C-reactive protein and coronary artery disease—what is the link?

Wolfgang Koenig and Christoph Wanner1

Department of Medicine, Division of Cardiology, University of Ulm and 1 Department of Medicine, Division of Nephrology, University of Würzburg, Germany

Correspondence and offprint requests to: C. Wanner MD, Department of Medicine, Division of Nephrology, University Hospital, Josef-Schneider-Strasse 2, D-97080 Würzburg, Germany. E-mail: c.wanner{at}medizin.uni-wuerzburg.de.

Evidence for inflammation in atherosclerosis

Inflammation of the vessel wall is now considered to play an essential role in the initiation and progression of atherosclerosis [1], and also in its final steps, i.e. plaque erosion or fissure, and eventually plaque rupture [2]. This notion is based on classical pathological studies showing the presence of inflammatory cells, such as monocyte-derived macrophages, T-lymphocytes, and mast cells not only at the site of rupture or superficial erosion [3] but rather at every stage of the disease, even in the very early lesions, the so-called fatty streaks. These morphologic changes are preceded by dysfunction of activated endothelial cells that produce so called adhesion molecules (ICAM-1, E-selectin) that interact with inflammatory cells [4]. The ability of monocyte-derived macrophages to secrete various cytokines (IL-1, IL-6, TNF-{alpha}), chemokines (MCP-1), and growth-factors (PDGF, bFGF, VEGF), further leads to activation and proliferation of smooth muscle cells, progression of the lesion, and finally weakening of vulnerable plaques by degradation of the fibrous cap. Yet atherosclerosis and its clinical complications are not only characterized by local inflammation. Recent prospective studies have shown that several markers of systemic inflammation may be used to predict future cardiovascular events [5].

C-reactive protein (CRP)

This classical acute-phase protein has several advantages over other acute-phase reactants. It is a highly sensitive marker of systemic (micro)-inflammation, tissue damage and infection [6] and upon stimulation its concentration responds over a 10000-fold dynamic range. Its plasma half-life (~19 h) is rapid, but is identical under all conditions. Consequently the rate of hepatic synthesis of CRP is the sole determinant of its plasma concentration [7]. Even modest elevations of the concentration of CRP were strongly predictive in various studies. To monitor such elevations, which are modest, compared to the major rises seen in routine clinical practice, highly sensitive immunoassays are required. CRP values in the very low range yield important novel information concerning the long-term prognosis in apparently healthy subjects at risk of cardiovascular complications, and even more so in those with manifest atherosclerosis. In addition, CRP values are also useful for short-term risk stratification in patients presenting with acute coronary syndromes, before and after intervention.

CRP is a long-term predictor of cardiovascular risk

Data from the Physicians' Health Study [8] and the MONICA-Augsburg Cohort Study [9] in initially healthy middle-aged men demonstrated a threefold increase in risk for future coronary events over 8–10 years of follow-up in subjects in the upper tertile of the CRP-distribution at baseline compared to the lowest tertile. This effect was independent of classical cardiovascular risk factors. CRP has also been prospectively associated with stroke and symptomatic peripheral arterial occlusive disease. The clinical usefulness of CRP measurement is further supported by the finding that it adds to the predictive value of total and HDL cholesterol in assessing long-term coronary risk [10].

CRP in acute coronary syndromes

Studies in patients with acute coronary syndromes have also clearly shown that those with increased levels of CRP (>3 mg/l) on admission are at a considerably higher risk for adverse events (PTCA, CABG, death) compared to those with lower values at entry despite similar clinical presentation [11]. Such increased risk persisted for months after discharge, and CRP levels were predictive even in the presence of negative troponin measurement [12]. This clearly shows that the evaluation of the `active', inflammatory state of patients with manifest atherosclerosis yields important prognostic information.

CRP in the renal patient

CRP levels in haemodialysis patients are approximately tenfold higher than in healthy controls [13]. To assess the risks of mortality or cardiovascular complications, such modest elevations in a range that may still be considered to be low yields information which is similar to that provided in apparently healthy men. Presumably reflecting stimulation of the inflammatory system, CRP not only predicts the long-term but also the short-term prognosis (2 years) in haemodialysis patients. Other acute phase reactants, such as albumin, fibrinogen, apolipoprotein A-I and lipoprotein (a) are correlated with CRP and several of these proteins may be additional predictors and/or causative factors for the high cardiovascular risk [13,14]. The cause(s) for the elevation of CRP in dialysis patients is (are) still unresolved and debate continues over the relative roles of cytokine driven mechanisms, dialysate contamination, or stimulation of inflammatory reaction by Gore-tex fistulas or haemodialysis membrane. Since patients with chronic renal failure who are not yet on maintenance haemodialysis or on CAPD treatment exhibit the same degree of elevation in CRP levels [15], factors unrelated to the haemodialysis procedure and related to uraemia per se such as increased oxidative stress are more likely to play a role. This yet undefined process develops in parallel with the decrease in glomerular filtration rate or the development of microalbuminuria and proteinuria. It activates the acute phase response even in early stages of diabetic [16] and non-diabetic renal disease [15]. Establishing the causes of such inflammation and correcting them may improve survival in the renal patient population.

Should we include CRP in the risk profile?

Based on the above solid and consistent evidence, for risk stratification in subjects at risk of cardiovascular events, the determination of CRP (by means of a highly sensitive assay) is recommended at least once at baseline. Alternative causes of elevated CRP must obviously be excluded. Since renal patients are considered to be in the highest risk group for developing cardiovascular disease, CRP should be included in routine laboratory evaluation. If the value is low, no further measurements are needed. However, if it is even modestly elevated, serial measurements (e.g. every 8 weeks in HD patients) are desirable to exclude transient short-term acute phase responses and to establish that the patient has a potentially threatening condition.

Hypothesis and future perspectives

Although strong and consistent information is available that argues for an important role of systemic inflammation in atherosclerosis, several questions remain to be answered.

It is unclear whether or not an inflammatory protein such as CRP is involved causally in atherosclerosis or merely represents a marker of disease
At least two observations are in favour of a causal role of CRP. Firstly, CRP measured many years before the acute event in apparently healthy subjects independently predicts future risk, and secondly, CRP activates the complement system and induces the expression of tissue factor, two mechanisms through which it might directly mediate increased cardiovascular risk. Even if there is no causal role for CRP, increased levels of this protein in the peripheral circulation or in various tissues, including the arterial vessel wall, might thus promote progression of existing atherosclerosis. But clearly, as an acute phase protein, CRP is also increased in response to an acute ischaemic event.

We need to know the underlying factor(s) that turn on the acute phase response
Several interleukins are known mediators of the acute phase response, and the presence of interleukin-1ß has been demonstrated in atherosclerotic lesions [17]. But which signal has stimulated endothelial cells, monocytes, T-lymphocytes, and mast cells to secrete these mediators? We do not know yet. The association between CRP and cardiovascular events persists after adjustment for conventional vascular risk factors; so factors are able to damage the endothelial cells and cause dysfunction, but obviously they cannot sufficiently explain this association. Chronic infections with Helicobacter pylori, Cytomegalovirus, and Chlamydia pneumoniae have been suggested as another potential cause [18]; but an increasing number of recently published prospective studies based on serological evidence argues against a strong and major causal role of these agents in atherogenesis. Alternatively, these infectious agents might induce an autoimmune response that triggers and perpetuates arterial disease.

If inflammation were to play an important causal role in atherosclerosis, should it become a therapeutic target?
It has been suggested that in addition to its antithrombotic effect, aspirin—as a potential additional mechanism—also modifies the inflammatory response [8]. There is also evidence that statins possess properties beyond lipid lowering, including anti-inflammatory effects which seem to be independent of their antilipaemic effect [19]. Yet the exact mechanisms are unknown and no trial has specifically addressed this issue.

Summary and conclusion

Clearly, there is evidence of inflammation in patients with cardiovascular disease in the absence or presence of renal disease, but we are not sure where it comes from and whether or not it constitutes a target to intervene. To answer these questions is crucial for further understanding the role of inflammation in atherosclerosis and remains a challenge for basic and clinical research.

References

  1. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999; 340: 115–126[Free Full Text]
  2. Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation 1995; 9: 657–671
  3. Van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflamatory process irrespective of the dominant plaque morphology. Circulation 1994: 89: 36–44[Abstract]
  4. Rubanyi GM. The role of endothelium in cardiovascular homeostasis and diseases. J Cardiovasc Pharmacol 1993; 22 [Suppl 4]: S1–S14[ISI][Medline]
  5. Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease. JAMA 1998; 279: 1477–1482[Abstract/Free Full Text]
  6. Pepys MB. The acute phase response and C-reactive protein. In: Weatherall DJ, Ledingham JGG, Warrell DA, eds. Oxford Textbook of Medicine. 2nd edn. Oxford: Oxford University Press; 1995: 1527–1533
  7. Vigushin DM, Pepys MB, Hawkins PN. Metabolic and scintigraphic studies of radioiodinated human C-reactive protein in health and disease. J Clin Invest 1993; 91: 1351–1357[ISI][Medline]
  8. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336: 973–979[Abstract/Free Full Text]
  9. Koenig W, Sund M, Fröhlich M, Fischer H-G, Löwel H, Döring A, Hutchinson WL, Pepys MB. C-reactive protein, a sensitive marker of systemic inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men. Results from the MONICA-Augsburg cohort study 1984–92. Circulation 1999; 99: 237–242[Abstract/Free Full Text]
  10. Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein adds to the predictive values of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation 1998; 97: 2007–2011[Abstract/Free Full Text]
  11. Toss H, Lindahl B, Siegbahn A, Wallentin L. Prognostic influence of increased fibrinogen and C-reactive protein levels in unstable coronary artery disease. Circulation 1997; 96: 4204–4210[Abstract/Free Full Text]
  12. Morrow DA, Rifai N, Antman EM, Weiner DL, McCabe CH, Cannon ChP, Braunwald E. C-reactive protein is a potent predictor of mortality independently of an in combination with troponin T in acute coronary syndromes: A TIMI 11A Substudy. J Am Coll Cardiol 1998; 31: 1460–1465[ISI][Medline]
  13. Zimmermann J, Herrlinger S, Pruy A, Metzger T. Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int 1999; 55: 648–658[ISI][Medline]
  14. Kaysen GA, Stevenson FT, Depner TA. Determinants of albumin concentration in hemodialysis patients. Am J Kidney Dis 1997; 29: 658–668[ISI][Medline]
  15. Stenvinkel P, Heimbürger O, Paultre F, Diczfalusy U, Wang T, Berglund L, Jogestrand T. Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int 1999; 55: 1899–1911[ISI][Medline]
  16. Zimmermann J, Schramm L, Wanner C, Mulzer E, Henrich HA, Langer R, Heidbreder E. Hemorrheology, plasma protein composition and von Willebrand Factor in type I diabetic nephropathy. Clin Nephrol 1996; 46: 230–236[ISI][Medline]
  17. Galea J, Armstrong J, Gadsdon P, Holden H, Francis SE, Holt CM. Interleukin-1ß in coronary arteries of patients with ischemic heart disease. Arterioscler Thromb Vasc Biol 1996; 16: 1000–1006[Abstract/Free Full Text]
  18. Libby P, Egan D, Skarlatos S. Roles of infectious agents in atherosclerosis and restenosis. An assessment of the evidence and need for future research. Circulation 1997; 96: 4095–4103[Free Full Text]
  19. Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins. Implications for cardiovascular event reduction. JAMA 1998; 279: 1643–1650[Abstract/Free Full Text]