© 1996 American Heart Association, Inc.
Articles |
Relation of Intima-Media Thickness to Atherosclerotic Plaques in Carotid Arteries
The Vascular Aging (EVA) Study
From INSERM U258, Hôpital Broussais (C.B.-K., D.C., P.D.), and Centre Diagnostic et de Prévention Neurovasculaire (P.-J.T.), Paris; INSERM U360, Paris (C.B.); and Centre d'examen EVA-INSERM, Nantes (C.L., F.M.), France.
Correspondence to Claire Bonithon-Kopp, MD, PhD, INSERM U258, Hôpital Broussais, 96 rue Didot, 75674 Paris cedex 14, France.
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Abstract |
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Abstract This study examined the relation between arterial wall thickness and local atherosclerosis in the carotid arteries (CAs) and their specific risk factors. B-mode ultrasonography of the CAs was performed in a cohort of 516 men and 756 women aged 59 to 71 years who had been recruited for the European Vascular Aging Study. Ultrasound examination included measurement of intima-media thickness of the common CA (CCA) and the sites of plaque in the internal CA and bifurcations. Significant associations between increases in CCA intima-media thickness and both the presence and severity of atherosclerotic plaque were found in men and women. Examination of specific risk factors for increases in CCA intima-media thickness in the presence of plaque showed that, after adjustment for sex, both ultrasound measurements were independently related to age, body mass index, hypertension, and ever smoking (versus never smoking). Diabetes and current smoking were associated with intima-media thickness only, whereas hypercholesterolemia was related to plaque only. However, when subjects who were taking lipid-lowering drugs were excluded, lipoproteins and apolipoproteins were more consistently related to intima-media thickness than to plaque. In subjects free from any antihypertensive treatment, both intima-media thickness and plaques were independently associated with systolic blood pressure. After adjustment for sex and other risk factors, the odds ratio for having at least one plaque associated with a 0.10-mm increase in CCA intima-media thickness was 1.18 (95% confidence interval, 1.05 to 1.32). In this relatively aged population, increases in intima-media thickness as measured in the CCAs were clearly related to locally detected atherosclerosis and known risk factors for atherosclerosis. Longitudinal studies are needed to clarify the role of arterial wall thickening in the atherosclerotic process.
Key Words: carotid arteries • ultrasound • intima-media thickness • plaque • epidemiology
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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The quantitative assessment of atherosclerosis in populations is essential to a better understanding of the pathophysiology of this disease and to the consequent development of optimal disease prevention strategies. In recent years, ultrasonographic methods capable of visualizing the arterial wall have been used increasingly to monitor the early stages of the atherosclerotic process, mainly in the CAs. Most epidemiological and clinical studies in progress are based on measurement of the CA intima-media thickness, a method first described by Pignoli et al.1 Thickening of the intima-media at any local site is generally considered to be an early marker of generalized atherosclerosis because such thickening has been associated with an unfavorable cardiovascular risk profile,2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 other localizations of atherosclerosis,20 21 22 and an increased risk of myocardial infarction.23 However, the pathophysiological significance of arterial wall thickening with regard to the atherosclerotic process is questionable. First, interpretation of results from ongoing studies is largely dependent on the methodology that is used to assess intima-media thickness, especially at the site of measurement and whether discrete atherosclerotic plaques are included or excluded from measurement. Second, because B-mode ultrasonography is unable to differentiate the intimal from the medial layer, the anatomic structure(s) involved in arterial wall thickening cannot be determined.
An indirect way of assessing the early stages of atherosclerosis consists of examining the relationships between intima-media thickening and confirmed plaques in the same arterial system. The major aims of the ultrasonographic study presented in this article were to relate intima-media thickness (as assessed in the CCA) to the presence of atherosclerotic plaques in the CB and the ICA and to examine whether some risk factors might be specifically associated with each type of lesion. Data in the present cross-sectional analyses were collected as part of a large, ongoing, longitudinal study on cognitive and vascular aging (the EVA Study).
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Methods |
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The EVA Study is a longitudinal, 4-year investigation of volunteers aged 59 to 71 years who were recruited from the electoral rolls of the city of Nantes (western France) and, to a lesser extent, via information campaigns. Whenever a subject was recruited, his or her spouse was always asked to participate in the study if she or he was in the correct age range. During the baseline visit, which occurred between June 1991 and July 1993, 1389 subjects were recruited and high-resolution B-mode ultrasound examinations of the CAs were performed in 1384 participants. The study protocol was approved by the Comité d'éthique du Centre Hospitalier Universitaire de Kremlin-Bicêtre, and written informed consent was obtained from all participants.
Ultrasonography
Ultrasound examinations were performed by
four sonographers who
used the Aloka SSD-650 at a transducer frequency of 7.5 MHz. This
system provides an axial resolution of 0.30 mm. Computer-assisted
acquisition, processing, and storage of B-mode images were performed
with software that had been specially designed for longitudinal
studies.24
The protocol involved scanning of the CCAs, the
CBs, and the origins
(first 2 cm) of the ICAs. Both the near and far walls of these
arterial segments were scanned longitudinally and
transversely to assess the occurrence of plaques, which were defined as
localized echo structures that encroached into the vessel lumen and for
which the distance between the media-adventitia interface and the
lesion surface facing the lumen was 
1 mm. Wherever a plaque was found
to be present, the examination focused on that arterial
site. Optimal "frozen" images (one longitudinal and one
transverse view) of the plaque along its greatest thickness were
selected by the sonographer and stored on an optical disk. Where
several plaques were found to be present on the same
arterial segment (ie, CCA or CB-ICA), the number of plaques
was recorded and examination was focused on the plaque that showed
the greatest encroachment into the lumen. When no plaques were
detected, two optimal frames of the CB (one longitudinal and one
transverse) were selected and stored on the optical disk.
Moreover, the study protocol also included systematic recording of longitudinal and transverse images of the CCAs. On a longitudinal B-mode image of the CCA, the far wall appears as two bright, parallel lines separated by a hypoechoic space. The inner line on the far wall image arises from the lumen-intima interface, whereas the outer line arises from the media-adventitia interface.Thus, the distance between the media-adventitia interface and the lumen-intima interface represents the intima-media thickness.1 When an optimal longitudinal image encompassing the middle and distal CCA was obtained, the image was frozen and stored on an optical disk, together with the corresponding transverse view.
All CA measurements were performed by the sonographer at the time of examination. The intima-media thickness on the far wall of the CCA was measured by using an automated edge-detection algorithm based on significant changes in density of a section between the lumen and subadventitial structures perpendicular to the vessel wall.24 Two measurements on longitudinal views of both right and left CCAs were made at a site with no discrete plaques. Thus, the mean of four measurements was generally used to define the CCA intima-media thickness. CCA intima-media thickness measurements (one measurement on each side) were also made on transverse views at the level of the longitudinal measurements.
Quantification of CA
plaques was performed by measuring the
intima-media thickness at the site of maximum lumen encroachment
perpendicular to the vessel wall. Our computer software did not include
automatic detection of interfaces at the plaque site. However, use of
the computer assisted in the identification of interfaces and placement
of electronic calipers by examining the inflections on the density
profile curve at the plaque site. No measurements were made in the CB
or ICAs when plaques were absent. A semiquantitative scale was used to
assess the extent and severity of plaques, which were graded as
follows: no plaque; unilateral plaque with a thickness 
2 mm, as
measured on a longitudinal view; unilateral plaque with a thickness >2
mm or bilateral plaques, including at least one with a thickness 2
mm; and bilateral plaques, both with a thickness >2 mm.
In a few cases (5% of participants), at least one CCA measurement was missing due to poor definition of interfaces or the presence of multiple plaques at that arterial site. Comparison of subjects with at least one missing value with subjects for whom four measurements of CCA intima-media thickness were available did not reveal any differences in age, sex, or prevalence of plaques. However, BMI was higher in subjects with missing values than in those with all four values (mean±SD, 27.1±4.2 versus 25.4±3.8 kg/m2; P<.001).
For quality-control assessment, random subsamples
of images of both
CCAs and CB-ICAs recorded by the four sonographers were sent to a
single expert sonographer (P.-J.T., Paris, France) several weeks later
and processed by the same computer software. Optical disks did not
contain any information on the results of measurements obtained at the
EVA center. The second reader had no choice of frames to read (optimal
frames were preselected by the EVA sonographers) but was required to
determine the optimal site for measuring intima-media thickness at
the CCAs and at the plaque site. Mean absolute differences and
correlation coefficients between repeated readings are
presented in Table 1
. Correlation coefficients
between repeated readings were greater for the CCA intima-media
thickness than for the intima-media thickness at the plaque site
and, for both ultrasound measurements, greater for longitudinal than
transverse views. Thus, only longitudinal measurements were used in
subsequent analyses.
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In previous work, we showed that both the interobserver and intraobserver variabilities of the CCA intima-media thickness that were associated with the scanning procedure were substantially reduced after using the repositioning functions of the Eurequa software. The aforementioned variabilities (expressed as absolute differences and correlation coefficients) were 0.10 mm, r=.58 and 0.10 mm, r=.62, respectively, with standard procedures, whereas corresponding values obtained with repositioning procedures were 0.07 mm, r=.71 and 0.06 mm, r=.77, respectively.24
Ultrasound examinations performed early in the study were considered unreliable and were excluded from analysis (n=77). Because our primary aim was to examine the relation between the intima-media thickness of the CCAs and the presence of plaques, subjects for whom longitudinal measurement of the CCA intima-media thickness was unavailable (n=9) were excluded from the present analysis. Subjects with discrete plaques in the CCAs (n=26) were also excluded to avoid any biases in measurements of CCA intima-media thickness. Thus, the final study sample included 1272 subjects (516 men and 756 women).
Medical History
All participants answered a standardized
questionnaire, which
requested information about demographic background, occupation, medical
history, drug use, and personal habits such as cigarette use and
alcohol consumption. With respect to smoking behavior, subjects were
classified as either current smokers versus nonsmokers or as ever
smokers versus never smokers. Alcohol consumption was determined from
each subject's estimate of the average amount of alcoholic beverages
ingested weekly and expressed in milliliters of alcohol per day. Two
independent measurements of SBP and DBPs were made with a digital
electronic tensiometer (SP9 Spengler) after a 10-minute rest, and the
means were used for analysis. Subjects with an SBP 160 mm Hg
or a DBP 95 mm Hg or who were taking antihypertensive medication were
considered hypertensive (n=408).
Hypercholesterolemia was defined as a total
cholesterol level 7.2 mmol/L (2.80 g/L) or use of
lipid-lowering drugs (n=505). Subjects who reported a history of
diabetes or use of antidiabetic drugs or those who had a fasting plasma
glucose level 7.8 mmol/L (1.40 g/L) were considered diabetic
(n=67).
BMI was computed as weight (in kilograms) divided by height squared (in
meters squared).
Laboratory Methods
Blood samples were drawn between 8 and 9
AM after a
12-hour fast. Total cholesterol and
triglyceride assays were performed by using the PAP
enzymatic cholesterol kit (Reference 61227) and the PAP
enzymatic triglyceride kit (Reference 759350),
respectively, supplied by Biomérieux. Glucose levels were
determined by the enzymatic glucose oxidase method (Reference 61274,
Boehringer). HDL cholesterol was measured
enzymatically after precipitation of apo B–containing lipoproteins
with phosphotungstic acid and Mg2+ (precipitant
Reference 543004, Boehringer). LDL cholesterol was
computed with the Friedewald formula.25 Apo A-I, apo B,
and Lp(a) were determined with an immunonephelometric fixed-time
method on a Behring nephelometric analyzer (Behring).
Antibodies, standards, and controls were supplied by Behring for apo
A-I and apo B and by ImmunoFrance for lipoprotein assays. All
determinations were made daily except those for Lp(a), which was stored
for no longer than 3 days at 4°C until assay.
Statistical Analysis
Standard procedures from Statistical
Analysis Systems
were used for univariate and multivariate
analyses. Descriptive data on CCA intima-media thickness
and plaques were listed separately for men and women. Linear trends for
increasing prevalence of plaque as a function of quintile of
intima-media thickness were tested by logistic regression. ANOVA
was used to examine the association between intima-media thickness
and the severity of plaque. Because these relations were similar in men
and women, subsequent analyses were performed for the entire
population, with systematic adjustment for sex. Independent
associations of intima-media thickness and plaques with each risk
factor were tested by logistic or linear regression, depending on
whether the dependent variable (risk factor) was categorical or
continuous. Although statistical testing was performed with
intima-media thickness as a continuous variable, for more
clarity, results are presented as means or proportions of each
risk factor according to the presence or absence of plaques for various
intima-media thicknesses. Intima-media thickness was divided
into approximate tertiles to obtain a sufficient number of subjects in
each category. Last, the association between intima-media thickness
(a continuous variable) and the presence of plaque, independent of
other risk factors, was examined in a multiple logistic regression
model in which intima-media thickness and other risk factors were
introduced as independent variables. A logarithmic transformation
of triglyceride values was done before statistical testing.
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Results |
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Univariate Association Between Intima-Media Thickness of the CCA and Plaques of the CB-ICA
The prevalence of atheromatous plaque in the CB or ICA was higher in men than women (25.6% versus 16.5%, P<.001). Similarly, the mean intima-media thickness of the CCA was greater in men than women (0.69±0.14 mm versus 0.65±0.11 mm, P<.001). The prevalence of plaque increased from the lowest to the highest quintile of intima-media thickness in both sexes (tests of linear trend: P<.006 in men and P<.001 in women; Figure
). The mean
intima-media thickness in subjects without plaques was lower than
in subjects with plaques (Table 2). Moreover, there was
an increasing linear trend for intima-media thickness with the
severity of plaque in both men (P<.03) and women
(P<.05).
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Independent Associations of Both Ultrasound Measurements With
Cardiovascular Risk Factors
Sex-adjusted proportions or means of
various risk factors
according to both the presence of plaque and the tertile of
intima-media thickness are shown in Tables 3 and
4. As shown in
Table 3, both intima-media thickness and the
presence of plaque were strongly related to age and hypertension and
weakly associated with ever smoking. Diabetes and BMI showed clear
associations with intima-media thickness but no or only a marginal
association with the presence of plaque.
Hypercholesterolemia was more frequent in
subjects with plaques than in those without, but this association was
more pronounced in subjects with a lower intima-media
thickness (significance of interaction for intima-media
thicknessxplaques, P<.02). No significant association was
found between alcohol consumption and either intima-media thickness
or the presence of plaque.
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Because many subjects were receiving
treatment for hypertension,
hypercholesterolemia, or diabetes,
sex-adjusted associations between ultrasound measurements and
BP levels and biological factors were examined in specific subgroups
who were not being so treated (Table 4
). In subjects who
were not taking lipid-lowering drugs, intima-media thickness
was positively related to LDL cholesterol,
triglycerides, and apo B and negatively to HDL
cholesterol and apo A-I, whereas the presence of plaque was
related to triglycerides and apo B only. Intima-media
thickness and the presence of plaque were not independently associated
with total cholesterol and Lp(a). Adjustment for age, BMI,
ever smoking, hypertension, and diabetes had relatively little effect
on the independent associations between ultrasound measurements and
lipoproteins or apolipoproteins. In subjects who were not being treated
for hypertension, SBP was significantly associated with both
intima-media thickness and the presence of plaque, but DBP was
associated with intima-media thickness only and this latter
association disappeared after adjustment for other risk factors. After
exclusion of subjects who were receiving antidiabetic drugs, neither
intima-media thickness nor the presence of plaque was related to
blood glucose.
Adjusted Associations Between Plaques of the CB-ICA and
Intima-Media Thickness of the CCA
Odds ratios for having a plaque
associated with a 0.10-mm increase
in intima-media thickness and other risk factors are
presented in Table 5. Even after adjustment for
sex, age, BMI, hypertension,
hypercholesterolemia, diabetes, and ever
smoking, the odds ratio for having a plaque associated with a 0.10-mm
increase in intima-media thickness remained significant
(P<.004). Other independent risk factors for the presence
of plaque were age (P<.003), hypertension
(P<.0001), and at borderline significance
hypercholesterolemia (P<.08) and
ever smoking (P<.09). After exclusion of subjects who were
being treated for hypertension,
hypercholesterolemia, or diabetes, substitution
of SBP, HDL and LDL cholesterol, and blood glucose levels
for hypertension, hypercholesterolemia, and
diabetes, respectively, yielded very close results. The odds ratio for
a 0.10-mm increase in intima-media thickness in the full model was
1.22 (95% confidence interval, 1.03 to 1.44; P<.02;
n=697).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The purpose of the present population-based study was to examine the relation between CA intima-media thickness and ultrasonographically confirmed atherosclerosis by using a methodological approach that clearly differentiates both types of lesions. Ultrasonographically defined intima-media thickening is an ambiguous term that may refer to diffuse thickening of the arterial wall, eccentric thickening, or even confirmed atherosclerosis, according to the methodology used for its assessment. There is no standardized way to measure intima-media thickness by ultrasonography. Although near and far walls can be imaged, far-wall measurements are generally considered more valid than the former.26 Some studies have combined measurements of several arterial segments, whereas other studies have focused on the CCA segment.
There are large variations in intima-media thickness according to the arterial site where it is measured. The greater intima-media thickness and more pronounced right skewness of the distribution curve for the ICA and CB relative to the CCA may be partially explained by the higher frequency of plaque at these sites.21 27 Despite the lesser atherosclerotic involvement in the CCA, it has increasingly become the "site of choice" for measurement of intima-media thickness because it is far easier to image reliably than other segments.28 Measurements are generally made in the thickest part of the distal 10 mm of the CCA whether a focal lesion is present or not. This procedure may explain the higher mean values and maximum values in other large population studies5 12 21 27 compared with ours. For example, in the study of Salonen and Salonen,5 the mean±SD intima-media thickness in men aged 60 years was 1.15±0.49 mm, with maximum and minimum values of 4.09 and 0.54 mm, respectively. In the ARIC Study,27 mean left CCA intima-media thickness for 65-year-old subjects was 0.80 mm in men and 0.73 mm in women, whereas the 5th and 95th percentiles were 0.50 and 1.30 mm in men and 0.47 and 1.04 mm in women, respectively, with maximum values >3 mm in both sexes. Values exceeding 3 or 4 mm probably reflect eccentric thickening or atherosclerotic plaques. In the present study, intima-media thickness was measured in the midportion of the CCA on a segment free of any focal atherosclerotic lesion, and the mean rather than the maximum value of four measurements was used. This straight segment was chosen because irregular or curved segments as well as bifurcations and branching zones are subject to hemodynamic turbulence and altered tensile stress that may lead to physiological changes in wall thickness.29 Because of possible alteration of the arterial wall in the vicinity of a plaque, we further excluded those few subjects who had plaques in the CCA. Thus, a greater intima-media thickness was likely to represent diffuse thickening of the arterial wall rather than confirmed atherosclerosis or eccentric thickening. However, other aspects of our study should be considered as possible explanations for the low values of CCA intima-media thickness observed in this elderly population of volunteers. First, selective survival as well as self-selection biases leading to an underrepresentation of diseased persons cannot be ruled out. Second, an important methodological limitation of this study lies in our inability to synchronize and therefore standardize the image recording with respect to the stage of the cardiac cycle. There is a significant decrease in intima-media thickness at peak systole that may partially account for the low mean values of intima-media thickness and that may lead to a decrease in statistical power.
The significance of an ultrasonographically defined intima-media
thickening with regard to the atherosclerotic process is unclear and
partially results from the technical inability to differentiate intima
from media. The possible heterogeneity of the subjects
with respect to altered anatomic structure may obscure the
relationships with risk factors and atherosclerotic disease. Despite
methodological differences with previous studies, the associations that
we found between intima-media thickness and known risk factors for
atherosclerosis, such as age, hypertension, lipid
alterations, smoking habits, and diabetes, are in good agreement with
those already
described.2 3 4 5 6 7 9 10 11 12 14 15 16 17 18 19 21
We extended
previous findings by examining whether intima-media thickness and
atherosclerotic plaques were independently related to these risk
factors. In our population, age and hypertension (or high SBP) appeared
to be the strongest determinants of the presence of plaque and
increased intima-media thickness. In another elderly population,
SBP was also more strongly correlated with maximum CCA intima-media
thickness than were lipoproteins.21 On the other hand,
hypercholesterolemia, defined by high levels of
total cholesterol and/or use of lipid-lowering drugs,
was clearly related to the presence of plaques but did not show any
association with increased intima-media thickness. This pattern of
associations contrasts with the inverse one in subjects who were not
being treated with lipid-lowering drugs. In these latter subjects,
intima-media thickness was positively related to LDL
cholesterol, triglycerides, and apo B but
negatively to HDL cholesterol and apo A-I, whereas the
presence of plaque was only weakly related to apo B and
triglycerides. An explanation may be that treatment with
lipid-lowering drugs reflects long-lasting lipid abnormalities,
which are probably necessary for the development of atherosclerotic
plaques. On the other hand, arterial wall thickness might
be more rapidly sensitive to lipid changes. A recent study showed that
increased CCA intima-media thickness was detectable from the age of
6 years in hypercholesterolemic
children.30 However, some limitations of our study also
need to be considered. First, detection of atherosclerotic plaques in
the CB and ICA and assessment of their intima-media thicknesses are
less reliable than quantitative evaluation of CCA intima-media
thickness. The greater variability in intima-media thickness
measurements at the plaque site is mainly due to the fact that they are
based on a single measurement (versus four measurements for the CCA)
and that the media-adventitia interface may be more difficult to
visualize at the site of a discrete plaque. Thus, underestimation of
the true relationships with risk factors might be greater for plaques
than for the CCA intima-media thickness. Furthermore, our liberal
definition of plaque implies that very small encroachments into the
lumen were considered as plaques, and this may contribute to the
weakness of the associations with risk factors. In fact,
reanalysis of our data using a more restrictive definition
of plaque thickness (1.5 mm) had no impact on our results.
This study suggests that, besides the primary role of aging and
hypertension, some atherogenic stimuli may be involved in
intima-media thickening. It does not necessarily imply that
intima-media thickening is atherosclerosis. Both
intimal and medial thickening have been considered as
nonatherosclerotic, adaptive responses to aging or mechanical stresses
by some
authors.29 31 32 33 34
Other factors potentially
involved in the growth or proliferation of smooth muscle cells or in
the synthesis of extracellular matrix might contribute to
arterial wall thickening. Thus, a recent report from the
EVA Study has suggested an association between high plasma
angiotensin-converting-enzyme activity and CCA
intima-media thickening, especially in subjects who are at low risk
for atherosclerosis.35 On the other hand,
the present analysis showed that increased intima-media
thickness was related to both the presence and the severity of plaques
in the CB and ICA, in accordance with previous
reports.17 36 37 38
Interestingly, despite the relative
weakness of this association, it was only partially explained by known
cardiovascular risk factors and may in fact be due to
measurement errors. Other factors, as yet unidentified, may also
account for the apparent association between the presence of plaque and
intima-media thickness. Alternatively, the aforementioned
association may support the hypothesis of a
pathophysiological link between them. Several
cross-sectional studies have shown that carotid plaques and, a
fortiori, stenoses occurred in older subjects than in those who
have only intima-media thickening,3 4 19
suggesting
that wall thickening may precede plaque formation. In a previous
longitudinal study using less sophisticated ultrasound methods, we
found a twofold increased risk for developing plaques in a 2-year
interval among middle-aged women whose baseline CCA
intima-media thickness was 0.75 mm.39 When the same
cutoff point was applied in the present study, the odds ratio for
having a plaque was strikingly similar (ie, 1.83 in men and 1.70 in
women). The sensitivity and specificity of intima-media thickening
(defined as mentioned above) in the detection of plaques were 29.3%
and 82.5%, respectively. This may be viewed as an indication that
arterial wall thickening is a preliminary but not
sufficient condition for plaque development. Because confirmed
atherosclerosis rarely occurs in the CCA except in
late, end-stage disease, it could be hypothesized that
arterial wall thickening in straight arteries reflects, at
least partially, thickening in bifurcations and branch zones and in
some circumstances that remain to be elucidated might represent
an early step in the development of
atherosclerosis.
In conclusion, this study showed that increased intima-media thickness measured in the CCAs was related to atherosclerosis detected in the CBs and the ICAs. Both longitudinal epidemiological studies and anatomic studies are needed to better understand the natural history of intima-media thickening and the respective roles played by early intimal and medial changes in the genesis of atherosclerotic lesions.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The EVA Study is organized under an agreement between INSERM and the Merck, Sharp and Dohme–Chibret Company. We thank ultrasound physicians Drs J.-M. Fève, C. Magne, and I. Ruelland. We acknowledge C. Delanoe, S. Bachelier, and N. Pajot for their secretarial and technical assistance.
Received January 11, 1995; accepted October 16, 1995.
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