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(Stroke. 1996;27:654-660.)
© 1996 American Heart Association, Inc.

Articles

Factors of Carotid Arterial Enlargement in a Population Aged 59 to 71 Years

The EVA Study

Claire Bonithon-Kopp, MD, PhD; Pierre Jean Touboul, MD; Claudine Berr, MD; Christine Magne, MD Pierre Ducimetière, PhD

From INSERM U 258 (C.B.-K., P.D.), Centre de Diagnostic et de Prévention Neurovasculaire (P.J.T.), and INSERM U 360 (C.B.), Paris; and Centre d'examen EVA (C.M.), Nantes, France.

Correspondence to Claire Bonithon-Kopp, MD, PhD, INSERM U 258, Hôpital Broussais, 96 rue Didot, 75674 Paris Cedex 14, France.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Factors of carotid arterial enlargement are not well known in general populations. The purpose of this study was to assess the cross-sectional associations of arterial wall lesions and cardiovascular risk factors with carotid lumen diameter in elderly subjects.

Methods B-mode ultrasound examinations of the carotid arteries and risk factor assessment were made in 1272 participants in the EVA (Etude sur le vieillissement artériel) Study, a longitudinal study designed to evaluate vascular and cognitive aging in men and women aged 59 to 71 years. Ultrasound examinations included measurements of intima-media thickness (IMT) and interadventitial and lumen diameters of the common carotid arteries and quantification of atherosclerotic plaques in extracranial carotid arteries.

Results Men showed greater IMT and interadventitial and lumen diameters of the common carotid arteries than did women. In both sexes, common IMT and plaque score were positively associated with common interadventitial and lumen diameters. Stepwise multiple regression analysis showed that male sex, body height and weight, common IMT, plaque score, systolic blood pressure, and alcohol consumption were positively and independently related to lumen diameter. On the other hand, an independent negative association was observed between low-density lipoprotein cholesterol and lumen diameter.

Conclusions In 59- to 71-year-old subjects, increased IMT and atherosclerotic plaques were accompanied by an increase in lumen diameter of the common carotid arteries, indicating an overcompensation. Luminal enlargement observed with several risk factors and with high blood pressure in particular might be partially counteracted by high lipid levels.

Key Words: aging • carotid arteries • epidemiology • ultrasonics

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Recent advances in high-resolution B-mode ultrasound technique have enabled the quantitative evaluation of atherosclerotic lesions in superficially located arteries such as carotid and femoral arteries. B-mode ultrasonography allows detection of minimal arterial wall abnormalities long before the appearance of luminal narrowing and hemodynamic disturbances. Until now, B-mode studies have mainly focused on assessment of IMT of the carotid arteries and on its relation to cardiovascular risk factors^{1 2 3 4 5 6 7 8 9 10 11 12 13 14 15} and to both prevalent^{16 17 18 19} and incident²⁰ cardiovascular disease. Relatively little attention has been given to variations in lumen diameter accompanying arterial wall thickening despite their potential importance in the development of symptoms and clinical complications of atherosclerosis. Some pathoanatomic studies have suggested that during the early stages of the atherosclerotic process, adaptive and compensatory mechanisms may prevent lumen reduction of the coronary arteries by increasing artery size.^{21 22 23} Recent ultrasonographic studies have also suggested that compensatory enlargement of the carotid arteries might occur in response to arterial wall thickening²⁴ and plaque progression.²⁵ However, other factors such as aging or hypertension may be involved in arterial enlargement²⁶ and account in part for its association with the atherosclerotic process. Thus, a systematic evaluation of factors likely to modify arterial lumen and to interfere with artery remodeling in the presence of atherosclerosis is needed for a better pathophysiological understanding of arterial wall behavior.

The present analysis, based on baseline data from the EVA Study, aimed to examine the cross-sectional relationships between ultrasonographic measurements of common carotid interadventitial and lumen diameters and both common IMT and atherosclerotic plaques and to determine which factors may influence these associations in an elderly general population.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The EVA Study is a 4-year longitudinal study on vascular and cognitive aging. The study population was composed of volunteers aged 59 to 71 years recruited from electoral rolls of the city of Nantes (western France) and, to a lesser extent, through information campaigns. When a subject was recruited, his or her spouse was systematically asked to participate in the study if he or she was in the desirable age range. During the baseline visit, which took place between June 1991 and July 1993, 1389 subjects were recruited, and high-resolution B-mode ultrasound examinations of the carotid arteries were performed in 1384 of them. The study protocol was approved by the Comité d'Ethique du Centre Hospitalier Universitaire de Kremlin-Bicêtre, and written consent was obtained from all participants.

Ultrasonography
Ultrasound examinations were performed by four sonographers using the Aloka SSD-650, with a transducer frequency of 7.5 MHz. This system provides an axial resolution of 0.30 mm. Acquisition, processing, and storage of B-mode images were computer-assisted with a software specially designed for longitudinal studies (EUREQUA, TSI).²⁷

Details of the protocol have been described elsewhere.¹⁵ All measurements were made at the time of examination. Briefly, it involved scanning of the common carotid arteries, the carotid bifurcations, and the origin (first 2 cm) of the internal carotid arteries. The IMT was measured on the far wall of the mid and distal common carotid artery as the distance between the lumen-intima interface and the media-adventitia interface²⁸ with the use of an automated edge detection algorithm. One transversal and two longitudinal measurements of IMT were completed on both the right and left common carotid arteries at a site free of any discrete plaques. Optimal images showing the far wall were stored on an optical disk. On such images, the lumen-intima interface is often more difficult to visualize on the near wall than the media-adventitia interface, and thus we chose to measure the interadventitial diameter (defined as the distance between both media-adventitia interfaces) rather than the lumen diameter. On each side, the lumen diameter was computed as the interadventitial diameter minus twice the transversal IMT. Generally, the means of the right and left IMT and diameters were used in the analysis.

Both near and far walls of all arterial segments were scanned longitudinally and transversely to assess the occurrence of plaques, defined as localized echo structures encroaching into the vessel lumen for which the IMT was 1 mm. The quantification of plaque thickness was made by measuring the IMT at the site of maximal encroachment perpendicular to the vessel wall, and the sonographer could be computer-assisted in the identification of interfaces and placement of electronic calipers by examining the inflections of the density profile curve taken at the site of plaque. When several plaques were present on the same arterial segment (ie, common carotid artery or bifurcation or origin of the internal carotid artery), the examination was focused on that showing the greatest encroachment into the lumen. When a plaque was mineralized, the sonographer had to obtain the best incidence so that the plaque could be visualized on the far wall, and an estimation of the IMT was made by extrapolating the adjacent media-adventitia interface. A plaque score was computed by averaging all plaque thicknesses measured on longitudinal views and graded as follows: 0, no plaque; 1, mean thickness 1 mm and 2 mm; 2, mean thickness >2 mm and 3 mm; and 3, mean thickness >3 mm. For all arterial segments, optimal longitudinal and transverse images were stored on an optical disk.

For quality assessment, a rereading study was made on random subsamples of images of both common carotid arteries and bifurcation or origin of internal carotid arteries as described elsewhere.¹⁵ Mean absolute differences and correlation coefficients between repeated readings were, respectively, 0.06 mm and 0.82 for longitudinal common IMT (n=81), 0.22 mm and 0.92 for common interadventitial diameter (n=81), 0.24 mm and 0.90 for common lumen diameter (n=74), and 0.40 mm and 0.78 for plaque thickness (n=52). In a previous work from our group, it was shown that both the interobserver and intraobserver variabilities of common IMT associated with the scanning procedure were substantially reduced after the repositioning functions of the EUREQUA software were used. The aforementioned variabilities (expressed as absolute differences and correlation coefficients) were 0.10 mm, r=.58 and 0.10 mm, r=.62, respectively, with standard procedures, whereas corresponding values obtained with repositioning procedures were 0.07 mm, r=.71 and 0.06 mm, r=.77, respectively.²⁷

Ultrasound examinations performed early in the study (June to October 1991) were considered unreliable and were excluded from the analysis (n=77). Subjects with missing data for IMT or interadventitial diameter measurements because of poor interface visualization (n=40) were also excluded. Thus, the study sample was composed of 1272 subjects (523 men and 749 women).

Medical History
All participants were administered a standardized questionnaire that gave information about demographic background, occupation, medical history, drug use, and personal habits such as cigarette and alcohol consumption. With respect to smoking behavior, subjects were classified as current smokers, former smokers, and never smokers. Alcohol consumption was determined from the subject's estimate of the average amount of alcoholic beverages ingested weekly and expressed in milliliters of alcohol per day. Two independent measurements of systolic and diastolic blood pressures were made with a digital electronic tensiometer (SP9 Spengler) after a 10-minute rest, and the mean was used in the analysis. Hypertension was defined as systolic blood pressure 160 mm Hg or diastolic blood pressure 95 mm Hg or use of antihypertensive drugs. The body mass index was computed as weight (in kilograms) divided by height (in meters) squared. A subject was considered diabetic if he reported medical history of diabetes or use of antidiabetic drugs or had a fasting plasma glucose level 7.8 mmol/L (1.40 g/L). History of coronary heart disease was defined as self-reported history of myocardial infarction or angina pectoris.

Laboratory Methods
Blood samples were drawn between 8 and 9 AM after a 12-hour fast. Total cholesterol and triglyceride assays were performed by enzymatic methods with the use of the PAP enzymatic cholesterol kit (Reference 61227) and the PAP enzymatic triglyceride kit (Reference 759350), respectively, supplied by Biomérieux. Glucose was determined by the enzymatic glucose oxidase method (Reference 61274, Boehringer). HDL cholesterol was measured enzymatically after precipitation of apolipoprotein B-containing lipoproteins with phosphotungstic acid and Mg²⁺ ions (precipitant: Reference 543004, Boehringer). LDL cholesterol was computed with the Friedewald formula.²⁹ All determinations were made daily.

Statistical Analysis
Standard procedures from the Statistical Analysis System (SAS) were used for univariate and multivariate analyses. Descriptive data on common interadventitial and lumen diameters and their associations with IMT and plaque score were given separately in men and women. Two-way ANOVA was used to examine whether the associations between common carotid diameters and IMT divided according to approximate quartiles were modified by the presence of carotid plaques. Because of the similarity of the associations between common carotid diameters and IMT, plaque score, and conventional risk factors in men and women, results were presented in both sexes combined after adjustment for sex and height by either ANOVA or linear regression analysis according to the categorical or continuous nature of the risk factor. The independent predictors of lumen diameter were examined in a stepwise regression model in which IMT (as a continuous variable), plaque score, and each risk factor significantly associated with lumen diameter in preceding analyses were introduced as independent variables (F statistic to enter and to stay in the model with a value of P<.05).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The B-mode ultrasound variables and the main clinical characteristics of the study population are presented in Table 1. Greater common interadventitial diameter, lumen diameter, and IMT were found in men compared with women (P<.0001). Although carotid plaques were more frequent in men than in women (P<.0001), there were no differences between sexes in the mean thickness of these plaques. Only two subjects had plaques inducing a stenosis of >40% of the lumen area.

View this table: [in this window] [in a new window]   Table 1. Ultrasound Variables and Main Clinical Characteristics of the Study Population

The regression coefficients of common interadventitial and lumen diameters on common IMT are first described for the right and left side separately in Table 2. Since the associations were very close for each side, the mean (right and left/2) diameters and IMT were used in subsequent analyses. As shown in Table 3, there was a progressive increase in both interadventitial and lumen diameters according to the quartile of IMT and to plaque score in men as well as in women. Body height was an important determinant of interadventitial and lumen diameters in both sexes (correlation coefficients ranging from 0.11 to 0.18). Thus, subsequent analyses were performed in the whole population after systematic adjustment for sex and height. The Figure shows the mean sex- and height-adjusted lumen diameter by quartiles of IMT and plaque status (presence or absence). The positive association between lumen diameter and IMT was similar in subjects with and in those without carotid plaques (the interaction term between IMT and plaque status was not significant in each sex separately or in both sexes).

View this table: [in this window] [in a new window]   Table 2. Linear Regression of Common Interadventitial and Lumen Diameters on Common IMT

View this table: [in this window] [in a new window]   Table 3. Common Interadventitial and Lumen Diameters by Quartiles of Common IMT and Carotid Plaque Score

View larger version (32K): [in this window] [in a new window]   Figure 1. Mean common carotid lumen diameter by quartiles of common IMT and plaque status. SEs are indicated.

The sex- and height-adjusted associations between common carotid diameters and conventional risk factors are shown in Table 4 (categorical variables) and Table 5 (continuous variables). Interadventitial and lumen diameters increased in subjects with a clinical history of hypertension, diabetes, or coronary heart disease. Greater diameters were also observed in drinkers of >40 mL/d of alcohol. Interadventitial diameter was slightly increased in ex-smokers and current smokers compared with nonsmokers, but this trend was not significant with lumen diameter. As indicated in Table 5, the strongest correlate of both interadventitial and lumen diameters was systolic blood pressure. Positive associations were also found between both common carotid diameters and age, diastolic blood pressure, body weight, alcohol consumption (as a continuous variable), triglycerides, and blood glucose. Weak negative associations were observed between HDL cholesterol and interadventitial diameter and between LDL cholesterol and lumen diameter.

View this table: [in this window] [in a new window]   Table 4. Sex- and Height-Adjusted Values of Common Interadventitial and Lumen Diameters According to Some Clinical Characteristics

View this table: [in this window] [in a new window]   Table 5. Linear Regression1 of Common Interadventitial and Lumen Diameters on Cardiovascular Risk Factors

All variables significantly associated with lumen diameter were considered as candidate variables in a stepwise multiple regression model. A preliminary multiple regression analysis had revealed that cardiovascular risk factors and use of antihypertensive, hypolipidemic, or antidiabetic drugs had no modifying effect on the relationships between lumen diameter and both common IMT and plaque score (interaction terms between each risk factor or drug use and IMT or plaque score were all insignificant). Stepwise multiple regression analysis presented in Table 6 showed that male sex, systolic blood pressure, body height, IMT, plaque score, body weight, and alcohol consumption were independently and positively associated with lumen diameter, whereas LDL cholesterol remained negatively related to lumen diameter. Altogether, these variables explained 31.9% of the lumen diameter variance. On the other hand, age, diabetes, triglycerides, glucose, and coronary heart disease did not enter the regression model. Exclusion of subjects who reported a clinical history of coronary heart disease did not consistently affect these results. Since many subjects were receiving drugs likely to alter the relationships between lumen diameter and some risk factors, stepwise regression analysis with the same candidate variables was repeated in subjects free of any treatment for hypertension, hypercholesterolemia, or diabetes. All variables except for alcohol consumption remained independently associated with lumen diameter. However, we noted that the association between lumen diameter and IMT was reduced by approximately 35% mainly because this association was much more pronounced in subjects taking antihypertensive drugs.

View this table: [in this window] [in a new window]   Table 6. Stepwise Multiple Linear Regression of Lumen Diameter on IMT, Plaque Score, and Cardiovascular Risk Factors

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The main finding of the present B-mode ultrasonographic study was that the common lumen diameter was closely related to modifications of the arterial wall. After the predominant effects of sex, systolic blood pressure, and body height had been ruled out, increased common IMT and plaque score remained major determinants of increased common lumen diameter. Furthermore, this study revealed that less expected factors such as alcohol consumption and low levels of LDL cholesterol contributed independently to increased common lumen diameter.

Several considerations should be kept in mind before interpreting these results. First, our population sample was composed of elderly subjects who volunteered to participate in the study. Because of possible survival and self-selection biases, we cannot exclude the possibility that subjects with severe atherosclerosis inducing lumen narrowing were more likely to refuse to participate. This is suggested by the scarcity of hemodynamically significant stenoses observed in the study subjects and their low mean levels of common IMT. Thus, it is clear that the positive associations we found between lumen diameter and alterations of arterial wall can only be generalized to elderly persons with a low degree of atherosclerosis. Second, an important limitation of our ultrasound methodology lies in the inability of our B-mode system to standardize the image recording according to the stage of the cardiac cycle, which may introduce a nonnegligible source of variability in our measurements and thus lead to decreased statistical power. However, because the systolic expansion of the arterial lumen is accompanied by a concomitant diminution of the wall thickness, this methodological limitation cannot be responsible for a spurious positive association and may only lead to an underestimation of the true relationship between lumen diameter and IMT. Third, this study is cross-sectional and thus does not allow us to determine the temporal sequence of the observed modifications.

In fact, the associations we found between common lumen diameter and both common IMT and plaque score are compatible with previous pathoanatomic observations suggesting that coronary arteries tend to enlarge in response to atherosclerosis.^{21 22 23} Recently, a large B-mode ultrasonographic study performed in men and women aged 45 to 64 years extended these findings to carotid arteries.²⁴ Some of their results showing a small negative correlation between lumen diameter and IMT in the common carotid arteries contrast with ours, which suggest an overcompensation of the arterial lumen in the presence of increased IMT. These discrepancies are probably due at least partially to differences in ultrasound methodology since in our study IMT was never measured at the site of plaques (no IMT values >1.5 mm), which are more likely to induce a lumen narrowing. Glagov et al²² demonstrated that the positive correlation between artery size and plaque area was particularly strong in the sections of the coronary arteries with 20% stenosis and that the decline in lumen area became evident only for stenosis values >40%. On the other hand, our study was performed in elderly subjects, and mechanisms by which lumen area and intima-media thickening are mutually adapted might be altered in the presence of degenerative changes in connective tissue associated with aging. The independent contribution of plaque score and increased IMT to increased lumen diameter may indicate that luminal enlargement reflects generalized atherosclerosis. However, it may also suggest that mechanisms underlying the association between luminal enlargement and increased IMT in the common carotid arteries may be different in part from those underlying its association with atherosclerosis. Furthermore, our study suggests that the mutual adaptation of lumen diameter and IMT does not depend on whether subjects have confirmed lesions of atherosclerosis.

Several cardiovascular risk factors were independently related to increased lumen diameter, which partially explains its association with IMT or plaque score. In addition to nonmodifiable risk factors such as sex and body height, increased systolic blood pressure appeared as one of the most important correlates of increased lumen diameter. An association between hypertension or high blood pressure and enlargement of the common carotid artery was reported in several noninvasive studies with the use of either B-mode ultrasonography^{10 12 30 31} or echo-tracking techniques^{32 33} but not in all.^{8 11 12 34} In our elderly population, the independent contribution of IMT and increased blood pressure, a known correlate of IMT, to increased lumen diameter suggests that the latter is not solely a compensatory response to wall thickening. It may also be due to the fatiguing effects of elevated blood pressure and cyclic stress on elastic fibers over many years, resulting in degenerative changes and stiffening of the arterial wall.²⁶ Other cardiovascular risk factors weakly contributed to increased lumen diameter in our population. As far as we know, the associations we observed between lumen diameter and both alcohol consumption and LDL cholesterol (inverse association) have never been described and thus need confirmation. There are few data concerning the relation of alcohol consumption to arterial wall characteristics. No association was found with IMT in the present study¹⁵ or in a previous ultrasonographic study in middle-aged subjects.³⁵ Moreover, no association has been reported between alcohol intake and carotid³⁵ or aortic³⁶ distensibility. Since alcohol intake has been positively associated with internal dimension of the left ventricle independently of blood pressure in a nonalcoholic general population,³⁷ we cannot exclude that some common mechanisms might underlie the association between alcohol consumption and increased vascular and ventricular internal dimensions. The most intriguing finding from this study was the weak negative association between LDL cholesterol and common lumen diameter. We are not aware of previous ultrasonographic studies that examined such an association in large populations. In a pathoanatomic study on coronary arteries, total cholesterol was not predictive of lumen area²³ and thus we cannot exclude that our finding may have been due to chance. On the other hand, a paradoxical increase in aortic distensibility with total or LDL cholesterol contrasting with the effects of blood pressure has been reported,^{36 38} but not consistently.³⁹ We have no clear explanation of the mechanisms by which lipid disorders might inhibit the general trend of the common carotid artery to dilate with aging and hypertension. Our data only suggest that intima-media thickening and early atherosclerotic plaques are not involved in the reduction of the lumen diameter associated with increased lipid levels.

In conclusion, our study indicates that increased common lumen diameter was independently associated with increased IMT, atherosclerotic plaques, and several modifiable lifestyle risk factors. It suggests that carotid arterial enlargement accompanying aging and high blood pressure may be partially counteracted by high lipid levels in elderly subjects. These results need to be confirmed in younger populations, and longitudinal studies are required to determine their significance with regard to the progression of atherosclerosis and development of symptoms.

	Selected Abbreviations and Acronyms

 

EVA = Etude sur le vieillissement artériel HDL = high-density lipoprotein IMT = intima-media thickness LDL = low-density lipoprotein

	Acknowledgments

 
The EVA Study is organized under an agreement between INSERM and the Merck, Sharp, and Dohme-Chibret Company. We thank the ultrasound physicians, Drs J.M. Fève, C. Leroux, and I. Ruelland. We are grateful to D. Courbon for her expert technical assistance in handling and controlling computerized data and to C. Delanoe and S. Bachelier for their secretarial and technical support.

Received October 26, 1995; revision received January 2, 1996; accepted January 5, 1996.

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