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


Etiology

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

ACP J Club. 1998 Jul-Aug;129:21. doi:10.7326/ACPJC-1998-129-1-021


Source Citation

Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease. Circulation. 1998 Feb 10; 97:425-8.


Abstract

Question

In apparently healthy men, are higher levels of C-reactive protein associated with an increased risk for peripheral vascular disease (PVD)?

Design

A nested case-control study in the Physicians' Health Study, a controlled trial of aspirin and β-carotene to prevent cardiovascular disease and cancer. Mean follow-up was 60 months.

Setting

United States.

Participants

144 men (physicians) who reported intermittent claudication or peripheral revascularization during follow-up were matched for age, smoking status, and length of follow-up with 144 control participants who were free of cardiovascular disease on the date of reported claudication or revascularization. Participants were predominantly white, and their mean age was 63 years. All men reported no history of claudication at baseline.

Assessment of risk factors

Baseline C-reactive protein levels reported in quartiles (< 0.55, 0.55 to 0.99, 1.0 to 2.1, and > 2.1 mg/L) with the lowest quartile given the relative risk (RR) of 1.0. Cardiovascular risk factors measured at baseline were age; smoking status; body mass index; history of diabetes, high cholesterol levels, and hypertension; parental history of premature atherosclerosis; and random allocation to receive aspirin.

Main outcome measures

Self-reported intermittent claudication or peripheral revascularization.

Main results

More patients with PVD than control-group participants reported a history of diabetes (10.4% vs 4.2%, P = 0.04), and a trend was shown toward a higher rate of reported family history of premature atherosclerosis (16.7% vs 9.2%, P = 0.06). Compared with men in the lowest quartile of C-reactive protein levels at baseline, men in the highest quartile had higher risks for PVD and peripheral revascularization (Table). Men with the lowest levels of C-reactive protein remained healthy, men with intermediate levels developed claudication, and men with the highest levels needed peripheral revascularization.

Conclusion

C-reactive protein levels were associated with an increased risk for intermittent claudication and peripheral revascularization in apparently healthy men.

Source of funding: National Heart, Lung, and Blood Institute.

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. Adjusted relative risks for intermittent claudication or peripheral revascularization associated with C-reactive protein levels in apparently healthy men (highest vs lowest quartiles)

Outcomes across quartiles Relative risk 95% CI P value for trend
Claudication 2.2 1.1 to 4.8 0.02
Peripheral revascularization 7.1 Not available 0.01

Commentary

Soluble intercellular adhesion molecule 1 was associated with an increased risk for MI 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.