food frequency questionnaire.

Specific questions about weight history, current

height and weight, age, education, and marital status

were included. Body mass index was then calculated

from height and weight information. Waist-to-hip ratio

was based on self measurement (a tape measure was

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94 4 Yochum et al.

included with the initial questionnaire) (16). Physical

activity (number of times per week participated in

moderate and vigorous physical activity), current and

past smoking, menopausal status, medication use, and

hormone replacement status was assessed through the

baseline questionnaire. Participants were also asked if

they had a history of diabetes, cancer, heart disease,

heart attack, or high blood pressure.

Participants were excluded if they had not reached

menopause at the time the questionnaire was completed

(n = 569), if they skipped more than 30 items on the

food frequency questionnaire

n

= 2,749), if they had

relatively extreme energy intakes (5,000 kcal

per day) (n = 313), or if they reported having prior

angina, heart disease, or heart attack (n = 3,713). After

these exclusions, 34,492 women remained.

Dietary assessment

The participant s diet was assessed using a 127-item

semiquantitative food frequency questionnaire similar

to that used in the Nu rses Health Study (17). Nutrient

values were based primarily on data from the US

Department of Agriculture (18). Since the US

Department of Agriculture data do not contain infor-

mation on flavonoids, these values were taken from

analyses performed by Hertog et al. (19, 20) in the

Netherlands and supplemented with values for addi-

tional US foods. These analyses concentrated on five

major flavonoids: quercetin, kaempferol, myricetin,

apigenin, and luteolin. Intake of individual flavonoids

was calculated based on the frequency of consumption

multiplied by the flavonoid content of the food. Total

flavonoid intake was the sum of the individual

flavonoids. Flavonoids can be further classified as

flavonols (quercetin, kaempferol, and myricetin) and

flavones (luteolin and apigenin) (21).

Although we did not validate the ability of the food

frequency questionnaire to assess flavonoid intake in

this population of Iowa w omen, validation of the ques-

tionnaire for this purpose has been done by others.

Feskanich et al. (22) assessed the ability of the ques-

tionnaire to measure intake of foods containing the

major source of flavonoids. Correlation coefficients

for foods contributing the most to flavonoid intake

were 0.77 for tea, 0.70 for apples, and 0.46 for broc-

coli,

comparing intake measured by the food frequen-

cy questionnaire to intake measured by 28-day diet

records in a study of female nurses (22). However,

onions and berries, two potentially important sources

of flavonoids, were not ascertained.

Members of this cohort were followed annually

through the State Health Registry of Iowa, which col-

lects information on deaths in Iowa. Deaths were also

identified through follow-up questionnaires in 1988,

1990,

and 1992 and, for nonresponders, through link-

age with the National Death Index. The cause of death

was determined using the International Classification

of Diseases,

Ninth Revision (ICD-9). Death was con-

sidered to be coronary heart disease if ICD-9 codes

410 through 414 or 429.2 were assigned or stroke if

ICD-9 codes 430 through 438 were assigned. The

cause of death coding was not validated; however,

other studies have found the validity of these codes for

CHD death to be relatively high (23).

Statistical analysis

Total person-years of follow-up were calculated for

each woman as time from completion of the baseline

questionnaire to date of death or December 31, 1995.

After 10 years of follow-up, 4 38 deaths from CH D and

131 deaths from stroke had been documented.

Our initial statistical analyses examined the relation

between total flavonoid intake and CHD mortality,

adjusting for age and energy intake. Total flavonoid

intake was divided by quintiles; mortality from CHD in

higher intake categories was compared with the lowest

category of intake using proportional hazards regression

analysis. We then performed two subsequent analyses:

The first was adjusted for potential nondietary con-

founders, including high blood pressure, diabetes, body

mass index, waist-to-hip ratio, estrogen replacement

therapy status, alcohol intak e, smok ing, physical activity,

marital status, and education; and the second was

adjusted for these variables as well as for intake of

cholesterol, saturated fat, vitamin E, whole grains, and

dietary fiber. The stroke analyses were performed in

similar manner. However, intakes of beta-carotene,

vitamin C, and fish were also adjusted for when stroke

mortality was examined.

The possible effect of individual flavonoids and of

foods high in flavonoid content was also assessed. The

associations of quercetin and kaempferol with death

from CHD were examined using methods similar to

those for total flavonoid intake. Since the proportion of

the population that consumed myricetin, luteolin, and

apigenin was relatively small, the effects of these

flavonoids w ere examined by comp aring the relative risk

ofCHDdeath for those estimated to have any intake ver-

sus those with no intake. For individual foods, consump-

tion categories were selected to ensure a reasonable dis-

tribution of the population across categories of intake.

R E S U L T S

As has been shown previously in this cohort, hyper-

tension, diabetes mellitus, cigarette smoking, a higher

body mass index, and higher waist-to-hip ratio have

been associated with a greater risk of death from CHD

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Dietary Flavonoid Intake and Risk of Cardiovascular Disease 94 5

(24). In addition, a lower risk of CHD has been asso-

ciated with a high level of physical activity (25 ), use of

estrogen replacement therapy (24), and intake of vita-

min E from foods (26) in this cohort.

Table 1 shows the distribution of these risk factors

by quintile of total flavonoid intake. Subjects who had

a lower average intake of flavonoids tended to smoke

and drink more and exercise less. Mean values of body

mass index and waist-to-hip ratio were similar across

quintiles. Subjects in the highest quintile of flavonoid

intake also had a higher average intake of energy, sat-

urated fat, cholesterol, vitamin E, whole grains, fiber,

vitamin C, beta-carotene, and fish.

The mean intake of total flavonoids in our cohort

was 13.9 mg/day. Mean intakes of flavonols were:

quercetin (9.7 mg/day), kaempferol (3.4 mg/day), and

myricetin (0.74 mg/day). Mean intakes of flavones

were considerably less: luteolin (0.05 mg/day) and api-

genin (0.01 mg/day). Individual flavonols were highly

correlated (quercetin and kaempferol, r = 0.84;

quercetin and myricetin, r 0.78; and kaempferol and

myricetin, r 0.77), while flavones were not (apigenin

and luteolin,

r =

0.26). Correlations b etween individ-

ual flavonols and flavones were all below

r =

0.25.

Foods inquired about that contributed the most to

flavonoid intake were tea (36 percent), apples (17 per-

cent), and broccoli (9 percent).

Table 2 shows age and energy-adjusted relative risks

of death from CH D by flavon oid intake. Total flavonoid

intake adjusted for age and energy intake was associat-

ed with a reduced risk of CHD for the highest fifth of

intake compared with the lowest (relative risk (RR) =

0.61, 95 percent confidence interval (CI) 0.46-0.79).

This association was not modified appreciably after

adjustment for additional nondietary confounders (RR

0.64, 95 percent CI 0.46-0.88). Relative risks for the

third versus the first intake category (RR = 0 .57 ,95 per-

cent CI 0.41-0.79) and the second versus the first (RR =

0.67, 95 percent CI 0.49-0.92) were also statistically

significant. However, the overall test for trend after

adjustment for nondietary variables was not statistically

significant

p

for trend = 0.14), indicating an inconsis-

tent dose-response relation. When these analyses were

further adjusted for dietary variables, there was no sig-

nificant change in th e overall test for trend pfor trend =

0.11) or the relative risks for any category of flavonoid

intake compared with the lowest.

There was no association between total flavonoid

intake and stroke mortality. Relative risks from the

highest intake category compared with the lowest

were: RR = 1.18, 95 percent CI 0.70-2.00 ; RR = 0.84,

95 percent CI 0.49-1.50; RR = 0.68 95 percent CI

0.37-1.26; and RR = 1.02, 95 percent CI 0.59-1.79 p

for trend = 0.83).

TABLE 1 . Distribution of coronary hea rt disease risk factors by quintile of flavonoid intake at

baseline in 34 492 postmenopausal women 1986

Median flavonoid intake

Range of flavonoid intake (mg/day)

Age (years)

Body mass index (kg/m

2

)

Waist-to-hip ratio

Current smoke r ( )

Diabetes mellitus ( )

Hype rtension ( )

High level of physical activity ( )

Current estrogen replacement

therapy ( )

Average nutrient intake

Total energy (kcal/day)

Saturated fat (g/day)

Cholesterol (mg/day)

Vitamin E (lU/day)

Fiber (g/day)

Whole grains (servings/week)

Alcohol (g/day)

Average servings per week

Apples

Broccoli

Tea

1 (low)

4.0

0-5.7

61.4

26.8

0.843

23.6

4. 9

35.1

16.7

36.6

1,492

25.8

27 6

8.7

16.2

6.8

4.5

1.1

0.5

0.2

Quintile of total flavonoid

2

7.2

5.8-8.7

61.4

26.9

0.835

16.2

5.3

35.8

21.2

37.6

1,700

24.7

27 4

9.3

18.3

8.3

4.2

2.0

0.4

0.4

3

10.4

8.8-12.2

61.5

27.0

0.834

13.8

5.2

36.4

27.3

38.8

1,822

23.8

27 3

9.8

20.2

9.4

3.7

3.2

1.1

0.8

intake

4

14.9

12.3-18.6

61.8

27.0

0.833

10.8

6.3

37.5

30.1

38.9

1,945

23.1

27 2

10.2

21.4

10.4

3.5

3.9

1.5

2.3

5 (high)

28.6

18.7-228

61.6

27.0

0.835

11.7

7.1

36.6

29.4

38.7

2,044

22.6

26 8

10.4

22.6

10.7

3.4

4. 7

1.7

11.5


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946 Yochumetal.

TABLE 2. Relative risk of death from coronary heart disease according to quintile of flavonoid intake in 34 492 postmenopausal

women 1986-1995

Total flavonoids

No.

of

deaths from CHD*

Median flavonoid intake (trig/day)

Range

of

flavonoid intake (mg/day)

RR

Age and energy adjusted

Adjustedfornondietary va riablest

Mult ivariate adjusted ^

Quercetin

No .of

deaths from CHD

Median quercetin intake (mg/day)

Range

of

quercetin intake (mg/day)

RR


Adjusted

for

nondietary variables

Multivariate adjusted

Kaempferol

No .

of

deaths from C HD

Median kaempferol intake (mg/day)

Rangeof kaempferol intake (mg/day)

RR


Adjustedfor nondietary variables


Apigenin

No .

of

deaths from C HD

Apigenin intake

RR


Adjusted

for

nondieta ry va riables


Luteolin

No .

of

deaths from C HD

Luteolin intake

RR


Adjusted

for

nondietary variables


Myricetin

No .ofdeaths from C HD

Myricetin intake

RR


Adjustedfor nondietary variables


1

(lowest)

120

4.0

0-5.7

1.0

1.0

1.0

113

3.3

0-4.5

1.0

1.0

1.0

112

0.4

0-0.5

1.0

1.0

1.0

43 7

None

1.0

1.0

1.0

31 3

None

1.0

1.0

1.0

37

None

1.0

1.0

1.0

RR *

0.65

0.67

0.67

0.74

0.82

0.82

0.65

0.66

0.66

0.93

0.81

0.83

0.79

0.79

0.80

(

0.74

0.85

0.86

2

95 C l*

79

7.2

5.8-8.7

0.49-0.85

0.49-0.92

0.49-0.92

86

5. 7

4.6-6.7

0.56-0.99

0.60-1.15

0.60-1.13

75

0.9

0.6-1.0

0.48-0.89

0.47-0.91

0.48-0.92

1

0.1-176

0.13-6.62

0.11-5.79

0.12-5.93

125

0.1-4.2

0.64-0.97

0.65-1.01

0.63-1.02

40 1

3.1-20.4

0.55-1.00

0.62-1.17

0.63-1.19

Quintileofflavonoid intake

RR

i

0.50

0.57

0.56

0.60

0.69

0.69

0.82

0.82

0.82

3

95 Cl

64

10.4

B.8-12.2

0.38-0.68

0.41-0.79

0.39-0.79

71

8. 0

6.8-9.2

0.46-0.81

0.49-0.96

0.49-0.97

94

1.5

1.1-2.5

0.62-1.10

0.60-1.11

0.59-1.12

RR

4

95 Cl

100

14.9

12.3-18.6

0.75

0.88

0.86

I

0.70

0.88

0.88

0.58

0.62

0.62

0.58-0.97

0.65-1.18

0.63-1.18

85

10.7

9.3-12.9

0.53-0.93

0.65-1.20

0.63-1.23

68

3.1

2.6-4.9

0.43-0.79

0.44-0.86

0.44-0.87

5 (highest)

RR 95 Cl

75

28.6

18.7-228

0.61 0.46-0.79

0.64 0.46-0.88

0.62 0.44-0.87

83

18.7

13.0-96.9

0.70 0.53-0.93

0.75 0.55-1.04

0.74 0.52-1.06

89

8.3

5.0-144.1

0.77 0.58-1.02

0.79 0.58-1.07

0.79 0.57-1.08

pfo r

trend

0.04

0.14

0.11

0.09

0.25

0.25

0.37

0.56

0.54

*

RR, relative risk; Cl, confidence interval; CHD, coronary heart disease.

t Adjusted for age, total energy intake, body mass index squared, waist-to-hip ratio, high blood pressure yes or no), diabetes yes or no),

estrogen replacement therapy current, former, or never), alcohol intake none, 40), and physical activity low,

moderate, or high level).

Adjusted for above covariates and intake of cholesterol, saturated fat, vitamin E, dietary fiber, and whole grains.

W hen individual flavonoids were examined, the risk

estimates for kaempferol and quercetin (two flavonols)

suggested

an

inverse association between intake

and

death from

CHD

(table

2 .

Each category

of

intake

above the first was associated with

a

decreased risk

of

death from CHD, although

not all

estimates reached

statistical significance.

A

dose-response relation

was

not evident after adjustment

for

nondietary

con-

founders

as

the test

for

trend w as

not

statistically sig-

nificant

for

either quercetin

p

for

trend

= 0.25 or

kaempferol p

for

trend

=

0.56). There was also

a

sug-

gestion

of an

inverse association between intake

of

luteolin

or

myricetin

and

death from CH D, although

neither

of

these associations

was

statistica lly signifi-

cant after multivariate adjustment. After additional

adjustment

for

dietary variables, there was

no

signifi-

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cant change in any risk estimates for individual

flavonoids.

The risk of CHD in relation to intake of three spe-

cific foods containing flavonoids is presented in table

3. When adjusted for age and energy intake, there was

a significant inverse dose-response association of

broccoli p for trend = 0.0001) and apple intake p for

trend = 0.01) with risk of death from CHD. After

adjustment for nondietary variables, the dose-

response relation for broccoli intake remained

p

for

trend = 0.0001), although the association for apples

was attenuated p for trend = 0.47). Further adjust-

ment for dietary variables had no significant effect on

the association between CHD death and broccoli

p

for trend = 0.0001) or apple p for trend = 0.42)

intake. Consumption of tea was not significantly

associated with risk of CHD death

p

for trend =

0.12). Intake of broccoli p for trend = 0.23), tea p

for trend = 0.40), and apples p for trend = 0.93) was

not associated with stroke mortality after multivariate

adjustment.

DISCUSSION

This study of postmenopausal women supports the

hypothesis that greater intake of dietary flavonoids is

associated with a decreased risk of death from CHD.

We observed a statistically significant 38 percent

reduction in CHD mortality in the highest category of

total flavonoid intake compared with the lowest.

Although the risk was decreased in each category of

flavonoid intake compared with the lowest, no dose-

response relation was observed. Analysis of individual

flavonoids (kaempferol, quercetin, myricetin, and lute-

olin) also suggested inverse relations consistent with

this hypothe sis, although not all relative risks were sta-

tistically significant. Broccoli, one of three foods con-

tributing a significant amount to flavonoid intake in

this population, showed a statistically significant

inverse dose-response relation with CHD mortality.

There was also a nonsignificant decrease in CHD mor-

tality associated with consumption of apples and tea,

two foods that made up most of the remaining

flavonoid intake assessed in this population. However,

TABLE 3. Relative risk of death from coronary heart disease according to quartile of intake of selected foods containing

flavonoids in 34 492 postmenopausal women 1986-199 5

Apples

No .

of deaths from CHD*

Range of apple intake

(times/week)

RR


Adjusted for nondietary variab lest

Multivariate adjusted^

Broccoli

No .of deaths from CH D

Range of broccoli intake

(times/month)

RR


Adjusted for nondietary variables


Tea

No .of deaths from C HD

Range of tea intake

(times/week)

RR


Adjusted for nondietary variables


1

(lowest)

129

1

1.0

1.0

1.0

115

0

1.0

1.0

1.0

20 0

0

1.0

1.0

1.0

RR*

0.89

0.99

0.98

0.65

0.63

0.63

0.83

0.86

0.86

2

95 C l *

93

1

0.68-1.16

0.74-1.33

0.73-1.32

125

1-2

0.51-0.84

0.48-0.83

0.48-O.83

65

0.5

0.62-1.09

0.64-1.17

0.64-1.17

Quartile of intake

RR

0.75

0.93

0.92

0.64

0.63

0.62

0.90

0.98

0.98

3

95 Cl

124

2 -4

0.59-0.96

0.71-1.22

0.71-1.22

129

3-4

0.50-0.82

0.48-0.83

0.47-O.82

88

1-4

0.70-1.15

0.74-1.29

0.74-1.29

4

RR

0.68

0.84

0.82

0.57

0.53

0.52

0.86

0.89

0.89

(highest)

95 Cl

92

5-42

0.52-0.89

0.62-1.14

0.60-1.12

69

4 -42

0.43-0.78

0.38-0.75

0.37-0.74

85

5-42

0.67-1.11

0.68-1.18

0.67-1.17

pfor

trend

0.01

0.47

0.42

0.0001

0.0001

0.0001

0.12

0.37

0.36

* RR, relative risk; Cl, confidence interval; CHD, coronary heart disease.

t Adjusted for age, total energy intake, body mass index squa red, waist-to-hip ratio, high blood pressure, diabetes, estroge n replacem ent

therapy, alcohol intake, education, marital status, pack-years of smoking, and physical activity.

XAdjusted for above covariates and intake of cholesterol, saturated fat, vitamin E, dietary fiber, and whole grains.


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94 8 Yochum et al.

we found no association between fiavonoid intake and

stroke mortality.

Our findings are consistent with a growing number

of studies that suggest fiavonoid intake may be related

to CH D mortality. Table 4 summarizes the prospective

epidemiolog ic studies that have examined this relation

to date. In a recently updated analysis of data using 10

years of follow-up from the Zutphen Elderly Study,

Hertog et al. (11) found a 53 percent reduction in risk

of death from CHD in the highest category of intake

compared with the lowest, which was consistent with

their previous findings based on a shorter period of

follow-up (10). Knekt et al. (12) found reduced risks

of CH D m ortality w ith higher fiavonoid intakes in men

(RR = 0.67) and women (RR = 0.73), although these

findings did not reach statistical significance. In addi-

tion, Rimm et al. (15) found a statistically nonsignifi-

cant decreased risk of CHD mortality with fiavonoid

intake, although this association was limited to men

with prevalent CHD .

In contrast, Hertog et al. (14) recently found a rela-

tive risk of 1.6 for CHD mortality in relation to

fiavonoid intake in a population of Welsh men. They

hypothesized that this result may have been due to

binding of flavonoids in tea with protein from milk,

which is frequently added to tea in Wales, thus reduc-

ing fiavonoid absorption. We observed a suggestion of

an inverse relation between tea consumption and CHD

mortality, whereas other investigators have reported

results ranging from no effect (15) to decreased risk

with increased tea consumption (10).

Although our findings are generally consistent with

studies that showed an inverse relation between

fiavonoid intake and CHD mortality, they did not sup-

port those of Keli et al. (13), who found a statistically

significant red uced risk of stroke incidence in the high-

est category of fiavonoid intake compared with the

lowest (RR = 0.27, 95 percent CI 0.11-0.70). The rel-

atively low number of strokes in our study may have

contributed to the lack of observed association.

Although it is possible that an alternate component of

food may be responsible for the observed decrease in

CHD mortality in our population, we could not identify

any such component. We examined the relation between

CHD mortality and fiavonoid intake after adjusting for

potential nondietary confounders. When additional

dietary variables were added to this model, the relative

risk estimates were not substantially modified.

A possible mechanism through which flavonoids

may help prevent coronary heart disease is their

antioxidant properties. Flavonoids are free-radical

scavengers (6-8) and can prevent LDL cholesterol oxi-

dation in vitro (9). Since oxidation of LDL cholesterol

is thought to promote atherosclerosis, it is plausible

that flavonoids may delay the development of athero-

sclerosis and ultimately decrease CHD mortality.

As is common in all epidemiologic studies of diet

and disease, the results of our study are limited by mis-

classification of dietary exposures. We also did not

measure any changes in diet that occurred during the

follow-up period, as our analyses were based on infor-

mation from a single food frequency questionnaire

administered at the start of our study. In addition, data

on the fiavonoid co ntent of foods are primarily limited

to analyses conducted in the Netherlands (19, 20),

rather than on foods in the U.S. market. The overall

fiavonoid intake in this population of postmenopausal

Iowa women was lower (13.9 mg/day) than in most

studies discussed previously (average intake, 20-26.2

mg/day). Part of the reason may be that the food fre-

quency questionnaire did not ask about onions and

berries, which are high in flavonoids.

Another potential limitation of our data is informa-

tion on CHD risk factors was based on self-report.

However, previous studies have documented the asso-

ciation of these risk factors with CHD in this cohort

(24-26). In addition, we did not measure blood cho-

lesterol levels or baseline history of stroke. Finally, we

TAB LE 4. Prospective epidemiolog ic studies of fiavonoid intake and occurrence of coronary heart disease and stroke

Study

(reference

no.)

Hertog et al. (11)

Hertog et al. (14)

Keli et al. (13)

Knekte t a l . (12)

Rimme t a l .(15)

Present study

Population

size

(no.)

804 men

1,900 men

552 men

2,748 men

2,385 women

34,789 men

34,492 women

Years

of

follow-up

1 0

1 4

15

26

6

10

Outcome

Death from CHD *

Incident fatal

Death from CHD

Fatal and nonfatal stroke

Death from CHD (men)

Death from CHD (women)

Nonfatal M l*

Death from CHD for men

with prevalent CHD

Death from CHD

R R '

(high vs.

low intake)

0.47

0.62

1.60

0.27

0.67

0.73

1.08

0.63

0.62

95 Cl

0.27-0.82

0.24-1.05

0.90-2.90

0.11-0.70

0.44-1.00

0.41-1.32

0.81-1.43

0.33-1.20

0.44-0.87

Mean fiavonoid intake

(mg/day) (high vs . low intake)

>29.9 vs. 34.0 vs. 28.6 vs. 4.8 vs. 5.5 vs. 2.4 mg/day (men)

40.0 vs. 7.1 mg/day (women)

32.2 vs. 4.3 mg/day

* RR, relative risk; CI, confidence interval; CHD, coronary heart disease; Ml, myocardial infarction.

Am J Epidemiol

Vol. 149, No. 10, 1999

by

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examined the relation between flavonoid intake, CHD

and stroke mortality, not incidence. Our results are

potentially biased if flavonoid intake is related differ-

ently to incidence as compared with mortality.

Overall, our results of a reduced risk of CHD mor-

tality with flavonoid intake are consistent with a grow-

ing number of studies and are the most definitive for

wom en to date. The association in this cohort w as rel-

atively strong, representing a 38 percent decreased risk

of CHD death in the highest consumption category

versus the lowest. The role of flavonoids as antioxi-

dants provides a plausible mechanism through which

flavonoids may decrease CHD risk. However, given

the limitations of the diet assessment and the observa-

tional study design, our results can not be considered

definitive. Nevertheless, our findings do contribute

additional information about a modifiable potential

risk factor for CHD.

ACKNOWLEDGMENTS

Supported by a research grant CA-39742 from the

National Institutes of Health.

The authors recognize Laura Sampson and Dr. Walter

Willett for use of the food frequency questionnaire in this

study.

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