Is atherosclerosis in part an inflammatory disease?
4-17 INFLAMMATION, ASPIRIN, AND THE RISK OF CARDIOVASCULAR DISEASE IN APPARENTLY HEALTHY MEN
Laboratory and pathological data support the idea that inflammation has a role in both the initiation and progression of atherosclerosis. Anti-inflammatory agents may have a role in the prevention of cardiovascular disease.
C-reactive protein is an acute-phase reactant — a marker for underlying systemic inflammation.
This study hypothesized that levels of C-reactive protein would predict the risk of myocardial infarction (MI) and stroke, but not venous thrombosis. (Venous thrombosis is generally not associated with atherosclerosis.) Does inflammation increase the risk of a first thrombotic event? Will the anti-inflammatory effect of aspirin decrease risk?
Conclusion: The base-line plasma concentration of C-reactive protein predicted the risk of future MI.
Anti-inflammatory agents such as aspirin may have benefits in preventing cardiovascular disease.

STUDY

1. A case-control study measured C-reactive protein in over 500 men who were apparently healthy at baseline and subsequently developed MI, stroke, or venous thrombosis over an 8-year follow-up.
2. Compared with a like number of matched participants who did not develop vascular disease.
3. Both subsets had been randomized at baseline to receive aspirin or placebo.
4. Measured plasma C-reactive protein at baseline.

RESULTS

1. Compared with levels in men who did not develop vascular disease, baseline C-reactive protein concentrations were higher among men who went on to have MI. (1.5 vs 1.1 mg/L) or ischemic stroke (1.4 vs 1.1 mg/L), but not venous thrombosis (1.26 vs 1.1 mg/L).
2. Men in the highest quartile of C-reactive protein levels had 3 times the risk of stroke than men in the lowest quartile. Risks were independent of smoking and other risk factors.
3. The use of aspirin was associated with a significant (56%) reduction in risk of MI in men in the highest quartile, but a non-significant (14%) reduction among those in the lowest quartile. The apparent benefit of aspirin appeared linear over quartiles.

DISCUSSION

1. "These prospective data indicate that the base-line plasma concentrations of C-reactive protein in apparently healthy men can predict the risk of first myocardial infarction and ischemic stroke."
2. The effect was independent of other risk factors.
3. The benefits of aspirin in reducing risk of a first MI diminished significantly with decreasing concentrations of C-reactive protein—an intriguing finding, since aspirin has anti-inflammatory as well as antiplatelet properties.
4. The relation of inflammation to vascular risk may be limited to the arterial circulation.
5. C-reactive protein is not simply a short-term marker of risk. It is a long-term marker of risk, even for events occurring 6 or more years later.

CONCLUSION
Baseline plasma concentration of C-reactive protein predicted the risk of future myocardial infarction and stroke. The reduction associated with the use of aspirin in the risk of a first MI appeared to be directly related to the level of C-reactive protein. Anti-inflammatory agents may have clinical benefit in preventing cardiovascular disease.
NEJM April 3, 1997; 336: 973-79 Original investigation, first author from Brigham and Womens Hospital, Boston, Mass.

An editorial in this issue (pp 1014-16) comments: The observation that most infarct-related arteries have no flow-limiting stenosis is driving the search for inflammatory mechanisms of acute myocardial ischemia. Inflammatory cell infiltrates are commonly found in chronic atherosclerosis, and evidence of immunologic activation in plaques can be found in both acute and chronic ischemic syndromes. Ischemic heart disease is appearing to be an ever more complex syndrome. Different pathogenic mechanisms are likely to require different therapeutic approaches.
Comment:
This relationship will require much more investigation to establish it as another important risk factor to add to the already tangled web of risk factors. Although not a practical point at this time, I believed the study provocative enough to abstract.
This is a subset of the "Physicians Health Study" which entered a total of over 22 000 men to determine if regular use of aspirin would reduce risk of MI. The study was terminated early because of a 44% reduction of a first MI in the aspirin group. RTJ

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