Soluble adhesion molecules and prediction of coronary heart disease: a prospective study and meta-analysis

doi:10.1016/S0140-6736(01)06104-9

The Lancet

Volume 358, Issue 9286, 22 September 2001, Pages 971-975

https://doi.org/10.1016/S0140-6736(01)06104-9 Get rights and content

Summary

Background

Previous studies have suggested that circulating concentrations of soluble adhesion molecules are useful predictors of risk of coronary heart disease (CHD). Larger studies are needed, however, to test this hypothesis.

Methods

We measured serum concentrations of four soluble cell adhesion molecules (intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1], E-selectin, and P-selectin) in the stored baseline serum samples of 643 men with coronary heart disease and 1278 controls nested in a prospective sutdy of 5661 men who were monitored for 16 years. We also did a meta-analysis of previous relevant studies to place our findings in context.

Results

Concentrations of soluble adhesion molecules were significantly associated with one another, with other markers of inflammation, and with some classic coronary risk factors. For ICAM-1, the odds ratio for CHD was 1·68 (95% Cl 1·32–2·14) in a comparison of men in the top third with those in the bottom third of baseline measurements after adjustments for age and town. This decreased to 1·11 (0·75–1·64) after adjustment for some classic coronary risk factors and indicators of socioeconomic status. For the three other cell adhesion molecules, the odds ratios for CHD, first adjusted for age and town only, and then additionally adjusted for other risk factors, were: VCAM-1: 1·26 (0·99–1·61) and 0·96 (0·66–1·40); E-selectin: 1·27 (1·00–1·61) and 1·13 (0·78–1·62); and P-selectin: 1·23 (0·96–1·56) and 1·20 (0·81–1·76).

Interpretation

The measurement of these adhesion molecules is unlikely to add much predictive information to that provided by more established risk factors.

Introduction

Atherosclerosis may, in part, be an inflammatory disease.¹ This suggestion is supported by the presence of mononuclear cells in arterial lesions and by the ability of various blood markers related to inflammation to predict major coronary events.1, 2, 3 Previous meta-analyses of long-term prospective studies have reported that the risk of coronary heart disease (CHD) is about 40% (95% CI 30–50%) greater in people with raised total blood leucocyte counts, and about 90% (50–130%) greater in those with raised circulating concentrations of C-reactive protein (a sensitive acute-phase reactant), in comparisons between people in the top third of these factors and those in the bottom third of baseline measurements.2, 3

Adhesion molecules facilitate the recruitment of circulating leucocytes to sites of inflammation.⁴ Transient rolling of leucocytes along endothelium is mediated by selectins, including E-selectin and P-selectin.⁵ Stronger attachment of white cells to endothelium is mediated by intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1).⁴ These cell adhesion molecules are detected more commonly in human atherosclerotic lesions than in healthy arterial tissue.6, 7 Moreover, knock-out mice deficient in E-selectin, P-selectin, or ICAM-1 develop fewer arterial lesions than normal mice.8, 9, 10, 11 Although increased cell surface expression of these molecules is difficult to quantify in vivo, soluble forms can now be measured in serum.¹² Preliminary studies have reported strong associations between concentrations of particular soluble adhesion molecules and CHD.13, 14 For example, one study of about 200 cases reported that CHD risk is five times greater in people with raised values of soluble ICAM-1, and two times greater in those with raised E-selectin.¹³

We report a prospective study with a larger number of CHD cases and more extended follow-up than previous studies of this topic, and have done a meta-analysis to place our results in context. Whereas most previous epidemiological studies have measured only one or two soluble adhesion molecules, we have measured serum concentrations of four cell adhesion molecules: ICAM-1, VCAM-1, E-selectin, and P-selectin. To investigate to what extent various soluble adhesion molecules are related to one another and to processes known, or suspected, to be relevant to CHD, we examined inter-relations of adhesion molecules with one another as well as with smoking habits, blood pressure, circulating markers of lipid metabolism, low-grade systemic inflammation, persistent infection, haemostasis and thrombosis, and indicators of socioeconomic status.

Section snippets

Study participants

To establish the British Regional Heart Study, 7735 men aged 40–59 years (response rate 78%) were randomly selected from general practice registers in each of 24 British towns between 1978 and 1980.¹⁵ Nurses administered questionnaires, took physical measurements, recorded an electrocardiogram, and, in 5661 men from 18 of the towns, collected non-fasting venous blood samples (which were centrifuged and then stored as aliquots of serum at −20°C).¹⁵ Additional questionnaires on car ownership and

Results

Measurements were available for: ICAM-1 (626 cases, 1253 controls), VCAM-1 (622 cases, 1249 controls), E-selectin (628 cases, 1253 controls), and P-selectin (627 cases, 1254 controls). The mean age at CHD event among cases was 62 years. There were significant differences between cases and controls with respect to established vascular risk factors, such as smoking, body-mass index, blood pressure, and blood lipids (table 1).

In control individuals without evidence of CHD at baseline, the

Discussion

The present long-term, community-based study assessed the predictive ability of baseline serum concentrations of four soluble adhesion molecules (ICAM-1, VCAM-1, E-selectin, and P-selectin) for fatal and non-fatal CHD. After making allowances for known risk factors, we found no strong associations of these adhesion molecules with CHD risk, and our findings have been reinforced by a meta-analysis of previously published prospective studies.

Our study adds considerable data to the available

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ArticlesSoluble adhesion molecules and prediction of coronary heart disease: a prospective study and meta-analysis

Summary

Background

Methods

Results

Interpretation

Introduction

Section snippets

Study participants

Results

Discussion

Cell

Immunol Today

Lancet

Atherosclerosis

J Am Coll Cardiol

Am J Cardiol

Am J Cardiol

Chest

Atherosclerosis: an inflammatory disease

N Engl J Med

Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies

JAMA

Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses

BMJ

The selectins: vascular adhesion molecules

FASEB J

Expression of the adhesion molecule ICAM-1 in atherosclerotic plaques: implications for positive-feedback monocyte recruitment in the pathogenesis of the plaque

Am J Pathol

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

J Pathol

Absence of P-selectin delays fatty streak formation in mice

J Clin Invest

Deficiency of inflammatory cell adhesion molecules protects against atherosclerosis in mice

Arterioscler Thromb Vasc Biol

Articles
Soluble adhesion molecules and prediction of coronary heart disease: a prospective study and meta-analysis