(Circulation. 1995;92:2127-2134.)
© 1995 American Heart Association, Inc.
Articles |
Carotid Intima-Media Thickness Is Only Weakly Correlated With the Extent and Severity of Coronary Artery Disease
From the Department of Cardiology (M.R.A., A.N., A.K., J.R., R.M., B.P.B., S.B.F., D.S.C.), Royal Prince Alfred Hospital; The Heart Research Institute (J.R., R.M., D.S.C.); and The NHMRC Clinical Trials Centre (A.K.), University of Sydney (Australia).
Correspondence to Dr David S. Celermajer, Department of Cardiology, Royal Prince Alfred Hospital, Missenden Rd, Camperdown 2050, Sydney, Australia.
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Abstract |
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Background Intima-media thickness (IMT) of the common carotid artery (CCA), measured with external vascular ultrasound, has been widely used in clinical trials as a surrogate marker for coronary atherosclerosis. Despite this, the degree of correlation between carotid IMT and the extent and severity of coronary artery disease (CAD) is not known.
Methods and Results Common carotid IMT was measured by ultrasound
in 350 consecutive subjects of age 60±10 years (range, 30 to 85 years)
on the day of coronary angiography. Carotid mean IMT was
0.83±0.20 mm (range, 0.43 to 1.80 mm), and maximum IMT was 1.04±0.27
mm (range, 0.49 to 2.19 mm). Coronary angiograms were
analyzed by independent observers for disease severity (number
of vessels with 
70% stenosis), extent score, and a modified
Gensini score. Mean carotid IMT was weakly but significantly correlated
with CAD severity (r=.26), extent (r=.23), and
modified Gensini score (r=.29, P<.0001 for all
correlations). Carotid IMT was not clinically useful, however, because
it was not specific or sensitive enough to identify patients with or
without significant CAD. Increasing age, male sex, and presence of
diabetes were all associated with a significantly (P<.01)
higher CAD score than the average for any level of carotid IMT,
suggesting differential effects of these traditional risk factors on
the coronary and common carotid arteries.
Conclusions Although carotid IMT is significantly correlated with extent and severity of CAD, the relationship is weak. This relatively poor correlation (r2<.10) should be considered in the interpretation of clinical trials that use carotid IMT as a surrogate end point for coronary atherosclerosis.
Key Words: arteries • ultrasonics • atherosclerosis
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Introduction |
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Noninvasive measurements that relate to the extent and severity of coronary atherosclerosis have long been sought for clinical screening of patients with chest pain syndromes and for use in clinical trials.1 B-mode ultrasound of the carotid circulation has been proposed as a useful measure,2 3 because autopsy studies have shown that the extent of extracranial carotid and coronary atherosclerosis is correlated, with Pearson's correlation coefficient values of r=.4 to .6.4 5 6 B-mode quantification of carotid plaque is inaccurate, however, with high interoperator variability.7 In contrast, B-mode ultrasound of the far wall of the CCA, an area not usually involved by plaque formation, is quick, painless, noninvasive, accurate, and reproducible.8 9 10 Furthermore, common carotid IMT is correlated with traditional vascular risk factors11 12 13 14 ; is higher in the presence of aortic, femoral, or carotid plaque5 ; and may predict the likelihood of acute coronary events.2 For these reasons, carotid IMT has been suggested as a surrogate marker for coronary atherosclerosis for use in clinical trials.1 2 10 15 16 More than 40 000 patients have been or are involved in more than 20 clinical trials and observational studies with carotid IMT as a primary end point.15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 Despite this, the precise degree of correlation between carotid IMT and the extent and severity of CAD has not been well documented.
We therefore measured carotid IMT and angiographic extent and severity of CAD in 350 consecutive patients undergoing elective coronary angiography to assess the strength of any relation between IMT and CAD scores and to analyze the different effects of traditional vascular risk factors on these measures of arterial disease in the common carotid and coronary circulations.
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Methods |
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Subjects
We studied 350 consecutive eligible patients who were undergoing elective coronary angiography at our institution. Subjects were excluded if they had a past history of coronary artery bypass graft surgery, coronary angioplasty, carotid surgery, or cerebrovascular accident. The indications for coronary angiography were stable angina pectoris in 146 (42%), unstable angina pectoris in 94 (27%), prognostic reasons after myocardial infarction in 32 (9%), important valvular disease in 32 (9%), atypical chest pain in 22 (6%), and other reasons in 24 patients (7%). Informed consent was obtained from all patients, and the study was approved by the institutional ethics committee.
Study Design
Before cardiac catheterization, patients were
administered a questionnaire to assess symptoms, risk factor profile,
and current medical therapy. Carotid ultrasound and coronary
angiography were performed on the same day.
Biochemical Studies
In 85 subjects, a fasting blood sample was collected at the
start of cardiac catheterization for detailed lipid
analysis. Total cholesterol and
triglyceride levels were determined enzymatically with a
Hitachi 747 autoanalyzer. HDL cholesterol was
measured after dextran sulfate magnesium precipitation. LDL was
calculated with Friedewald's method.37 Lipoprotein(a) was
measured with an immunoradiometric assay (Pharmacia).
Definition of Risk Factors
Hypercholesterolemia was defined
as total plasma cholesterol of >210 mg/dL in the previous
12 months or documented hypercholesterolemia
requiring lipid-lowering drug therapy. Hypertension was defined as
documented elevation of blood pressure requiring drug therapy or two
elevated readings diagnosed as hypertension by a physician. Smoking
status was recorded as never smoked or current or former cigarette
smoking, and the lifetime number of pack-years smoked was estimated
from the patient's history. A family history of premature
coronary disease was defined as a history of angina, myocardial
infarction, coronary angioplasty, or coronary artery
bypass graft surgery in a first-degree relative less than 60 years
old. Diabetes was defined as present if it had been previously
diagnosed by a physician.
Ultrasound Imaging
B-mode ultrasound examinations were performed with a 128 XP/10
mainframe (Acuson) with a 7.0-MHz linear array transducer. All scans
were performed by the same operator, who was not involved in image
analysis. The scanning protocol involved studying the right and
left CCAs in the first 100 subjects. Because the results from these
first 100 subjects were similar with left or mean right and left IMT in
terms of correlation with coronary disease, only the left CCA
was scanned in the next 250 subjects. The scanning method used was
similar to that of Salonen and Salonen10 and Blankenhorn
et al,13 who used images of the far wall of the distal 10
mm of the left or right CCA, respectively. Three scanning angles were
used in each case: anterior oblique, lateral, and posterior oblique.
The image was focused on the posterior (far) wall, and images of the
distal 10 mm of the CCA were recorded from the angle showing the
greatest distance between the lumen-intima interface and the
media-adventitia interface (IMT), as described
previously.10 Log compression and magnification settings
were kept constant throughout the study; however, gain settings were
changed between patients. In 35 cases, scans were also obtained on the
same day by a second independent operator to assess interoperator
variability. All scans were recorded on super-VHS videotape for
later off-line analysis.
Ultrasound Analysis
The distance between the characteristic echoes from the
lumen-intima and the media-adventitia interfaces was taken as
the measure of IMT, as described by Pignoli et al38 and
others.10 13 Scans from all 350 patients were of
sufficient quality to be analyzed with a computerized
edge-detection system. Two end-diastolic frames (as
judged from the simultaneous ECG recording) were
selected by each observer, digitized, and analyzed for mean and
maximum IMT, and the average reading from these two frames was
calculated. In each case, the observer was blinded to the subject's
identity and the results of the coronary angiogram.
Analysis was carried out on two occasions only: the first after
100 patients had been scanned, and then at the end of the study. There
was no evidence of "observer drift" over time, with no
significant correlation between IMT normalized for coronary
disease score and case number (1 through 350) (r=-.04,
P=.37).
Images were digitized with a commercially available video frame-grabber with an eight-bit gray scale (Video Associates Labs) and a 486DX2/66 computer interfaced with a Panasonic AG7350 super-VHS videocassette recorder. Edge-detection software was developed in-house. The software program automatically identifies intimal and medial points from the region of interest of the far wall of the CCA, as defined by the observer. It requires the observer to select a region of interest, and the program detects the intima and the back of the media as the points of most rapid change of pixel value on either side of the media. The program uses a statistical algorithm to automatically reject points that appear to be erroneous but allows the observer to modify this selection if necessary by including rejected points or excluding selected points (otherwise, it does not permit the observer to modify the selection). Each point corresponds to a pixel. The mean IMT is calculated from the nonrejected points, converting the value in pixels to millimeters with a calibration factor derived from digitized calibration marks recorded on the original image. A typical analysis would be made on 150 to 200 points per 10 mm horizontally, with 15 to 20 pixels representing 1 mm of intimal thickness. Automated computerized edge-tracking of this type has been shown to reduce measurement variability twofold to fourfold compared with manual methods.39 In 20 randomly selected cases, we assessed the difference between mean IMT measured by computerized edge detection and mean IMT calculated as the average of 10 measurements made manually with electronic calipers placed at 1-mm intervals. The difference between the two measurements of IMT was 0.01±0.01 mm (range, 0 to 0.04 mm). In addition, images from 100 subjects were analyzed with the computerized program by a second independent observer to assess interobserver variability.
Coronary Angiography and Scoring
All patients were catheterized percutaneously
via the femoral vessels, with standard Judkins technique, or via the
right brachial artery, with the Sones technique. Angiographic scoring
was performed by observers who were blinded to the carotid IMT scores
and whose only involvement in the study was scoring the angiograms.
Coronary angiograms were interpreted visually, were always
analyzed in two orthogonal views, and were scored by three
techniques, as follows.
With the severity score, the number of major vessels with luminal
stenoses 50% or 70% (lumen diameter reduction) are scored
from 0 to 3 (for right, left anterior descending, and circumflex
arteries). Left main stenosis 70% was scored as
one-vessel disease if there was no lesion 70% in other vessels
(n=4).
The modified Gensini score has been described and validated previously.40 The most severe stenosis in each of eight coronary segments was graded from 1 to 4 (1, 1% to 49% lumen diameter reduction; 2, 50% to 74% stenosis; 3, 75% to 99% stenosis; 4, 100% occlusion) to give a total score of between 0 and 32. This score therefore gives a measure of both severity and extent of coronary atherosclerosis.
The extent score was developed to indicate the percentage (0% to 100%) of the coronary surface involved by atheroma, and it is described in detail elsewhere.41 The proportion of each vessel involved by atheroma, as identified by lumen irregularity, was multiplied by a factor for each vessel: left main, 5; left anterior descending, 20; main diagonal branch 10; first septal perforator, 5; left circumflex, obtuse marginal, and posterolateral vessels, 10; right coronary, 20; and main posterior descending branch, 10. When the major lateral wall branch was a large obtuse marginal or intermediate vessel, the factor used was 20, with a factor of 10 for the left circumflex. When a vessel was occluded and the distal vessel was not visualized, the proportion of the vessel not visualized was given the mean score of the remaining vessels. The scores for each of the vessels were summed to give a total score, with a maximum possible value of 100 (ie, the percentage of the total coronary intimal surface involved by atheroma).
The severity and modified Gensini scores were based on the consensus
opinion of two experienced angiographers. An independent observer then
scored CAD severity in 35 randomly selected angiograms and had complete
concordance in every case. The extent score was derived by one
observer, whose intraobserver error was low (CV, 3%). The
intraobserver error of extent score has been reported previously from
our laboratory (
5%).41
Statistical Analysis
Data were analyzed with SPSS FOR WINDOWS
6.0 (Chicago, Ill) and the statistical package
SPIDA.42 All descriptive data are expressed
as mean±SD. In the variability studies (interobserver and
interoperator), the mean and SD values were used to calculate the CV as
CV=[(SD
)/mean]x100%, as described
elsewhere.16 Univariate analysis of
the associations between each potential risk factor and carotid IMT and
between risk factors and CAD scores was performed with standard
regression techniques for continuous variables (age, pack-years
smoked, and so on) and for categorical variables (sex, family
history, and so on). Because IMT and CAD were both recorded as
continuous variables, they were correlated with linear regression.
The interaction between risk factors IMT and CAD was then examined with
multiple stepwise regression analysis. Statistical significance
was inferred at P<.05.
To assess the clinical usefulness of IMT as a marker of CAD, we constructed a curve for receiver operating characteristic, as described elsewhere.43 This charts the accuracy of the test under study (IMT) to predict the given outcome (absence of significant CAD) across the range of test results observed in the study population and is not adjusted for the presence or absence of any of the traditional risk factors.
To assess the differential effect of traditional risk factors on carotid IMT versus CAD scores, the residuals between the 350 observed points and the expected values on the regression line of IMT on CAD score were regressed against the traditional risk factors for vascular disease.
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Results |
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Subjects
There were 249 (71%) men and 101 (29%) women in the study (age, 60±10 years; range, 30 to 85 years). One hundred nineteen (34%) had never smoked cigarettes, 32 (9%) were current smokers, and 199 (57%) were former smokers. The average lifetime smoking dose was 22±10 pack-years (range, 2 to 140 pack-years). There were 45 (13%) patients with diabetes mellitus (all had type II or non–insulin-dependent diabetes mellitus), and 118 (34%) patients had a history of hypertension. One hundred (29%) subjects had a family history of premature vascular disease. In total, 152 (43%) subjects gave a history of hypercholesterolemia, although only 48 (14%) were taking lipid-lowering drugs. In the 85 patients who had detailed lipid studies, LDL cholesterol was 3.8±1.0 mmol/L (146±39 mg/dL), HDL cholesterol was 1.2±0.3 mmol/L (46±13 mg/dL), triglycerides were 2.0±1.8 mmol/L (177±159 mg/dL), and lipoprotein(a) was 21±21 mg/dL.
Carotid IMT
Overall mean left IMT for all 350 subjects was 0.83±0.20 mm
(range, 0.43 to 1.8 mm), and maximum left IMT was 1.04±0.27 mm (range,
0.49 to 2.19 mm). In the 100 patients who had bilateral carotid
studies, the mean right IMT was 0.78±0.16 mm (range, 0.48 to 1.27 mm)
and the maximum right IMT was 0.99±0.24 mm (range, 0.56 to 1.75 mm)
(P=NS compared with the left IMT measurements in the same
100 subjects: 0.82±0.19 and 1.02±0.25 mm, respectively). The mean IMT
for combined left and right images was 0.81±0.19 mm (range, 0.47 to
1.8 mm), and maximum IMT for left and right was 1.04±0.26 mm (0.56 to
2.19 mm); these were also not significantly different than left IMT
values. In these patients, the correlations between bilateral IMT
values and CAD scores were almost identical; therefore, the IMT values
presented throughout are for the left carotid measurements,
which were acquired in all 350 subjects. The interobserver error for
mean IMT was 0.035±0.03 mm (range, 0 to 0.17 mm; CV, 2.5%), and the
interoperator error was 0.07±0.07 mm (range, 0 to 0.26 mm; CV,
6%).
Angiographic Results
One hundred twenty-three patients (35%) had no vessels with
70% stenosis, 91 (26%) had one-vessel disease, 81
(23%) had two-vessel disease, and 55 (16%) had three-vessel
disease. The mean modified Gensini score was 9.8±5.0 (range, 0 to 20),
and the extent of CAD score was 57±31 (range, 0 to 100). The extent
and severity scores for CAD were all positively correlated
(r>.6, P<.0001 in every case).
Correlation of Carotid IMT With CAD
The mean and maximum IMT values were significantly but weakly
correlated with the scores for the severity and extent of CAD; the
correlation coefficients were r=.26 and .26 with severity
score, r=.29 and .28 with modified Gensini score, and
r=.23 and .20 with extent score, respectively
(P<.0001 for each). Although carotid IMT is significantly
higher in subjects with more severe coronary
atheroma, there is considerable overlap between subjects
with and without disease (Figs 1
and 2).
The scatterplots in Fig 3 demonstrate the relatively
poor correlation between carotid IMT and each of the CAD scores; in
each case, r<.30
(r2<.10). These correlations were
not improved by excluding patients with previous myocardial infarction
(n=102), by excluding those with one or more complete coronary
occlusions (n=133), or by using the number of vessels with 50%
rather than 70% stenosis. In addition, the correlations
between IMT and CAD scores were similar in patients who had had their
usual nitrate therapy on the morning of the angiogram (n=210).
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Risk Factor Correlations With IMT and CAD
All of the major traditional risk factors for CAD were
significantly correlated with both carotid IMT and CAD scores (Table 1). In the subset of subjects who had detailed lipid
analysis, of whom 15 were taking lipid-lowering drugs, LDL
cholesterol and lipoprotein(a) did not correlate with CAD
severity or extent (r<.2, P=NS) or with carotid
IMT (r<.2, P=NS). HDL cholesterol,
however, correlated inversely with CAD severity and extent
(r=-.38, P<.0001) and with carotid IMT
(r=-.17, P=.02).
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The best multivariate model (exhaustive
search)42 to predict carotid IMT identified older age,
male sex, hypertension, and
hypercholesterolemia as significantly
associated variables (Table 2). The best
multivariate model for predicting severity of
coronary disease included older age, male sex,
hypercholesterolemia, and diabetes as
significantly associated variables (Table 3). The
addition of mean or maximum carotid IMT did not improve this model for
prediction of CAD.
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Multivariate analysis was used to assess
whether different risk factors affected carotid IMT and CAD to
significantly different degrees. Increasing age (P<.0001),
male sex (P<.0001), and presence of diabetes
(P=.005) each were associated with a significantly higher
CAD score than the average for any level of carotid IMT, suggesting
differential effects of these risk factors on IMT versus CAD scores
(Table 4).
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Clinical Use of Carotid IMT for "Screening"
The receiver operating characteristic plot for mean carotid IMT as
a test for the absence of significant CAD is shown in Fig 4 and demonstrates only a low sensitivity and
specificity of carotid IMT as a diagnostic test, regardless
of the level of IMT chosen as a cutoff point for abnormality.
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Discussion |
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In this study of patients undergoing elective coronary angiography, IMT of the far wall of the CCAs was significantly but only weakly correlated with the extent and severity of CAD, with r<.30 and r2<.10. These data have important implications for the interpretation of the large number of trials that have used or are using carotid IMT measurement as a noninvasive marker of the atherosclerotic process.15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 The reasons for this relatively poor correlation may be biological, because intima-media thickening is a different pathological process to atheromatous plaque formation1 10 and there are different risk factor influences on the carotid and coronary circulations and technical factors may make contributions, for example, the accuracy of B-mode ultrasonic measurement of submillimeter distances.
Biological Discordance: Carotid IMT Versus Coronary
Atheroma
Typical correlation coefficients for atheroma between
the major coronary arteries at postmortem study are
approximately .6.5 Similarly, many studies have examined
the relation between coronary and carotid atheroma
at autopsy and found correlation coefficients of .4 to
.64 5 6 ; however, carotid atheroma per se (as a
surrogate for coronary atheroma) is very difficult
to measure accurately in vivo. The internal carotid artery, in which
occlusive carotid plaque most often occurs, cannot be measured
precisely with ultrasound in a large proportion of
patients,8 and the ultrasound-based quantification of
carotid plaque is only poorly reproducible.7 In contrast,
IMT of the CCA is easily and reproducibly measured.10 13
The relation of CCA IMT with carotid atheroma, however, is
less well established. Persson et al9 showed that CCA IMT
is higher in subjects with than in those without internal carotid
plaque disease, but there was considerable overlap between patients and
control subjects. In straight nonbranching arteries, such as the distal
CCA, the intimal cell layer is very thin (
0.02 mm),10
so most of the observed "IMT" is media. In this segment of the
carotid, where most IMT studies are done, fatty streaks and early
fibrosis are nearly ubiquitous,44 but progressive
thickening is slow and actual plaque formation is rare. In contrast,
the progression of atheromatous plaque largely is due
to eccentric intimal thickening and usually occurs at sites of
nonlaminar turbulent flow, such as in the proximal internal carotid or
at bifurcations in the coronary arteries.45
Therefore, the pathological processes leading to intima-media
thickening in the distal CCA and to eccentric coronary plaque
formation are not similar. Furthermore, there are territorial
differences in vascular beds and their responses to risk
factors,46 and even coronary arteries within the
same individuals are not uniformly affected by
atheroma.5 For example, the carotid and
coronary circulations are differently associated with some of
the traditional vascular risk factors, with
hypercholesterolemia being more strongly
associated with coronary atheroma than with carotid
disease,47 and carotid atheroma often
appearing later in life than coronary plaques.1
Although the major risk factors were significantly associated with both
IMT and CAD scores in the present study, there was a differential
effect of some of these factors on IMT compared with coronary
disease extent and severity, and this may have contributed to the weak
correlation observed between these two measures of arterial
disease.
Technical Issues: Ultrasonic Resolution
The theoretical axial resolution of high-frequency external
vascular ultrasound with 7- to 10-MHz transducers is approximately 0.1
mm, but in practice most ultrasound machines use pulses with multiple
cycles and have an axial resolution of approximately 0.3
mm.2 16 38 The difference between "control" and
"risk factor" groups in many observational studies of carotid IMT
has been <0.2 mm.13 15 16 Although the precision to
detect differences between group mean values is higher than for
individual measurements, most studies measure IMT in individuals to the
nearest 0.1 mm or even 0.01 mm, which may be beyond the limits of
resolution of the ultrasound used. As the intima-media distances
being measured are small, most groups have reported interobserver and
interoperator variations of 5% to 10%, usually corresponding to
actual IMT measurement variations of 0.03 to 0.07 mm.8 10
In the present study, the reproducibility was similar. These
potential measurement errors may therefore also contribute to the
relatively weak correlation between CCA-IMT and the extent and severity
of coronary disease.
Previous Studies
Two other groups have assessed the relation between B-mode
ultrasound measures of carotid IMT and coronary
atherosclerosis. In two reports, the Bowman-Gray group
used a complex B-mode carotid score to assess the correlation with
angiographically determined CAD. In 1990, Craven et al14
compared subjects with severe CAD (one or more vessels with 50%
stenosis) with subjects with no CAD on angiography and found
that IMT was higher in patients than in control subjects, and in 1991,
Wofford et al3 found that the addition of the B-mode
carotid score added little to models with traditional risk factors in
predicting the extent of CAD. As the data in these studies were
presented as categorical variables (B-mode quartiles,
"presence" or "absence" of CAD), the actual strength of the
correlation between IMT and CAD could not be assessed accurately. In
our study, similar analyses also showed similarly highly
significant associations between IMT and CAD (Fig 2
) but relatively
weak correlations when these arterial measurements were
analyzed as continuous variables (which is how they were
actually measured) (Fig 3).
B-mode scores, such as those used in the above studies, have not been adopted widely by other investigators. The score is a composite of 12 IMT measurements obtained from the near and far walls of the internal, common carotid, and bulb areas bilaterally. Sonographers require special training, the procedure is time consuming, and there are no published data to indicate that this complex score is either more sensitive or specific for predicting the extent or severity of CAD than the simpler technique of measuring IMT of the far wall of the left or right CCA, as performed by Salonen and Salonen, Blankenhorn et al, and other groups.12 13 15 16 17 29 30 Preliminary data from 86 patients studied with the B-mode score (mean of the maximum IMT at 12 sites) and quantitative coronary angiography (percent diameter stenosis) showed a correlation coefficient of r=.27 (P=.01),48 similar to the values we obtained with CCA IMT alone. Furthermore, with the B-mode score, the internal carotid artery cannot always be interrogated adequately,14 and the measurements of near-wall IMT are theoretically less accurate than far-wall measurements,49 although near- and far-wall measurements are well correlated.50 These considerations may lessen the applicability and accuracy of this B-mode scoring method.
Blankenhorn and Hodis1 also reported on IMT-CAD correlation with a single mean IMT measurement of the distal CCA. In an undefined subgroup of 57 subjects from the CLAS study, the mean IMT from the far wall of the distal right CCA was correlated with the average coronary artery percent stenosis at angiography. In this study, r=.27 (P<.05), which is very similar to the present study, also suggesting that less than 10% of the variability of CAD can be related to variations in IMT.1 Although this group concluded that a case finding and treatment strategy for presymptomatic coronary disease based on IMT might be possible, our data on larger numbers of similarly studied subjects suggest little clinical usefulness for this approach.
Interestingly, Salonen and Salonen2 reported that thicker common carotid IMT values in middle-aged men may be independently associated with higher subsequent risk of acute coronary events. In this study, the event rate was less than 3% over 3-year follow-up, and the baseline CCA IMT measurements ranged from 0.6 to 4.08 mm; half of the subjects who had late coronary events had actual plaque in their distal CCA rather than just intima-media thickening, and this may explain the observed relation. Whether increased CCA IMT in the more normally observed range (0.6 to 1.6 mm) is associated with a graded increase in subsequent risk of coronary events awaits further prospective study.
Study Limitations
Because community-based data were unavailable for the extent
and severity of coronary disease seen at angiography, we
studied a consecutive group of patients undergoing elective cardiac
catheterization. This selection bias means that the
correlations we obtained between carotid IMT and CAD may not be
applicable to the general population. Nevertheless, about one third of
study patients had no coronary stenosis 70% and had
a mean IMT of 0.77±0.18 mm, and mean age was 58±11 years. These
values are similar to IMT data acquired in community-based studies;
the disease-free group in Persson's ultrasound study had mean IMT
of 0.73±0.13 mm,9 and in the large ARIC database, the
mean IMT in the distal CCA was approximately 0.73 mm for healthy
60-year-old men. It is likely, therefore, that our patients without
important CAD are similar to age-matched unselected subjects,
although they may have had a higher prevalence of traditional vascular
risk factors.
Reliance on coronary angiography as a valid measure of the severity or extent of coronary atherosclerosis may lack accuracy and reproducibility. Consensus readings for number of vessels involved and the modified Gensini score have been used by us and others3 51 to maximize reproducibility. The extent score that we previously reported also has a relatively low measurement error.41 Although computer-assisted scoring may improve reproducibility, our IMT-CAD correlation is almost identical to those found by both Blankenhorn and Hodis1 with data from the CLAS study and Herrington et al,48 who used computerized angiographic scoring systems. Coronary angiography, regardless of the method of analysis, consistently underestimates the severity of atherosclerotic disease52 and allows only visualization of the lumen (whereas ultrasound delineates the vessel wall). Despite this, there is a significant correlation between greater severity of atheroma and smaller lumen diameter at angiography,53 and CAD measured angiographically relates to subsequent risk of coronary events,54 suggesting that angiography is a reasonable method for measuring CAD extent and severity.
Clinical Implications
The correlation between common carotid IMT and CAD is positive,
highly significant, and at least as good as the association between the
major vascular risk factors and CAD, which are also correlated with
values of r=.2 to .3.55 56 57 58 However, carotid IMT
does not add to the predictive value of risk factor–based
multivariate models, and the large overlap in IMT
values between subjects with and without significant CAD appears to
preclude its use as a "screening test" for subjects considered
for coronary angiography. Furthermore, this relatively weak
correlation should be considered in interpretation of observational
studies and clinical regression trials, where carotid IMT is used as a
surrogate end point for the extent and severity of CAD. It is possible
that changes in carotid IMT with time in an individual may mirror
corresponding changes in the CAD score, and prospective studies may be
able to address this question.
Conclusions
IMT of the CCA is only weakly correlated with the extent and
severity of CAD assessed angiographically. This may be due to the
different underlying pathological processes of IMT and
atherosclerosis and/or to differential effects of the
traditional vascular risk factors on the carotid and coronary
circulations.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by grants from the National Health and Medical Research Council of Australia (NHMRC), the National Heart Foundation of Australia, and the Royal Australasian College of Physicians. Dr Adams is supported by the University of Sydney, and Dr Celermajer is supported by the NHMRC. We thank Thomas Lumley for statistical assistance.
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Footnotes |
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1 In this abstract, values that appear as r2 values were actually r values, as clarified at the presentation.
Received December 12, 1994; revision received April 27, 1995; accepted May 3, 1995.
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References |
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Y. Arad, D. Newstein, F. Cadet, M. Roth, and A. D. Guerci Association of Multiple Risk Factors and Insulin Resistance With Increased Prevalence of Asymptomatic Coronary Artery Disease by an Electron-Beam Computed Tomographic Study Arterioscler Thromb Vasc Biol, December 1, 2001; 21(12): 2051 - 2058. [Abstract] [Full Text] [PDF]
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T.-C. Su, J.-S. Jeng, K.-L. Chien, F.-C. Sung, H.-C. Hsu, and Y.-T. Lee Hypertension Status Is the Major Determinant of Carotid Atherosclerosis: A Community-Based Study in Taiwan Stroke, October 1, 2001; 32(10): 2265 - 2271. [Abstract] [Full Text] [PDF]
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W. F. Terpstra, J. F. May, A. J. Smit, P. A. de Graeff, F. H. Schuurman, B. M.-d. Jong, and H. J. G. M. Crijns Silent ST Depression and Cardiovascular End-Organ Damage in Newly Found, Older Hypertensives Hypertension, April 1, 2001; 37(4): 1083 - 1088. [Abstract] [Full Text] [PDF]
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P. Angerer, S. Stork, W. Kothny, P. Schmitt, and C. von Schacky Effect of Oral Postmenopausal Hormone Replacement on Progression of Atherosclerosis : A Randomized, Controlled Trial Arterioscler Thromb Vasc Biol, February 1, 2001; 21(2): 262 - 268. [Abstract] [Full Text] [PDF]
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C. Held, P. Hjemdahl, S.V. Eriksson, I. Bjorkander, L. Forslund, and N. Rehnqvist Prognostic implications of intima-media thickness and plaques in the carotid and femoral arteries in patients with stable angina pectoris Eur. Heart J., January 1, 2001; 22(1): 62 - 72. [Abstract] [PDF]
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M. A. Sader, K. A. Griffiths, R. J. McCredie, D. J. Handelsman, and D. S. Celermajer Androgenic anabolic steroids and arterial structure and function in male bodybuilders J. Am. Coll. Cardiol., January 1, 2001; 37(1): 224 - 230. [Abstract] [Full Text] [PDF]
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J. Hulthe, L. Bokemark, and B. Fagerberg Antibodies to Oxidized LDL in Relation to Intima-Media Thickness in Carotid and Femoral Arteries in 58-Year-Old Subjectively Clinically Healthy Men Arterioscler Thromb Vasc Biol, January 1, 2001; 21(1): 101 - 107. [Abstract] [Full Text] [PDF]
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 S A Morre, W Stooker, W K Lagrand, A J C van den Brule, and H W M Niessen Microorganisms in the aetiology of atherosclerosis J. Clin. Pathol., September 1, 2000; 53(9): 647 - 654. [Abstract] [Full Text] [PDF]
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M. Heras and A. Chamorro Atherosclerosis: a systemic condition that requires a global approach Eur. Heart J., June 1, 2000; 21(11): 872 - 873. [PDF]
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M. Zureik, P. Ducimetiere, P.-J. Touboul, D. Courbon, C. Bonithon-Kopp, C. Berr, and C. Magne Common Carotid Intima-Media Thickness Predicts Occurrence of Carotid Atherosclerotic Plaques : Longitudinal Results From the Aging Vascular Study (EVA) Study Arterioscler Thromb Vasc Biol, June 1, 2000; 20(6): 1622 - 1629. [Abstract] [Full Text] [PDF]
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F. Buttitta, U. Limbruno, A. S. Petronio, R. Baglini, G. Strata, R. Mariotti, M. Ciccone, M. Mariani, and A. Balbarini Usefulness of Carotid Intima-Media Thickness Measurement and Peripheral B-Mode Ultrasound Scan in the Clinical Screening of Patients with Coronary Artery Disease Angiology, April 1, 2000; 51(4): 269 - 279. [Abstract] [PDF]
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K. S. Woo, P. Chook, O. T. Raitakari, B. McQuillan, J. Z. Feng, and D. S. Celermajer Westernization of Chinese Adults and Increased Subclinical Atherosclerosis Arterioscler Thromb Vasc Biol, October 1, 1999; 19(10): 2487 - 2493. [Abstract] [Full Text] [PDF]
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J. Hung, B. M. McQuillan, M. Nidorf, P. L. Thompson, and J. P. Beilby Angiotensin-Converting Enzyme Gene Polymorphism and Carotid Wall Thickening in a Community Population Arterioscler Thromb Vasc Biol, August 1, 1999; 19(8): 1969 - 1974. [Abstract] [Full Text] [PDF]
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 M. Reza Mehrabi, C. Ekmekcioglu, F. Tatzber, A. Oguogho, R. Ullrich, A. Morgan, F. Tamaddon, M. Grimm, H. D Glogar, and H. Sinzinger The isoprostane, 8-epi-PGF2{alpha}, is accumulated in coronary arteries isolated from patients with coronary heart disease Cardiovasc Res, August 1, 1999; 43(2): 492 - 499. [Abstract] [Full Text] [PDF]
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B. M. McQuillan, J. P. Beilby, M. Nidorf, P. L. Thompson, and J. Hung Hyperhomocysteinemia but Not the C677T Mutation of Methylenetetrahydrofolate Reductase Is an Independent Risk Determinant of Carotid Wall Thickening : The Perth Carotid Ultrasound Disease Assessment Study (CUDAS) Circulation, May 11, 1999; 99(18): 2383 - 2388. [Abstract] [Full Text] [PDF]
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I. Kallikazaros, C. Tsioufis, S. Sideris, C. Stefanadis, and P. Toutouzas Carotid Artery Disease as a Marker for the Presence of Severe Coronary Artery Disease in Patients Evaluated for Chest Pain Stroke, May 1, 1999; 30(5): 1002 - 1007. [Abstract] [Full Text] [PDF]
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O. T. Raitakari, M. R. Adams, and D. S. Celermajer Effect of Lp(a) on the Early Functional and Structural Changes of Atherosclerosis Arterioscler Thromb Vasc Biol, April 1, 1999; 19(4): 990 - 995. [Abstract] [Full Text] [PDF]
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A. Schmidt-Trucksass, D. Grathwohl, A. Schmid, R. Boragk, C. Upmeier, J. Keul, and M. Huonker Structural, Functional, and Hemodynamic Changes of the Common Carotid Artery With Age in Male Subjects Arterioscler Thromb Vasc Biol, April 1, 1999; 19(4): 1091 - 1097. [Abstract] [Full Text] [PDF]
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S. Ebrahim, O. Papacosta, P. Whincup, G. Wannamethee, M. Walker, A. N. Nicolaides, S. Dhanjil, M. Griffin, G. Belcaro, A. Rumley, et al. Carotid Plaque, Intima Media Thickness, Cardiovascular Risk Factors, and Prevalent Cardiovascular Disease in Men and Women : The British Regional Heart Study Stroke, April 1, 1999; 30(4): 841 - 850. [Abstract] [Full Text] [PDF]
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M-D Enderle, S Schroeder, R Ossen, C Meisner, A Baumbach, H U Haering, K R Karsch, and M Pfohl Comparison of peripheral endothelial dysfunction and intimal media thickness in patients with suspected coronary artery disease Heart, October 1, 1998; 80(4): 349 - 354. [Abstract] [Full Text]
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K. A. Matthews, J. F. Owens, L. H. Kuller, K. Sutton-Tyrrell, H. C. Lassila, and S. K. Wolfson Stress-Induced Pulse Pressure Change Predicts Women's Carotid Atherosclerosis Stroke, August 1, 1998; 29(8): 1525 - 1530. [Abstract] [Full Text] [PDF]
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S. Rosfors, S. Hallerstam, K. Jensen-Urstad, M. Zetterling, and C. Carlstrom Relationship Between Intima-Media Thickness in the Common Carotid Artery and Atherosclerosis in the Carotid Bifurcation Stroke, July 1, 1998; 29(7): 1378 - 1382. [Abstract] [Full Text] [PDF]
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J. Nowak, T. Nilsson, C. Sylven, and T. Jogestrand Potential of Carotid Ultrasonography in the Diagnosis of Coronary Artery Disease : A Comparison With Exercise Test and Variance ECG Stroke, February 1, 1998; 29(2): 439 - 446. [Abstract] [Full Text] [PDF]
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P. M. Okin, M. J. Roman, J. E. Schwartz, T. G. Pickering, and R. B. Devereux Relation of Exercise-Induced Myocardial Ischemia to Cardiac and Carotid Structure Hypertension, December 1, 1997; 30(6): 1382 - 1388. [Abstract] [Full Text]
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K. Shinozaki, Y. Hattori, M. Suzuki, Y. Hara, A. Kanazawa, H. Takaki, M. Tsushima, and Y. Harano Insulin Resistance as an Independent Risk Factor for Carotid Artery Wall Intima Media Thickening in Vasospastic Angina Arterioscler Thromb Vasc Biol, November 1, 1997; 17(11): 3302 - 3310. [Abstract] [Full Text]
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J. Hulthe, J. Wikstrand, H. Emanuelsson, O. Wiklund, P. J. de Feyter, and I. Wendelhag Atherosclerotic Changes in the Carotid Artery Bulb as Measured by B-Mode Ultrasound Are Associated With the Extent of Coronary Atherosclerosis Stroke, June 1, 1997; 28(6): 1189 - 1194. [Abstract] [Full Text]
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S. D.J.M. Kanters, A. Algra, M. S. van Leeuwen, and J.-D. Banga Reproducibility of In Vivo Carotid Intima-Media Thickness Measurements : A Review Stroke, March 1, 1997; 28(3): 665 - 671. [Abstract] [Full Text]
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L. Niskanen, R. Rauramaa, H. Miettinen, S. M. Haffner, M. Mercuri, and M. Uusitupa Carotid Artery Intima-Media Thickness in Elderly Patients With NIDDM and in Nondiabetic Subjects Stroke, November 1, 1996; 27(11): 1986 - 1992. [Abstract] [Full Text]
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H. V. Anderson Estrogen Therapy, Atherosclerosis, and Clinical Cardiovascular Events Circulation, October 15, 1996; 94(8): 1809 - 1811. [Full Text]
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I. Wendelhag, O. Wiklund, and J. Wikstrand On Quantifying Plaque Size and Intima-Media Thickness in Carotid and Femoral Arteries: Comments on Results From a Prospective Ultrasound Study in Patients With Familial Hypercholesterolemia Arterioscler Thromb Vasc Biol, July 1, 1996; 16(7): 843 - 850. [Abstract] [Full Text]
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