Circulating soluble adhesion molecules ICAM-1 and VCAM-1 and incident coronary heart disease: The PRIME Study

doi:10.1016/S0021-9150(03)00280-6

Atherosclerosis

Volume 170, Issue 1, September 2003, Pages 169-176

https://doi.org/10.1016/S0021-9150(03)00280-6 Get rights and content

Abstract

The Epidemiological Study of Myocardial Infarction Study which enrolled 9758 apparently healthy men aged 50–59 years, is a prospective cohort study designed to evaluate markers of coronary risk. Soluble forms of the intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) levels were measured in plasma obtained at baseline from 317 subjects who suffered a coronary event during the 5-year follow-up and in twice the number of control subjects who were matched for center, age and day of inclusion in a nested case-control design. The relative risk associated with the highest compared with the lowest thirds of ICAM-1 (>625 versus <502 ng/ml) was 2.45 (95% CI: 1.64–3.65, P<0.001) without adjustment; it decreased moderately (RR: 2.09; 95% CI: 1.34–3.24, P<0.001) after control for lipid and non-lipid factors and remained significantly elevated after adjustment for C-reactive protein (CRP) (RR: 1.90; 95% CI: 1.21–2.96, P=0.005). Plasma ICAM-1 was essentially associated with the risk of myocardial infarction or coronary death and also with angina pectoris. Subjects with CRP presented elevated coronary risk only if ICAM-1 was high. An elevated level of VCAM-1 was not associated with any risk of future acute coronary event, or with angina pectoris. This data indicates that plasma levels of ICAM-1 may serve as risk markers for future coronary events whatever their clinical presentation and that risk is better defined using simultaneous measurements of ICAM-1 and CRP than any of these levels separately.

Introduction

Coronary heart disease (CHD) is one of the main causes of premature death in industrialized countries [1] and its prevalence has been increasing in developing ones [2]. Advances in our knowledge of the molecular and cellular pathophysiology of atherosclerotic lesion make it possible to develop molecular markers that can be measured in plasma and used to identify individuals at high risk of CHD. Recent studies provide evidence that an inflammatory reaction is an essential component in the appearance and development of the atherosclerotic lesion [3], [4]. This inflammatory process is associated with the expression of adhesion molecules such as intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 at the surface of endothelial cells. These molecules interact with leukocyte integrins and promote the atherosclerotic lesion [5], [6]. The role of ICAM-1 and VCAM-1 in the development of atherosclerotic lesion is suggested by the demonstration of their presence in these lesions [7], [8], [9], [10], [11], [12].

Circulating forms of adhesion molecules have been described that are probably generated by cleavage to a site close to membrane insertion [13], [14]. The amount of ICAM-1 released has been demonstrated to be directly correlated with the surface expression of ICAM-1 in endothelial cells in culture [15] and a correlation between plasma VCAM-1 and VCAM-1 mRNA has been reported in human atherosclerotic aorta [16].

A few prospective cohort studies indicate that ICAM-1, but not VCAM-1, was elevated in the plasma of subjects with future myocardial infarction (MI) [17], [18], [19], [20]. However, opinions diverge as to the clinical relevance of the plasma measurement of these adhesion molecules. Indeed, epidemiological studies have established the role of C-reactive protein (CRP) as a marker of the inflammatory process in atherosclerosis. As the expression of both CRP and adhesion molecules appears to increase in response to the artery inflammatory process, partial correlations between them have been observed [18]. It is therefore questionable whether measurement of ICAM-1 or VCAM-1 add predictive information to that provided by CRP. A threshold effect observed in the association between ICAM-1 and CHD has also been discussed [20]. We therefore tested the hypothesis that plasma soluble ICAM-1 and VCAM-1 were related to coronary risk. To do so, we measured these adhesion molecules using baseline plasma samples from subjects included in a prospective cohort study, the Epidemiological Study of Myocardial Infarction (PRIME) Study, which was set up to investigate the possible determinants of CHD incidence in French and Northern Irish populations [21]. Furthermore, prospective cohort studies to assess CHD factors have generally analyzed the predictive value of parameters for MI and coronary death, but none has made any evaluation for angina pectoris.

In this paper, different issues have therefore been studied: (1) the predictive value of ICAM-1 and VCAM-1 plasma levels as risk factors for coronary death and non-fatal MI on the one hand and angina on the other hand, (2) the predictive value of the simultaneous measurement of CRP and adhesion molecules.

Section snippets

Materials and methods

We used a nested case-control study design within the PRIME prospective cohort Study. Details of the protocol and conduct of the PRIME Study have previously been described in Ref. [21]. Overall, 9758 apparently healthy men aged 50–59 years and with no prior CHD event were recruited in France and Northern Ireland between April 1991 and January 1994 and followed up for 5 years. Over this follow-up, 1.4% French and 0.8% Northern Irish were lost [22]. On entry, a plasma sample was obtained from

Statistical analysis

Statistical analysis was carried out using the statistical sas package (SAS institute, Cary, NC). All data is presented as means ±S.D., with the exception of triglycerides, ICAM-1 VCAM-1 and CRP which are presented as medians because they were skewed rightward. Relationships between the adhesion molecules and potential CHD risk factors were evaluated with Spearman's rank correlation coefficients in the set of controls. The significance of any difference between cases and controls was tested

Baseline characteristics according to clinical outcome

The sample participants in the nested case-control study included 318 total CHD cases and 613 controls. Cases had MI or coronary death (n=165) or angina (n=158). The average age of cases and controls was very similar by design and not significantly different, 55.4 and 55.2 years, respectively. Anthropometric and risk factor data is presented in Table 1. As expected, baseline body mass index (BMI), cholesterol, LDL-cholesterol, triglycerides and CRP were higher and HDL-cholesterol lower in cases

Discussion

The PRIME prospective cohort study in apparently healthy men of moderate age assessed the predictive ability of baseline plasma concentrations of two soluble adhesion molecules, ICAM-1 and VCAM-1 for two categories of CHD events, MI and coronary death on the one hand, angina on the other hand. The present data shows that (1) ICAM-1 was predictive of acute coronary events such as MI or coronary death and angina, while VCAM-1 was not associated with the occurrence of a first CHD event, (2) the

Acknowledgements

We are indebted to Ms Emmanuelle Lee for her technical assistance with this project. We thank the following organizations which authorized the recruitment of the PRIME subjects: the Health screening centers organized by the Social Security of Lille (Institut Pasteur), Strasbourg, Toulouse and Tourcoing; Occupational Medical Services of Haute-Garonne, of the Urban Community of Strasbourg; the Association Inter-entreprises des Services Médicaux du Travail de Lille et environs; the Comité pour le

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Cardiovascular health is strongly influenced by diet. The levels of inflammatory factors like ICAM-1 and VCAM-1 are high in patients with atherosclerosis or predisposing factor for heart disease. Antioxidant and anti-inflammatory functions are attributed to zinc. We systematically reviewed cell culture, human or animal studies for determining the relationship between zinc status and ICAMs or VCAM-1 levels.
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After screening and removing unrelated or duplicate articles by the title and abstract by two independent reviewers, 15 articles were included. Results indicating an inverse relationship between zinc status with ICAM-1 or VCAM-1 levels and the development of endothelial inflammation, plaque formation, or atherosclerosis. A direct relationship between zinc status and PPAR-α or γ levels was also observed. Zinc oxide (ZnO), zinc nanoparticles, or ions can cause endothelial activation and increased levels of ICAM-1 and VCAM-1.
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The cross-sectional study included a total of 189 Chinese adults: 90 patients with moderate to severe OSA (apnea-hypopnea index≥15 events/h) alone, 40 patients with moderate to severe OSA and CAD, and 59 controls without OSA or with mild OSA and without CAD. We used high-throughput Multiplex Immunobead Assay technology to simultaneously test plasma levels of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1). The associations between the levels of circulating adhesion molecules and CAD in moderate to severe OSA patients were evaluated by multivariate logistic regression analysis.
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^☆: Part of this study was presented at the American Heart Association Meeting, Anaheim, 2001.

¹: Present address: Faculty of Pharmacy, Nantes, France.

²: See Appendix A

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Circulating soluble adhesion molecules ICAM-1 and VCAM-1 and incident coronary heart disease: The PRIME Study☆

Abstract

Introduction

Section snippets

Materials and methods

Statistical analysis

Baseline characteristics according to clinical outcome

Discussion

Acknowledgements

Cell

Biochem. Biophys. Res. Commun.

Lancet

Atherosclerosis

J. Am. Coll. Cardiol.

Trends in cardiovascular disease mortality in industrialized countries since 1950

World Health Stat. Q

The burden of cardiovascular diseases mortality in Europe. Task Force of the European Society of Cardiology on Cardiovascular Mortality and Morbidity Statistics in Europe

Eur. Heart J.

Atherosclerosis—an inflammatory disease

N. Engl. J. Med.

Cytokines regulate vascular functions related to stability of the atherosclerotic plaque

J. Cardiovasc. Pharmacol.

The integrin VLA-4 supports tethering and rolling in flow on VCAM-1

J. Cell Biol.

Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis

Science

An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium

Arterioscler. Thromb.

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.

The expression of the adhesion molecules ICAM-1, VCAM-1, PECAM, and E-selectin in human atherosclerosis

J. Pathol.

Increase in the adhesion molecule P-selectin in endothelium overlying atherosclerotic plaques. Coexpression with intercellular adhesion molecule-1

Am. J. Pathol.

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

Soluble forms of vascular adhesion molecules, E-selectin, ICAM-1, and VCAM-1: pathological significance

Ann. NY Acad. Sci.