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(Stroke. 1997;28:348-353.)
© 1997 American Heart Association, Inc.

Articles

Relationship Between Carotid Intima-Media Thickness and Symptomatic and Asymptomatic Peripheral Arterial Disease

The Edinburgh Artery Study

Paul L. Allan, FRCR; Philip I. Mowbray, BSc; Amanda J. Lee, PhD F. Gerald R. Fowkes, FRCPE

the Department of Radiology, Royal Infirmary of Edinburgh National Health Service Trust (P.L.A.), and the Wolfson Unit for Prevention of Peripheral Vascular Diseases, Department of Public Health Sciences, Medical School (P.I.M., A.J.L., F.G.R.F.), Edinburgh, Scotland.

Correspondence to Professor F.G.R. Fowkes, Wolfson Unit for Prevention of Peripheral Vascular Diseases, Department of Public Health Sciences, Medical School, Teviot Place, Edinburgh EH8 9AG, Scotland. E-mail gerry.fowkes@ed.ac.uk.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Ultrasonic evaluation of intima-media thickness (IMT) is one method of assessing the development of early atherosclerosis. This report describes the distribution of IMT within the general population and is one of the first to investigate its association with noninvasively assessed symptomatic and asymptomatic peripheral arterial disease.

Methods Ultrasonic evaluation of IMT was included in the 5-year follow-up examination of participants of the Edinburgh Artery Study. Valid readings of IMT were recorded in 1106 subjects aged 60 to 80 years, and the maximum from the right and left sides of the neck was used in the analysis. Existing symptomatic and asymptomatic peripheral arterial disease and coronary heart disease were also assessed at follow-up using previously validated noninvasive techniques.

Results IMT increased continuously with age (P.01), and its distribution was positively skewed in both sexes. The results suggest that levels of atherosclerotic development in the common carotid artery are 5 to 10 years more advanced in men than in women. In this population, the overall prevalence of moderate to severe disease was very low (only 1.2% of study participants had IMT values >2 mm). The presence of symptomatic (intermittent claudication) or asymptomatic (ankle brachial pressure index 0.9) peripheral arterial disease was significantly associated with increased IMT (P.05).

Conclusions Although the prevalence of advanced atherosclerosis was very low, small changes in IMT were associated with clinically significant development of atherosclerosis in the peripheral arteries. However, further longitudinal studies are needed that standardize measurement techniques and would allow accurate comparisons across studies.

Key Words: peripheral vascular diseases • atherosclerosis • carotid arteries • duplex scanning

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
It has been suggested that the IMT of the CCA may be the most sensitive marker for the earliest stages of atherosclerosis.¹ Much of the literature concerning carotid atherosclerosis has been based on studies conducted on hospital patients or small selected samples that have not been representative of the general population.^{2 3 4 5 6 7 8 9} This was inevitable in earlier studies because the distribution of asymptomatic atherosclerosis could only be assessed at autopsy or by angiography of patients with severe disease.^{10 11 12 13} However, over the last decade, development of noninvasive ultrasound techniques has made the visualization and measurement of the layers of the arterial wall and plaques possible in large population samples.

It has also been shown that atherosclerotic lesions in their earliest stages may progress without a reduction in lumen diameter because of simultaneous dilation of the arterial wall,^{14 15 16} making recognition of stenosis on arteriography difficult. Because ultrasonographic measurement of the IMT is not affected by lumen diameter, it may therefore be the most accurate method of assessing early development of atherosclerosis in large representative population samples. Unfortunately, few recent studies have measured IMT as the primary disease variable^{8 9 16 17 18} ; many have used the presence of stenotic plaques, which are relatively late manifestations, as measures of disease severity.^{4 5 6 19 20 21}

Although ARIC demonstrated a relationship between carotid IMT and preexisting symptomatic peripheral arterial disease,²² Bots et al²³ are the only authors to report an association between IMT and asymptomatic peripheral arterial disease within a general population. Similarly, the Edinburgh Artery Study assesses noninvasively both carotid atherosclerosis and peripheral arterial disease in a large representative population sample. The main objectives of this report are (1) to describe the distribution of ultrasonographically detected CCA IMT and (2) to assess the relationship between CCA IMT and noninvasively assessed peripheral arterial disease.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Study Population
The Edinburgh Artery Study began in 1988 as a cross-sectional survey of 1592 male and female participants aged 55 to 74 years. The study examined an age-stratified random sample of the age-sex registers of 10 general practices whose catchment populations were spread geographically and socioeconomically across the city. The study had a 65% response rate. Basic demographic information was obtained for a random sample of 20% of the nonresponders from each practice and showed no substantial bias. Complete details of the study procedures and recruitment have been discussed previously.²⁴ The study was approved by the Lothian Health Board Ethics Committee, and informed consent was obtained from each participant.

Identification of Cardiovascular Events
Throughout the 5-year follow-up, a range of cardiovascular events was recorded using criteria adapted from the American Heart Association.²⁵ Details concerning procedures used to identify fatal and nonfatal cardiovascular events have been described previously.²⁶ In brief, records were flagged at the UK National Health Service Central Registry to identify deaths. Information on nonfatal events was sought from general practitioners, hospitals, and the Information Services Division of the Scottish Office Home and Health Department and by annual questionnaire to the participants. All cardiovascular events and deaths were further investigated using hospital or general practice notes. For the current cross-sectional analysis, intermittent claudication was recorded if either of the following was true: (1) evidence²⁷ of intermittent claudication by WHO criteria (grade 1, 2, or probable²⁸ ) at baseline or during follow-up or (2) clinical diagnosis of intermittent claudication investigated by the general practitioner or hospital. Angina pectoris was recorded if there was WHO evidence of angina plus either subject recall of a doctor's diagnosis or electrocardiographic evidence of ischemia at either baseline or during follow-up. Subjects were recorded as having had a myocardial infarction if any two of WHO evidence, electrocardiographic evidence, or subject recall of a doctor's diagnosis existed at baseline or follow-up examination. In addition, myocardial infarctions recorded during follow-up were also included. Coronary heart disease was defined as either angina pectoris or myocardial infarction defined by the above criteria.

Five-Year Follow-up Examination
A total of 1156 subjects attended the 5-year follow-up examination between November 1992 and March 1994. Complete details of this examination procedure have been described previously.²⁶ Briefly, subjects completed a self-administered questionnaire that included questions concerning new cardiovascular events, personal characteristics, the WHO angina and intermittent claudication questionnaires,²⁷ smoking history, and current medication.

After 5 minutes of rest, right-arm brachial systolic and diastolic blood pressures were measured using a Hawksley random zero sphygmomanometer. Femoral, posterior tibial, and dorsalis pedis arteries were then palpated, and ankle pressures were measured using a Sonicaid Doppler ultrasound probe.

The B-mode ultrasound scanning of the carotid arteries was performed using an ATL UM9, HDI Duplex Scanner (Bothwell). A 10-MHz transducer was used to provide imaging at 10 MHz and spectral Doppler at 7 MHz. The subject lay supine with the neck extended and the chin turned contralateral to the side being examined. The scanning protocol involved examination of the carotid arteries first in a transverse plane and then longitudinally. A record was made as to whether each of the four arterial segments (internal, external, common carotid, and bulb) was identifiable on each side. Measurement of IMT was made at a point on the far wall of the CCA, 2 cm proximal to the bifurcation, from a longitudinal scan plane that showed the intima-media boundaries most clearly. It was decided to measure the IMT at this section of the carotid artery because it is well documented that accuracy of visualization of vessels, and particularly the intima-media boundary, on B-mode ultrasound images is related to depth and anatomic configuration of the vessel.^{29 30 31 32} Furthermore, CCA IMT has been shown to be as strong a predictor of disease as IMT measured within the internal carotid artery.¹⁸ On the screen displaying the frozen magnified image of the far wall of the CCA, two cursors were positioned on the boundaries of the intima-media. The distance between these cursors was recorded to the nearest 0.1 mm (maximum axial resolution of the scanner) as the IMT. The procedure was repeated for each side of the neck.

All scan images were recorded on videotape, and any images of insufficient quality to make an accurate measurement of IMT or that suggested potentially significant carotid disease were reviewed by the consultant radiologist (P.L.A.) and a member of the study team. A decision was then made as to whether a rescan conducted by the consultant was necessary. Forty-one subjects had at least one of the variables recorded during the ultrasound examination later amended by the consultant.

Data Analysis
Information on the questionnaires and recording forms was checked by the clinic staff and entered onto a DBASE IV database. Error rates were determined by dual entry of all data, and reference was made to original records in cases with any discrepancy. Data files were transferred onto a Sun workstation for analysis using the SPSS statistical package.^{33 34 2} tests were used to test for differences in sex and social class between the initial sample examined at baseline and the subgroup examined at follow-up.

Values for IMT from the right and left sides of the neck were compared, and the final outcome variable, IMT, was calculated as the maximum of these two values and used throughout all subsequent analysis. Unlike the present study, previous reports have used the mean IMT value from the two sides, not the maximum.^{8 9 17 18 35 36 37} However, we consider that by using the side of the neck with the more advanced disease within each subject, we obtain a more realistic indicator as to the severity of the atherosclerosis. In particular, if the difference in the level of IMT between the two sides is large, the mean over both sides would generally underestimate the overall stage and clinical significance of the atherosclerosis. Twenty-seven participants (2.4%) had IMT for only one side of the neck recorded, and this value was taken as the maximum. Although such a small group would be very unlikely to bias inferences made concerning the entire sample, a t test to compare the mean IMT within this subgroup with that of the remainder of the population was nonsignificant (P=.489).

Because the distribution of IMT displayed a high level of positive skew, a logarithmic transformation of this variable was used in all tests that assume normality of the dependent variable, and geometric means are quoted when IMT values are compared between groups. The ABPI at follow-up was calculated for each leg by dividing the ankle pressure by the brachial pressure. In the analysis, the lower of these two values was used as a measure of disease severity. ANOVA was used to compare the distribution of IMT across categorical variables. ANCOVA was then used to conduct a similar analysis after adjustment for the confounding effects of age and sex. Multiple regression was used to assess the linear relationship between IMT and ABPI (as a continuous variable) both univariately and after adjustment for age and sex.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Of the 1592 subjects who were recruited at the baseline examination, 1156 (72.6%) attended the 5-year follow-up examination and completed a questionnaire, a further 131 (8.2%) completed the questionnaire only, and there were 203 deaths (12.8%). There was no significant difference in the distribution of sex or social class between the entire baseline population and the subsample who attended the follow-up examination (P>.05). However, this subsample had a slightly lower average age at baseline than the whole population (mean difference, -0.64 year; P.005).

Of the 1156 subjects, 1106 (95.7%) had values for IMT recorded on at least one side of the neck. The geometric mean IMT for the whole study sample was 0.756 mm (n=1092) for the right CCA and 0.791 mm (n=1093) for the left. The values for IMT from the two sides showed strong statistical correlation (Pearson, .514; P.01), which was almost identical when considering the sexes separately. However, a paired t test indicated that there was a statistically significant difference in IMT values between the right and left sides (P.01). Among the1079 subjects with valid readings of IMT for both sides of the neck, 377 (34.9%) had greater IMT on the right, 477 (44.2%) had greater IMT on the left, and 225 (20.9%) had the same IMT on each side.

In the present study, men were found to have significantly higher IMT values than women in all 5-year age groups (Table 1), although the difference reached statistical significance in the 65- to 69-year age group only (P.05). After adjustment for age, the overall mean IMT was significantly higher in men than in women (P.01).

View this table: [in this window] [in a new window]   Table 1. Geometric Mean IMT by Age and Sex in the Edinburgh Artery Study

The figure shows box plots denoting the median and interquartile range of the distribution of IMT for each age group. These show a continuous increasing relationship of IMT with age group in both sexes. These values tended to be higher in men than women, suggesting that men aged 60 to 80 years were more likely to suffer from moderate to severe disease (defined as IMT >2 mm¹⁷ ). In both sexes, the distribution of IMT at younger ages was less skewed, and there was greater variance in men than women, suggesting that men were more susceptible to atherosclerotic development earlier in life. There was also greater variance in the distribution of IMT at older ages, particularly in men.

View larger version (18K): [in this window] [in a new window]   Figure 1. Distribution of CCA IMT across age group in men (a) and women (b) in the Edinburgh Artery Study. The box plots show medians and 25th and 75th percentiles (bottom and top of rectangles). The vertical bars denote those values of IMT that lie within 1.5 interquartile ranges of the limit of the interquartile range.

Table 2 shows unadjusted and age- and sex-adjusted geometric means for IMT across selected levels of ABPI and presence of both intermittent claudication and coronary heart disease. ABPI was classified into two groups using the conventional 0.9 cutoff³⁸ : subjects with an ABPI 0.9 had significantly higher IMT levels than those with an ABPI >0.9 (P.01). The significance was not affected by adjustment for age and sex. The linear relationship between ABPI and IMT (log transformed) was assessed by multiple regression. After adjustment for age and sex, the probability value just failed to make statistical significance (P=.054), although the negative regression coefficient (b=-0.116, SE=0.06) suggested that the level of IMT was greater in individuals with lower ABPI. Subjects with a history of intermittent claudication showed significantly higher values of IMT than those without (P.01), and the significance remained after adjustment for age and sex. Both the univariate and age- and sex-adjusted mean IMTs were higher in those subjects with coronary heart disease, although the differences were not statistically significant (P>.05).

View this table: [in this window] [in a new window]   Table 2. Geometric Mean IMT in Subjects With and Without Peripheral Arterial Disease and Coronary Heart Disease, Unadjusted and Adjusted for Age and Sex

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
It has recently been argued that ultrasonography of the peripheral vessels, rather than coronary arteriography, is the most accurate measure of the extent of atherosclerosis.³⁹ B-mode ultrasonography allows accurate visualization of the arterial wall and measurement of the IMT. There is mounting evidence to suggest that IMT is an indicator of the severity of atherosclerosis in its earliest stages.^{1 2 6 14 15 16 17 18 20 35} In this study, IMT increased with age in both sexes, although it was higher in men than in women at all ages. "Detectable atherosclerotic lesions" defined by Salonen et al¹⁷ as IMT >0.12 cm, signifying moderate to severe disease, were more frequent in men (12% compared with 7% in women in the present study). However, the overall prevalence of more advanced atherosclerotic plaque (1.2% had IMT >2 mm) was low in comparison with other studies,^{16 17 18} although it was similar to that from the Rotterdam Elderly Study.⁴⁰ However, as discussed below, these studies used different scanning and measurement protocols, which can affect the distribution of IMT.

Some studies have reported difficulty in visualizing the far-wall intima-media boundary sufficiently to measure IMT. ARIC also postulated that IMTs in nonvisualized segments may differ from those that are visualized.¹⁶ However, visualization is mainly related to vessel depth and tortuosity, which are clearly not associated with IMT. With a visualization rate of 94.5% in the present study, which is similar to that in other reports, our data would appear to provide a good representation of the general population.

Table 3 compares study samples, measurement protocols, and distributional results from a selection of large epidemiological studies of ultrasonographically detected IMT. It illustrates consistency in the basic descriptive statistics between the four studies. As expected, values for IMT from both the KIHD³⁵ and CHS¹⁸ were slightly higher than in ARIC¹⁶ or in the present study, since they measured IMT at the point of greatest thickness over the whole CCA. IMT in the KIHD was raised further as a result of the all-male sample taken from an area with extremely high incidence of ischemic heart disease. The sample in CHS was slightly older than in our study, possibly explaining the increased IMT. The clearest difference in the distribution of IMT between ARIC and our study was the presence of a larger number of older subjects (particularly men) with moderate to high IMT in the Edinburgh Artery Study, and there was less clustering around the mean value (greater variance). Again, this is partly explained by the different techniques for measurement of IMT.

View this table: [in this window] [in a new window]   Table 3. Distribution of CCA IMT in the Edinburgh Artery Study and Other Population Studies

Interstudy variation in protocols for measurement of IMT affects the nature of the distribution of ultrasonographically measured IMT in these studies. B-mode scanning equipment (eg, manufacturer of scanning equipment, frequency of ultrasound used) also differed between studies, and such factors should be taken into account before any comparisons are drawn between results. Further epidemiological research involving B-mode ultrasound evaluation of IMT as a measure of carotid atherosclerosis would benefit from the standardization of both equipment and protocol for the measurement and recording of IMT.

Probably the strongest evidence to date as to the validity of IMT as a measure of atherosclerosis has been the consistent observation of strong relationships between the IMT and both cardiovascular risk factors and events.^{17 18 35 36 37 40 41 42 43} In particular, lifetime smoking and serum LDL cholesterol concentrations have consistently been found to be strongly related to IMT. A longitudinal study of Finnish men reported IMT as predictive of incident myocardial infarction⁴³ and also found that the progression of IMT was predicted by smoking and blood lipid levels.³⁶ ARIC reported an association between the distribution of ultrasonographically evaluated IMT and the known distribution of atherosclerosis, as reported by the multicenter International Atherosclerosis Project⁴⁴ as evidence of the validity of this method.¹⁶ In addition, Pignoli et al² found strong correlations between ultrasound and histological measurements from both atherosclerotic and disease-free carotid arteries.

This is one of the first studies to illustrate a strong relationship between previously validated indicators of peripheral arterial disease and CCA IMT. Those subjects with an ABPI 0.9 had a significantly higher age-sex–adjusted IMT within the CCA than subjects with an ABPI >0.9. A linear regression analysis confirmed that low ABPI was associated with higher IMT. Furthermore, values of IMT for the 122 subjects with claudication were also found to be significantly higher than those of subjects without claudication. These findings are in accord with those of Bots et al,²³ who found a negative relationship between IMT and ABPI in the Rotterdam Study. However, in the present study, the relationship between coronary heart disease and CCA IMT was not statistically significant.

We were somewhat surprised by the significance of the paired (within-subject) comparison of IMT on the left and right sides of the neck. Many more subjects (9.27% ) had greater IMT on the left side than on the right side of the neck (P.01). This clearly suggested some tendency to greater thickening on the left side within our study. Review of the scanning procedure provided no simple explanation for a substantial inconsistency. The only other article, of which we are aware, to report an analogous finding was that from the European Carotid Surgery Trial, in which 55% of 1590 patients had symptomatic lesions located on the left side,⁴⁵ a similar proportion to that reported here. There may be anatomic or hemodynamic explanations for increased IMT on the left side. Although investigation of this was not an objective of this study, further research to confirm (or refute) these findings would be beneficial.

The Figure illustrates clear differences in the distribution of IMT both between age groups and between the sexes. In findings similar to those reported by ARIC,¹⁶ the prevalence of moderate to severe disease was greater in men than women at all ages, and each of the 25th, 50th, and 75th percentiles increased continuously across the four age groups for both sexes. The distribution of IMT for women was more closely centered around the mean, with fewer moderately high values (although similar extremes). This would suggest that men are more likely to be affected by moderate to severe disease and that low levels of carotid atherosclerosis develop at an earlier age in men. With regard to age, particularly evident in men was an increase in the variance (or spread) of the distribution in older subjects. This correlation between spread of IMT and age has also been reported by both Salonen and Salonen³⁵ and ARIC.¹⁶

Because our data for IMT displayed a high level of positive skew, a logarithmic (log) transformation was used in any statistical tests that assumed a normally distributed dependent variable. Data for IMT from Finland³⁵ was also positively skewed, but it was stated that a log transformation yielded results almost identical to those obtained using the untransformed IMT. In contrast, neither ARIC¹⁶ nor CHS¹⁸ reported any use of a log transformation of IMT, although Bots et al⁴⁶ reported that the relationship between IMT measurement reproducibility and IMT disappeared after log transformation. For our data, all linear models using log(IMT) as the dependent variable accounted for more of the overall variance than the corresponding models with the untransformed variable, suggesting some nonlinearity in the relationship between IMT and age. This may be explained using the longitudinal analysis from Finland,³⁶ in which the rate of progression of IMT was found to increase with age. This is in contrast with the CHS,¹⁸ which found no nonlinearity in the relationship between IMT and age, and a large study in Kentucky³⁷ of patients with a history of smoking, which found lower levels of carotid plaque in subjects over 80 years than in those one to two decades younger. However, the latter study would have been particularly sensitive to a "healthy participant" effect, by which elderly subjects with high IMT were underrepresented because of early mortality. Salonen and Salonen³⁶ estimated the annual increase in CCA IMT to be 0.06 mm/y, which was approximately six times greater than the estimates from the cross-sectional studies.^{16 18} However, this may be partly due to differences in measurement technique and loss of subjects with high IMT values.¹⁸ In the present study, we estimated average rates of progression of IMT as 0.012 mm/y in men and 0.010 mm/y in women, and the rates increased with advancing age.

This cross-sectional analysis of a representative population sample of subjects aged 60 to 80 years illustrates a strong association between IMT and both symptomatic and asymptomatic peripheral arterial disease. Men tended to experience mild atherosclerotic development earlier in life than women and were more likely to suffer from clinically significant intima-media thickening at older ages. Further longitudinal studies are required to investigate the nature of the progression of intima-media thickening with age and to standardize measurement techniques that would then permit accurate comparisons across studies.

	Selected Abbreviations and Acronyms

 

ABPI = ankle brachial pressure index ARIC = Atherosclerosis Risk in Communities Study CCA = common carotid artery CHS = Cardiovascular Health Study IMT = intima-media thickness KIHD = Kuopio Ischemic Heart Disease Risk Factor Study WHO = World Health Organization

	Acknowledgments

 
Financial support was provided by the British Heart Foundation. We would like to thank the following for their contributions to the study. General Practices: Bruntsfield Health Centre; Dr S. Channell and partners; Crewe Road Medical Centre; Dr J.J.C. Cormack and partners; Edinburgh University Department of General Practice; Dr J.G. Ledingham and partners; Muirhouse Medical Group; Dr I.R.F. Ross and partners; Whinpark Medical Centre; and Dr P. White and partners. Clinic staff: J. Dunbar, M. Carson, E. Kerracher. Research secretary: K. Purves. Data preparation: N. Wright and M. Whiteman.

Received August 13, 1996; revision received October 17, 1996; accepted October 17, 1996.

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