(Stroke. 2001;32:1120.)
© 2001 American Heart Association, Inc.
Original Contributions |
Acoustic Shadowing on B-Mode Ultrasound of the Carotid Artery Predicts Ischemic Stroke
The Atherosclerosis Risk in Communities (ARIC) Study
From the Departments of Epidemiology (K.J.H., G.H.) and Biostatistics (L.E.C.), University of North Carolina, Chapel Hill; Departments of Public Health Sciences (G.W.E.) and Neurology (C.H.T.), Wake Forest University Baptist Medical Center, Winston-Salem, NC; Division of Epidemiology, University of Minnesota, Minneapolis (A.R.F.); and National Heart, Lung, and Blood Institute, Bethesda, Md (A.R.S.).
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Abstract |
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Background and Purpose—We examined the relationship of carotid artery lesions (CALs), with and without acoustic shadowing (AS), to incident ischemic stroke events in the Atherosclerosis Risk in Communities study cohort.
Methods—The study population consisted of 13 123 men and women aged 45 to 64 years, and free of stroke, examined during 1986–1989. Over an average follow-up time of 8.0 years, 226 incident ischemic stroke cases (thromboembolic brain infarctions) were identified and classified by a standardized protocol. Three levels of exposure were defined on the basis of the presence of B-mode ultrasound–detected CALs and AS in a 3-cm segment of the carotid arteries centered at the bifurcation.
Results—The hazard ratio for ischemic stroke adjusted for age, ethnicity, and study site for women with a CAL without AS, compared with those without a CAL, was 1.92 (95% CI, 1.23, 3.01), and the hazard ratio comparing those with a CAL with AS with those without a CAL was 4.01 (95% CI, 2.28, 7.06). The corresponding hazard ratios for men were 1.99 (95% CI, 1.36, 2.91) and 2.23 (95% CI, 1.32, 3.79). Although adjustment for diabetes, hypertension medication, systolic blood pressure, left ventricular hypertrophy score, fibrinogen, von Willebrand factor antigen, and smoking status attenuated these associations somewhat, when compared with no evidence of CALs, CALs with AS remained statistically significant predictors of ischemic stroke in women, while CALs without AS were predictive of ischemic stroke in men.
Conclusions—B-mode ultrasound–detected CALs and AS serve as markers of atherosclerosis and thus are predictive of ischemic stroke.
Key Words: carotid arteries • cerebral infarction • incidence • risk factors • ultrasonography
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Introduction |
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Many clinical studies have reported relationships between carotid artery plaque characteristics and cerebrovascular events.1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Histology studies have characterized the constituents of carotid artery plaques, while B-mode ultrasound has been used for the noninvasive assessment of plaque morphology.16 17 18 19 20 21 22 23 24 25 26 A number of classification systems have been developed to describe B-mode ultrasound plaque morphology; the most commonly used is attributed to Gray-Weale et al21 and defines 4 mutually exclusive categories based on intensity (echolucent versus echogenic) and pattern (homogeneous versus heterogeneous) of reflections. Generally, studies involving the relationship of plaque composition and morphology with cerebrovascular events have focused on plaque ulceration, hemorrhage, and lipid content. In contrast, despite the recent interest in coronary calcification,27 28 the implications of calcification or mineralization within carotid artery plaques remain largely unexplored. Acoustic shadowing (AS) on B-mode ultrasound is commonly accepted as a marker of arterial mineralization or calcification26 29 30 31 32 and is defined as a reduction in amplitude of echoes caused by intervening structures with high attenuation.
We report on the relationship between carotid artery plaque, with and without mineralization, as indexed by AS, and incident ischemic cerebrovascular events in the Atherosclerosis Risk in Communities (ARIC) Study cohort.
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Subjects and Methods |
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Study Population
The ARIC Study is an ongoing population-based study of the etiology and natural history of atherosclerosis and its sequelae. The ARIC Study cohort consists of 15 792 men and women aged 45 to 64 years who were examined at baseline during 1986–1989 in 4 communities: Jackson, Mississippi; Forsyth County, North Carolina; northwest suburbs of Minneapolis, Minnesota; and Washington County, Maryland. Probability sampling was used to select ARIC cohort participants from these communities; blacks were oversampled in Forsyth County and exclusively sampled in Jackson. Response rates for the ARIC baseline examination were 66%, 46%, 67%, and 65% for Forsyth County, Jackson, Minneapolis, and Washington County, respectively. Detailed sampling procedures and the study design have been published.33 The study was approved by an institutional review committee, and subjects gave informed consent.
Baseline ARIC Examination
The baseline ARIC cohort examination consisted of a
standardized medical examination that included interviews, measurement
of blood pressure, an ECG, anthropometry, a fasting
venipuncture, and an ultrasound
examination.34 Trained
interviewers ascertained information on basic demographic
variables, medical history, medication use, and habits, including
smoking history. Medical history included information on diagnoses of
stroke, hypertension, and diabetes. In addition, participants were
asked to bring the containers of all medications they had used during
the 2 weeks before their visit.
Systolic and diastolic (fifth phase) blood pressures were measured 3 times with a random zero sphygmomanometer after the participant was at rest and seated for 5 minutes. The average of the second and third measurements was used in the analysis. Left ventricular hypertrophy (LVH) score was determined by Cornell voltage criteria for the resting ECG.35 All anthropometric measurements were obtained while the participant was fasting, wearing a scrub suit, wearing nonconstricting underwear, and had an empty bladder. Body mass index (BMI) was calculated as weight (kg) divided by the square of height (m).
Lipids, hemostatic factors, and clinical chemistries were measured at the ARIC Central Lipid Laboratory, the ARIC Central Hemostasis Laboratory, and the ARIC Central Clinical Chemistries Laboratory, respectively. Participants were asked to fast for 12 hours before their examination. A Cobas-Bio centrifugal analyzer using commercial reagents determined total cholesterol.36 HDL cholesterol level was measured after precipitation of apolipoprotein B–containing lipoproteins with magnesium chloride and dextran sulfate. The hexokinase/glucose-6-phosphate dehydrogenase method was used to measure serum glucose. Fibrinogen was measured by the thrombin-time titration method originally described by Clauss,37 and von Willebrand factor (vWF) antigen was determined by a commercially obtained ELISA kit. Automated hematology procedures were used to determine hematocrit and hemoglobin at each field center.
Prevalent stroke at baseline was defined, for exclusion, as
a positive response to the following question: "Has a doctor ever
said you had any of the following: stroke?" Prevalent diabetes was
defined as a fasting blood glucose value 
7.0 mmol/L (126 mg/dL),
a nonfasting glucose value 11.1 mmol/L (200 mg/dL), reported
physician diagnosis of diabetes, or being on diabetes
medication.
B-Mode Ultrasound
B-mode ultrasound evaluations of
atherosclerosis were completed on bilateral segments of
the extracranial carotid arteries. The Biosound 2000 IIsa was used to
obtain the ultrasound images at each of the 4 study centers. Ultrasound
tapes were read at a central Ultrasound Reading Center. Sonographers
and readers were required to complete central training and obtain
annual recertification. In addition, quality control measures included
a repeated scan of a randomly selected carotid segment in each study
participant and complete rereadings of a subset of the ultrasound
tapes.38 Detailed
descriptions of ultrasound scanning and reading
protocols34 previously have
been
published.39 40
The primary goal of ultrasound imaging was to obtain precise
measurements of the intima-media thickness (IMT) from fixed angles
rather than to achieve optimal visualization of atherosclerotic
lesions. For the ARIC exams, the carotid artery was divided into 3
segments: the 1-cm section of the common carotid immediately proximal
to the beginning of the dilation of the bifurcation, a 1-cm section of
the bifurcation immediately proximal to the tip of the flow divider,
and a 1-cm section of the internal carotid immediately distal to the
tip of the flow divider. Readers were asked to measure IMT within these
1-cm regions and to report whether they saw evidence of a lesion and
whether or not AS was present. Lesions were not defined explicitly;
readers were asked to judge the presence of a lesion on the basis of
abnormal arterial wall thickness, shape, or texture. AS was
defined as a reduction in amplitude of echoes caused by intervening
structures with high attenuation.
AS on ultrasound is commonly accepted as a marker of arterial mineralization. Although studies have not validated that AS only occurs in the presence of mineralization, the only reported nonartifactual cause of AS is mineralization.26 29 30 31 32 In addition, studies comparing histology with ultrasound findings have reported a positive correlation between mineral and the echogenicity of lesions.26 29 30 31 32
On the basis of the aforementioned definitions and information from the 6 available sites, 3 levels of carotid atherosclerosis status were defined: (1) individuals without carotid artery lesion (CAL) or AS identified at any site, (2) those with lesions identified at 1 or more sites but no evidence of AS associated with those lesions, and (3) those with 1 or more lesions characterized by AS. Because arterial mineralization does not develop in the absence of a lesion and AS can occur as an artifact of the imaging process, individuals who had evidence of AS but no record of lesions were excluded (n=86). Furthermore, among individuals "without lesions or AS at any site," those who were missing lesion and/or AS information at either the right or left bifurcation, or at any 2 or more of the 6 sites, were excluded (n=1526). In contrast, individuals "with lesions at any site" remained in the analysis regardless of missing ultrasound information at other sites.
In addition, mean far wall extracranial carotid IMT was derived on the basis of information available from the 6 carotid artery sites.40 41 42 43 Because 38% of individuals were missing IMT information at some carotid artery site, IMT was imputed for missing sites on the basis of sex- and race-specific multivariate linear models of mean IMT as a function of age, BMI, and arterial depth. On average, values were imputed for 2.3 sites per person. Additionally, mean far wall IMT was adjusted for site-specific reader differences and downward measurement drifts over the baseline visit. Detailed information on mean far wall IMT in ARIC has been previously published.40 41 42 43
Incident Events
The ARIC surveillance component provided standardized
ascertainment and classification of incident cerebrovascular events for
all cohort
members.34 44 45
Information concerning events was obtained during annual follow-up
telephone interviews, by reviewing local hospital discharge lists, and
by checking death certificates. A computer algorithm and an expert
reviewer independently classified each eligible case using criteria
adapted from the National Survey of
Stroke46 ; these criteria
included autopsy evidence, results of neuroimaging and other
diagnostic procedures, and information on combinations of
symptom type, duration, and severity. Differences in diagnosis were
adjudicated by another reviewer.
Cerebrovascular events in this analysis were restricted to definite or probable hospitalized ischemic stroke events, including thrombotic brain infarction and embolic brain infarction.34 44 45 Definite thrombotic brain infarction required either autopsy evidence of nonhemorrhagic infarct of the brain, or 1 major or 2 minor neurological symptoms lasting at least 24 hours or until death, and CT or MRI showing evidence of infarct without evidence of hemorrhage. Events were classified as probable thrombotic brain infarctions when CT or MRI evidence obtained within 48 hours of event onset was negative or nonspecific but indicated no evidence of hemorrhage, and any information obtained from a spinal tap provided further evidence that the stroke was not hemorrhagic. The distinction between lacunar and nonlacunar infarcts was only made in the case of definite thrombotic brain infarctions. Because of the small number of lacunar strokes (n=68), for purposes of these analyses thrombotic brain infarctions include lacunar and nonlacunar strokes. Definite and probable embolic brain infarction required the evidence previously mentioned for thrombotic brain infarction as well as an identifiable source of cerebral embolus. Incident cerebrovascular events were defined as events occurring after a participant’s initial entry into the ARIC cohort through the end of 1996, among those without prevalent stroke at baseline.
Statistical Analyses
Prospective analyses were performed in which
the presence of CALs, with and without AS as an index of plaque
mineralization, determined a participant’s exposure status. Two
indicator variables defined the 3 levels of carotid
atherosclerosis status, and comparisons were made
between each of these 3 levels. The outcome of interest was incident
ischemic stroke.
Covariates of interest included age, sex, ethnicity center (Forsyth County whites, Forsyth County blacks, Minneapolis whites, Jackson blacks, and Washington whites), total cholesterol, HDL cholesterol, systolic blood pressure, LVH score, fibrinogen (dichotomized at the mean: 3.013 g/L), vWF antigen, BMI, hemoglobin, hematocrit, smoking status (current, former, and never), use of hypertension medication, diabetes status, and mean far wall IMT. The linear and logistic regression methods proposed by Zhao47 were used to determine age-, sex-, and ethnicity center–adjusted baseline means and proportions for covariates at each level of carotid atherosclerosis status. The distribution of mean far wall IMT for each level of carotid atherosclerosis status was examined with the use of histograms. Furthermore, Poisson regression was used to determine adjusted sex-specific stratified rates of incident ischemic stroke for each level of carotid atherosclerosis status.
Cox proportional hazard models were used to calculate sex-specific hazard ratios for ischemic stroke in relation to carotid atherosclerosis status. Throughout the analyses, interaction terms between sex and the carotid atherosclerosis status variables were used to determine sex-specific hazard ratios within a single model. The association between carotid atherosclerosis status and incident ischemic stroke was then assessed after controlling for covariates. Age, total cholesterol, HDL cholesterol, systolic blood pressure, LVH score, BMI, hemoglobin, hematocrit, vWF antigen, and mean far wall IMT were modeled as linear in the log (hazard) scale. Models with and without the appropriate interaction terms were compared to identify interactions within each sex category between covariates and the 3 levels of carotid atherosclerosis; a P-value of 0.05 was used as a nominal value of statistically significant interaction. The assumption of proportional hazards was evaluated for each of the covariates of interest and the main exposure variable with the use of log(-log survivorship) plots and by testing differences between hazard ratios estimated for each of 3 periods of follow-up (first 3 years, next 3 years, and afterward).
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Results |
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Exclusions for these analyses included individuals with prevalent stroke or unknown stroke status at baseline (n=329), individuals without ultrasound information on lesion and/or AS (n=1526), individuals with evidence of AS without evidence of a lesion (n=86), and those of neither black nor white descent, plus blacks from either the Minneapolis or Washington County field center (n=80), those missing other key baseline variables (n=647), and 1 individual lost to follow-up. Hence, the study population for these analyses included 13 123 ARIC Study participants who had been followed an average of 8.0 years. At the end of 1996 this cohort had experienced 226 incident ischemic stroke events.
Baseline means and proportions, stratified by carotid
atherosclerosis status and adjusted for age, sex, and
ethnicity center, were calculated for covariates
(Table 1
). Of the 13 123 participants, 8464 (64%) had
no evidence of CALs, 3755 (29%) had CALs without AS, and 904 (7%) had
CALs with AS.
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The distribution of mean far wall IMT for each level of
carotid atherosclerosis status is shown in
Figure 1 (analysis was limited to the 12 756
individuals with mean far wall IMT information available). Of the 1058
individuals with a mean far wall IMT of 1.00 mm, 94.4% had
evidence of a CAL either with (or without) AS; however, only 42.4% of
the individuals with a CAL with AS and 16.6% of the individuals with a
CAL without AS had a mean far wall IMT of 1.00 mm.
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During the follow-up period, 45, 34, and 17 ischemic
stroke events occurred, respectively, in the 5085 women without
evidence of CALs, the 1762 with a CAL without AS, and the 391 with a
CAL with AS; corresponding counts for men were 48 of 3379, 62 of 1993,
and 20 of 513. Age- and ethnicity center–adjusted rates of incident
ischemic stroke for each level of carotid
atherosclerosis status stratified by sex are
illustrated in Figure 2. Rates of incident ischemic stroke were higher in those with CALs compared with those without CALs; among
those with CALs, rates of incident ischemic stroke were higher
in those with evidence of AS.
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The hazard ratio for ischemic stroke adjusted for
age and ethnicity center for women with a CAL without AS, compared with
those without a CAL, was 1.92 (95% CI, 1.23, 3.01); the hazard ratio
comparing those with a CAL with AS with those without a CAL was 4.01
(95% CI, 2.28, 7.06)
(Table 2). The corresponding hazard ratios for men were
1.99 (95% CI, 1.36, 2.91) and 2.23 (95% CI, 1.32, 3.79). Furthermore,
the global P-value for the
interaction between the carotid atherosclerosis
variables and sex was 0.25.
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Evaluation of covariates indicated that sex, age, diabetes
status, smoking status, systolic blood pressure, hypertension
medication, LVH score, fibrinogen, and vWF antigen were independent
predictors of incident ischemic stroke. Sex-specific hazard
ratios for incident ischemic stroke in relation to carotid
atherosclerosis were somewhat attenuated after
adjustment for these independent predictors of stroke and were
substantially attenuated after further adjustment for mean far wall
IMT, an established marker of subclinical
atherosclerosis
(Table 2
). After adjustment for mean far wall IMT, although
not statistically significant, women and men with a CAL without AS had
a 38% to 42% increased hazard for ischemic stroke compared
with women and men without evidence of a CAL. Additionally, women with
a CAL with AS had a 112% increased hazard for ischemic stroke
compared with women without evidence of a CAL (statistically
significant), while the corresponding hazard in men was increased only
10%.
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Discussion |
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Overview
We were interested in the ability of carotid artery atherosclerosis status, as defined by evidence of CALs and AS at 6 carotid artery sites, to predict ischemic stroke incidence. In women, CALs with AS were significantly stronger predictors of ischemic stroke than CALs without AS, whereas in men, CALs with and without AS predicted ischemic stroke equally well. Although adjustment for age, ethnicity center, diabetes, hypertension medication, systolic blood pressure, LVH score, fibrinogen, vWF antigen, and smoking status attenuated these associations somewhat, when compared with no evidence of CALs, CALs with AS remained significant predictors of ischemic stroke in women, while CALs without AS were predictive of ischemic stroke in men.
Additionally, we compared how the 3 discrete levels of
carotid atherosclerosis status defined in this report
compared with an established measure of subclinical
atherosclerosis on a continuous scale, namely, mean far
wall IMT.42 Although 94.4%
of individuals with a mean far wall IMT 1.00 mm had evidence of
a CAL (with or without AS), the majority of individuals with CALs both
with and without AS had a mean far wall IMT <1.00 mm. After
adjustment for mean far wall IMT, when compared with no evidence of
CALs, CALs without AS were not significant predictors of stroke in
women or men, while CALs with AS were significant predictors of stroke
in women but not in men.
Historically, arterial mineralization has been
accepted as a marker of advanced atherosclerosis.
However, it has not been determined whether mineralization, independent
of atherosclerosis status, plays a protective or
deleterious role relative to incident ischemic stroke events.
Arguments for a protective role include the ability of mineralization
to stabilize soft lipid plaques; arguments for a deleterious role
include loss of distensibility of the arterial wall and a
weakening at the interface between the arterial wall and
fibrous
material.48 49 50
Studies indicate that although mineralization is correlated with
overall plaque burden, individuals with similar levels of
atherosclerosis have varying levels of mineralization;
they also indicate that advanced nonmineralized lesions do occur,
indicating that lesion formation does not always trigger the process of
mineralization.51
Furthermore, a differential risk factor profile was found for those
with CALs with and without AS in an earlier study of the baseline ARIC
cohort and in
Table 1.52 Male
sex and increased total and LDL cholesterol levels were
associated only with the presence of a CAL, while smoking and
hypertension were associated both with the presence of a CAL and with
the presence of AS among those with a CAL. If mineralization is a
regulated process similar to bone formation, as current evidence
suggests, the process of arterial mineralization could be
the body’s protective response to the development of
atherosclerosis.53 54 55 56
Unfortunately, epidemiological studies are limited in their
ability to control for overall level of atherosclerosis
in assessing the effects of arterial mineralization at
specific arterial sites. Hence, it is hard to determine
whether mineralization within any individual lesion is protective or
deleterious. First, we established that CAL with AS and CAL without AS
were predictive of ischemic stroke in both women and men
(Table 2, model 1). Next, we attempted to control for the
established stroke risk factors, despite the fact that many of these
risk factors are atherosclerotic risk factors, to determine whether CAL
with AS and CAL without AS were independent predictors of
ischemic stroke
(Table 2, model 2). Finally, we attempted to control for
overall level of atherosclerosis, while assessing the
predictive value of AS within CALs, by controlling for mean far wall
IMT; however, residual confounding by atherosclerosis
level may be responsible for the elevated risk in women associated with
CAL with AS
(Table 2, model 3).
The present results are similar in both magnitude and direction to the results of a parallel analysis of carotid atherosclerosis status and incident coronary heart disease (K.J. Hunt, PhD, unpublished data, 2000). The risk factor–adjusted hazard ratios for CAL without AS compared with no CAL were similar for women and men: 1.78 and 1.59 for CHD and 1.52 and 1.77 for ischemic stroke (sex-related differences were not significant). Thus, CALs without AS predict disease similarly in women and men. However, the comparison of CALs with AS to CALs without AS is quite different: hazard ratios are 1.73 in women versus 1.04 in men for coronary heart disease (sex interaction, P<0.10) and 1.88 in women versus 0.86 in men for ischemic stroke (sex interaction, P<0.05). The sex-related differences persist for both coronary heart disease and ischemic stroke after further adjustment for IMT. Biological differences are one potential explanation for the differential associations consistently observed between women and men. For example, in postmenopausal women arterial mineralization may serve as a marker for the extent of estrogen deficiency.57
Finally, lesions in the extracranial carotid arteries may be related to cerebrovascular events either directly or primarily because they represent a measure of overall level of atherosclerosis.12 Atherosclerosis, the same process we have imaged in the carotid arteries, is almost always the pathology underlying coronary heart disease, whereas various fibrotic and other arteriosclerotic processes affect the very small intracranial arteries and arterioles responsible for many of the stroke events. Yet cerebral arteries, unlike the coronaries, are downstream from the carotid arteries. Therefore, the strength of the carotid lesion association with coronary heart disease and its similarity to the association with stroke we report here imply that the carotid lesions serve as good markers of the general extent of atherosclerosis.
Strengths and Limitations
The present study is one of the first
population-based studies to examine carotid artery calcification, as
indexed by AS, in relation to incident ischemic stroke. As end
points we included only validated definite or probable thromboembolic
brain infarctions. A participant’s physician was notified when a
residual carotid artery lumen of 
2 mm or a lesion of potential
clinical significance, in the opinion of an experienced neurologist,
was found, such as the presence of a mobile component or large
ulceration. The combined frequency of these referrals was 1.5% of all
scans.
Unfortunately, the B-mode ultrasound information available to us provided only a crude indicator of the presence or absence of mineralization in identified CALs. CAL morphology could not be further characterized on the basis of intensity (echolucent versus echogenic) and pattern (homogeneous versus heterogeneous) of reflections with the use of an accepted classification system.21 The role mineralization plays as atherosclerosis develops may be dependent on the pattern in which it is distributed throughout a lesion. New methods, such as electron beam CT, subsecond helical CT, and modified MRI have been developed with an enhanced ability to detect and quantify calcification in various arterial territories, but their use is not as widespread as that of B-mode ultrasound.
The ARIC ultrasound scanning and reading protocols were developed with the aim of measuring IMT precisely, not identifying and characterizing lesions in the carotid arteries. Nevertheless, lesions and AS identified during the ARIC examination are believed to represent true findings of lesions and AS; hence, the false-positive rate is expected to be low. By contrast, the false-negative rate may be high. Repeatability of the carotid atherosclerosis status variable has been determined on the basis of repeated ultrasound readings in a subset of the population; however, repeated information was not available on the ultrasound scanning procedure. Kappa statistics based on 974 repeat ultrasound readings were 0.65 (95% CI, 0.60, 0.69) for the carotid atherosclerosis status variable (weighted for the degree of agreement across the 3 defined levels of carotid atherosclerosis status), 0.56 (95% CI, 0.47, 0.66) for the determination of AS, and 0.55 (95% CI, 0.44, 0.66) for the determination of AS among the 297 individuals with evidence of CALs.58 59
Future Studies
Atherosclerosis typically leads to
multiple lesions and to various degrees of involvement in different
arterial beds. Hence, findings of prospective studies based
on a single arterial bed are not specific enough to
determine the mechanisms through which morphological attributes of
lesions promote or inhibit cardiovascular events.
Prospective studies that follow multiple arterial sites and
detailed morphological characteristics of lesions identified over time
could be informative.60 To
date, epidemiological studies of subclinical
atherosclerosis indicate that the presence of
atherosclerosis is largely explained by known risk
factors. However, what causes some individuals with
atherosclerosis to develop ischemic stroke,
while most silently carry the disease, remains unknown. Understanding
both the mechanism(s) through which arterial mineralization
develops and how the morphology of a lesion influences the likelihood
of an ischemic event may provide insight into who will sustain
strokes.
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Acknowledgments |
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This study was supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55017, N01-HC-55018, N01-HC-55019, N01-HC-55020, and N01-HC-55021. The research and writing of the manuscript were conducted under the sponsorship of a National Research Service Award (contract 5-T32-HL07055) for the National Heart, Lung, and Blood Institute. The authors thank the staff and participants in the ARIC Study for their important contributions.
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Footnotes |
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Reprint requests to Gerardo Heiss, MD, PhD, Department of Epidemiology, CVD Program, University of North Carolina at Chapel Hill, 137 E Franklin St, Bank of America, Suite 306, Chapel Hill, NC 27514.
Received September 5, 2000; revision received November 23, 2000; accepted January 18, 2001.
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