(Circulation. 1995;92:2142-2150.)
© 1995 American Heart Association, Inc.
Articles |
Dietary Antioxidants and Carotid Artery Wall Thickness
The ARIC Study
From the Department of Preventive Medicine, University of Tennessee, Memphis (S.B.K., H.P.-R.); the Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, Bethesda, Md (T.S.); the Collaborative Studies Coordinating Center, Department of Biostatistics (B.D., M.C.), and the Department of Epidemiology, School of Public Health (G.H.), University of North Carolina, Chapel Hill; the Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis (J.H.E.); and the Department of Public Health Sciences, Bowman Gray School of Medicine, Winston-Salem, NC (G.S.T.).
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Abstract |
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Background Evidence that dietary antioxidants may prevent atherosclerotic disease is growing. The relationship between the intake of dietary and supplemental vitamin C,
-tocopherol,
and provitamin A carotenoids and average carotid artery wall thickness
was studied in 6318 female and 4989 male participants 45 to 64 years
old in the Atherosclerosis Risk in Communities
Study.
Methods and Results Intake was assessed by use of a 66-item
semiquantitative food-frequency questionnaire. Carotid artery
intima-media wall thickness was measured as an indicator of
atherosclerosis at multiple sites with B-mode
ultrasound. Among men and women >55 years old who had not recently
begun a special diet, there was a significant inverse relationship
between vitamin C intake and average artery wall thickness adjusted for
age, body mass index, fasting serum glucose, systolic and
diastolic blood pressures, HDL and LDL
cholesterol, total caloric intake, cigarette use, race, and
education (test for linear trend across quintiles of intake,
P=.019 for women and P=.035 for men). An
inverse
relationship was also seen between wall thickness and
-tocopherol intake but was significant only in women
(test for linear trend, P=.033 for women and
P=.13 for men). There was a significant inverse association
between carotene intake and wall thickness in older men (test for
linear trend, P=.015), but the association weakened after
adjustment for potential confounders. No significant relationships were
seen in participants <55 years old.
Conclusions These data provide limited support for the hypothesis
that dietary vitamin C and -tocopherol may protect
against atherosclerotic disease, especially in individuals >55 years
old.
Key Words: antioxidants • diet • carotid arteries • atherosclerosis
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Over the past several years, evidence has been accumulating that the oxidation of LDL is an important step in the atherogenic process.1 2 Oxidized LDL possesses a number of atherogenic properties that native LDL lacks: it can be recovered from atherosclerotic lesions but not from normal arteries, and antibodies to oxidized LDL epitopes bind to atherosclerotic lesions but not to normal artery walls.1 2 3 If LDL oxidation is an important step in atherosclerosis, it may be that substances that prevent LDL oxidation, ie, antioxidants, may slow the atherosclerotic process. Indeed, in several animal species, the dietary administration of various antioxidant compounds reduces the susceptibility of LDL to oxidation and retards the development of atherosclerosis.4 5 6 7 8
The role of dietary antioxidants in human atherosclerotic disease remains unclear. For the most part, three antioxidants have been studied: vitamin C, vitamin E, and ß-carotene. All three have been shown to reduce the susceptibility of LDL to oxidation in vitro, and vitamins E and C can reduce its susceptibility to oxidation in individuals taking large doses.3 9 10 11 12 However, epidemiological data concerning the role that these substances may play in atherosclerotic disease are inconsistent with regard to both plasma levels and dietary intake.13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
As reviewed by Steinberg et al,2 the oxidation of LDL
seems to be an important early step in atherogenesis, promoting the
development of foam cells and endothelial injury before
the establishment of organized arterial plaque. If this is
true, antioxidant substances are likely to exert their effects at the
earliest stages of the atherogenic process. Thus, ideally, the role of
antioxidants should be evaluated with respect to the development of
preclinical disease. We report the relationship between
intake of the dietary antioxidants vitamin E (in the form of
-tocopherol), vitamin C, and provitamin A
carotenoids (primarily ß-carotene) and carotid artery wall
thickness, a measure of incipient atherosclerosis
measured at the baseline examination in the
Atherosclerosis Risk in Communities Study (ARIC). A
measure of carotid artery wall thickness in
asymptomatic individuals has the advantage that dietary
information is presumably unbiased by knowledge of their disease
state.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Study Population
The ARIC study has been described in detail elsewhere.31 32 Briefly, ARIC is a prospective cohort study designed to investigate the predictors and sequelae of atherosclerosis. Four thousand adults 45 to 64 years old were sampled from each of four US communities: Forsyth County, North Carolina; Jackson, Miss; suburban Minneapolis, Minn; and Washington County, Maryland. The baseline visits took place from late 1986 through 1989. Of the 15 792 adults examined at baseline, 11 307 are included in this analysis. The study received institutional review board approval, and informed consent was obtained. We applied the following exclusion criteria: participant neither black nor white (n=48), no dietary interview (n=26), dietary interview of unacceptable quality in the judgment of the interviewer (n=726), more than nine missing items on the food frequency questionnaire (n=3), extremely high or low total caloric intake for sex (<600 or >4200 kcal/d for men and <500 or >3600 kcal/d for women; n=275). Because this analysis focused on the role of diet early in the atherosclerotic process, those with symptomatic or prevalent CHD at baseline were excluded (n=1603). For diseased individuals, a measure of current diet may not reflect the diet consumed during the development of atherosclerosis. Indeed, 38% of those with symptomatic CHD reported being on a special diet (as opposed to 16% among those without CHD at baseline), and approximately half of those (46%) began this diet within 2 years of the baseline examination. Finally, participants with missing ultrasound measurements or with ultrasound examinations performed before May 15, 1987, a period for which the quality of ultrasound data is not equivalent to that in the rest of the study, were excluded (n=1804).
Dietary Intake
Usual dietary habits, defined as the average
intake over the
past year, were estimated by a 66-item semiquantitative
food-frequency questionnaire, modified after the 61-item
questionnaire originally developed and validated by Willett et
al.33 Three principal modifications were made: (1) a few
items were split into detailed subcategories (for example, a single
question regarding fish consumption was separated into three specific
fish items); (2) some food items were added; and (3) questions
regarding the consumption of wine, beer, and hard liquor were moved to
a separate questionnaire. The questionnaire was administered by trained
interviewers.
Participants were asked how often, on average, they had
consumed
a specified portion size of each food (eg, 8-oz glass of whole milk)
during the preceding year. Nine response categories were available,
ranging from "almost never" to "more than 6 times per
day."
Daily nutrient intake was calculated by multiplying the nutrient
content of the specified portion of each food item, including alcoholic
beverages, by the frequency of its daily consumption and summing over
all items. Food values for calories and vitamin C were from US
Department of Agriculture sources.34 Provitamin A
carotenoid values of foods were computed from the portion of total
vitamin A activity that could not be accounted for by their preformed
vitamin A content.35 -Tocopherol values
were derived from USDA Handbook No. 8-4 and values reported
by McLaughlin and Weihrauch.36
Use of Supplements
Dietary supplement users were identified
from a survey of
medication use. Participants were asked to bring to the field center
the medications/supplements that they had taken in the preceding 2
weeks. The names of all medications/supplements were transcribed and
coded. If a participant had forgotten any medications/supplements, the
information was collected over the phone at a later time. Dose and
duration of use were not ascertained.
Carotid Artery Ultrasound Measurements
Real-time, B-mode
ultrasound was used to evaluate the
carotid arterial wall thickness as an indicator of
atherosclerosis.37 Carotid artery wall
thickness is strongly associated with known risk factors of
coronary heart disease, eg, smoking, hypertension, elevated LDL
cholesterol, and low HDL
cholesterol38 39 and predicts angiographically
determined coronary artery stenosis.40
Moreover, data from Salonen and Salonen38 show that the
2-year risk of myocardial infarction increases 11% with each
additional 0.1 mm of carotid artery intimal-medial thickness. The
Biosound 2000 II SA was used at each of the four ARIC field centers,
which used a common scanning protocol. The carotid arteries were
examined bilaterally in the areas of the common carotid (1 cm proximal
to the dilatation of the carotid bulb), the carotid bifurcation (1 cm
proximal to the flow divider), and the internal carotid artery (1 cm
distal to the flow divider). The distribution of wall thicknesses for
ARIC participants has been reported elsewhere.41 To
optimize the reproducibility of the carotid artery measurements,
standardized interrogation angles were used.
All ultrasonograms were read at the ARIC Ultrasound Reading Center. Measurements of the carotid artery intimal-medial wall thickness were performed by the technique developed and validated by Pignoli et al.42 The measure used in the present analysis is the average of an individual's carotid artery far-wall thickness derived from the intimal-medial thickness measurements taken at each of six sites. To minimize potential bias resulting from the inability to visualize some segments, maximum-likelihood techniques were used to estimate far-wall thickness when data were missing.43 The reproducibility of the study techniques and a description of the quality control procedures can be found elsewhere.32 44 45
Other Measures
Height and weight were measured in light
clothing (scrubs) and
without shoes. Body mass index was calculated as weight (in kilograms)
divided by height (in meters) squared. Cigarette use, race, and
educational attainment were assessed with an
interviewer-administered questionnaire. Blood pressure was measured
three times with a random-zero sphygmomanometer; the average of the
second and third measurements is used here. Plasma
cholesterol, LDL and HDL cholesterol, and serum
glucose measurements were measured after a 12-hour fast.31
Nonfasting values were set to missing.
Statistical Analysis
ANCOVA was used to relate the level of
dietary antioxidant
intake to the average carotid artery wall thickness.46 The
models were fit separately for men and women. Early in the
analysis, it became clear that the associations differed
markedly by age. Therefore, all analyses were also performed
separately within two age strata (45 to 54 and 55 to 64 years).
Participants were assigned to age- and sex-specific antioxidant
intake quintiles. Users of multivitamin supplements were then
reassigned to appropriately higher intake levels on the assumption that
multivitamin users took one tablet containing 100 percent of the
recommended daily allowance for vitamins E and C per day. For the
purposes of this study, vitamin C and vitamin E supplement use was
defined to include preparations containing only vitamin C or E or
in combination with just a few other specific nutrients. Those taking
vitamin C, vitamin E, or ß-carotene supplements were reassigned
to the highest quintile of the appropriate antioxidant. The average
carotid artery wall thickness was calculated for each intake level with
the covariates weighted by their proportion in the sample, and a test
for linear trend across intake levels was performed. A list of
covariates included in the models is shown in the footnotes to Tables
5
, 6, and 7. Except where
mentioned, the models included each
antioxidant individually. The variables included were risk factors
for coronary heart disease, demographic variables, and
total caloric intake. Each risk factor included was independently and
statistically significantly associated (P<.01) with carotid
artery wall thickness in at least one sex-age group.
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A large number of
participants reported being on a special diet at
baseline. For these individuals, the dietary assessment may not reflect
the dietary conditions under which carotid artery thickening developed,
since the dietary instrument measures recent usual diet. To account for
this, all analyses were also performed excluding those who
reported being on a special diet for 
5 years (n=1417).
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Results |
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Table 1
shows characteristics of the ARIC study
population. A high proportion of participants reported using a dietary
supplement containing antioxidants in the preceding 2 weeks.
Multivitamins accounted for much of the supplement use, but vitamin C
supplement use was also common; vitamin E supplement use less so. Fewer
than 1% of the participants reported taking ß-carotene
supplements. Table 2 shows the average daily intakes of
energy and antioxidants within each age-sex stratum. As expected,
younger participants consumed more total calories than the older
participants, and men more than women. Despite the differences in
caloric intake, on average, older participants consumed more
antioxidants than younger ones, and women had higher median intakes of
vitamin C and provitamin A carotenoids and higher intakes of
-tocopherol per kilocalorie than did men (data not shown).
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Tables 3 and 4 show the relationship
between dietary antioxidant intake and mean carotid artery wall
thickness for women and men, respectively. There was little evidence
for an association between any of the dietary antioxidants and wall
thickness among the younger women. Among older women, those consuming
more vitamin C or -tocopherol had less artery wall thickening. The
average wall thickness was statistically significantly different
between high and low intake categories for both vitamin C and
-tocopherol, and there was a statistically significant inverse
linear trend across intake categories. Little association was seen
between carotenoid intake and carotid artery wall thickness.
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Among the younger men (Table 4
), carotenoid intake was
inversely
associated with wall thickness, while neither vitamin C intake nor
-tocopherol intake showed much association. In older men, the
intakes of all three antioxidants were inversely associated with
carotid artery wall thickness. The relationships were stronger for
vitamin C and carotenoid intake. For -tocopherol, wall thickness
tended to be lower with increasing intake over the first four intake
quintiles, but the linear trend did not hold into the highest intake
quintile. In this quintile, the mean wall thickness was greater than in
either the third or fourth quintile.
Tables 5 and 6 show the relationships
between antioxidant intake and carotid artery wall thickness adjusted
for potential confounding factors in women and men, respectively. Among
younger women, no important differences were seen between the
unadjusted and adjusted relationships. Among older women, adjustment
weakened the inverse association for both vitamin C and
-tocopherol. For vitamin C, the difference in mean
wall thickness between extreme intake quintiles diminished from 0.026
mm before adjustment to 0.013 mm after adjustment. For -tocopherol,
the difference diminished from 0.033 mm to 0.021 mm. In younger men
(Table 6), adjustment weakened the association between
carotenoid
intake and wall thickness. In older men, adjustment minimally affected
the magnitude of the relationship between vitamin C and wall thickness
but strengthened the inverse relationship between wall thickness and
-tocopherol (the difference between extreme quintiles is 0.011 mm
before adjustment and 0.017 mm after adjustment). Adjustment also
diminished the magnitude of the relationship between wall thickness and
carotenoid intake (the difference between extreme quintiles decreased
0.005 mm).
In the context of a cross-sectional study, recent dietary changes
would not reflect the dietary milieu under which carotid artery
thickening developed. Therefore, Tables 5 and 6
also show results
separately for the subset of participants who denied having begun a
special diet within the past 5 years. Among both older women and
men with stable diets, there was a statistically significant inverse
trend between wall thickness and vitamin C intake. The difference in
wall thickness between extreme intake quintiles increased from 0.013 to
0.022 mm in older women and from 0.025 to 0.032 mm in older men in
comparison with the study population generally. The omission of study
participants who started a special diet strengthened the inverse
association between wall thickness and -tocopherol intake in older
women but diminished it in older men. The strength of association for
carotenoid intake weakened in older men after exclusion of those
reporting recent dietary change.
Table 7 shows the covariate-adjusted differences in
wall thickness by supplement use. Only a qualitative assessment of the
role of dietary supplementation and carotid artery wall thickness is
possible, since neither duration nor frequency of use was ascertained.
Among the younger women, only vitamin C use was associated with
decreased wall thickness, although the role of chance could not be
excluded. Among older women, users of both vitamin E and multivitamin
supplements users tended to have less wall thickening than
nonusers. Among men, there were no statistically significant
differences in wall thickness by supplement use in either age group,
although both older and younger male vitamin E supplement users had
thicker artery walls than nonusers.
Among older women who had not recently changed their diet, the
associations between dietary vitamin C and -tocopherol intake and
artery wall thickness attenuated when those reporting supplement use
were omitted. The difference in wall thickness between extreme intake
quintiles of vitamin C was 0.010 mm, excluding those who reported
taking either multivitamins or vitamin C supplements (compared with
0.022 mm overall). The linear trend across the quintiles was not
statistically significant (t=-1.36,
P=.17). The
difference in wall thickness between the extreme quintiles of
-tocopherol intake was 0.021 mm, excluding those taking either
multivitamins or vitamin E supplements (compared with 0.028 mm
overall). The linear trend across intake quintiles was not
statistically significant (t=-1.17,
P=.24).
Among older men who had not recently changed their diet, omitting
supplement users from the analysis strengthened the inverse
relationship between both vitamin C and -tocopherol and wall
thickness. The difference in wall thickness between extreme intake
quintiles of vitamin C was 0.044 mm (P=.013), excluding men
who reported taking either multivitamins or vitamin C supplements
(compared with 0.032 mm overall). The linear trend across the quintiles
was statistically significant (t=-2.62,
P=.009).
The difference in wall thickness between the extreme quintiles of
-tocopherol intake was 0.025 mm, excluding men taking either
multivitamins or vitamin E supplements (compared with 0.007 mm
overall). The linear trend across intake quintiles was statistically
significant (t=-2.04, P=.042). In
younger women
and in men, omitting supplement users from the analysis did not
materially affect the relationship between dietary intake and artery
wall thickness described above (data not shown).
The intake of dietary -tocopherol and intake of vitamin C were
statistically significantly correlated. Among those who had not
recently started a special diet, the Spearman correlation coefficients
ranged from .46 to .49 across the four age-sex strata (all values
of P<.001). Among older women who had not recently started
a special diet, when both -tocopherol and vitamin C were included in
the same model, there was little difference in the strength of the
linear trend in wall thickness between vitamin C intake
(t=-1.44, P=.15) and -tocopherol
intake
(t=-1.35, P=.18). In older men, the
trend across
levels of vitamin C intake was significant (t=-2.16,
P=.031) but not across -tocopherol intake
(t=-0.52, P=.60).
Two studies in men have found that the protective effect of provitamin A carotenoids against cardiovascular disease was manifest primarily in smokers.18 23 In the present study, a formal test of interaction between carotenoid intake and smoking status failed to reach statistical significance in any age-sex strata. However, there was evidence for an inverse linear trend between wall thickness and carotenoid intake in both the younger and older smoking women (t=-1.78, P=.07 and t=- 1.84, P=.06, respectively) but not among nonsmoking women (data not shown). The relationship between carotenoid intake and wall thickness differed little between nonsmoking and smoking men (data not shown).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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In the ARIC baseline population, dietary consumption of vitamin C was inversely associated with carotid artery wall thickness in women and men between 55 and 64 years old. A similar inverse association with
-tocopherol intake was somewhat weaker. Provitamin A
carotenoids were inversely associated with wall thickness, primarily in
older men, but this association attenuated after control for potential
confounders. There are relatively few epidemiological studies of dietary antioxidant intake and cardiovascular disease with which to compare the present findings. In women, two studies have found vitamin C intake to be inversely associated with CHD mortality,14 29 although other studies have failed to find a relationship with either incident or prevalent disease.15 17
In men, the findings have been both stronger14 15 and weaker29 than those found in women, and in a large prospective study of male health professionals, Rimm et al18 found no relationship between vitamin C intake and coronary heart disease risk.
In two large prospective studies, one in women and one in men, vitamin
E intake in the form of dietary supplements was associated with
decreased risk of coronary heart disease.18 24
Knekt et al29 found dietary vitamin E intake to be
associated with reduced mortality from coronary heart disease
in both men and women (supplement use was too infrequent to account for
the results). In a randomized trial of a supplement containing 50 mg/d
of -tocopherol versus placebo in male Finnish smokers,
supplementation failed to significantly affect the rate of
ischemic heart disease mortality over the study
period.30 In the ARIC study, the use of dietary
supplements accounted for some of the association seen among the older
women but not in men. In fact, wall thickness was greater among men
taking vitamin E supplements in ARIC.
The literature relating to dietary carotenoids or ß-carotene and cardiovascular disease is inconsistent. In a report by Bolton-Smith et al,15 ß-carotene was inversely associated with the prevalence of clinically unrecognized coronary disease in men but not in women. Provitamin A carotenoid consumption was inversely related with coronary heart disease risk primarily in smokers in the Male Health Professionals Study.18 However, in a randomized trial of ß-carotene in Finnish male smokers, there was a slightly higher rate of ischemic heart disease mortality (rate ratio, 1.11) in the experimental group.30 Other results from randomized trials suggest a benefit from supplements containing ß-carotene.28 47
It is unclear why dietary supplements were related to less wall thickening in the older women in ARIC but not the older men. Several issues concerning the measurement of supplement use should be borne in mind. First, length of use was not ascertained. Given the long period of time over which wall thickening occurs, recent supplement use is relevant only insofar as it reflects long-term use. The number of long-term users may have been lower among men. Second, frequency of use was not determined, only any use during the previous 2 weeks. Men may be more sporadic users; hence, dietary sources of antioxidants would appear more important. Third, how supplements are taken might be important, especially for vitamin E, since it may be absorbed more readily from the intestinal tract when ingested with fat.48 Fourth, it may be that the vitamins themselves are not the protective factor; rather, other substances found in foods rich in vitamin C and E or other protective aspects of life-style may be associated with reduced wall thickness. The differential effect of supplement use would be seen if the protective factor was correlated with vitamin use in women but not in men. Finally, the difference in the association with vitamin use seen between men and women may be a chance observation. However, the fact that omitting supplement users greatly attenuated the relationship between dietary intake and wall thickness in women but enhanced it in men argues against this interpretation.
The difference in results between the older and younger ARIC participants was not hypothesized a priori. The failure to find an association in the younger age group could not be explained by a differing shape of wall thickness distributions compared with the older age group. It may be that exogenous antioxidants become increasingly important if endogenous antioxidant systems decline with advancing age. There is evidence that superoxide dismutase and glutathione reductase levels do decline with advancing age, although it is not known whether these enzymes play a role in preventing LDL oxidation.49 50 Alternatively, if dietary antioxidants slow age-dependent thickening, it may be that those in the younger age groups have not aged enough for an antioxidant effect to manifest itself.
The food frequency questionnaire used in the ARIC study was not developed specifically for the ARIC study; it was adapted from the questionnaire used in the Nurses Health Study.33 The nutrient intakes reported by ARIC participants are roughly similar to those determined by food frequency questionnaire in the validation study of the original questionnaire. The validation sample consisted of 173 Boston area women 34 to 59 years old whose total caloric intake was 1371 kilocalories per day (excluding alcohol intake). The younger ARIC women's total caloric intake was 1483 kilocalories per day (excluding alcohol intake). Mean vitamin C intakes (omitting supplements) were 112 and 117 mg/d for the validation study and the ARIC study, respectively. Estimates of dietary intake using a food frequency questionnaire are low compared with other assessment methods. This serves to emphasize that the proper use of a food frequency questionnaire is not in estimating exact dietary amounts but rather in allowing the ordering of individuals within a study population with respect to intake of a given nutrient. Even for this goal, the food frequency questionnaire is an imperfect tool. In the Nurse's Health Study food frequency questionnaire validation, there was a correlation of 0.50 between vitamin C intake measured by the 61-item questionnaire and intake measured by four 1-week diet records.33 Correlations between serum levels of vitamin E and carotenoids and dietary intake as measured by food frequency questionnaires are modest as well (on the order of 0.3) but improve when intake in the form of supplements is included.51 52 When there is exposure measurement error that is independent of outcome, observed differences will tend to be smaller than the differences that would have been observed with perfect measurement (Reference 53, p 86). We expect that the error of our diet assessment is uncorrelated with the wall thickness, since carotid wall thickness is an asymptomatic condition. Those with symptomatic disease were specifically excluded from consideration. Thus, we anticipate that our findings underestimate the true magnitude of the differences in mean wall thickness between intake levels.
The limitations of the present study should be noted. Because it is a cross-sectional study, the basis for causal inference is inherently limited. The results, therefore, should be considered more exploratory than definitive. The timing of dietary intake with respect to the development of artery wall thickness is not known. However, by excluding those with symptomatic disease and those who had recently changed their diet, we attempted to relate diet to wall thickness at the biologically relevant time. As noted above, the food frequency questionnaire is an imperfect measure of usual dietary intake but is sufficient for many epidemiological applications. Given the large number of strata examined and statistical tests performed, the reported probability values are better considered as interpretive guides than as formal tests of hypotheses.
The strengths of the study should also be recognized. The ARIC participants represent samples from their constituent communities. As such, the study populations are likely to include the full spectrum of dietary habits and atherosclerotic disease seen in typical US populations. Since the ARIC study was designed to study cardiovascular disease, measurements of a great number of potential confounding variables are available. Although it is a proxy for the extent of atherosclerotic disease, carotid artery wall thickness is particularly suited for studies of the potential effects of dietary antioxidants. Since antioxidants are hypothesized to operate at the earliest stages of atherogenesis, measures from early in the atherogenic process are ideal. Finally, the ability to measure a wall thickness in asymptomatic individuals precludes bias introduced by dietary changes adopted in the face of symptoms of disease.
In summary, the ARIC study provides limited support for the hypothesis
that the dietary antioxidants vitamin C and -tocopherol may slow the
progression of atherosclerosis in both men and women
>55 years old. Although the hypothesis that oxidized LDL is
atherogenic provided the impetus for the present analysis,
these findings cannot rule in or out a particular mechanism of disease.
Given the cross-sectional nature of the study, longitudinal data
are required to confirm this finding.
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Acknowledgments |
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This research was supported by grant HL-47408 and contracts N01-HC-55015, N01-HC-55016, NO1-HC-55017, NO1-HC-55019, N01-HC-55020, N01-HC-55021, and NO1-HC-55022 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. The authors thank the representatives of the four clinical centers and the coordinating and service centers that made this report possible: the University of North Carolina, Chapel Hill (Department of Epidemiology): Catherine Paton, Jeannette Bensen, MSc, Delilah Posey, Amy Haire; the University of Mississippi Medical Center, Jackson: Bobbie J. Alliston, RN, Faye A. Blackburn, Catherine W. Britt, Barbara L. Davis; the University of Minnesota, Minneapolis: Karen Birkholz, Laurie Wormuth, Gina Tritle, Janet Jeremiason; the Johns Hopkins University, Baltimore, Md: Joel G. Hill, Patricia M. Crowley, Joyce B. Chabot, Patricia Hawbaker; the University of Texas Medical School, Houston: Valerie Stinson, Pam Pfile, Hoang Pham, Teri Trevino; the Methodist Hospital, Houston: Doris Epps, Selma Soyal, Maria Laura Messi, Val Creswell; the Bowman-Gray School of Medicine, Winston-Salem, NC: Regina deLacy, Delilah Cook, Carolyn Bell, Teresa Crotts, Suzanne Pillsbury; and the University of North Carolina, Chapel Hill (Department of Biostatistics): George Williams, Kiduk Yang, Marston Youngblood, Ding-Yi Zhao.
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Footnotes |
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Reprint requests to Stephen B. Kritchevsky, PhD, Division of Biostatistics and Epidemiology, Department of Preventive Medicine, University of Tennessee at Memphis, 877 Madison Ave, Memphis, TN 38163.
Received August 30, 1994; revision received May 3, 1995; accepted May 6, 1995.
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