Current issues of ACP Journal Club are published in Annals of Internal Medicine


Etiology

Soluble intercellular adhesion molecule 1 was associated with an increased risk for MI in healthy men

ACP J Club. 1998 Jul-Aug;129:20. doi:10.7326/ACPJC-1998-129-1-020


Source Citation

Ridker PM, Hennekens CH, Roitman-Johnson B, Stampfer MJ, Allen J. Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men. Lancet. 1998 Jan 10;351:88-92.


Abstract

Question

In apparently healthy men, is soluble intercellular adhesion molecule 1 (sICAM-1) associated with an increased risk for myocardial infarction (MI)?

Design

A nested case-control study within the Physicians' Health Study, a controlled trial of aspirin and β-carotene to prevent cardiovascular disease and cancer. Patients were followed for up to 9 years.

Setting

United States.

Participants

474 men (physicians) who had a confirmed first MI were matched on age, smoking status, and length of follow-up with 474 control participants who were free of vascular disease on the date of the MI. Participants were predominantly white, and their mean age was 58 years.

Assessment of risk factors

Baseline sICAM-1 levels reported in quartiles (< 193, 193 to 225, 226 to 260, and > 260 ng/mL) with the lowest quartile given the relative risk of 1.0. Cardiovascular risk factors measured at baseline were age, smoking status, body mass index, hypertension, history of diabetes and high cholesterol levels, and parental history of coronary artery disease. Baseline plasma levels of total, high-, and low-density lipoprotein (LDL) cholesterol; tissue-type plasminogen-activator antigen; D-dimer; fibrinogen; total homocysteine; and C-reactive protein were measured and controlled for in multivariate analysis.

Main outcome measure

Confirmed MI using the World Health Organization criteria.

Main results

After adjustment for all risk factors, men in the highest quartile of sICAM-1 levels had an increased risk for MI. A similar pattern was seen in men who did not smoke (Table). The risk for MI associated with sICAM-1 levels was independently associated with 8 other laboratory values, including markers of coagulation and inflammation, lipid levels, and homocysteine levels (P ≤ 0.05).

Conclusion

The risk for a first myocardial infarction in apparently healthy men was associated with an increased level of soluble intercellular adhesion molecule 1.

Sources of funding: National Heart Lung and Blood Institute and American Heart Association.

For correspondence: Dr. P.M. Ridker, Brigham and Women's Hospital, 900 Commonwealth Avenue East, Boston, MA 02115-1204, USA. FAX 617-734-1437.


Table. Risk factors for a first myocardial infarction in relatively healthy men with high levels of soluble intercellular adhesion molecule 1

Population Relative risk 95% CI P value
All men 1.8 1.1 to 2.8 0.007
Nonsmokers 1.8 1.1 to 3.0 0.01

Commentary

C-reactive protein levels were associated with an increased risk for peripheral vascular disease in healthy men

The idea that an inflammatory process may be responsible for the initiation and promotion of atherosclerosis is not new. As early as 1856, Virchow (1) hypothesized a role for inflammation in atherosclerosis. The importance of the foam cell in the pathophysiology of atherosclerosis was shown in the early 1960s, and subsequent technological advances allowed the identification of macrophages, T-lymphocytes, and smooth muscle cells as the primary cellular constituents of early and advanced lesions of atherosclerosis. The presence of macrophages and T-lymphocytes in the atherosclerotic lesion strongly suggested inflammation as a key factor in the development of atherosclerosis.

In vitro and animal studies have shown that endothelial and smooth muscle cells present membrane adhesion molecules that act as monocyte receptors when stimulated by cytokines, thrombin, and oxidized LDL cholesterol. Membrane adhesion molecules may also play an important role in the migration of monocytes through the vascular endothelium. Many cytokines have been identified in the atherosclerotic plaque and likely play an important role in the regulation of this local inflammatory process and in the regulation of hemostatic factors (2), smooth muscle cell proliferation, collagen synthesis, endothelial cell activation (3), and oxidized LDL cholesterol uptake by macrophages and their transformation into foam cells.

Although substantial evidence from the basic sciences implicates an inflammatory process in the development of atherosclerosis, evidence from epidemiologic investigations of humans is just starting to emerge. One hypothesis from these investigations is that the local inflammatory process that occurs in persons who have atherosclerosis or who have had an acute ischemic syndrome differs in some way from those who have not. Ridker and colleagues constructed a nested case-control study within the Physicians' Health Study in an attempt to ascertain if exposure to higher levels of sICAM-1 were associated with greater risk for acute MI. An identical approach was used by the same investigators to examine the association of plasma concentration of C-reactive protein (a systemic marker of inflammation) with the development of PVD. The results showed an increased risk for MI in U.S. male physicians who had higher sICAM-1 levels. The second study showed a similar finding for C-reactive protein levels and PVD.

These results provide interesting and preliminary evidence for the role of inflammation in the initiation and development of atherosclerosis and suggest that levels of sICAM-1 and C-reactive protein could be used to identify persons at risk for the development of atherosclerotic vascular disease. The authors acknowledge a potential therapeutic role for agents capable of blocking the adhesion and migration of monocytes into the arterial wall. The sICAM-1 test is not readily available, and neither test should change the average physician's current clinical approach—successful intervention studies would be needed first. In the meantime, we should all encourage our patients to stop smoking and should treat their hypertension and hypercholesterolemia.

Allan D. Kitching, MSc, MD
McMaster UniversityHamilton, Ontario, Canada


References

1. Virchow R. Phlogose und Thrombose in Gefassystem. In: Virchow R, ed. Gesammelte Abhandlungen zur Wissenschaftlichen Medizin. Berlin: Meidinger Sohn und Co; 1856.

2. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993; 362:801-9.

3. Libby P. Molecular bases of the acute coronary syndromes. Circulation. 1995;91: 2844-50.