1 Division of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC.
2 Department of Health Evaluation Sciences, PSU Hershey Medical Center, Hershey, PA.
3 Division of General Medicine, Columbia-Presbyterian Medical Center, New York, NY.
4 Department of Epidemiology, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD.
5 Department of Public Health, Bowman Gray School of Medicine, Winston-Salem, NC.
6 Division of Hypertension, University of Mississippi Medical Center, Jackson, MS.
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ABSTRACT |
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carotid artery; common; education; elasticity
Abbreviations: ARIC, Atherosclerosis Risk in Communities; PADC, pulsatile arterial diameter change.
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INTRODUCTION |
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Noninvasive ultrasound interrogation and measurement techniques have led to the identification and measurement of both the structural and functional components of atherosclerosis in large population-based studies and smaller clinical studies (8,9
). For example, B-mode ultrasound imaging techniques have been successfully developed to measure the thickness of the carotid arterial wall and the presence of plaque (10
12
). Ultrasound echo-tracking of the carotid artery during consecutive cardiac cycles has led to the assessment of arterial function by the measurement of pulsatile arterial diameter change (PADC) (13
). Measurement of arterial diameter change in relation to blood pressure parameters permits the calculation of various indices that putatively measure the elasticity of the vessel. Some of these measures consider the vessel as a hollow structure (compliance, distensibility); others evaluate the constituents of the arterial wall (elastic moduli) (14
). Although there is controversy regarding the conceptual appropriateness of some of these indices and the methodological approaches employed in calculating them (15
), these properties (or perhaps a single property) of the vessel are clearly related to age (16
,17
). Degree of postmortem coronary atherosclerosis (18
), hypercholesterolemia (19
,20
), hyperglycemia, and diabetes mellitus (21) are directly related to decreased arterial elasticity, whereas the association with hypertension is controversialdecreased (22
) or normal (23
25
).
A previous Atherosclerosis Risk in Communities (ARIC) study, which found an inverse association of socioeconomic status with both prevalent coronary heart disease and preclinical atherosclerosis (measured as carotid artery intima-media wall thickness) (6), explored the roles of candidate lifestyle, biochemical, and physiologic variables as potential intervening factors on the pathways from socioeconomic status to atherosclerosis and its clinical sequellae. These factors fully explained the socioeconomic status association with preclinical atherosclerosis, but substantial residual association remained after adjustment for these factors for clinical coronary heart disease. Arterial stiffness as a precursor of clinically important atherosclerosis has been reviewed (26
). The purpose of the present study was to extend this line of research to explore the relation of socio-economic status to carotid artery stiffness in the ARIC population sample of individuals who were free of clinical coronary heart disease and cerebrovascular disease. This was done by determining whether there was an association of socioeconomic status with carotid artery diameter change during the cardiac cycle and, when such an association was detected, by ascertaining whether the established cardiovascular disease risk factors, which vary by socioeconomic status, explained the association.
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MATERIALS AND METHODS |
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When the data from visit 1 and visit 2 were pooled, 11,478 African Americans and European Americans had data permitting the calculation of elasticity of the left common carotid artery. For this study, the sample was further reduced through the following exclusions: 1) African-American examinees in Minnesota and Washington County (n=39); 2) participants with aberrant data on blood pressure (i.e., systolic blood pressure <70 mmHg or pulse pressure 0 mmHg (n=6)); 3) subjects with prevalent coronary heart disease (n=722) or a history of neurologic symptoms consistent with stroke/transient ischemic attack (n=604); and 4) participants with missing data on educational attainment (n=16). The final study sample comprised 10,091 subjects, of which 2,404 were African Americans and 7,687 European Americans; 5,756 were female and 4,335 were male.
Participants included in this study had a more favorable profile than the total ARIC cohort with respect to the distribution of atherosclerosis risk factors (data not shown), as a result of the exclusion of subjects with symptomatic cardiovascular disease. They had higher educational achievement levels, were leaner, smoked less, and consumed less alcohol. They had slightly lower systolic and diastolic blood pressures, less atherosclerosis as measured by intima-media wall thickness of the carotid arteries, and lower levels of biologic cardiovascular disease risk factors, particularly for insulin, total cholesterol, and fibrinogen.
The clinical examinations
Details on the standardized ARIC procedures are provided elsewhere (27). In brief, participants were asked about their educational status during the prebaseline examination interview, during which they reported the highest level of schooling they had completed. The clinical examinations for visits 1 and 2 were conducted at the field centers in the four study communities. Each examination contained staff-administered interviews on demographic factors (age, gender), disease status (coronary heart disease, diabetes, hypertension, stroke, transient ischemic attack), and cardiovascular disease-related behavioral factors (current and former alcohol and cigarette consumption, current use of medications). Physical examinations (height, weight, waist and hip girth, sitting blood pressure) were performed, and fasting blood was drawn for clinical chemical analyses (glucose, insulin, high density lipoprotein cholesterol, low density lipoprotein cholesterol, total cholesterol, and triglycerides).
A noninvasive assessment of atherosclerosis was performed on participants at the baseline ARIC visit and subsequently at the follow-up visit approximately 3 years later. This protocol included B-mode ultrasound scanning of the thickness of the right and left carotid arteries, echo-tracking of arterial diameter in the left common carotid artery, and supine blood pressure measurements taken at 5-minute intervals. Because reliable echo-tracking data were not available until after the majority of participants had completed their baseline examination, in this paper we selected information from visit 2 (90 percent), and if it was not available, we used data from the baseline examination (10 percent). Given the cross-sectional design of our study, the examination in which the covariates were measured was matched to that of the measurement of PADC.
Definition of study variables
The primary outcome measure of this study, pulsatile changes in the diameter of the left common carotid artery during the cardiac cycle, was obtained by echo-tracking methods during the B-mode ultrasound examination of the carotid arteries. The echoes, which correspond to the diametrically opposite media-adventitia interfaces, were identified on an oscilloscopic screen. Employing an arterial wall tracker (Autrec 4881-AWT (Autrec, Winston-Salem, North Carolina)) that used phase-locked loop techniques, centrally trained sonographers positioned electronic gates to track these two interfaces in order to precisely measure online the time interval between the arrival of these two echoes. Assuming a speed in the tissue of 1,540 m/second, the distance between these interfaces as a function of time during consecutive cardiac cycles was automatically calculated, digitized, and displayed on a strip-chart recording for immediate sonographer review (13). Repeat measures of PADC were obtained in a subset of participants at both the baseline and follow-up visits. Over this time, the mean difference in PADC between examination 1 and examination 2 was -6 µm (standard deviation 115), and the Pearson and Spearman correlation coefficients for these measurements were 0.66 and 0.66, respectively (unpublished ARIC data).
PADC was computed as the average difference between the systolic and diastolic adventitial diameters over five cardiac cycles. Supine blood pressure was measured automatically (with DINAMAP equipment (Critikon, Inc., Tampa, Florida)) from the right brachial artery at 5-minute intervals during the ultrasound examination and immediately before and after the PADC measurements were obtained (13). The smaller the PADC, the stiffer the common carotid artery.
Noninvasive ultrasonic B-mode imaging techniques were used to measure arterial wall intima-media thickness from three segments of both extracranial carotid arteries. All measurements were collected and read according to standardized protocols under stringent quality control. The scans were recorded on broadcast-quality videocassettes that were read centrally at the ARIC Ultrasound Reading Center in Winston-Salem, North Carolina (13). The intrasonographer correlation coefficient for maximal far wall thickness was 0.81, and the interobserver coefficient was 0.93 (33
, 34
). Intima-media thickness was defined in two ways: 1) as an overall grand mean intima-media thickness of the six carotid sites, indicative of the general atherosclerotic burden, and 2) as left common carotid artery far wall thickness, indicative of the local burden at the site of PADC measurement.
Self-reported educational achievement was ascertained during the home interview of the baseline examination, and was then collapsed into six levels: 1) grade school, 2) high school without graduation, 3) high school with graduation, 4) vocational school, 5) some college, and 6) graduate or professional school. The demographic factors included a composite variable containing ethnicity and center, to account for the sampling design and the high variability of arterial stiffness measurement across centers. This variable had five categories: African Americans in Jackson and Forsyth County and European Americans in Forsyth County, Minnesota, and Washington County. Age was used as a continuous variable. The behavioral factors included measures of lifetime cigarette and alcohol consumption. Smoking was defined in two ways: 1) as a categorical variable with three levels, never, former, and current smoking, and 2) as a continuous variable assessing lifetime cigarette use in pack-years. Self-reported alcohol consumption was converted into grams of alcohol per week for current drinkers.
The comorbidity variables included histories of coronary heart disease and stroke/transient ischemic attack, as exclusion criteria for creation of the study population, and diabetes and hypertension, for assessment of the effect of comorbid conditions on the associations between socioeconomic status and PADC. Information on prevalent coronary heart disease was derived from the electrocardiographic data or from a history of myocardial infarction, bypass surgery, or angioplasty (35). Prevalent stroke/transient ischemic attack was defined by a self-reported history of neurologic symptoms consistent with a diagnosis of these diseases (36
). Non-insulin-dependent diabetes mellitus was defined as a blood glucose level
140 mg/dl and/or a history of diabetes or oral hypoglycemic medication use. Hypertension was defined as sitting systolic blood pressure
140 mmHg or diastolic blood pressure
90 mmHg, or current use of antihypertensive medication. Sitting blood pressure was measured three times on the right arm of the seated participant with a random-zero sphygmomanometer after a rest period of 5 minutes, before the ultrasound examination. The fifth phase of Korotkoff sounds was used to mark diastolic blood pressure. The mean of the last two measurements was used for blood pressure values (37
).
Anthropometric characteristics included height, body mass index (weight (kg)/height (m)2), and a measure of central obesity (waist:hip circumference ratio). Body mass index was derived from height measured at visit 1 and weight measured at the clinical examination from which the PADC was measured, with the subject in light clothing and no shoes (38). The waist:hip variable was the ratio of waist circumference, measured at the umbilicus, to hip girth, measured at the maximal gluteal protrusion.
For measurement of biologic factors, subjects were asked to fast for 12 hours prior to the clinical examination. Details have been reported elsewhere for blood collection (39,40
) and for centralized measurement of plasma cholesterol (41
,42
), triglycerides (41
,43
), high density lipoprotein cholesterol (41
), calculated low density lipoprotein cholesterol (44
), fibrinogen (45
,46
), and glucose (47
).
Statistical analyses
Summary statistics for variables that might explain the socioeconomic status-PADC associations were computed for the study population, stratified by educational level. Crude and multivariable regression analyses were then performed to assess the potential role of the traditional atherosclerosis-related demographic, behavioral, and biomedical factors in the relation of educational level with PADC. Tests of interaction of selected variables with education in their association with PADC were performed using the full model.
The association between PADC and education was evaluated by means of least-squares regression. Mean PADC (± standard error of the mean) by educational level was adjusted for age, height, diastolic diameter and sitting blood pressure, and linear and squared pulse pressure based on the operational definition of PADC in a previous study of the same population (13). The statistical significance for the association of PADC with education was assessed using the nominal value of p<0.05. The contribution of covariates to the association between education and PADC was evaluated. These covariates were grouped on the basis of commonality of function into: 1) demographic factorsgender and ethnicity/center; 2) behavioral factorsalcohol consumption and cigarette smoking; 3) anthropometric factorsheight, body mass index, and waist:hip ratio; 4) co-morbidity factorsprevalent hypertension and diabetes; 5) biologic risk factorsglucose, insulin, high density lipoprotein and low density lipoprotein cholesterol, triglycerides, and fibrinogen; and 6) atherosclerosis factorsintima-media thickness. The choice of terms was based on theoretical plausibility, prior empirical findings, and their demonstrated association with both education and PADC in this study population. The explanatory effect of these classes of variables was measured by their influence on the pattern of association and the magnitude of the p value for trend upon successive addition of terms to the models.
All analyses were performed using SAS software, version 6.12 (SAS Institute, Cary, North Carolina).
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RESULTS |
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The common carotid artery systolic and diastolic adventitial diameters and both measures of wall thickness (global intima-media thickness and left far wall thickness) monotonically decreased with increasing educational level (table 2). Crude PADC increased as educational level increased, varying by a magnitude of 24 µm between the extreme educational levels. The population distribution of PADC was slightly skewed but unimodal (data not shown).
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DISCUSSION |
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There is renewed interest in studying large artery mechanical properties owing to a set of findings. First, large scale epidemiologic studies have shown that systolic blood pressure, a major correlate of arterial elasticity, is a stronger determinant than diastolic blood pressure for cardiovascular events such as left ventricular hypertrophy, stroke, carotid atherosclerosis, cardiac failure, and death (4852
). Second, disease of large vessels has been demonstrated to differ from disease of small vessels (53
). Finally, recent data on patients with allograft coronary artery disease (54
,55
) and patients who have undergone coronary angioplasty (56
) suggest that impairment of arterial dilation may precede arterial wall thickening.
Classical indices of arterial elasticity are ratios expressing the arterial strain (artery relative diameter change) in response to a given stress (blood pressure variations) (31,32
). Because of the nonlinear elastic and viscous nature of the artery wall constituents, arterial mechanical properties are strongly dependent on level of blood pressure, and therefore they vary throughout the cardiac cycle. The nonlinear characteristic of this dose-response curve has led investigators to find ways to account for blood pressure dependency. This has been achieved in several ways. The first approach expanded the study of vascular functional properties by exploring the microscopic properties of wall tissues and their structural arrangement. This approach, though the most accurate, has two disadvantages: 1) measurements are made experimentally, far from physiologic conditions, and 2) analyses of these measurements require the incorporation of a large number of parameters into the statistical models (57
). Second, Gribbin et al. (58
) took a mechanical approach, by blocking the arm where measurements were made in a cuff, in order to maintain a constant blood pressure. This approach was informative, but it is not practical for large scale epidemiologic studies. The third method is phenomenologic, whereby investigators derive an empirical, specific function that matches the experimental data. This approach has been widely used in clinical settings since Tardy et al.'s influential study (14
). This method requires both arterial diameter and blood pressure pulsatile data. Once the best function is found, i.e., the one that yields the least residual mean square of the regression of diameter on blood pressure, classical ratio indices of elasticity are used wherein diameter is expressed as a function (the best) of pressure. This method has two advantages: 1) the diameter-pressure relation is modeled by nonlinear regression and 2) subgroups are compared at the same distending pressure. It is this method that first yielded the controversial result that large artery elasticity is not impaired in hypertensive persons compared with age-matched normotensive persons (23
,24
). Finally, a variant of the previous method, which we term "analytical," consists of modeling the shape of the diameter-pressure association in the statistical analysis phase. This can be done either by using an index that is independent (data proven) of blood pressure, such as the arterial stiffness beta index (29
,30
), or by statistically adjusting for blood pressure in such a way as to obtain a nonlinear associatione.g., blood pressure modeled as a quadratic term (13
). The elasticity index that we used belongs to the latter: The absolute pulsatile adventitial diameter change is adjusted for pulse pressure modeled as a quadratic term (13
). In the ARIC Study, the curve relating PADC to pulse pressure has a nonzero intercept (15
). Thus, modeling strain as the outcome variable and stress as the predictor avoids the nonzero intercept assumption imposed by the use of ratio indices. However, one weakness of fitting a polynomial on a nonlinear association is the potential lack of fit at the extreme ranges of blood pressure. Nevertheless, the analytical approach is the only one that can be used when only one kind of pulsatile data is available.
Because the purpose of this investigation was to describe and quantify the relation of educational achievement level with carotid artery elasticity, it is useful to identify the causal pathways linking these two characteristics. We envision them as being at two distinct levels of organization: educational achievement as a surrogate, summary index of socioeconomic status and PADC as an index of carotid artery elasticity. Socioeconomic status reflects the command of societal resources which individuals can marshal. It encompasses material, financial, prestige, and knowledge dimensions, which singly or interactively influence health-relevant behaviors and physical, social, and psychological environmental exposures. The intervening links from the societal to the psychological to the arterial level constitute the established cardiovascular risk factors. The plausibility of this conceptualization was demonstrated in the finding of strong inverse associations of educational achievement with carotid artery intima-media thickness in the ARIC cohortassociations which were completely statistically accounted for by the established coronary heart disease risk factors (6). The associations were present among individuals who were free of clinical coronary heart disease, and the measure of wall thickness served as an indicator of preclinical atherosclerosis. It was postulated for the present study that intima-media thickness might predominantly reflect the atherotic component and that PADC might describe the sclerotic component of the pathologic complex of atherosclerosis.
The results of this study are consistent with the conceptual framework: They indicated that arterial elasticity of the common carotid artery was directly associated with education in this population, which was free of coronary heart disease and/or stroke/transient ischemic attack. This association was independent of age, height, artery size, and blood pressure and was further accounted for by ethnicity/center, obesity (body mass index, waist:hip ratio), biologic factors (glucose, insulin, lipids, fibrinogen), hypertension, and diabetes. Alcohol consumption did not contribute to this association at all, but covariates measured with error such as this one may bias estimates of their effects in either direction (59). Measures of elasticity varied markedly by study center, and statistical control for center site eliminated the overall statistical significance of the association of educational level with arterial elasticity. Data with which to assess the possibility of measurement (operator) differences across centers were not available. Furthermore, the strong association of educational level with study center raises the question of center-specific socioenvironmental influences on arterial elasticity for which statistical adjustment may be inappropriate in the context of the present investigation of socioeconomic status effects.
In this cross-sectional study, PADC was strongly and nonlinearly associated with left far wall carotid intima-media thickness, the index of local atherosclerosis burden, and was borderline and linearly associated with global carotid intima-media thickness. This finding may be explained by the site-specificity of indices of arterial elasticity. The site-specificity results from the tubular and distributed nature of the arterial system, which leads to difference in absolute pressure along the arterial tree at the same point in time, and from the difference in the artery wall composition along this tree. As a consequence, both dimensions and pressure should ideally be measured at the same site (60). Brachial blood pressure correlates very well with intracarotid pressure, though it is higher as a result of the amplification phenomenon (60
). Brachial peak systolic pressure has been reported to be higher than that in the aorta by 1520 mmHg, and brachial pulse pressure has been reported to be higher than carotid pulse pressure by 1015 percent (16
). Another point to consider is the measurement of external rather than internal carotid arterial diameter in the ARIC Study. The external diameter is indeed subject to the compensatory enlargement; i.e., as the degree of atheroma (approximated by intima-media thickness) increases, the adventitial diameter increases up to a certain point where it starts to level off, resulting in a constant and then decreased internal diameter (61
). Thus, the association between PADC and any risk factor should ideally be investigated with the data stratified by intima-media thickness.
All cardiovascular risk factors except smoking impacted on PADC in the expected direction. Participants who reported being current smokers had the largest PADCs. Similarly, PADC increased with pack-years of cigarette smoking in a nonlinear manner. This association was not statistically explained by blood pressure or by viscosity factors evaluated by fibrinogen and/or hematocrit measurement. Smoking increases blood viscosity, which has been reported to increase shear stress, which in turn stimulates nitric oxide production (62). Most of the literature reports a harmful effect of cigarette smoking on both arterial dilatation and thickening (63
), though recent experimental or very small scale in vivo studies have reported endothelium-dependent dilatation of the carotid artery (64
) and pulmonary circulation (65
) and an increase of cerebral blood flow by acute smoking (66
). Smokers had a positive, though not significant, distensibility coefficient in the SMART (Second Manifestations of Arterial Disease) Study (67
). Smoking has also been found to be associated with greater interadventitial and internal diameters of the common carotid artery, a finding possibly related to elastin damage or production of functionally deficient elastin (68
). The structural or functional decrease in elastin, however, cannot explain the increase in PADC among the smokers.
In conclusion, low educational achievement is associated with increased stiffness of the common carotid artery. If arterial dilation/elasticity impairment precedes arterial wall thickening in the atherosclerotic process, as recent studies on endothelial dysfunction suggest, these results indicate that low socioeconomic status may lead to early pathophysiologic changes of large arteries. This effect appears to be mediated by known risk factors such as obesity, lipids, glucose, fibrinogen, hypertension, diabetes, and carotid thickeningcardiovascular risk factors which are more prevalent among individuals of lower socioeconomic status. The findings of the ARIC Study suggest a continuous direct relation of increasing arterial elasticity with increasing education.
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ACKNOWLEDGMENTS |
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The authors thank the staff of the ARIC Study for their important contributions.
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NOTES |
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REFERENCES |
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