Inflammation, aspirin and the risk of cardiovascular disease

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Inflammation, aspirin and the risk of cardiovascular disease

F. Haverkate, TNO-PG Gaubius Laboratory, Leiden

It has been known for a long time that the etiology of atherosclerosis is closely associated with inflammatory reactions at the site of the vascular wall . It is surprising therefore that an association between inflammation and the risk of cardiovascular events has only become evident in the past few years, since the finding of an association between cardiovascular risk and increased blood levels of C-Reactive Protein (CRP), a sensitive inflammatory marker which is synthesized in the liver and levels of which increase during an acute-phase response. The collaborators of the ECAT Angina Pectoris study, a large prospective study on patients with angina have to be credited with the discovery of CRP as a cardiovascular risk factor , . The MRFIT study showed that CRP was increased in those at high risk partly because of cigarette smo-king . Ridker et al. were the first to establish CRP as a risk factor in healthy people, regardless of the smoking status. Over 20,000 apparently healthy, USA male physicians, age between 40 and 84, were enrolled in a prospective study, the Physicians' Health Study. CRP was determined in the plasma of 14,916 patients. Coronary events and stroke were reported during a follow-up period of over 8 years; final statistical analyses were performed on data of 543 cases and 543 controls of the cohort.

The first conclusion from Ridker's study is that the baseline plasma concentration of CRP predicts the risk of future myocardial infarction (MI) and stroke. Men in the quartile with the highest CRP concentration (>2.1 mg/L) had three times the risk of MI and twice the risk of ischaemic stroke. Risks were not significantly modified by lipids, smoking and other risk factors. As CRP was determined in healthy people, increase of CRP due to ischemia can be excluded. A new and surprising result of Ridker's study is the association between CRP levels, the use of aspirin and cardiovascular risk. The magnitude of the beneficial effect of aspirin in preventing MI was directly related to CRP levels at baseline. This finding is most intriguing and suggests the possibility that the benefit of aspirin may have due, at least in part, to anti-inflammatory effects.

A definite explanation of the results can certainly not be given. CRP seems to be increased in subjects at risk by a continuous, low-grade inflammatory response. It is still unknown whether the response originates in atherosclerotic lesions, or elsewhere in the body from chronic infections known as cardiovascular risk factors, such as Chlamydia pneumoniae or bronchitis . If the benefit of aspirin may have due, at least in part, to anti-inflammatory effects, it may be speculated that inflammation is not only a consequence of atherosclerosis, but also may contribute to the occurrence of coronary events. It will then become worthwile to develop other anti-inflammatory drugs in the fight against cardiovascular disease which are more specific than the previously applied glucocorticoid therapy.

It can be anticipated that Ridker's results would improve if the variation of CRP levels between and within individuals had been suppressed by repeated blood collection at baseline to produce more than one CRP value per person . It is somewhat disappointing that Ridker et al.5 do not reveal whether aspirin influences the CRP levels. On the basis of his results one would expect that it may lower CRP levels. At the time of blood collection for CRP analysis, all patients were on aspirin and it is questionable whether results would have been similar if patients had not been treated with aspirin before randomization. Despite this minor criticism, the study of Ridker et al.5 is a great contribution in the field.

Ridker's study includes the implicit warning that an established drug like aspirin with a beneficial effect in cardiovascular disease does not necessarily follow the mechanism of action (antiplatelet action) we ascribe to it. A similar trend has recently been shown for statines doing more than just lowering cholesterol . The findings on CRP as a cardiovascular risk factor, regardless of whether or not it is a causal factor in the disease, may have some implications for diagnosis and therapy. CRP is a risk factor which does not depend on lipids5,10. According to the ECAT Angina Pectoris study , low CRP levels appeared to be associated with low risk, despite high levels of cholesterol which may help to better identify patients at risk. Furthermore, CRP may be useful in identifying people for whom aspirin is likely to be more or less effective5.

Cardiovascular risk in relation to inflammatory components such as cytokines and markers of leucocyte functions may become an exciting research field in the near future. It may contribute to a better understanding of the etiology of cardiovascular disease, and hopefully improve diagnosis, therapy and prevention of the disease.

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