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Circulation. 1995;92:2127-2134

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(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

Mark R. Adams, MBBS, FRACP; Akihiro Nakagomi, MD; Anthony Keech, MBBS, MEpidemiol, FRACP; Jacqui Robinson, RN; Robyn McCredie, BSc; Brian P. Bailey, MBBS, FRACP; S. Ben Freedman, MBBS, PhD, FRACP; David S. Celermajer, MBBS, PhD, FRACP

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.


*    Abstract
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 *Abstract
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 down arrowResults
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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


*    Introduction
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 up arrowAbstract
 *Introduction
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 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
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.


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
 down arrowDiscussion
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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.


*    Results
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 up arrowMethods
 *Results
down arrowDiscussion
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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 1Down and 2Down). The scatterplots in Fig 3Down 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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  		Figure 1. Far-wall CCA IMT of 0.61 mm in a 58-year-old man with two-vessel coronary disease (left) and IMT of 0.89 mm in a 62-year-old woman with angiographically normal coronary arteries.



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  		Figure 2. Box plot of the relation between average IMT of the CCAs and the number of major coronary arteries with >=70% stenosis, showing a highly significant relation but with considerable overlap of IMT values. Boxes represent the interquartile range with the mean indicated by the vertical lines, and the error bars indicate the range containing 95% of the values.




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  		Figure 3. Scatterplot of IMT versus (A) the number of major coronary arteries with >=70% stenosis in 350 consecutively studied subjects, (B) the modified Gensini score of coronary disease, and (C) the extent score of coronary disease (see "Methods").

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 1Down). 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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  		Table 1. Univariate Correlations Between Traditional Vascular Risk Factors and Carotid IMT or Coronary Atherosclerosis Score in 350 Consecutive Subjects Undergoing Elective Coronary Angiography

The best multivariate model (exhaustive search)42 to predict carotid IMT identified older age, male sex, hypertension, and hypercholesterolemia as significantly associated variables (Table 2Down). The best multivariate model for predicting severity of coronary disease included older age, male sex, hypercholesterolemia, and diabetes as significantly associated variables (Table 3Down). The addition of mean or maximum carotid IMT did not improve this model for prediction of CAD.


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  		Table 2. Best Multivariate Model for Prediction of Carotid IMT in 350 Participants


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  		Table 3. Best Multivariate Model for Prediction of CAD (Modified Gensini Score) in 350 Participants1

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 4Down).


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  		Table 4. Best Multivariate Model for Predicting More Severe Coronary Disease Than Average for Any Given Level of Carotid IMT (Residuals From Regression of Modified Gensini Score on Mean IMT)

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 4Down 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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  		Figure 4. Receiver operating characteristic plot for use of carotid IMT to predict the absence of significant coronary disease (mean IMT predicting no vessels with >=70% stenosis). The "line of chance" is the diagonal line, reflecting a test with no predictive value; the receiver operating characteristic plot is the solid line. There is no value of IMT on this curve, which demonstrates both high (>80%) sensitivity and specificity simultaneously, suggesting that IMT is not a clinically useful test for predicting the absence of significant CAD.


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
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 ({approx}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 2Up) but relatively weak correlations when these arterial measurements were analyzed as continuous variables (which is how they were actually measured) (Fig 3Up).

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.


*    Selected Abbreviations and Acronyms
 
CAD = coronary artery disease
CCA = common carotid artery
IMT = intima-media thickness


*    Acknowledgments
 
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.


*    Footnotes
 
1 In this abstract, values that appear as r2 values were actually r values, as clarified at the presentation. Back

Received December 12, 1994; revision received April 27, 1995; accepted May 3, 1995.


*    References
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