Activated protein C resistance

It may be a marker not only of acute illness but also of future cardiovascular disease

Creactive protein (CRP) has traditionally been used as an acute phase marker of tissue injury, infection, and inflammation, but the use of high sensitivity assays has recently shown that increased C reactive protein values predict future cardiovascular disease.

The C reactive protein response has no diagnostic specificity, but serial measurements can be helpful in clinical management. It is a powerful screening test for organic disease and is useful in monitoring known infectious or inflammatory diseases and their response to treatment.[1] Although a high value is unequivocal evidence of tissue damaging disease, C reactive protein values (unlike most other clinical laboratory tests) can really only be interpreted when all other clinical and laboratory information is available. Nevertheless, serial measurements of C reactive protein, added to the full clinical picture, contribute usefully to diagnosis, prognosis, and management.[1]

C reactive protein is a trace protein in healthy subjects, with a median concentration of around 1 mg/l, but values can exceed 400 mg/l in the acute phase response. Routine applications in adult medicine require measurement above 5-10 mg/l, but the development of high sensitivity assays has recently allowed clinicians to explore the role of C reactive protein in atherosclerotic disease.

Predictor of coronary events

Increased C reactive protein values significantly predict coronary events in outpatients with stable or unstable angina[2] and in hospital patients with severe unstable angina[3] and predict outcome after coronary angioplasty.[4] Even in healthy asymptomatic people in the general population individuals with baseline C reactive protein values in the top third of the distribution (geometric mean 2.4 mg/l) have twice the future risk of a coronary event than with those with values in the bottom third (mean 1.0 mg/l).[5] Similar relationships exist for stroke and peripheral vascular disease.

C reactive protein values increase with smoking and body mass index but the association with coronary events remains after adjustment for these potential confounders. The same is true for some other inflammatory markers, suggesting an association between inflammation and atherothrombosis. Inflammation is a central component of atherogenesis and is important in plaque instability and rupture, leading to thrombosis. However, it is not known whether increased C reactive protein production reflects arterial inflammation or inflammation elsewhere in the body. Chronic low grade infections may be risk factors for coronary heart disease, but C reactive protein concentrations do not correlate with serological markers of Helicobacter pylori or Chlamydia pneumoniae infection in the general population.[5]

In contrast, the association between C reactive protein values and body mass index probably reflects the importance of adipose tissue as a source of baseline circulating interleukin-6, the main cytokine mediator of increased C reactive protein production.[6] Increased C reactive protein values within the normal reference range may thus reflect mass of adipose tissue rather than actual inflammation. The question also arises of whether C reactive protein itself might contribute to atherothrombosis.

A pathogenefic role?

C reactive protein selectively binds to low density lipoprotein, particularly the partly degraded low density lipoprotein found within atherosclerotic plaques, and is generally present together with it, and activated complement, within such plaques.[7 8] Bound C reactive protein activates complement, is proinflammatory, and may thus contribute to atherogenesis. C reactive protein may also increase macrophage production of tissue factor,[9] the coagulation initiator responsible for occlusive thrombotic events. However, it will be possible to test whether C reactive protein has a pathogenetic role only when drugs are developed that selectively inhibit C reactive protein production or binding. Meanwhile, it is of interest that statins lower C reactive protein values,[10] suggesting that some of their protective effects may be mediated through suppression of inflammation or cytokines.

In contrast to the uncertain role of C reactive protein in the artery wall, there is strong evidence that C reactive protein increases ischaemic myocardial damage. C reactive protein production increases in all patients with myocardial infarction, peaking at about 50 hours, and high values are associated with a poor short term and long term prognosis. All fatal acute infarcts contain C reactive protein alongside activated complement,[11] and in experimental studies complement activation contributes importantly to infarct size. It has now been confirmed that human C reactive protein, via its capacity to activate complement, greatly increases infarct size after experimental coronary artery ligation,[12] and this presumably also happens in patients.

A spur to research

Routine empirical measurement of C reactive protein is a valuable aid to patient management across a broad range of clinical practice. Sensitive C reactive protein assay may become a new risk assessment marker for cardiovascular disease, and guidelines for its application are under discussion. While the potential management implications of a raised C reactive protein value in asymptomatic subjects are not yet clear, in those with active coronary disease a raised value definitely identifies a high risk group likely to require interventions. The possibility that C reactive protein may contribute to pathogenesis of atherothrombosis, and the fact that it increases ischaemic myocardial injury, should spur the development of specific drugs to inhibit C reactive protein.

Finally, it is intriguing to wonder whether the excellent correlation between plasma C reactive protein concentrations and disease activity reflects not just the acute phase response to the original underlying pathological process, but also the capacity of C reactive protein to exacerbate existing tissue damage: possibly the more C reactive protein you produce, the sicker you get.

Mark B Pepys professor of medicine (m.pepys@rfc.ucl.ac.uk)

Department of Medicine, Royal Free and University College Medical School, London NW3 2PF

Abi Berger science editor, BMJ

MBP has received fees for speaking and consulting about C reactive protein from Abbott Laoratories and for speaking from Dade-Behring and has collaborated on C reactive protein testing with Roche Diagnostics.

[1] Pepys MB. The acute phase response and C-reactive protein. In: Weatherall DJ, Ledingham JGG, Warrell DA, eds. Oxford textbook of medicine. Vol 2. 3rd ed. Oxford: Oxford University Press, 1995:1527-33.

[2] Haverkate F, Thompson SG, Pyke SDM, Gallimore JR, Pepys MB. Production of C-reactive protein and risk of coronary events in stable and unstable angina. Lancet 1997;349:462-6.

[3] Liuzzo G, Biasucci LM, GallimoreJR, Grillo RL, Rebuzzi AG, Pepys MB, et al. The prognostic value of C-reactive protein and serum amyloid A protein in severe unstable angina. N Engl J Med 1994;331:417-24.

[4] Buffon A, Liuzzo G, Biasucci LM, Pasqualetti P, Ramazzotti V, Rebuzzi AG, et al. Preprocedural serum levels of C-reactive protein predict early complications and late restenosis after coronary angioplasty. J Am Coll Cardiol 1999;34:1512-21.

[5] Danesh J, Whincup J, Walker M, Lennon L, Thomson A, Appleby P, et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ 2000;321:199-204.

[6] Yudkin JS, Stehouwer CDA, Emeis JJ, Coppack SW. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol 1999;19:972-8.

[7] Bhakdi S, Torzewski M, Klouche M, Hemmes M. Complement and atherogenesis. Binding of CRP to degraded, nonoxidized LDL enhances complement activation. Arterioscler Thromb Vasc Biol 1999;19:2348-54.

[8] Zhang YX, Cliff WJ, Schoefl GI, Higgins G. Coronary C-reactive protein distribution: its relation to development of atherosclerosis. Atherosclerosis 1999;145:375-9.

[9] Cermak J, Key NS, Bach RR, Balla J, Jacob HS, Vercellotti GM. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor. Blood 1993;82:513-20.

[10] Ridker PM, Rifai N, Pfeifer MA, Sacks F, Braunwald E. Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation 1999;100:230-5.

[11] Lagrand WK, Niessen HWM, Wolbink G-J, Jaspars LH, Visser CA, Verheugt FWA, et al. C-reactive protein colocalizes with complement in human hearts during acute myocardial infarction. Circulation 1997;95:97-103.

[12] Griselli M, Herbert J, Hutchinson WL, Taylor KM, Sohail M, Krausz T, et al. C-reactive protein and complement are important mediators of tissue damage in acute myocardial infarction. J Exp Med 1999;190:1733-40.

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