American Journal of Epidemiology

Copyright 1999 by The Johns Hopkins University School of Hygiene and Public Health
All rights reserved
Vol. 149, No. 10
Printed in USA.
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
properties. They prevent low density lipoprotein oxidation in vitro and thus may play a role in the prevention of
coronary heart disease (CHD). In 1986, in a prospective study of 34,492 postmenopausal women in Iowa, the
authors examined the association of flavonoid intake with CHD and stroke mortality. Over 10 years of follow-up,
438 deaths from CHD and 131 deaths from stroke were documented. Total flavonoid intake was associated with
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).There 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 with 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 Epidemiol 1999; 149:943-9.
antioxidants; coronary heart disease; diet; flavonoids; postmenopausal 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 lipid
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 21,1998, 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 CHD (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 women 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 Women'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
943

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944 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 (<600 or >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 Nurses' 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 women, 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, 438 deaths from CHD 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 intake, smoking, 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 were examined by comparing the relative risk
of CHD death 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.
RESULTS
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 945
(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 between 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 CHD by flavonoid 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 the overall test for trend (p for 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 heart 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 smoker (%)
Diabetes mellitus (%)
Hypertension (%)
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
276
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
274
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
273
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
272
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
268
10.4
22.6
10.7
3.4
4.7
1.7
11.5
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946 Yochum et al.
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
Adjusted for nondietary variablest
Multivariate adjusted^
Quercetin
No. of deaths from CHD
Median quercetin intake (mg/day)
Range of quercetin intake (mg/day)
RR
Age and energy adjusted
Adjusted for nondietary variables
Multivariate adjusted
Kaempferol
No. of deaths from CHD
Median kaempferol intake (mg/day)
Range of kaempferol intake (mg/day)
RR
Age and energy adjusted
Adjusted for nondietary variables
Multivariate adjusted
Apigenin
No. of deaths from CHD
Apigenin intake
RR
Age and energy adjusted
Adjusted for nondietary variables
Multivariate adjusted
Luteolin
No. of deaths from CHD
Luteolin intake
RR
Age and energy adjusted
Adjusted for nondietary variables
Multivariate adjusted
Myricetin
No. of deaths from CHD
Myricetin intake
RR
Age and energy adjusted
Adjusted for nondietary variables
Multivariate adjusted
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
437
None
1.0
1.0
1.0
313
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% Cl *
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
401
3.1-20.4
0.55-1.00
0.62-1.17
0.63-1.19
Quintile of flavonoid 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
p for
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, <4 g per day, 4-<10 g per day, or >10 g per day), education
(no high school diploma, high school diploma, college or vocational school but no degree, or college degree), marital status (currently
married, never married, separated or divorced, or widowed), pack-years of smoking (none, 1-19, 20-39, or >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.
When 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 was 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 CHD, although
neither of these associations was statistically signifi-
cant after multivariate adjustment. After additional
adjustment for dietary variables, there was no signifi-
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Dietary Flavonoid Intake and Risk of Cardiovascular Disease 947
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 hypothesis, 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, 1986-1995
Apples
No. of deaths from CHD*
Range of apple intake
(times/week)
RR
Age and energy adjusted
Adjusted for nondietary variablest
Multivariate adjusted^
Broccoli
No. of deaths from CHD
Range of broccoli intake
(times/month)
RR
Age and energy adjusted
Adjusted for nondietary variables
Multivariate adjusted
Tea
No. of deaths from CHD
Range of tea intake
(times/week)
RR
Age and energy adjusted
Adjusted for nondietary variables
Multivariate adjusted
1
(lowest)
129
1
1.0
1.0
1.0
115
0
1.0
1.0
1.0
200
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% Cl *
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 squared, waist-to-hip ratio, high blood pressure, diabetes, estrogen replacement
therapy, alcohol intake, education, marital status, pack-years of smoking, and physical activity.
X Adjusted for above covariates and intake of cholesterol, saturated fat, vitamin E, dietary fiber, and whole grains.
Am J Epidemiol Vol. 149, No. 10, 1999

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948 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 CHD mortality. Table 4 summarizes the prospective
epidemiologic 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 CHD mortality with 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 reduced 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 content 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
TABLE 4. Prospective epidemiologic 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)
Knekt et al . (12)
Rimm et al . (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
10
14
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 Ml *
Death from CHD for men
with prevalent CHD
Death from CHD
RR'
(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. <19.0 mg/day
>34.0 vs. <19.0 mg/day
>28.6 vs. <18.3 mg/day
>4.8 vs. <2.1 mg/day
>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

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Dietary Flavonoid Intake and Risk of Cardiovascular Disease 949
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
women to date. The association in this cohort was 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.
REFERENCES
1. Witztum JL, Steinberg D. Role of oxidized low density
lipoprotein in atherogenesis. J Clin Invest 1991;88:1785-92.
2. Parthasarathy S, Steinberg D, Witztum JL. The role of oxi-
dized low-density lipoproteins in the pathogenesis of athero-
sclerosis. Ann Rev Med 1992;43:219-25.
3. Palinski W, Rosenfeld ME, Yla-Herttuala S, et al. Low densi-
ty lipoprotein undergoes oxidative modification in vivo. Proc
Natl Acad Sci U S A 1989,86:1372-6.
4. Catapano AL. Antioxidant effect of flavonoids. Angiology
1997;48:39-44.
5. Kandaswani C, Middleton E. Free radical scavenging and
antioxidant activity of plant flavonoids. Adv Exp Med Biol
1994;336;351-76.
6. Robak J, Gryglewski RJ. Flavonoids are scavengers of super-
oxide anion. Biochem Pharmacol 1988;37:83-8.
7. Husain SR, Cillard J, Cillard P. Hydroxy radical scavenging
activity of flavonoids. Phytochemistry 1987;26:2489-92.
8. Sorata Y, Takahama U, Kimura M. Protective effect of
quercetin and rutin on photosensitized lysis of human erythro-
cytes in the presence of hematoporphyrin. Biochem Biophys
Acta 1982;799:313-17.
9. De Whalley CV, Rankin SM, Hoult JRS, et al. Flavonoids
inhibit the oxidative modification of low-density lipoproteins
by macrophages. Biochem Pharmacol 1990;39:1743-50.
10. Hertog MGL, Feskens EJM, Hollman PCH, et al. Dietary
antioxidant flavonoids and risk of coronary heart disease. The
Zutphen Elderly Study. Lancet 1993;342:1007-ll.
11. Hertog MGL, Feskens EJ, Kromhout D. Antioxidant flavonols
and coronary heart disease risk. (Letter). Lancet 1997;349:699.
12. Knekt P, Jarvinen R, Reunanen A, et al. Flavonoid intake and
coronary mortality in Finland: a cohort study. BMJ 1996;
312:478-81.
13. Keli SO, Hertog ML, Feskens EJM, et al. Dietary flavonoids,
antioxidant vitamins, and incidence of stroke. Arch Intern Med
1996;156:637-42.
14. Hertog MG, Sweetnam PM, Fehily AM, et al. Antioxidant
flavonols and ischemic heart disease in a Welsh population of
men: the Caerphilly Study. Am J Clin Nutr 1997;65:1489-94.
15. Rimm E, Katan MB, Ascherio A, et al. Relation between
intake of flavonoid and risk for coronary heart disease in male
health professionals. Ann Intern Med 1996;125:384-9.
16. Kushi LH, Kaye SA, Folsom AR, et al. Accuracy and reliabil-
ity of self-measurement of body girths. Am J Epidemiol
1988;128:740-8.
17. Willett WC, Sampson L, Browne ML, et al. The use of a self-
administered questionnaire to assess diet four years in the past.
Am J Epidemiol 1988;127:188-99.
18. Consumer and Food Economics Institute. Composition of
foods. Washington, DC: US Department of Agriculture,
Human Nutrition Information Service, 1989.
19. Hertog MGL, Feskens EJM, Hollman PCH, et al. Content of
potentially anticarcinogenic flavonoids of 28 vegetables and 9
fruits commonly consumed in the Netherlands. J Agric Food
Chem 1992;40:2379-83.
20. Hertog MGL, Hollman PC, van de Putte B. Content of poten-
tially anticarcinogenic flavonoids in tea infusions, wines and
fruit juices. J Agric Food Chem 1993;41:1242-6.
21. Manach C, Regerat F, Texier O, et al. Bioavailability, metabo-
lism, and physiological impact of 4-oxo-flavonoids. Nutr Res
1996;16:517-44.
22. Feskanich D, Rimm EB, Giovannucci EL, et al. Reproducibility
and validity of food intake measurements from a semiquantita-
tive food frequency questionnaire. J Am Diet Assoc 1993;93:
790-6.
23. Kircher T, Nelson J, Burdo H. The autopsy as a measure of
accuracy of the death certificate. N Engl J Med 1985;
313:1263-9.
24. Prineas RJ, Folsom AR, Kaye SA. Central adiposity and
increased risk of coronary artery disease mortality in older
women. Ann Epidemiol 1993;3:35-41.
25. Kushi LH, Fee RM, Folsom AR, et al. Physical activity and mor-
tality in postmenopausal women. JAMA 1997;277:1287-92.
26. Kushi LH, Folsom AR, Prineas RJ, et al. Dietary antioxidant
vitamins and death from coronary heart disease in post-
menopausal women. N Engl J Med 1996;334:1156-62.
Am J Epidemiol Vol. 149, No. 10, 1999

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