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Circulation. 1997;96:4219-4225

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(Circulation. 1997;96:4219-4225.)
© 1997 American Heart Association, Inc.

Articles

Circulating Adhesion Molecules VCAM-1, ICAM-1, and E-selectin in Carotid Atherosclerosis and Incident Coronary Heart Disease Cases

The Atherosclerosis Risk In Communities (ARIC) Study

Shih-Jen Hwang, PhD; Christie M. Ballantyne, MD; A. Richey Sharrett, MD; Louis C. Smith, PhD; Clarence E. Davis, PhD; Antonio M. Gotto, Jr, MD; ; Eric Boerwinkle, PhD

From the Human Genetics Center (S.-J.H., E.B.) and Institute of Molecular Medicine (E.B.), University of Texas–Houston Health Science Center; the Department of Medicine, Baylor College of Medicine (C.M.B., L.C.S., A.M.G.), Houston, Tex; the Epidemiology and Biometry Program, National Heart, Lung, and Blood Institute, Bethesda, Md (A.R.S.); and the Department of Biostatistics, University of North Carolina School of Public Health, Chapel Hill (C.E.D.).

Correspondence to Eric Boerwinkle, PhD, Human Genetics Center, PO Box 20334, Houston, TX 77225. E-mail eboerwin{at}gsbs.uth.tmc.edu


*    Abstract
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Background Recruitment of circulating leukocytes at sites of atherosclerosis is mediated through a family of adhesion molecules. The function of circulating forms of these adhesion molecules remains unknown, but their levels may serve as molecular markers of subclinical coronary heart disease (CHD).

Methods and Results To determine the ability of circulating vascular cell adhesion molecule-1 (VCAM-1), endothelial-leukocyte adhesion molecule-1 (E-selectin), and intercellular adhesion molecule-1 (ICAM-1) to serve as molecular markers of atherosclerosis and predictors of incident CHD, we studied 204 patients with incident CHD, 272 patients with carotid artery atherosclerosis (CAA), and 316 control subjects from the large, biracial Atherosclerosis Risk In Communities (ARIC) study. Levels of VCAM-1 were not significantly different among the patients with incident CHD, those with CAA, and control subjects. Higher levels of E-selectin and ICAM-1 were observed for the patients with CHD (means [ng/mL]: E-selectin, 38.4; ICAM-1, 288.7) and those with CAA (E-selectin, 41.5; ICAM-1, 283.6) compared with the control subjects (E-selectin, 32.8; ICAM-1, 244.2), but the distributions were not notably different between the patients with CHD and CAA. Results of logistic regression analyses indicated that the relationship of ICAM-1 and E-selectin with CHD and CAA was independent of other known CHD risk factors and was most pronounced in the highest quartile. The odds of CHD and CAA were 5.53 (95% CI, 2.51–12.21) and 2.64 (95% CI, 1.40–5.01), respectively, for those with levels of ICAM-1 in the highest quartile compared with those in the lowest quartile. Odds of CAA were 2.03 (95% CI, 1.14–3.62) for those with levels of E-selectin in the highest quartile compared with those in the lowest quartile.

Conclusions These data indicate that plasma levels of ICAM-1 and E-selectin may serve as molecular markers for atherosclerosis and the development of CHD.


Key Words: atherosclerosis • coronary heart disease • adhesion molecules


*    Introduction
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Atherosclerosis and its clinical sequelae remain the leading causes of morbidity and mortality in both men and women of all racial groups in the United States and most westernized societies.1 Development of atherosclerosis is characterized by a steady accumulation of inflammatory molecules, complex lipids, and fibrin sometimes culminating in clinically recognized events (ie, CHD).2–6 Accumulated evidence indicates that a majority of clinical events result from mild to modest coronary lesions that abruptly progress to severe obstructions.7 Lesions prone to plaque disruption are those with a large core lipid pool and a structurally weakened fibrous cap.8 Lipid-lowering therapy has proved to be efficient in deterring plaque progression.9 However, the cost-effectiveness of lipid-lowering therapy varies with CHD risk factors and duration of intervention.10 Early detection programs rely on diagnostic techniques such as ultrafast CT scans11 and positron emission tomography or coronary angiography, which are expensive and cannot be easily offered in all practice settings.12 Advances in our knowledge of the molecular basis of atherosclerosis make possible the development of molecular markers that can be measured in plasma or serum and used for the identification of individuals at high risk of CHD.13

Binding and recruitment of circulating leukocytes to the vascular endothelium and further migration into the subendothelial spaces are major processes in the development of atherosclerosis and are mediated through a diverse family of cellular adhesion molecules that are expressed on the surface of vascular endothelial cells.14 Among the identified adhesion molecules, the expression and biological properties of VCAM-1, endothelial-leukocyte adhesion molecule-1 (E-selectin), and ICAM-1 are well characterized.15–22 The accumulated data imply that selectins mediate initial rolling of leukocytes along the endothelium and that VCAM-1 and ICAM-1 play important roles in the firm attachment and transendothelial migration of leukocytes. These molecules have been observed consistently within the milieu of the atherosclerotic plaque. Results of immunohistochemical studies show different levels of expression of these molecules that reflect their unique structural and functional characteristics.23–28 Circulating forms of VCAM-1, E-selectin, and ICAM-1 have been detected in plasma and are elevated during inflammatory conditions in which detailed pathology studies have documented increased expression of cellular adhesion molecules on endothelial cells and other tissue types.15,29,30 The origins of circulating VCAM-1, E-selectin, and ICAM-1 are unclear, but they may arise from shedding or proteolytic cleavage from endothelial cells.31,32 The present study is based on the hypothesis that circulating levels of VCAM-1, E-selectin, and ICAM-1 may be useful markers for increased expression of cellular adhesion molecules in atherosclerosis. To test the hypothesis, we examined the relationship between levels of circulating VCAM-1, E-selectin, ICAM-1, and the extent of atherosclerosis as identified by B-mode ultrasound. We also tested whether the levels of circulating adhesion molecules predict the risk of incident CHD in the ARIC study, in which the CHD patients were identified during a 5-year follow-up period.


*    Methods
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 *Methods
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The sample for this investigation was selected from the large, biracial ARIC study. This cohort study was designed to investigate the causes of atherosclerosis and its clinical sequelae and variation in cardiovascular risk factors. The study population consisted of 15 792 adults 45 to 64 years old in four US communities: Forsyth County, North Carolina; Jackson, Miss; the northwestern suburbs of Minneapolis, Minn; and Washington County, Maryland. All subjects in Jackson and 12% of those in Forsyth County were black; most others were white. A complete description of the design, objectives, sampling strategies, and examination techniques of the ARIC study was published previously.33 For this analysis, three groups were defined: patients with incident CHD, those with CAA, and control subjects. The CHD cases consisted of patients with fatal and nonfatal events, including surgical revascularization procedures and undiagnosed myocardial infarction, that were identified after the first examination of the cohort (November 1986 to November 1989) and who had complete data as of July 1994. The criteria for fatal CHD were based on chest pain, the underlying cause of death from the death certificate, and other medical information. The criteria for nonfatal CHD events were based on combinations of chest pain symptoms, ECG changes, cardiac enzyme levels, and surgical revascularization procedures. All potential CHD events were reviewed by two members of the ARIC Morbidity and Mortality Classification Committee, and differences between the two reviewers were adjudicated by the chairperson of the committee. Carotid artery wall thickness was measured by a bilateral high-resolution B-mode ultrasound examination of the extracranial carotid arteries at three segments (the distal section of the common, the bifurcation, and the proximal portion of the internal carotid arteries).34 CAA patients are ARIC participants having a minimum average intima-media far-wall thickness >1.0 mm at visits 1 and 2. The control subjects were identified as having an average intima-media far-wall thickness <0.68 mm at visits 1 and 2. These intima-media thickness cutpoints correspond approximately to the 95th and 30th percentiles, respectively, of the ARIC cohort. One or two control subjects were randomly selected for each CAA case within relevant sex and age (<55 years, >=55 years) strata. These ultrasound-defined patients and control subjects could not have symptomatic cardiovascular or cerebrovascular disease at visit 1 or 2, and they could not have already been identified as incident CHD patients. Exclusion criteria included reported prevalent coronary heart disease at visit 1, a <12-hour fast before the examination, and races other than black or white.

Blood samples and the data presented here were collected at the baseline examinations. Levels of plasma lipids and hemostatic factors were measured in centralized laboratories by standard and validated methods reported previously.35–37 Information about medical history, cigarette smoking, and ethanol consumption was elicited from standardized and validated interviewer-administered questionnaires. Prevalent hypertension was defined as a systolic blood pressure >=160 mm Hg, a diastolic blood pressure >=95 mm Hg, or current use of antihypertensive medications. Prevalent diabetes mellitus was defined as a fasting glucose level >=140 mg/dL, nonfasting glucose >=200 mg/dL, or a history of or treatment for diabetes. Circulating VCAM-1, E-selectin, and ICAM-1 levels were determined by commercially available ELISA and standards (R&D System Europe Ltd). Those who had extreme values of VCAM-1, E-selectin, or ICAM-1 (mean±3 SD) were deleted from analyses for that adhesion molecule (n=13, 8, and 6 for VCAM-1, E-selectin, and ICAM-1, respectively).

All statistical analyses were conducted by use of SAS version 6.10.38 Characteristics of the patients and control subjects were evaluated with Student's t test for the continuous variables and {chi}2 test for the categorical variables. The skewed distributions of VCAM-1, E-selectin, and ICAM-1 were compared between patients and control subjects by the Wilcoxon rank-sum test.39 Relationships between the adhesion molecules and potential CHD risk factors were evaluated with Spearman's rank correlation coefficients for the continuous variables and with the Wilcoxon rank-sum test for the categorical variables. Unconditional logistic regression analysis was used to determine the odds of incident CHD in the follow-up study or the odds of CAA in the cross-sectional study.40 Because of their use in the selection of control subjects for matching to the CAA patients, all regression analyses were adjusted for the concomitant effects of race, age, and sex. Initially, regression analyses were conducted to identify the odds of disease risk for each SD change of the adhesion molecules. To further identify whether the associations between the adhesion molecules and disease are the same across the range of values, logistic regression analyses were conducted if levels of the adhesion molecules were considered as categorical variables defined by quartiles of their race-specific distributions. We then tested for a threshold effect by testing for departures from linearity using a restricted cubic spline model.41 A value of P<.05 was considered statistically significant for all analyses.


*    Results
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The sample of 792 ARIC participants includes 204 incident CHD patients (33 blacks and 171 whites), 272 CAA patients (44 blacks and 228 whites), and 316 control subjects (72 blacks and 244 whites). For CHD and CAA patients, levels of total cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, fibrinogen, the atherogenic potential of the diet (Keys score),42 and white blood cell count were significantly higher than those for control subjects in whites. For both CHD and CAA patients, frequencies of hypertension (43% in CHD, 37% in CAA) and diabetes mellitus (22% for CHD patients, 12% for CAA patients) were significantly higher than those for control subjects (hypertension, 19%; diabetes mellitus, 3%). Plasma HDL cholesterol levels were significantly lower in the incident CHD patients (mean, 1.07 mmol/L) than in the CAA patients (mean, 1.12 mmol/L), but the levels of plasma LDL cholesterol or triglycerides were not significantly different. The frequency of diabetic patients was significantly higher for CHD patients than for CAA patients. In blacks, the differences between patients and control subjects were consistent with those observed in whites, but because of the smaller number of subjects, the difference did not always reach statistical significance.

Means and SDs of VCAM-1 were not statistically different among the CHD patients, CAA patients, and control subjects (Table 1Down). Consistent associations of levels of E-selectin and ICAM-1 with CHD and CAA were observed in whites and blacks. In whites, average E-selectin levels were significantly higher in incident CHD patients (38.4 ng/mL) and CAA patients (41.5 ng/mL) than in the control group (32.8 ng/mL). Likewise, for ICAM-1, the CHD patients (288.7 ng/mL) and the CAA patients (283.6 ng/mL) had significantly higher levels than the control subjects (244.2 ng/mL). There was no significant difference in E-selectin or ICAM-1 levels between the CHD and the CAA patients. In blacks, significantly elevated E-selectin levels were observed in both the incident CHD and CAA patient groups compared with the control subjects. For ICAM-1, elevated levels were observed in both patient groups. When only the control subjects were considered, levels of VCAM-1 and ICAM-1 were significantly lower in blacks than in whites.


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  		Table 1. Number of Subjects, Mean and SD of VCAM-1, E-Selectin, and ICAM-1 for the Incident CHD Patients, CAA Patients, and Control Subjects

Among the control subjects, the correlation between levels of E-selectin and ICAM-1 was r=.22 (P=.0001); between VCAM-1 and ICAM-1, r=.17 (P=.004); and between VCAM-1 and E-selectin, r=.006 (P=.92). VCAM-1 levels were significantly correlated with age, von Willebrand factor, and white blood cell count (Table 2Down). E-selectin level was positively correlated with body mass index, triglyceride, fibrinogen, and white blood cell count and was negatively correlated with HDL cholesterol. ICAM-1 level was positively correlated with cigarette-years for smokers and white blood cell count. Levels of VCAM-1 were significantly higher for those with diabetes than for nondiabetics (Table 3Down). For E-selectin, subjects with hypertension had significantly higher levels than their normotensive counterparts. Levels of E-selectin were significantly higher in subjects with diabetes than in nondiabetics. Women had higher levels of ICAM-1 than men. Levels of ICAM-1 were significantly higher for those with diabetes. For those who had smoked or still smoked cigarettes, levels of ICAM-1 were significantly higher than those who never smoked.


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  		Table 2. Spearman Rank Order Correlation Coefficients (P value) Among Adhesion Molecules (VCAM-1, E-Selectin, and ICAM-1) and Potential CHD Risk Factors


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  		Table 3. Number of Subjects, Mean and SD for VCAM-1, E-Selection, and ICAM-1 by Sex, Hypertension, Diabetes, and Cigarette Smoker (Including Current and Former Smokers)

Table 4Down shows the results of logistic regression analyses predicting the risk of incident CHD and the probabilities of being a CAA patient. There was no significant relationship between VCAM-1 and CHD or CAA. E-selectin was significantly associated with incident CHD (OR, 1.54; 95% CI, 1.27–1.86). However, this association was not significant after adjustment for effects of established CHD risk factor variables (age, sex, body mass index, total cholesterol, HDL cholesterol, cigarette-years for smokers, hypertension, and diabetes) and factors related to levels of the adhesion molecules (triglyceride, fibrinogen, von Willebrand factor, and white blood cell count).43 The level of ICAM-1 was a significant predictor of incident CHD in all models. The odds of incident CHD in the fully adjusted model increased by 1.88 for each SD increase in ICAM-1 level. The relationship between level of E-selectin and the occurrence of CAA was significant in all models (OR, 1.36; 95% CI, 1.09–1.70). The association between levels of ICAM-1 and CAA was also statistically significant in all models (OR, 1.34; 95% CI, 1.07–1.68).


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  		Table 4. Odds Ratios and 95% CIs of CHD and CAA Patients vs Control Subjects per SD Change of VCAM-1, E-Selectin, and ICAM-1

To evaluate whether the associations between plasma levels of E-selectin, ICAM-1, and disease were present across the range of values or were restricted to those with high levels, subjects were grouped by race-specific quartiles and the analyses were repeated with the corresponding categorical variables. Table 5Down shows the odds of incident CHD or the occurrence of CAA for those with levels of E-selectin and ICAM-1 in the second, third, and fourth quartiles compared with those with levels in the first quartile. These data indicate that the risk of developing CHD was highest in those with E-selectin and ICAM-1 levels in the highest quartile. The risk of incident CHD for those with E-selectin in the fourth quartile was significantly elevated (OR, 2.98; 95% CI, 1.74–5.10). The association between E-selectin and incident CHD was not significant after the effects of a set of established risk factors and factors related to levels of the circulating adhesion molecules were considered. In contrast, after the effects of the established risk factors and those variables related to adhesion molecule levels were considered, the odds of developing clinical CHD for those in the upper quartile of the ICAM-1 distribution was 5.53 times (95% CI, 2.51–12.21) higher than those in the lowest quartile. Elevated levels of E-selectin were significantly associated with the occurrence of CAA in the models adjusted for well-established CHD risk factors and variables related to adhesion molecule levels. Individuals with CAA were 2.03 times (95% CI, 1.14–3.62) more likely to be in the highest quartile of E-selectin distribution at the baseline examination compared with the control groups. For ICAM-1, the odds of being a CAA case for those in the upper quartile of the ICAM-1 distribution were 2.64 (95% CI, 1.40–5.01) times higher than those in the lowest quartile after the effects of established risk factors and those variables related to adhesion molecule levels were considered. However, a formal statistical test (see "Methods") did not indicate a statistically significant threshold effect for ICAM-1 in predicting incident CHD or the occurrence of CAA.


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  		Table 5. Odds Ratios and 95% CIs of Incident CHD and CAA Occurrence for Those With E-Selectin or ICAM-1 in the Second, Third, and Fourth Quartiles


*    Discussion
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 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
Our results showed that levels of circulating ICAM-1 predict CAA and incident CHD and that this relationship cannot be accounted for by the confounding effects of other CHD risk factors. The results also demonstrated a significant association between levels of circulating E-selectin and occurrence of CAA. A significant association between circulating ICAM-1, E-selectin, and sequelae of atherosclerosis has been reported in previous studies.44,45 Blann and McCollum44 reported significantly higher values of circulating ICAM-1 in patients with peripheral vascular disease and ischemic heart disease than in healthy control subjects. Squadrito et al45 reported significantly higher levels of circulating ICAM-1 and E-selectin in patients with acute myocardial infarction than in patients with chronic stable angina and healthy control subjects. The present study is the first one to comprehensively examine the ability of circulating VCAM-1, E-selectin, and ICAM-1 to predict incident CHD. This is also the first study to evaluate the relationship between circulating adhesion molecules and atherosclerosis and CHD in both blacks and whites. However, the number of black incident CHD patients is relatively small, so prudence is necessary in interpretation of their results.

On the basis of the "response to injury" hypothesis, atherosclerosis parallels the inflammatory process, and one of the earliest events in both is the adhesion of circulating monocytes to intact endothelial cells.46,47 Local accumulation of leukocytes in the vascular wall includes initial marginalization and rolling of the leukocytes along the endothelium, a process mediated by the selectins, then attachment to endothelial cells and transmigration into the intimal spaces, a process mediated by the adhesive molecules expressed by activated endothelium.14 VCAM-1, E-selectin, and ICAM-1 have been consistently observed within the milieu of the atherosclerotic plaque. Although the presence of ICAM-1 has been observed on normal arterial endothelium, consistent and strong expression of ICAM-1 has been associated with atherosclerotic lesions.23,25 Focal expression of endothelium-specific E-selectin on atherosclerotic lesions has also been reported consistently. Despite the large body of literature on the expression and function of the cellular adhesion molecules, the biological properties and function of the circulating form of these molecules remain unclear. Therefore, any discussion of the potential mechanisms relating circulating adhesion molecule levels to CAA and incident CHD is necessarily speculative. There is a large body of literature documenting an association between plasma levels of the circulating adhesion molecules and the occurrence of chronic inflammatory diseases.15

We report here the distributions of circulating VCAM-1, E-selectin, and ICAM-1 for CAA and incident CHD patients and control subjects in the ARIC study and evaluate their relationship with long-standing risk factors (eg, total cholesterol). The observed relationships were, in general, consistent with data from both in vivo and in vitro experimental studies. Cockerill et al48 reported decreased expression of VCAM-1, E-selectin, and ICAM-1 on endothelial cell cultures that were exposed to isolated HDL particles. A previous study also showed increased levels of soluble ICAM-1 in patients with marked elevation of triglycerides and low HDL cholesterol.49 In the present study, levels of E-selectin were significantly correlated with HDL cholesterol in the control group. Significantly higher levels of the adhesion molecules were observed for those diagnosed with diabetes, which is consistent with previous studies showing elevated levels of E-selectin and ICAM-1 in diabetic patients.50,51 It is unknown whether this association is the consequence of accompanying atherosclerosis or whether there is a direct effect of hyperglycemia/hyperinsulinemia on the expression of the adhesion molecules, which has been demonstrated in experimental rabbits.52 We observed significantly higher levels of ICAM-1 for smokers than for nonsmokers as well as significant correlation between ICAM-1 and cigarette-years for smokers, and a positive relationship has been observed in an in vitro study. Kalra et al53 reported that cigarette smoke condensate induced ICAM-1 expression in cultured human umbilical vein cells and hypothesized a direct effect of cigarette smoking in stimulating ICAM-1 expression. We evaluated the relationship of ICAM-1 with incident CHD and CAA in multivariate logistic regression models and showed that the association between ICAM-1 level and CHD and CAA were independent of well-accepted risk factors and factors correlated with circulating VCAM-1, E-selectin, and ICAM-1 levels.

The level of E-selectin was positively related to the degree of atherosclerotic burden, as measured by carotid artery wall thickness, but was not a significant predictor of clinical CHD after multivariate analysis, as shown in Tables 4Up and 5Up. In light of the known function of E-selectin in the initial margination and rolling of leukocytes along the vascular endothelium,20 the association of E-selectin with CAA but not CHD indicates that E-selectin might be involved in the early steps of atherosclerosis. In contrast, there was a consistent relationship between the levels of circulating ICAM-1 and both incident CHD and CAA. One possible explanation for these data is that levels of circulating ICAM-1 are more closely related to the activity of atherosclerosis. Increased levels of ICAM-1 may be important in migration of increased numbers of T lymphocytes into active lesions.54 Another possibility is that patients with higher circulating levels of ICAM-1 have an increased number of plaques prone to rupture, thrombi, or other events leading to clinical CHD. The interaction between fibrinogen and ICAM-1 observed in an in vitro study provides evidence suggesting an association between ICAM-1 and thrombosis/ischemic events.55 Another explanation for these observations is that atherosclerosis in different arterial beds such as the carotid and coronary arteries may have differential expression of cell adhesion molecules.

It is unknown why the level of circulating VCAM-1 was not associated with either CAA or CHD. Results of immunohistochemical studies have consistently shown much weaker VCAM-1 expression than those for E-selectin and ICAM-1.23,25,26 VCAM-1 is different from ICAM-1 with respect to the ligand it binds to, the time duration of its expression, and the cell and tissue type in which it is expressed.56 In an animal model, Walpola et al57 observed upregulation of VCAM-1 and downregulation of ICAM-1 by low shear stress and upregulation of both VCAM-1 and ICAM-1 by high shear stress. The accumulated data imply that VCAM-1 may play an important role in early atherogenesis but a less important role in advanced, complex lesions. However, further studies are clearly necessary.

In summary, we have defined significant relationships of circulating E-selectin and ICAM-1 levels with the burden of atherosclerosis, as measured by carotid B-mode ultrasound, and CHD, as measured by the number of incident patients in the ARIC study. The results of this study bode well for the utility of the circulating adhesion molecules to serve as indicators of subclinical disease, although they do not directly indicate their use as such at this time. Clearly, more data are necessary on the validity of their use as molecular markers of atherosclerosis and comparison with other tests, both invasive and noninvasive. The present study has the limitation of recruiting control subjects with thin carotid arterial walls; therefore, the odds ratios for incident CHD patients reported here are most likely overestimates of those estimated from a random sample from the general population.58 However, it is worth pointing out that average VCAM-1, E-selectin, and ICAM-1 levels for the ARIC thin-wall control subjects were not different from those reported from other control groups.59–61 The data presented here should provide an impetus for further studies defining the utility of plasma measures of these adhesion molecules to predict plaque progression, regression, and CHD. The availability of a molecular marker for preclinical atherosclerosis will facilitate diagnosis and more-directed intervention strategies targeted at those at increased risk.


*    Selected Abbreviations and Acronyms
 
ARIC = Atherosclerosis Risk In Communities
CAA = carotid artery atherosclerosis
CHD = coronary heart disease
ICAM-1 = intercellular adhesion molecule-1
VCAM-1 = vascular cellular adhesion molecule-1


*    Acknowledgments
 
This work was supported by contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022 from the National Heart, Lung, and Blood Institute. We thank Myra Carpenter and Charmaine Marquis (University of Carolina, Chapel Hill, Coordinating Center) for statistical assistance. We are indebted to ARIC investigators Phyllis Johnson, Marilyn Knowles, Catherine Paton (University of North Carolina, Chapel Hill); Dawn Scott, Nadine Shelton, Carol Smith, Pamela Williams (University of North Carolina, Forsyth County); Betty Warren, Dorothy Washington, Mattye Watson, Nancy Wilson (University of Mississippi Medical Center, Jackson); Margaret Skelton, Gina Tritle, Shirley VanPilsum, Lori Vitelli (University of Minnesota, Minneapolis); John Nelling, Rodney Palmer, Serena Bell, Joyce Chabot (Johns Hopkins University, Baltimore, Md); Valarie Stinson, Pam Pfile, Hogan Pham, Teri Trevino (University of Texas Medical School, Houston); Wanda R. Alexander, Doris J. Harper, Charles E. Rhodes, Selma M. Soyal (The Methodist Hospital, Atherosclerosis Clinical Laboratory, Houston); Linda Allred, Carolyn Bell, Nancy Bourne, Charlene Kearney-Cash (Bowman-Gray School of Medicine, Ultrasound Reading Center, Winston-Salem, NC); and Marston Youngblood, Ding-Yi Zhao, Paula Bell, and Hope Bryan (University of North Carolina, Chapel Hill, Coordinating Center).


*    Footnotes
 
Guest editor for this article was Michael J. Davies, MD, St George's Hospital Medical School, London, UK.

Received May 16, 1997; revision received September 3, 1997; accepted September 12, 1997.


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