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(Circulation. 2002;106:820.)
© 2002 American Heart Association, Inc.

Clinical Investigation and Reports

Soluble Intercellular Adhesion Molecule-1, Soluble Vascular Adhesion Molecule-1, and the Development of Symptomatic Peripheral Arterial Disease in Men

From the Center for Cardiovascular Disease Prevention (A.D.P., N.R., P.M.R.), the Leducq Center for Molecular and Genetic Epidemiology of Cardiovascular Disorders (A.D.P., N.R., P.M.R.), the Divisions of Cardiology (A.D.P., P.M.R.) and Preventive Medicine (A.D.P., P.M.R.), Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass; and the Department of Pathology (N.R.), Children’s Hospital Medical Center and Harvard Medical School, Boston, Mass.

Correspondence to Dr Paul M. Ridker, Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, 900 Commonwealth Ave E, Boston, MA 02115-1204. E-mail pridker{at}partners.org

	Abstract

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Background— Elevated levels of soluble cellular adhesion molecules have been linked to the development of occlusive coronary events in otherwise healthy individuals. It is not certain, however, whether similar relationships exist for the development of early systemic atherosclerosis.

Methods and Results— In a prospective, nested case-control study conducted among 14 916 middle-aged men, we evaluated the relationship between baseline levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and the subsequent development of symptomatic peripheral arterial disease (PAD) during a 9-year follow-up period. Median levels of sICAM-1 but not sVCAM-1 were significantly higher at baseline among men who developed PAD than among those who did not (285.2 versus 267.8 ng/mL [P=0.005] for sICAM-1 and 701.0 versus 709.3 ng/mL [P=0.8] for sVCAM-1). In analyses adjusted for age and smoking, the odds ratio in the highest compared with the lowest quartile of sICAM-1 was 3.9 (95% CI 1.7 to 8.6; P_trend=0.001). After additional adjustment for lipid and nonlipid risk factors, including C-reactive protein, elevated sICAM-1 remained significantly associated with subsequent PAD (OR 3.5, 95% CI 1.4 to 8.5, P_trend=0.008). Whereas a monotonic dose-response relationship was evident over the full spectrum of ICAM-1 levels, elevated sVCAM-1 was not associated with future PAD in either age- and smoking-adjusted or fully adjusted models.

Conclusions— Elevated levels of sICAM-1 are independently associated with the development of accelerated atherosclerosis among otherwise healthy men even in the absence of acute coronary occlusion.

Key Words: cell adhesion molecules • peripheral vascular disease • men

	Introduction

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Leukocyte adherence to the vascular endothelium is one of the earliest demonstrable events in atherosclerosis. The process of leukocyte adhesion and transendothelial migration is mediated by cellular adhesion molecules (CAMs), which are expressed on the endothelial surface in response to a variety of atherogenic stimuli, including several inflammatory cytokines such as interleukin-1, tumor necrosis factor-, and interferon-.^1,2 Intercellular CAM-1 (ICAM-1) and vascular CAM-1 (VCAM-1) are 2 prototypic members of the immunoglobulin superfamily of CAMs that are important in focal leukocyte accumulation in subendothelial regions of atheroma. Both ICAM-1 and VCAM-1 are expressed within atherosclerotic lesions,^3–6 and elevated plasma levels of soluble forms of these molecules suggest a role in plaque disruption.^7,8

See p 766

Although elevated soluble ICAM-1 (sICAM-1) levels have been shown to predict the development of occlusive cardiovascular events in otherwise healthy individuals,^9–11 and both sICAM-1 and soluble VCAM-1 (sVCAM-1) appear elevated among patients with known coronary disease who are at risk for subsequent vascular occlusion,^12,13 data are limited with regard to the association between these immunologic biomarkers and risk of systemic atherosclerosis progression. To address this issue, we evaluated the role of sICAM-1 and sVCAM-1 as determinants of symptomatic peripheral arterial disease (PAD) among a large prospective cohort of otherwise healthy men.

	Methods

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Study Population
The study population consisted of apparently healthy men participating in the Physician’s Health Study.¹⁴ In brief, 14 916 men aged 40 to 84 years who had no prior history of cardiovascular disease or cancer provided baseline EDTA plasma specimens that were frozen at -80°C until analysis. Participants were monitored over an average follow-up period of 9 years for the occurrence of incident health events, including the development of intermittent claudication and hospitalizations for peripheral arterial revascularization procedures. Case subjects were those who subsequently developed either of these PAD end points. Control subjects were selected at random from the remaining study participants who were free of reported cardiovascular disease. Controls were matched with cases on the basis of age, smoking status, and year of follow-up. No participant had a baseline history of intermittent claudication or prior lower-extremity revascularization procedures. Because the study design focused on symptomatic lower-extremity PAD, participants who underwent revascularization of either the renal or carotid arteries were not considered.

Measurements of Biochemical Parameters
Baseline plasma samples from case and control subjects were thawed and assayed for sICAM-1 and sVCAM-1 by ELISA with commercially available analytic systems (R&D Systems). C-reactive protein (CRP) and lipid levels were measured as described previously.¹⁵ Samples were analyzed in randomly ordered case-control pairs to reduce systematic bias and interassay variation.

Statistical Analysis
We used the Student t test and the ² statistic to evaluate differences in means and proportions between cases and controls. Because the distributions of sICAM-1 and sVCAM-1 were skewed, differences in medians were assessed by the Wilcoxon rank sum test. To evaluate the relationship between these biomarkers and subsequent PAD risk, the study population was divided into quartiles based on control values for each parameter. We then used logistic regression, adjusting for matching factors, to estimate the odds ratio (OR) for future PAD associated with increasing quartiles of each adhesion molecule. Multivariable ORs were obtained that, in addition to the matching variables of age and smoking, were adjusted for total cholesterol to HDL cholesterol ratio (TC:HDL), hypertension, body mass index, family history of coronary artery disease, diabetes, and exercise frequency. Tests for trend were computed to evaluate for a linear increase in ORs across quartiles. In secondary analyses, we adjusted for baseline concentrations of CRP to assess the residual predictive role of sICAM-1. In addition, to evaluate a potential joint role of CRP and sICAM-1 in predicting PAD risk, we computed ORs among 4 groups defined by the median cutpoint of each biomarker. The dose-response relationships between plasma concentration of sICAM-1, sVCAM-1, and the adjusted OR for PAD were estimated by generalized additive logistic regression.¹⁶ To evaluate time-dependent effects, we performed stratified analyses in which the OR associated with sICAM-1 levels above the 75th percentile for controls was calculated for individuals diagnosed during the first 2 years, years 2 through 4, and >4 years of follow-up.

	Results

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As expected, men who subsequently developed PAD were more likely than controls to have traditional coronary risk factors at baseline (Table 1). However, in this study of healthy male physicians with no prior history of cardiovascular disease, the overall prevalence of atherosclerotic risk factors was low: 11.9% with a family history of premature coronary artery disease; 24.0%, 10.7%, and 3.9% with a history of hypertension, hypercholesterolemia, and diabetes, respectively; and 20.9% with a history of current smoking. There were no differences in mean age or smoking status, because these risk factors were matching variables. Physical activity levels were virtually identical at baseline among the case and control groups.

Median sICAM-1 levels were higher at baseline among men who subsequently developed PAD than among controls (285.2 versus 267.8 ng/mL, P=0.005; Table 1). By contrast, there was no significant difference in median sVCAM-1 levels (701.0 versus 709.3 ng/mL, P=0.8). Total cholesterol, LDL cholesterol, HDL cholesterol, triglyceride levels, and TC:HDL were all significantly higher among cases than among controls. Spearman age-adjusted partial correlation coefficients showed moderate associations between sICAM-1 and HDL (-0.22, P<0.001), triglycerides (0.18, P=0.002), and TC:HDL (0.23, P<0.001). These associations were not present for sVCAM-1 (all P0.1). The correlation coefficient between sICAM-1 and sVCAM-1 was 0.16 (P=0.007). In analyses that controlled for matching variables, increasing levels of sICAM-1 were associated with increasing relative odds for PAD (Table 2). Additional adjustment for TC:HDL and other nonlipid risk factors minimally attenuated this association. In fully adjusted models, the OR associated with plasma sICAM-1 levels in the highest compared with the lowest quartile was 3.2 (95% CI, 1.4 to 7.4; P_trend=0.01). This result was unaffected by additional control for baseline triglyceride levels (3.2 [95% CI, 1.3 to 7.5]; P_trend=0.01). No evidence of association was observed for sVCAM-1 in either quartile-specific estimates or linear-trend analysis. Adjustment for randomized treatment assignment to aspirin or beta-carotene did not materially alter these results; specifically, the ORs for PAD in the highest versus lowest quartile were 3.5 (95% CI, 1.5 to 8.2; P_trend=0.006) and 1.2 (95% CI, 0.5 to 2.5; P_trend=0.94) for sICAM-1 and sVCAM-1, respectively.

Because CRP was correlated with sICAM-1 (Spearman age-adjusted partial correlation coefficient, 0.34; P<0.001) and is a known predictor of PAD risk in this population,^15,17 we additionally adjusted for CRP to minimize potential confounding effects of elevations in sICAM-1 that could more broadly relate to systemic subclinical inflammation. In this analysis that controlled for CRP modeled in quartiles, the fully adjusted ORs across quartiles of sICAM-1 were 1.0, 2.8, 4.3, and 3.5 (P_trend=0.008). Almost identical effects were observed in analyses that controlled for CRP as a continuous variable. To evaluate the potential joint role of CRP and sICAM-1 in predicting PAD risk, we stratified the population into 4 groups based on the median cutpoint of each biomarker. As shown in Figure 1, the OR for men with baseline elevations in both biomarkers appears greater than for those with low levels of both CRP and sICAM-1 or with elevations of either marker alone.

View larger version (10K): [in this window] [in a new window]   Figure 1. ORs for PAD according to baseline CRP and sICAM-1 levels. Population was stratified according to median cutpoints for each biomarker among controls. ORs are adjusted for matching factors (age and smoking status).

In models that assessed for dose-response relationships, the adjusted OR for future PAD was monotonically related to baseline sICAM-1 but not sVCAM-1 (Figure 2). In addition, we evaluated for time-dependent effects in analyses stratified by duration of follow-up at time of diagnosis (Table 3). The OR for PAD associated with baseline sICAM-1 levels >323.5 ng/mL, the 75th percentile cutpoint for control subjects, appeared to be greatest in the first 2 years of follow-up (OR 3.1, 95% CI 1.0 to 9.9, P=0.05) and lower thereafter. Compared with control subjects at baseline, median levels of sICAM-1 were significantly higher among case subjects who developed an event during the first 2 years of follow-up (312.4 versus 283.1 ng/mL, P=0.04) and remained higher for case events that occurred during years 2 through 4 and >4 years. However, at these later time points, case-control differences were diminished, and at >4 years of follow-up, they were no longer statistically significant.

View larger version (9K): [in this window] [in a new window]   Figure 2. Dose-response relationships between (A) sICAM-1, (B) sVCAM-1, and adjusted ORs for PAD. Reference level is median level in first quartile of plasma values in study population (196 and 537 ng/mL for sICAM-1 and sVCAM-1, respectively). Dose-response curves were estimated by locally weighted generalized additive logistic regression models adjusted for age, smoking status, TC:HDL, body mass index, family history of premature coronary artery disease, hypertension, diabetes, exercise frequency, and randomized treatment assignment to aspirin or beta-carotene. To improve symmetry of CAM levels over range of prediction, baseline values were log-transformed in prediction models and back-transformed for ease of interpretation of graphs. Dashed line indicates OR of 1.0.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
In this prospective evaluation, baseline levels of sICAM-1 but not sVCAM-1 were independently associated with the future development of symptomatic PAD. The relationship between sICAM-1 and the OR for PAD appeared to be positively graded throughout the range of clinical values and was additive to that of CRP. In addition, we found modest evidence for a time-dependent effect, which suggests that the association between sICAM-1 and symptomatic PAD may primarily be a late phenomenon in disease progression.

Atherosclerosis is a chronic process that involves cellular and humoral inflammatory responses. Leukocyte recruitment is an early event in the atherogenesis and continues during plaque maturation. ICAM-1 and VCAM-1 facilitate these processes by coordinating leukocyte adhesion and subsequent transendothelial migration.^18,19 Both adhesion molecules are transmembrane glycoproteins that bind ß-integrins on white cells. ICAM-1 interacts with ß2-integrins present on all white cells and is constitutively expressed by endothelial cells. ICAM-1 is strongly upregulated by inflammatory cytokines in many cell types, including endothelial cells, fibroblasts, epithelial cells, and multiple cells of hematopoietic lineage. In the absence of generalized inflammatory conditions, ICAM-1 is expressed on few cells, and ICAM-1 induction may be an important means of regulating diverse intercellular interactions that participate in the host immune response. VCAM-1, in contrast, is mononuclear cell selective, serving as a counterligand for ß1-integrins present on lymphocytes and monocytes. Although VCAM-1 expression is also modulated by several cytokines with similar kinetics as observed for ICAM-1, the vascular distribution of VCAM-1 is more anatomically restricted to activated endothelial cells in lesion-prone areas⁴ and is more prominent on intimal neovasculature than on the arterial luminal surface of complex lesions.^20,21 ICAM-1 and VCAM-1 expression may also differ in that perturbations in laminar blood flow selectively upregulate ICAM-1 but not VCAM-1, at least in vitro.²² Thus, although ICAM-1 and VCAM-1 share structural and functional similarities, characteristic differences in tissue distribution, counterreceptor specificity, and response to hemodynamic forces may critically influence discernible associations in clinical studies of systemic atherosclerosis.

The present findings, which establish a relationship between elevated levels of sICAM-1 and future risk of symptomatic PAD, have several important implications. First, our results extend previous observations from this and other cohorts in which elevated sICAM-1 levels were predictive of first myocardial infarction and stroke,^9–11 but sVCAM-1 levels were not.²³ Endothelial activation and inflammation appear to be important precursors to systemic atherosclerosis initiation and progression. It is also possible, however, that the observed increase in plasma sICAM-1 may be indicative of generalized inflammation and upregulation in nonendothelial cells rather than an anatomically localized event in atheromatous vascular beds. Indeed, CRP, a sensitive marker of systemic inflammation, is positively correlated with sICAM-1, although in the present report and our previous study of incident myocardial infarction,¹⁰ the OR associated with elevated sICAM-1 was undiminished by adjustment for CRP, and elevations in both biomarkers appeared to identify individuals at the greatest risk. These findings, coupled with the existence of experimentally documented biologic mechanisms, the magnitude of the observed effect, and the probable endothelial origin of soluble CAMs,²⁴ suggest an independent role for ICAM-1 in the clinical development of peripheral atherosclerosis and raise the possibility that antiadhesive therapies may prevent or ameliorate progression of this disease.

Second, our observation that sICAM-1 levels are primarily elevated in the 2 years immediately preceding the development of symptomatic PAD, although somewhat limited by the number of case-control pairs assessed, is a finding that requires further investigation. Previously reported time-dependent associations between sICAM-1 and the development of myocardial infarction in healthy individuals have suggested that sICAM-1 elevation appears to be an early phenomenon in coronary atherothrombosis. Mechanisms involved in acute coronary syndromes that commonly result from sudden luminal occlusion by thrombus formation may differ from those involved in the pathogenesis of peripheral arteriosclerosis, which is generally associated with gradual luminal narrowing. ICAM-1 amplification in comparatively large areas of involvement in peripheral atherosclerosis as opposed to the coronary circulation may occur late in disease onset, during which biomechanical regulation of ICAM-1 may predominate.

Third, our null findings for sVCAM-1 should not be construed to imply the absence of a physiological role in atherogenesis. Animal models of nascent atherosclerosis indicate that VCAM-1 is a mediator of plaque initiation, ²⁵ and histopathological studies demonstrate preferential expression of VCAM-1 in association with inflammatory cell infiltration in intimal neovasculature of complex lesions.^20,21 Therefore, atherosclerotic lesions that do not exhibit substantial intimal neorevascularization may not sustain appreciably elevated levels of this marker. In addition, cross-sectional studies of associations between soluble CAMs and the extent of PAD indicate that sVCAM-1 as opposed to sICAM-1 may be more predictive of angiographically²⁶ or echographically²⁷ determined atherosclerotic burden while being less well correlated with clinical staging.²⁶ In this regard, epidemiological data have shown that among patients with overt coronary artery disease, in contrast to studies of healthy individuals, elevated sVCAM-1 levels may discriminate those at high risk for subsequent cardiovascular events.¹²

Potential limitations of the present study merit consideration. First, the use of self-reported symptomatic PAD as our primary a priori end point may have resulted in misclassification bias. However, our study participants were physicians, a group in whom validation rates for several other self-reported vascular and nonvascular end points have consistently been excellent.¹¹ Furthermore, any potential misclassification introduced on this basis would, if anything, tend to bias these data toward the null. Second, although plasma concentrations of soluble isoforms of cell-bound adhesion molecules are thought to derive from proteolytic cleavage and "shedding" from endothelial cells, ²⁴ it is currently unknown whether systemic release of soluble CAMs varies with vascular origin, and factors influencing clearance of these immunologic markers remain uncertain. Furthermore, the shedding process may be different for different CAMs, such that levels of sVCAM-1 may be disproportionately attenuated compared with sICAM-1 purely on this basis. In addition, because our blood samples were stored at -80°C until analysis, we cannot exclude the possibility of protein degradation. However, observed levels of sICAM-1 and sVCAM-1 in these data are similar to values obtained in studies using fresh plasma, and if unaccounted sources of protein instability were present, their effects would minimally impact the validity of the present results because all samples were handled identically, and relative differences between cases and controls should not be materially altered. Third, because the present study cohort comprised otherwise healthy men, our results may not be generalizable to women, who experience equivalent overall rates of PAD. However, at least with regard to myocardial infarction and stroke, sICAM-1 levels have been predictive in women as well as men.¹¹

In conclusion, elevated levels of sICAM-1 are associated with subsequent risk of symptomatic PAD in otherwise healthy men. These data, while confirming the association between endothelial activation, inflammation, and systemic atherosclerosis, raise the possibility that cellular immune mechanisms and the associated temporal sequence of events in clinical PAD progression may differ from those related to acute coronary occlusion.

	Acknowledgments

 
This work was supported by grants from the National Heart, Lung, and Blood Institute (HL07575, HL58755, and HL63293), the Leducq Foundation, and a Distinguished Clinical Scientist Development Award from the Doris Duke Foundation (Dr Ridker).

	Footnotes

 
Dr Ridker is listed as a coinventor on patents filed by the Brigham and Women’s Hospital that relate to inflammatory markers in vascular disease.

Received April 15, 2002; revision received May 29, 2002; accepted May 29, 2002.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Dustin ML, Rothlein R, Bhan AK, et al. Induction by IL 1 and interferon-gamma: tissue distribution, biochemistry, and function of a natural adherence molecule (ICAM-1). J Immunol. 1986; 137: 245–254.[Abstract]

2. Pober JS, Gimbrone MA Jr, Lapierre LA, et al. Overlapping patterns of activation of human endothelial cells by interleukin 1, tumor necrosis factor, and immune interferon. J Immunol. 1986; 137: 1893–1896.[Abstract]

3. Cybulsky MI, Gimbrone MA Jr. Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science. 1991; 251: 788–791.[Abstract/Free Full Text]

4. Li H, Cybulsky MI, Gimbrone MA Jr, et al. An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium. Arterioscler Thromb. 1993; 13: 197–204.[Abstract/Free Full Text]

5. Iiyama K, Hajra L, Iiyama M, et al. Patterns of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression in rabbit and mouse atherosclerotic lesions and at sites predisposed to lesion formation. Circ Res. 1999; 85: 199–207.[Abstract/Free Full Text]

6. Davies MJ, Gordon JL, Gearing AJ, et al. The expression of the adhesion molecules ICAM-1, VCAM-1, PECAM, and E- selectin in human atherosclerosis. J Pathol. 1993; 171: 223–229.[CrossRef][Medline] [Order article via Infotrieve]

7. Ogawa H, Yasue H, Miyao Y, et al. Plasma soluble intercellular adhesion molecule-1 levels in coronary circulation in patients with unstable angina. Am J Cardiol. 1999; 83: 38–42.[Medline] [Order article via Infotrieve]

8. O’Malley T, Ludlam CA, Riemermsa RA, et al. Early increase in levels of soluble inter-cellular adhesion molecule-1 (sICAM-1): potential risk factor for the acute coronary syndromes. Eur Heart J. 2001; 22: 1226–1234.[Abstract/Free Full Text]

9. Hwang SJ, Ballantyne CM, Sharrett AR, et al. 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. Circulation. 1997; 96: 4219–4225.[Abstract/Free Full Text]

10. Ridker PM, Hennekens CH, Roitman-Johnson B, et al. Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men. Lancet. 1998; 351: 88–92.[CrossRef][Medline] [Order article via Infotrieve]

11. Ridker PM, Hennekens CH, Buring JE, et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000; 342: 836–843.[Abstract/Free Full Text]

12. Blankenberg S, Rupprecht HJ, Bickel C, et al. Circulating cell adhesion molecules and death in patients with coronary artery disease. Circulation. 2001; 104: 1336–1342.[Abstract/Free Full Text]

13. Malik I, Danesh J, Whincup P, et al. Soluble adhesion molecules and prediction of coronary heart disease: a prospective study and meta-analysis. Lancet. 2001; 358: 971–976.[CrossRef][Medline] [Order article via Infotrieve]

14. Steering Committee of the Physicians’ Health Study Research Group. Final report on the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med. 1989; 321: 129–135.[Abstract]

15. Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C- reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA. 2001; 285: 2481–2485.[Abstract/Free Full Text]

16. Hastie T, Tibshirani R. Generalized Additive Models. London, UK: Chapman & Hall/CRC; 1990.

17. Ridker PM, Cushman M, Stampfer MJ, et al. Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease. Circulation. 1998; 97: 425–428.[Abstract/Free Full Text]

18. Price DT, Loscalzo J. Cellular adhesion molecules and atherogenesis. Am J Med. 1999; 107: 85–97.[Medline] [Order article via Infotrieve]

19. Gearing AJ, Newman W. Circulating adhesion molecules in disease. Immunol Today. 1993; 14: 506–512.[CrossRef][Medline] [Order article via Infotrieve]

20. O’Brien KD, Allen MD, McDonald TO, et al. Vascular cell adhesion molecule-1 is expressed in human coronary atherosclerotic plaques: implications for the mode of progression of advanced coronary atherosclerosis. J Clin Invest. 1993; 92: 945–951.[Medline] [Order article via Infotrieve]

21. O’Brien KD, McDonald TO, Chait A, et al. Neovascular expression of E-selectin, intercellular adhesion molecule- 1, and vascular cell adhesion molecule-1 in human atherosclerosis and their relation to intimal leukocyte content. Circulation. 1996; 93: 672–682.[Abstract/Free Full Text]

22. Nagel T, Resnick N, Atkinson WJ, et al. Shear stress selectively upregulates intercellular adhesion molecule-1 expression in cultured human vascular endothelial cells. J Clin Invest. 1994; 94: 885–891.[Medline] [Order article via Infotrieve]

23. de Lemos JA, Hennekens CH, Ridker PM. Plasma concentration of soluble vascular cell adhesion molecule-1 and subsequent cardiovascular risk. J Am Coll Cardiol. 2000; 36: 423–426.[Abstract/Free Full Text]

24. Pigott R, Dillon LP, Hemingway IH, et al. Soluble forms of E-selectin, ICAM-1 and VCAM-1 are present in the supernatants of cytokine activated cultured endothelial cells. Biochem Biophys Res Commun. 1992; 187: 584–589.[CrossRef][Medline] [Order article via Infotrieve]

25. Cybulsky MI, Iiyama K, Li H, et al. A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J Clin Invest. 2001; 107: 1255–1262.[Medline] [Order article via Infotrieve]

26. Peter K, Nawroth P, Conradt C, et al. Circulating vascular cell adhesion molecule-1 correlates with the extent of human atherosclerosis in contrast to circulating intercellular adhesion molecule-1, E-selectin, P-selectin, and thrombomodulin. Arterioscler Thromb Vasc Biol. 1997; 17: 505–512.[Abstract/Free Full Text]

27. De Caterina R, Basta G, Lazzerini G, et al. Soluble vascular cell adhesion molecule-1 as a biohumoral correlate of atherosclerosis. Arterioscler Thromb Vasc Biol. 1997; 17: 2646–2654.[Abstract/Free Full Text]

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				B. J. Herron, C. Rao, S. Liu, L. Laprade, J. A. Richardson, E. Olivieri, C. Semsarian, S. E. Millar, L. Stubbs, and D. R. Beier A mutation in NFkB interacting protein 1 results in cardiomyopathy and abnormal skin development in wa3 mice Hum. Mol. Genet., March 1, 2005; 14(5): 667 - 677. [Abstract] [Full Text] [PDF]

				T. C. Register, K. P. Burdon, L. Lenchik, D. W. Bowden, G. A. Hawkins, B. J. Nicklas, K. Lohman, F.-C. Hsu, C. D. Langefeld, and J. J. Carr Variability of Serum Soluble Intercellular Adhesion Molecule-1 Measurements Attributable to a Common Polymorphism Clin. Chem., November 1, 2004; 50(11): 2185 - 2187. [Full Text] [PDF]

				R. Stocker and J. F. Keaney Jr. Role of Oxidative Modifications in Atherosclerosis Physiol Rev, October 1, 2004; 84(4): 1381 - 1478. [Abstract] [Full Text] [PDF]

				E. Zouridakis, P. Avanzas, R. Arroyo-Espliguero, S. Fredericks, and J. C. Kaski Markers of Inflammation and Rapid Coronary Artery Disease Progression in Patients With Stable Angina Pectoris Circulation, September 28, 2004; 110(13): 1747 - 1753. [Abstract] [Full Text] [PDF]

				D. H. Endemann and E. L. Schiffrin Endothelial Dysfunction J. Am. Soc. Nephrol., August 1, 2004; 15(8): 1983 - 1992. [Abstract] [Full Text] [PDF]

				J. F. Keaney Jr, J. M. Massaro, M. G. Larson, R. S. Vasan, P. W. F. Wilson, I. Lipinska, D. Corey, P. Sutherland, J. A. Vita, and E. J. Benjamin Heritability and correlates of intercellular adhesion molecule-1 in the Framingham Offspring Study J. Am. Coll. Cardiol., July 7, 2004; 44(1): 168 - 173. [Abstract] [Full Text] [PDF]

				D. J Baer, J. T Judd, B. A Clevidence, and R. P Tracy Dietary fatty acids affect plasma markers of inflammation in healthy men fed controlled diets: a randomized crossover study Am. J. Clinical Nutrition, June 1, 2004; 79(6): 969 - 973. [Abstract] [Full Text] [PDF]

				E. Lutgens, R.-J. van Suylen, B. C. Faber, M. J. Gijbels, P. M. Eurlings, A.-P. Bijnens, K. B. Cleutjens, S. Heeneman, and M. J.A.P. Daemen Atherosclerotic Plaque Rupture: Local or Systemic Process? Arterioscler Thromb Vasc Biol, December 1, 2003; 23(12): 2123 - 2130. [Abstract] [Full Text] [PDF]

				R. V. Perez, C. Q. Huang, J. R. Johnson, B. J. Gallay, M. M. Gandhi, J. P. McVicar, and C. Troppmann Pretransplantation Soluble Adhesion Molecule Expression Predicts Outcome After Living Donor Renal Transplantation Arch Surg, October 1, 2003; 138(10): 1113 - 1120. [Abstract] [Full Text] [PDF]

				E. L. Schiffrin and R. M. Touyz Multiple actions of angiotensin II in hypertension: benefits of AT1 receptor blockade J. Am. Coll. Cardiol., September 3, 2003; 42(5): 911 - 913. [Full Text] [PDF]

				O. Hamdy, S. Ledbury, C. Mullooly, C. Jarema, S. Porter, K. Ovalle, A. Moussa, A. Caselli, A. E. Caballero, P. A. Economides, et al. Lifestyle Modification Improves Endothelial Function in Obese Subjects With the Insulin Resistance Syndrome Diabetes Care, July 1, 2003; 26(7): 2119 - 2125. [Abstract] [Full Text] [PDF]

				K. Tsong Tan and A. D. Blann To stroke or not to stroke: Is ICAM-1 or CRP the answer? Neurology, June 24, 2003; 60(12): 1884 - 1885. [Full Text] [PDF]

				C. F. Maurus, D. Schmidt, M. K.J. Schneider, M. I. Turina, J. D. Seebach, and G. Zund Hypoxia and reoxygenation do not upregulate adhesion molecules and natural killer cell adhesion on human endothelial cells in vitro Eur. J. Cardiothorac. Surg., June 1, 2003; 23(6): 976 - 983. [Abstract] [Full Text] [PDF]

				C. M. Ballantyne and M. L. Entman Soluble Adhesion Molecules and the Search for Biomarkers for Atherosclerosis Circulation, August 13, 2002; 106(7): 766 - 767. [Full Text] [PDF]

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