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Elevated Midlife Blood Pressure Increases Stroke Risk in Elderly Persons
The Framingham Study
Sudha Seshadri, MD;
Philip A. Wolf, MD;
Alexa Beiser, PhD;
Ramachandran S. Vasan, MD;
Peter W. F. Wilson, MD;
Carlos S. Kase, MD;
Margaret Kelly-Hayes, EdD, RN;
William B. Kannel, MD, MPH;
Ralph B. D'Agostino, PhD
Arch Intern Med. 2001;161:2343-2350.
ABSTRACT
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Background Stroke risk predictions are traditionally based on current blood pressure
(BP). The potential impact of a subject's past BP experience (antecedent BP)
is unknown. We assessed the incremental impact of antecedent BP on the risk
of ischemic stroke.
Methods A total of 5197 stroke-free subjects (2330 men) in the community-based
Framingham Study cohort were enrolled from September 29, 1948, to April 25,
1953, and followed up to December 31, 1998. We determined the 10-year risk
of completed initial ischemic stroke for 60-, 70-, and 80-year-old subjects
as a function of their current BP (at baseline), recent antecedent BP (average
of readings at biennial examinations 1-9 years before baseline), and remote
antecedent BP (average at biennial examinations 10-19 years earlier), with
adjustment for smoking and diabetes mellitus. Models incorporating antecedent
BP were also adjusted for baseline BP. The effect of each BP component (systolic
BP, diastolic BP, and pulse pressure) was assessed separately.
Results Four hundred ninety-one ischemic strokes (209 in men) were observed
in eligible subjects. The antecedent BP influenced the 10-year stroke risk
at the age of 60 years (relative risk per SD increment of recent antecedent
systolic BP: women, 1.68 [95% confidence interval, 1.25-2.25]; and men, 1.92
[95% confidence interval, 1.39-2.66]) and at the age of 70 years (relative
risk per SD increment of recent antecedent systolic BP: women, 1.66 [95% confidence
interval, 1.28-2.14]; and men, 1.30 [95% confidence interval, 0.97-1.75]).
This effect was evident for recent and remote antecedent BP, consistent in
hypertensive and nonhypertensive subjects, and demonstrable for all BP components.
Conclusions Antecedent BP contributes to the future risk of ischemic stroke. Optimal
prevention of late-life stroke will likely require control of midlife BP.
INTRODUCTION
STROKE IS the leading neurological cause of mortality and morbidity
worldwide. The annual incidence of stroke in the United States has been estimated
at more than 600 000.1 The most important
modifiable risk factor for stroke is an elevated blood pressure (BP),2 and this fact is recognized in stroke risk prediction
models, developed by the Framingham Study researchers and adopted by the American
Stroke Association.1, 3 These risk
prediction models, however, consider the BP at the time of risk prediction
(current BP) but do not adjust for the potential impact of BP levels experienced
by individuals in the past (antecedent or past BP). Some investigators4 have suggested that consideration of the current BP
provides adequate information for predicting stroke risk, and in clinical
trials,5 most of the stroke prevention effect
of lowering BP is achieved within a few years of starting treatment. On the
other hand, some of the known stroke risk factors in observational studies,
such as the presence of electrocardiographic left ventricular hypertrophy3, 6 and increased echocardiographic left
ventricular mass,7 are related to long-term
elevations of BP. In addition, midlife BP has been shown to be predictive
of the degree of carotid stenosis (a direct precursor of atherothrombotic
stroke) in elderly persons.8
The availability of well-standardized, prospectively collected, population-based
data on the BP of participants during a 50-year period in the Framingham Study
provided us with a unique opportunity to address the importance of past BP
measurements in estimating the future risk of stroke. Our objective was to
assess the impact of past BP levels on the future risk of stroke in older
adults (aged  60 years), after accounting for the influence of current
BP.
SUBJECTS AND METHODS
The 5209 subjects enrolled in the Framingham Study between Sepember
29, 1948, and April 25, 1953, are referred to as the original Framingham cohort.9 Our study sample was composed of the 5197 subjects
(2330 men; age range, 30-62 years) free of prevalent stroke at the index examination.
The BP was recorded at every biennial examination that the subject attended,
and the mean of 2 BP measurements recorded by a physician was taken as the
subject's BP at the examination. All BP measurements were made in the left
arm of the seated subject, using a mercury column sphygmomanometer and a cuff
of appropriate width. Readings were recorded to the nearest even number. The
fifth (disappearance) Korotkoff sound was used as an index of diastolic BP
(DBP) unless the sound persisted to zero, in which case the fourth Korotkoff
sound was recorded. The pulse pressure (PP) was calculated as the difference
between the mean systolic BP (SBP) and DBP values at the examination of interest.
Other cardiovascular risk factors were also measured at each biennial examination.
There was active continuous surveillance for incident stroke during
the study period. The methods and effectiveness of our stroke surveillance
have been previously described.10
We grouped subjects by age, pooling subjects who reached the age of
interest alive and free of stroke (ischemic stroke or intracranial hemorrhage),
regardless of the calendar year when they made this transition. We also defined
an optimal follow-up period for stroke risk assessment as 10 years, because
in this elderly cohort, longer periods of follow-up can result in increased
misclassification of subject's exposure status, as BP levels changed during
the period of follow-up.11 Thus, a 40-year-old
subject enrolled in 1950 would, if he or she reached the age of 60 years alive
and free of stroke, provide 10 years of follow-up information from 1970 to
1980. If the same individual reached the age of 70 years alive and free of
stroke, he or she then provided an additional 10 years of follow-up information
as a 70-year-old individual. We chose to group subjects by age rather than
by calendar year or index examination because the risk of stroke is greatly
dependent on age.
EXPOSURE VARIABLE
The exposure variable was BP, assessed as a continuous variable. We
separately examined each individual component of the BP (SBP, DBP, and PP)
to assess if there was a differential effect of any specific component when
considering the contribution of past BP measurements to the future risk of
stroke.12 Three aspects of BP were considered:
(1) the current BP at the time of risk prediction (baseline age, 60, 70, or
80 years); (2) the recent past BP, in the decade immediately preceding the
time of risk prediction (BP at the age of 50-59, 60-69, and 70-79 years, respectively);
and (3) the remote past BP (10-20 years before the time of risk prediction,
ie, at the age of 40-49 years for a baseline age of 60 years, at the age of
50-59 years for a baseline age of 70 years, and at the age of 60-69 years
for a baseline age of 80 years at the time of stroke risk prediction).
OUTCOME
The primary outcome of interest was time to first completed ischemic
stroke. Transient ischemic attacks were not included as either an end point
or an exclusion criterion. We excluded subjects with intracranial (intracerebral
or subarachnoid) hemorrhage from our analysis because many intracerebral hemorrhages
in elderly persons are lobar hemorrhages secondary to amyloid angiopathy,
a cause known to be independent of the BP level.13
Thus, intracranial hemorrhage was not an end point; however, because recognition
of an ischemic stroke may be difficult in subjects with a prior intracranial
hemorrhage, such subjects were censored from further follow-up at the time
of development of the hemorrhagic stroke.
The diagnosis of stroke was based on the documentation of a focal neurological
deficit of abrupt onset, either maximal from the onset or progressive, lasting
for more than 24 hours.2 Individual stroke
subtypes were categorized according to an algorithm based on preestablished
diagnostic criteria that include clinical features, imaging studies and other
laboratory criteria, noninvasive vascular studies, cardiac evaluations for
a source of embolus, and, when available, information from autopsy studies.
An ischemic brain infarction was diagnosed if a focal deficit was documented
on medical history or physical examination but a contemporaneous brain image
showed no hemorrhage or if an ischemic brain infarct was found on autopsy.
Computed tomographic or magnetic resonance imaging confirmation was available
in 85% of all strokes included in this study.
The ischemic brain infarct was classified as an atherothrombotic brain
infarction (ABI) if no cardiac sources of emboli could be found. The category
of ABI included large-artery infarcts, lacunar infarcts, and infarcts of unknown
origin. The brain infarct was classified as cardioembolic if a source of embolus
was found. Such sources included atrial fibrillation, significant mitral valve
disease, a mechanical prosthetic valve, endocarditis, left ventricular thrombus
or left atrial thrombus on an echocardiogram, atrial myxoma, dilated cardiomyopathy,
recent cardiac surgery, and recent myocardial infarction.
STATISTICAL ANALYSES
We used multivariate sex-specific Cox proportional hazards regression
models14 to assess the relative risk (RR) of
stroke per unit increase in each BP component. An initial analysis assessed
the effect of a 1-SD change in current BP (SBP, DBP, or PP) on the 10-year
risk of stroke in 60-, 70-, and 80-year-old subjects, without adjusting for
past BP. A subsequent analysis assessed the additional effect of a 1-SD change
in recent BP after adjusting for current BP. Similarly, we assessed the incremental
prognostic utility of remote BP over current BP alone. Covariates included
in these models were the presence or absence of diabetes mellitus and smoking
status at baseline (defined as current smoker or nonsmoker). We did not include
the cardiac risk factors for ischemic stroke3
(left ventricular hypertrophy, coronary artery disease, and atrial fibrillation)
in the overall multivariate analysis because these risk factors are correlated
with long-standing BP elevations and, thus, would obscure the effect of past
BP elevations.
ADJUSTMENT FOR REGRESSION-DILUTION BIAS
We used multiple measurements for antecedent BP (2-5 BP readings, depending
on the number of available examinations during the decade of interest) to
reduce the effects of regression-dilution bias.15-17
We considered the possibility that the incremental utility of the antecedent
BP over the current BP may be due to an underestimation of the true association
between current BP and 10-year risk of stroke, because current BP was more
likely to be affected by a regression-dilution bias. To address this issue,
we repeated our analyses using the BP recorded at a single random examination
within the decade of interest to represent the antecedent BP during that period.
Additional secondary analyses explored the consistency of the observed
association after stratifying the sample by current BP status (nonhypertensive
[SBP of <140 mm Hg and DBP of <90 mm Hg] vs hypertensive), by treatment
status (whether the subject had ever taken antihypertensive medication), and
by the year in which the baseline age (60, 70, or 80 years) was reached (pre-1975
or post-1975). We also evaluated the association of current and antecedent
BP measures with the independent risks of ABI alone and cardioembolic stroke
alone. Finally, we determined if the impact of BP on stroke risk was modified
by the sex of the subject. All analyses were performed using SAS statistical
software (SAS Institute Inc, Cary, NC).
RESULTS
STUDY SAMPLE CHARACTERISTICS
A total of 3761 subjects reached the age of 60 years alive, were free
of stroke, and had information for the variables of interest in our analysis.
Similarly, 3049 subjects were able to provide information for the baseline
age of 70 years and 1203 for the baseline age of 80 years. The study sample
characteristics of the population at the ages of 60, 70, and 80 years are
shown in Table 1. The mean and
SD of each BP component at the ages of 60, 70, and 80 years are also described.
As expected, the mean SBP and PP increased with age and the mean DBP declined
with age in both sexes. The proportion of subjects taking antihypertensive
medication increased with age, reaching nearly 50% in 80-year-old women. The
proportion of current smokers declined with age, reflecting decreased survival
in smokers and subjects who had quit smoking. The mean serum cholesterol levels
and body mass index in the study cohort are higher than recommended by current
guidelines, in part because the study period spans 50 years.
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Table 1. Characteristics of the Study Sample*
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STROKES
Overall, there were 830 completed ischemic strokes during a 50-year
period in the 5197 subjects in the original Framingham cohort, and 740 of
these were initial strokes in subjects aged 60 to 89 years. Of these strokes,
only 521 occurred in the 4275 subjects who attended a biennial examination
within 1 year of their baseline age (60, 70, or 80 years) and hence could
provide reliable information on current BP at baseline. Four hundred ninety-one
of these 521 strokes occurred in the 3761 subjects with adequate information
regarding smoking and diabetes mellitus status at the baseline age, and the
distribution of these events is as follows. There were 71 strokes in 2197
women and 71 in 1564 men between the ages of 60 and 69 years; the corresponding
numbers were 130 strokes in 1875 women and 101 in 1174 men between the ages
of 70 and 79 years and 81 strokes in 791 women and 37 in 412 men between the
ages of 80 and 89 years.
IMPACT OF CURRENT BP
The RRs of stroke per SD increment in current BP are presented in Table 2. The RRs of stroke for the antecedent
BP measurements, after adjustment for current BP, are also shown. As expected
and shown in earlier studies,2-3,12
higher levels of BP at the time of risk prediction were associated with increases
in the 10-year risk of stroke by up to 103%, depending on the age at the time
of risk assessment and the BP measure used (SBP, DBP, or PP) to predict risk.
The effect of current BP was strongest at the age of 60 years and weakest
at the age of 80 years, and the RRs were more marked for SBP and PP than for
DBP at the age of 80 years.
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Table 2. Regression of Ischemic Stroke Incidence on Current and Antecedent
Blood Pressure Measurements, by Blood Pressure Component*
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INCREMENTAL IMPACT OF ANTECEDENT BP
After adjusting for current BP, the antecedent BP further increased
the 10-year risk of stroke. The magnitude of the effect ranged from a 68%
to 92% increased risk at the age of 60 years to a 14% to 72% increased risk
at the age of 70 years and up to a 32% increased risk even at the age of 80
years. This effect was seen not only for the recent antecedent BP but was
also noted for the remote antecedent BP. For instance, in men aged 70 years,
the effect of remote BP (42%-51% increase in stroke risk) was at least as
powerful as the impact of recent antecedent BP (14%-37% increase in stroke
risk). The effect of current and antecedent BP was most powerful at the age
of 60 years, with the RRs decreasing at the ages of 70 and 80 years. The analyses
demonstrated that overall, all 3 components of antecedent BP were good predictors
of future stroke risk. In 70-year-old men, the SBP and PP were relatively
more informative than the DBP. In 70-year-old men, while current or recent
DBP was not a statistically significant risk predictor, remote DBP remained
predictive (Table 2).
SECONDARY ANALYSES
Adjustment for Regression-Dilution Bias
We found that the association between antecedent BP and risk of stroke
persisted even when we used a single, random BP reading, although the magnitude
of the risk ratio diminished. The RRs using single-random SBP recordings (in
contrast to time-averaged SBP measures), for recent and remote SBP measurements,
in subjects aged 60 and 70 years at baseline are shown in Table 3.
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Table 3. Regression of Ischemic Stroke Incidence on Current and Antecedent
Blood Pressure Measurements, Using a Randomly Selected Single Measure Recorded
at Baseline or During the Decade of Interest*
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Effect in Nonhypertensive Subjects
We repeated the analyses including only those subjects who at the baseline
age had an SBP of less than 140 mm Hg and a DBP of less than 90 mm Hg. The
RRs of stroke per SD increment in current BP are presented in Table 4. Even in subjects who were nonhypertensive, there was an
incremental impact of antecedent BP measurements, recent and remote, on the
future risk of stroke.
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Table 4. Regression of Ischemic Stroke Incidence on Current and Antecedent
Blood Pressure Measurements in Nonhypertensive Subjects*
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Other Interactions
We looked for a potential differential impact of past BP measures on
stroke risk in men vs women, but found no significant effect modification
by sex (P>.30; results not presented). The effect
of antecedent BP was seen in subjects who had taken antihypertensive medication
at some time in their life and in subjects who had never taken medication,
although the smaller numbers in each subgroup reduced the statistical power
of this secondary analysis (results not presented). In evaluating for a change
in the impact of BP on stroke risk over time, we found that in men and women,
the effect of recent antecedent SBP on future stroke risk remained statistically
significant in the pre-1975 stratum (P = .03) and
the post-1975 stratum (P<.001) (results not presented).
Stroke Subtype Analyses
We found a similar effect of past BP on the risk of each stroke subtype
evaluated, ie, ABI and cardioembolic stroke (results not presented). The number
of events was too small to permit separate analysis of large-artery infarcts
and lacunar strokes.
COMMENT
Stroke is predominantly a disease of elderly persons. The risk of stroke
doubles in each successive decade after the age of 55 years, and 72% of all
strokes occur after the age of 65 years.1 To
reduce the population burden of stroke, it is important to address the possible
reasons for this increasing risk with age. The cumulative effect of long-term
exposure to risk factors such as an elevated BP may partly explain this age-associated
increase in risk.
PRINCIPAL FINDINGS
We found that the antecedent BP increased the future risk of ischemic
stroke even after adjusting for current BP levels. This effect was robust,
consistent in both sexes, evident at baseline ages 60 and 70 years, demonstrable
for all BP components evaluated, and significant in hypertensive and nonhypertensive
subjects.
In the Framingham Study,18 28% of all
ABIs occurred in subjects whose current BP was in the nonhypertensive range.
While this is not entirely surprising given the continuum of risk, the importance
of a past BP elevation as a potentially modifiable risk factor for the prevention
of stroke in this group should not be overlooked. Similarly, earlier observations
from the Framingham Study described a higher risk of stroke at comparable
levels of BP elevation in subjects taking antihypertensive agents compared
with subjects who were not.19 The higher risk
in treated individuals may be explained, in part, by the fact that subjects
with more concomitant risk factors and those with target organ damage are
more likely to be treated. Our data suggest that an additional explanation
may be the residual effect of high antecedent BP.
The present investigation was not designed to address the relative utility
of the individual measures of antecedent BP (SBP, DBP, and PP) in predicting
the future risk of ischemic stroke. We found that all 3 components were good
predictors of future risk in 60-year-old men and women and in 70-year-old
women, while the SBP and PP were relatively more useful than the DBP in 70-year-old
men. This may be because the DBP peaks earlier in men compared with women.20 Also, we did not address the incremental utility
of "remote" over "recent" past BP recordings.
COMPARISON WITH PRIOR STUDIES
A recent review11 of 11 prospective studies
exploring the association of hypertension with stroke found that all these
studies defined hypertension based on BP measurements taken at a single visit.
Sytkowski et al,21 in an earlier study from
Framingham, Mass, did examine the risk of cardiovascular disease (CVD) and
CVD-related mortality in subjects with long-term sustained hypertension, but
did not assess stroke as a separate end point. In their study, long-term sustained
hypertension was defined as an SBP of 160 mm Hg or higher and/or a DBP of
95 mm Hg or higher in at least 3 of 5 consecutive biennial examinations. No
distinction was made between current and past BP.
Only 3 prior studies have specifically addressed whether "elevated BP
levels in the past convey additional risk, given recent BP levels."22(p2) Prentice et al22
studied the relation between the 2-year risk of stroke and BP recorded at
4 preceding biennial examinations in middle-aged Japanese adults enrolled
in the Hiroshima and Nagasaki Adult Health Study. They reported that, in addition
to current SBP, the SBP 2 to 4 years before baseline did predict the future
risk of ischemic stroke. However, they could not demonstrate any additional
impact of SBP recorded 4 to 6 years before baseline on the future stroke risk.
The age and ethnic differences between the 2 cohorts may account for the differences
between our results and those of the Hiroshima and Nagasaki Adult Health Study,
in which 90% of the subjects were younger than 65 years. Furthermore, the
Japanese study did not assess the effect of remote antecedent BP.
Keli et al23 studied 630 men (aged 50-69
years) enrolled in the Zutphen Study. They compared a single observation of
the SBP in subjects with the SBP averaged over 10 years, and found that the
latter measure was a stronger predictor of 15-year stroke incidence. However,
they did not study women or assess the effect of remote antecedent BP.
Harris et al24 assessed the future risk
of CVD in 1254 persons from the Framingham Study who reached the age of 65
years without a prior CVD. They found a consistent small increase in risk
of all cardiovascular events among those with a higher SBP before the age
of 65 years, even after controlling for the average of 3 SBP measurements
recorded at the age of 65 years. However, the association between BP and CVD
risk was statistically significant only in subjects with an average SBP (before
the age of 65 years) of 160 mm Hg or higher. Important differences between
the present study and the study by Harris et al deserve emphasis. Harris et
al restricted their analysis to untreated subjects, did not examine the end
point of stroke, and did not assess the impact of individual BP components
(DBP and PP). Furthermore, their analyses did not distinguish between recent
and remote antecedent BP and did not examine the effect in subjects older
than 65 years.
The present investigation is, therefore, unique in addressing the incremental
value of recent and remote antecedent BP in predicting the future risk of
ischemic stroke and in examining the effect of DBP and PP as well as SBP.
Furthermore, it addresses the issue in elderly subjects, a group at highest
risk for incident stroke and a history of hypertension.
POSSIBLE MECHANISMS
The pathophysiological mechanisms whereby hypertension leads to stroke
are not entirely clear. An elevated BP is an independent risk factor for carotid
atherosclerosis, after adjusting for age, sex, smoking status, and serum cholesterol
level.8, 25 In addition, hypertension
may directly cause mechanical damage to blood vessel walls that may persist
after the systemic BP has been lowered to nonhypertensive levels by medications.
Chronic hypertension has been associated with medial thickening of arterial
walls, hyaline degeneration, fibrinoid necrosis, formation of microaneurysms
in the intraparenchymal arterioles, and inadequate development of intracranial
collaterals in response to carotid occlusive disease.26-27
Such changes may be responsible for the long-term adverse effects of an elevated
BP seen in our study subjects.
STRENGTHS AND LIMITATIONS
The availability of antecedent BP data, collected by the Framingham
Study researchers during a 50-year period, is a unique strength of this study.
Almost all participants are white, and this limits the generalizability of
the results to other racial and ethnic groups.
CLINICAL AND PUBLIC HEALTH IMPLICATIONS
The results of our study, while based on observational data, strongly
suggest that midlife BP levels continue to affect the future risk of stroke
not only over a short span, such as 5 years, but over more prolonged periods,
up to 30 years. Traditional analyses of the benefits of BP control at a given
age use estimates of the 5-year (or 10-year) absolute risk of adverse events
for a subject at that age to estimate a "number needed to treat" to prevent
a single event during a limited time. Such analyses may underestimate the
long-term risk reduction achievable with adequate BP control in midlife.
Recent national data suggest that the awareness, treatment, and control
of hypertension may be deteriorating. This insouciance may be greater in middle-aged
adults facing fewer short-term risks.28 Our
findings reinforce the importance of Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure guidelines,29 emphasizing the need to prevent and control an elevated
BP at all ages. Emphasizing the long-term adverse effects of midlife BP elevations
may serve to motivate middle-aged adults to become aware of and address their
elevated BP levels. While the reduction in risk achieved by antihypertensive
treatment is impressive at any age and particularly in elderly persons,30-32 treatment of hypertension
in older subjects who have been exposed to elevated BP levels for many years
leaves their risk well above that of nonhypertensive subjects.
Healthy People 2000,33 the statement
of national objectives for promoting health and preventing disease, called
for a 34% reduction in the number of deaths caused by stroke from the 1987
stroke mortality rate of 30.4 per 100 000. By 1997, less than 50% of
this target reduction was achieved.33 The present
study suggests that to achieve optimal reductions in the risk of ischemic
stroke in elderly persons, it may be necessary to prevent, diagnose, and manage
BP elevations throughout adulthood. The primary prevention of hypertension
through nonpharmacological measures throughout adult life, and the early detection
and treatment of hypertension in middle-aged and older adults, promises to
yield sustained benefits in the form of lower stroke risks later in life.
AUTHOR INFORMATION
Accepted for publication March 13, 2001.
This study was supported by grant NS17950 from the National Institute
of Neurological Disorders and Stroke, National Institutes of Health; and contract
HC38038 from the National Heart, Lung, and Blood Institute, National Institutes
of Health, Bethesda, Md.
Corresponding author and reprints: Philip A. Wolf, MD, Department
of Neurology (Neurological Epidemiology and Genetics Division), Boston University
School of Medicine, 715 Albany St, Room B-608, Boston, MA 02118-2526 (e-mail: pawolf{at}bu.edu).
From the National Heart, Lung, and Blood Institute's Framingham Study,
Framingham, Mass (Drs Seshadri, Vasan, and Kannel); the Departments of Neurology
(Drs Seshadri, Wolf, Kase, and Kelly-Hayes), Preventive Medicine and Epidemiology
(Drs Vasan and Kannel), and Medicine (Dr Wilson), Boston University School
of Medicine; Department of Epidemiology and Biostatistics, Boston University
School of Public Health (Dr Beiser), and Department of Mathematics, Boston
University (Dr D'Agostino), Boston, Mass.
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ABSTRACT
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