Atherosclerotic Changes in the Carotid Artery Bulb as Measured by B-Mode Ultrasound Are Associated With the Extent of Coronary Atherosclerosis
Background and Purpose Ultrasound is increasingly used to measure atherosclerotic development in carotid and femoral arteries. The aim of this study was to investigate the relationship between coronary atherosclerosis as measured by quantitative angiography and peripheral atherosclerosis as measured by ultrasound in three different arterial regions.
Methods Patients (n=32) with at least two coronary segments with visible signs of atherosclerosis as defined in a computer-assisted analysis of coronary angiograms were also examined with B-mode ultrasound. The extent of coronary atherosclerosis was expressed as the average diameter stenosis of coronary segments, and peripheral atherosclerosis was defined as intima-media thickness (IMT) and plaque occurrence in the common carotid artery, the carotid bulb, and the common femoral artery.
Results The results showed a significant correlation between the ultrasound measurement of IMT of the carotid bulb and diameter stenosis of the included coronary segments (r=.68, P=.01) and of carotid plaques and diameter stenosis (P<.001). The correlation between common carotid IMT and diameter stenosis of included coronary segments was not statistically significant (r=.31, NS). There were no significant relationships between common femoral IMT or femoral plaques and diameter stenosis of included coronary segments.
Conclusions Although this study is small, it points to a very important aspect of ultrasound measurements of atherosclerosis: measurements performed in the common carotid artery or the femoral artery may not relate to coronary atherosclerosis in the same way as measurements performed in the carotid bulb. The findings underline the importance of measuring IMT not only in the common carotid artery but also in the carotid bulb and present data separately. These results have to be confirmed in a larger-scale study.
The development of the B-mode ultrasound technique has made it possible to noninvasively study early atherosclerotic changes in the carotid and femoral arteries by measuring the intima-media complex. Measurements of IMT are used in pathophysiological studies of the atherosclerotic process, eg, in studies of the factors regulating the early development of atherosclerosis in the carotid and femoral arteries. An increased IMT is also used as a marker of generalized atherosclerosis, including coronary atherosclerosis.1 2 IMT has been shown to be associated with coronary risk factors such as age, smoking, hypertension, and LDL cholesterol.3 4 5 Several preventive trials have recently presented results showing a beneficial effect on IMT after cholesterol-lowering therapy.6 7 8 9 These studies raise the important question of the usefulness of IMT measurements as surrogate markers for coronary atherosclerosis.
Some studies regarding the association between ultrasound variables and coronary artery disease have also been published.10 11 12 13 14 These studies showed a varying degree of correlation between carotid IMT and coronary artery disease. None of these studies have, however, compared coronary atherosclerosis with IMT measurements of the carotid bulb, a segment of the carotid vessel that may be more like the coronary arteries in terms of hemodynamic properties.15 The aim of this study was to investigate the relationship between coronary atherosclerosis as measured by quantitative angiography and peripheral atherosclerosis as measured by B-mode ultrasound in three different arterial regions: the common carotid artery, the carotid artery bulb, and the common femoral artery.
Subjects and Methods
The Multicenter Anti-Atheroma Study (MAAS), a double-blind randomized trial, studied the effects of the cholesterol-lowering medication simvastatin on coronary atheroma as measured by coronary angiography.16 The patients included at the Gothenburg center also underwent a B-mode ultrasound examination of the carotid and femoral arteries close to the 4-year coronary angiography examination. Patients (n=32) included 28 men and 4 women with a mean age of 59.8 years (range, 44 to 71 years). Patients selected for the MAAS study had at least two coronary segments with visible signs of atherosclerosis, as defined by an angiogram carried out according to the standards required for quantitative analysis, and were selected provided that serum total cholesterol was between 5.5 and 8.0 mmol/L and fasting triglyceride levels were lower than 4 mmol/L.17 Paired observations for both coronary angiogram and high-quality ultrasound images from the common carotid artery were available in 27 patients, for the carotid bulb in 25 patients, and for the common femoral artery in 26 patients.
The mean value for total cholesterol for the patients included in the present analyses when recruited to the MAAS study was 6.33±0.98 mmol/L; body height and weight were 173±7 cm and 77.8±12.9 kg, respectively; and body mass index was 25.9±3 kg/m2. At the time of the 4-year examination, there were 9 patients (28%) that had never smoked, 20 patients (63%) who were past smokers, and 3 patients (9%) who were current smokers. Eight patients had had a myocardial infarction, but none had had a stroke.
Analyses of total cholesterol, HDL cholesterol, and triglyceride levels were made using standardized methods at the MAAS-lipid reference laboratory in Rotterdam, The Netherlands.16
Examination was performed with an ultrasound scanner (Acuson 128) equipped with a 7-MHz linear transducer and a transducer aperture of 38 mm. The electrocardiographic signal (lead II) was simultaneously recorded to synchronize the image capture to the top of the R wave to minimize variability during the cardiac cycle.18
The right carotid artery was scanned at the level of the bifurcation, as described earlier in detail.19 The examination included approximately 2 cm of the common carotid artery, the carotid bulb, and 1 cm of the internal and external arteries. The right femoral artery was examined distal to the inguinal ligament at the site where the artery divides into the superficial femoral artery and the profound femoral artery. The femoral artery was scanned approximately 4 cm proximal and 1 cm distal to the flow divider. These regions were scanned longitudinally and transversely to assess the occurrence of plaques. If a plaque was present, a frozen B-mode image of the thickest part of the plaque in the longitudinal view was recorded on videotape. The procedure was repeated three times to achieve three separate images for analysis. A short sequence of real-time images was also recorded to assist in the interpretation of the frozen images. Pulsed Doppler was used to provide information on velocity of blood flow.
Images for IMT measurements were recorded from the carotid bulb, the common carotid artery and the common femoral artery, respectively. IMT measurements were not performed in the internal carotid artery because of the high percentage of missing images from this area.20 21 At the position of the thickest part of the far wall (visually judged), a frozen longitudinal image was captured and recorded on videotape. The procedure was repeated three times to achieve three separate images for analysis. Again, a short sequence of real-time images was recorded on videotape to assist in the interpretation of the frozen images.
Measurement of IMT
The ultrasound images from the videotape were analyzed in a computerized analyzing system.22 IMT was defined as the distance from the leading edge of the lumen-intima interface to the leading edge of the media-adventitia interface of the far wall. The measurement of IMT in the carotid artery was made along a 10-mm-long section in the common carotid artery and in the carotid bulb. About 10 boundary points were marked along each echo interface by use of a digitizer table and a mouse. Between these marked points, the echo interfaces were interpolated by the computer so that 100 boundary points were analyzed for each 10-mm section. The computer program calculated the average thickness along the 10-mm-long section (IMTmean) and also the maximum thickness of the analyzed section (IMTmax). Measurements in the common femoral artery were made in the same way as for the carotid artery but along a 15-mm-long section proximal to the bifurcation.19 The means of three separately analyzed images in the common carotid artery, the carotid bulb, and the common femoral artery, respectively, were used in the analyses.
Most of the examinations were performed by the same investigator, and all analyses of IMT and plaque occurrence were made by the same observer. In a previous study of reproducibility, 17 patients with familial hypercholesterolemia and 18 control subjects were examined on two different occasions within 7 to 14 days to estimate intraobserver variability. The coefficient of variation for recording and measurements in the common carotid artery was 10.6% for IMTmean and 10.4% for IMTmax. The corresponding figures for measurements in the carotid bulb were 13.2% and 17%, respectively. Measurements of IMTmean and IMTmax in the common femoral artery had coefficients of variation of 11.9% and 14.4%, respectively.19
Assessment of Plaque Occurrence
A semiquantitative subjective scale was used to grade the size of plaques.19 This analysis included plaques in the near and far walls of the vessel. A plaque was defined as a distinct area with an IMT >50% thicker than neighboring sites (visually judged).19 Grade 0 was defined as no plaque; grade 1 as one or more small plaques (each less than approximately 10 mm2 in the carotid artery and 20 mm2 in the femoral artery); and grade 2, moderate to large plaques. The differentiation between grades 1 and 2 was made subjectively in most cases, and quantitative measurements were made in the computerized analyzing system22 only when the correct classification was not obvious to the observer. Grade 3 was defined as large plaques that caused a hemodynamic change in blood flow in the carotid artery, as defined by the pulsed Doppler curve, if peak systolic velocity was >1.2 m/s at 60° Doppler angle23 and in the femoral artery if there was a 100% increase in peak systolic velocity at the site of the plaque in relation to the segment proximal to the plaque concomitant with a loss of reverse flow.24 However, in the present study, no large plaque of grade 3 was found in the carotid artery, and only one subject had a plaque of grade 3 in the femoral artery. Therefore, plaques of grades 2 and 3 were merged into one group of moderate to large plaques.
Coronary Angiography and Quantitative Analysis
Coronary angiography was performed according to standards required for quantitative analysis,25 which have been described in detail elsewhere.16 17 The intention was to have 9 to 10 analyzable segments: 3 proximal segments in the right coronary artery, 3 to 4 in the circumflex, and 3 in the left anterior descending and left main stem. The angiogram was accepted only if at least 5 segments were analyzed according to the protocol.16 All angiograms were sent to the angiographic reference laboratory in Rotterdam and assessed by two members of the MAAS angiography committee, who selected the coronary segments suitable for quantitative analysis, irrespective of the presence of lesions. Quantitative analyses were done by the computer-assisted CAAS system.25 Two efficacy variables that allow measurement of absolute lumen diameter were defined17 26 : (1) the per-patient average mean lumen diameter of all segments included and (2) the per-patient average minimum lumen diameter of all segments that were angiographically diseased, defined as diameter stenosis >20%. As a third parameter, the per-patient average of diameter stenosis was also reported for all angiographically diseased segments.
All statistics were analyzed using SPSS for Windows 6.1. Nonparametric Spearman’s rank correlation test was used in the correlation analysis, with the relationship illustrated by Pearson’s correlation coefficient (r). For comparison of plaque occurrence in the common carotid and common femoral arteries with angiographic variables, Mantel-Haenszel’s test for linear association was used. For comparison between groups, the Mann-Whitney U test was used. Furthermore, a t-distributed variable was used to calculate 95% CIs for differences. Two-sided values of P<.05 were regarded as statistically significant.
IMTmean and IMTmax measured in the common carotid artery (n=27) were 0.84±0.18 and 0.99±0.22 mm, respectively. Corresponding figures in the carotid bulb (n=25) were 1.23±0.50 and 1.72±0.75 mm, respectively, and in the common femoral artery (n=26), 1.57±0.86 and 2.02±1.04, respectively. These mean values are significantly larger than those in a reference group with similar characteristics but free from cardiovascular disease (data on file19 ).
IMT in Relation to Angiographic Variables
When common carotid IMT was compared with the CAAS angiographic variables (mean lumen diameter, minimum lumen diameter, and diameter stenosis), no significant correlations were found. IMTmean and IMTmax measured in the carotid bulb were, however, significantly correlated with percent diameter stenosis of coronary segments (r=.68 and r=.69, respectively; P=.01) (Table⇓, Fig 1⇓). There were no significant correlations between IMT of the femoral artery and any of the three angiographic variables (Table⇓, Fig 1⇓).
Plaque Occurrence in Relation to Angiographic Variables
Mean and minimum lumen diameter and diameter stenosis of coronary segments were all tested against plaque occurrence in the carotid and the femoral arteries separately. A significant correlation was seen between percent diameter stenosis and plaque occurrence in the carotid artery (P<.001; Fig 2⇓). No significant correlation was seen between diameter stenosis and plaque occurrence in the femoral artery (NS; Fig 2⇓).
Relationship Between IMT Measured in Different Arterial Regions
There was no correlation between IMT measured in the two different arteries. The relationships between IMT of the common carotid artery and IMT of the common femoral artery was r=.08 (NS); between the IMT of the carotid bulb and IMT of the common femoral artery, it was r=.21 (NS). The correlation between IMT measured in two different regions of the same artery, IMT of the common carotid artery and IMT of the carotid bulb, was r=.35 (NS).
The results of this study showed an association between the severity of coronary atherosclerosis expressed as percent diameter stenosis of coronary segments and carotid atherosclerosis defined as IMTmean and IMTmax of the carotid bulb. The degree of diameter stenosis was also related to plaque status in the carotid artery. No significant correlation was found when comparing diameter stenosis and IMT of the common carotid artery, although a tendency to an association was noted (Table⇑). Furthermore, no correlations were found when comparing diameter stenosis with either IMT or plaque status in the femoral artery.
The value of carotid IMT as a surrogate variable for coronary artery disease has been investigated in several previous studies. Some of these studies used an IMT scoring system to evaluate the carotid arteries in patients undergoing coronary angiography. These studies reported that the extent of carotid artery disease was related to the extent of coronary artery disease.10 11 A more commonly used parameter in ultrasound studies is common carotid IMT. Good-quality images of the far wall of the straight part of the common carotid artery are easy to obtain, and IMT can be measured in nearly all subjects. However, only poor positive correlations between far-wall common carotid IMT and the extent of coronary artery disease have been observed.12 13 14 These results accord well with the findings in the present study. One recently published study showed a rather weak but statistically significant correlation between common carotid IMT and the extent and severity of coronary artery disease (r=.23 and r=.26, respectively; n=350; P<.001). The authors concluded that the relatively poor correlation should be considered in the interpretation of clinical trials that use carotid IMT as a surrogate variable for coronary atherosclerosis.14 These authors did not study the carotid bulb.
Plaque in the coronary arteries has been shown to occur more frequently at regions of flow separation and of low and oscillating shear stress.15 A similar hemodynamic situation with flow separation and low oscillating shear stress is also found in the internal carotid artery and in the carotid bulb, and the development of atherosclerosis in carotid arteries also typically begins with an increased IMT in the bifurcation area. This may explain why IMT of the carotid bulb may be more closely related to coronary artery disease than IMT of the common carotid artery.
It is interesting to note that no significant relationship was observed between coronary atherosclerosis and IMT measured in the femoral artery or between IMT of the carotid artery and IMT of the femoral artery. These results corroborate findings in an earlier study performed in patients with familial hypercholesterolemia, in which no significant relationship was noted between common carotid IMT and common femoral IMT.9 One might speculate that partly different factors may be involved in regulating the development of atherosclerosis in the femoral artery compared with the factors that regulate atherosclerosis development in the carotid artery and in the coronary arteries.9 27
Coronary atherosclerosis was defined by the CAAS variables: mean lumen diameter, minimum lumen diameter, and diameter stenosis. In our study, only percent diameter stenosis turned out to be significantly correlated to ultrasound findings. Mean lumen diameter and minimum lumen diameter are both absolute measurements. Diameter stenosis, on the other hand, is dependent on a relative diameter, which is determined by comparing the diameter at the site of maximal reduction with the diameter in adjacent areas that appear to be either normal or only minimally diseased. One problem is that this “normal” portion of the vessel could be atheromatous in a diffuse manner, leading to calculation of a less severe lesion.26 Nevertheless, one might speculate that diameter stenosis, being a relative measure, better mirrors wall thickness than mean lumen diameter and minimum lumen diameter in the type of cross-sectional study that we have performed. In prospective studies, on the other hand, in which each patient serves as his or her own control, the other variables are of great value.
One of the limitations when comparing the degree of atherosclerosis in peripheral and coronary arteries is that different methods are used. In ultrasound studies of carotid arteries, IMT is the main variable studied, whereas with coronary angiography, residual lumen or relative stenosis is measured and not wall thickness. According to findings presented by Glagov et al,15 large increases in wall thickness due to atherosclerosis may be seen both in carotid and coronary arteries before a decrease in lumen diameter and stenosis development occurs. Therefore, it is to be expected that ultrasound and coronary angiography will yield different findings during the early development of atherosclerosis. Another problem is that coronary angiography cannot be performed in healthy subjects for ethical reasons, which limits the study population to subjects who undergo coronary angiography for medical reasons.
A subsequent question is whether the relationship would be better if intracoronary ultrasound were used to define coronary atherosclerosis. Intracoronary ultrasound and noninvasive ultrasound of carotid and femoral arteries, in addition to lumen diameter, both measure IMT. Therefore, in future studies, it would be of interest to compare findings from external ultrasound of carotid and femoral arteries with intravascular ultrasound from coronary arteries.
In conclusion, our study showed an association between IMT measured in the carotid bulb and coronary atherosclerosis. However, an association was not seen between IMT in the common carotid artery and coronary atherosclerosis or between the common femoral artery IMT and coronary atherosclerosis. These findings underline the importance of measuring IMT not only in the common carotid artery but also in the carotid bulb and presenting the results separately for these two arterial segments.28 Although this study is small, it used refined, computerized, quantitative techniques, both for ultrasound measurement of IMT and for angiographic measurement of coronary atherosclerosis. The results point to a very important aspect of ultrasound measurement of atherosclerosis: measurements performed in the common carotid artery or the femoral artery may not relate to coronary atherosclerosis in the same way as measurements performed in the carotid bulb. These results have to be confirmed in a larger-scale study.
Selected Abbreviations and Acronyms
|CAAS||=||Cardiovascular Angiography Analysis System|
|MAAS||=||Multicenter Anti-Atheroma Study|
This study was supported by grants from the Swedish Heart-Lung Foundation, the Swedish Medical Research Council (projects B94-27X-10880-01A, B95-27X-10880-02B, and B96-27X-10880-03A), and Astra Hässle, Mölndal, Sweden. We thank Christina Jonsteg for valuable help.
The MAAS study was sponsored by Merck, Sharp & Dohme Research Laboratories, but it is the authors’ judgment that this support does not relate, directly or indirectly, to the subject of the present cross-sectional study.
- Received December 17, 1996.
- Revision received March 3, 1997.
- Accepted March 21, 1997.
- Copyright © 1997 by American Heart Association
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