C-reactive protein and cardiovascular disease: linked by complement?

W. K. Lagrand1, C. A. Visser1, C. E. Hack3,4, H. W. M. Niessen2 and R. Nijmeijer1,2

1 Departments of Cardiology, 2 Pathology, and 3 Internal Medicine University Hospital Vrije Universiteit 4 Lab. For Experimental and Clinical Immunology Sanquin Blood Supply Foundation Amsterdam, The Netherlands

Sir,

We read with great interest the article of Koenig and Wanner regarding the link between C-reactive protein (CRP) and coronary artery disease [1]. CRP is considered to be an independent risk factor for cardiovascular disease. When corrected for established cardiovascular risk factors CRP levels still add to the prediction of adverse cardiovascular events or a worse outcome in healthy individuals as well as in patients with manifest cardiovascular disease. As briefly outlined in the paper by Koenig and Wanner, several hypotheses are proposed to explain the relation between CRP and cardiovascular disease. In most articles in the literature, regarding CRP as a cardiovascular risk factor, this link is considered to be indirect; i.e. that it reflects an epiphenomenon. However, CRP also exerts pro-inflammatory effects in ischaemic heart disease: i.e. that CRP is able to activate complement via the classical pathway after binding to a suitable ligand. Although this ability of CRP has already been described in 1974 by Kaplan and Volonakis [2], in our opinion, too little attention is paid to this aspect of CRP in literature, as is the case in this paper by Koenig et al.

In a recent study we found CRP being colocalized with activated complement fragments in human infarcted myocardium [3]. Koenig and colleagues themselves recently described the same colocalization of CRP and complement in atherosclerotic vessels, indicating that such a pro-inflammatory role for CRP is very likely [4]. Using an assay that specifically detects CRP-mediated complement activation in vivo [5], we also found that patients with acute myocardial infarction (AMI) have increasing plasma levels of CRP-specific complement activation fragments. With the same assay elevated values of CRP-complement complexes were found in homogenates of human infarcted myocardium, taken from patients who died after AMI (manuscripts in preparation). These results together strongly suggest that CRP enhances inflammation in cardiovascular disease by activating complement.

A pro-inflammatory role of CRP could very well explain the observed associations with cardiovascular disease as recently described [6]. Intervention studies should reveal whether our hypothesis that the link between CRP and cardiovascular disease is based on its pro-inflammatory role is correct and clinically relevant.

References

  1. Koenig W, Wanner C. C-reactive protein and coronary artery disease—what is the link? Nephrol Dial Transplant1999; 14: 2798–2800[Free Full Text]
  2. Kaplan MH, Volanakis JE. Interaction of C-reactive protein complexes with the complement system, I: consumption of human complement associated with the reaction of C-reactive protein with pneumococcal polysaccharide and with choline phosphatides, lecithin and sphingomyelin. J Immunol1974; 112: 2135–2145[ISI][Medline]
  3. Lagrand WK, Niessen HWM, Wolbink GJ, Jaspars LH, Visser CA, Verheugt FWA, Meijer CJLM, Hack CE. C-reactive protein colocalizes with complement in human hearts during acute myocardial infarction. Circulation1997; 95: 97–103[Abstract/Free Full Text]
  4. Torzewski J, Torzewski M, Bowyer DE, Froelich M, Koenig W, Waltenberger J, Fitzsimmons C, Hombach V. C-reactive protein frequently colocalizes with the terminal complement complex in the intima of early atherosclerotic lesions of human coronary arteries. Arterioscler Thromb Vasc Biol1998; 18: 1386–1392[Abstract/Free Full Text]
  5. Wolbink GJ, Brouwer MC, Buysmann S, ten Berge IJM, Hack CE. CRP-mediated activation of complement in vivo. Assessment by measuring circulating complement-C-reactive protein complexes. J Immunol1996; 157: 473–479[Abstract]
  6. Lagrand WK, Visser CA, Hermens WTh, Niessen HWM, Verheugt FWA, Wolbink GJ, Hack CE. C-reactive protein as a cardiovascular risk factor: more than an epiphenomenon? Circulation1999; 100: 96–102[Abstract/Free Full Text]

 

Reply

W. König1 and C. Wanner2

1 Department of Internal Medicine II, Division of Cardiology, University Hospital Ulm 2 Department of Medicine, Division of Nephrology, University Hospital Würzburg, Germany

Lagrand et al. underline in their comment the potential direct effects of CRP in the development of atherosclerosis through complement activation, complex binding and deposition in atherosclerotic lesions, and infarcted myocardium. Such a pro-inflammatory effect of CRP has been mentioned in our editorial and its potential role in atherosclerosis is currently investigated by several groups. Indeed, new intriguing experimental data from Griselli et al. [1] support the observations and conclusions by Lagrand et al. [2] and suggest that CRP exacerbates tissue injury during the acute phase of myocardial infarction (MI) by activating the complement system. Injection of human CRP in a rat model of acute MI enhanced infarct size by approximately 40% and in vivo complement depletion abrogated this effect. In addition to these findings, Bhakdi and colleagues [3] recently extended the knowledge in this field by showing that enzymatic, non-oxidative, modification of tissue-deposited low density lipoprotein is conferring the CRP-binding capacity onto the molecule. They showed that exposure of native CRP to phosphorylcholine groups from degraded LDL particles generates the targets for binding. Staining of CRP in fatty streaks of human coronary arteries localized the molecule to the deeper part of the fibroelastic layer and in the fibro-muscular layer of the intima adjacent to the media. Further pathophysiologic effects of CRP might involve the stimulation of monocyte chemotaxis via a specific CRP receptor, a mechanism possibly important in the early steps of atherogenesis, and potentially independent of its complement activating capacity [4]. Additional recent autopsy studies in 68 cases (290 human coronary artery sections, Zhang et al. [5] confirmed CRP localization at the site of relapsing inflammatory/necrotic process to the coronary intima.

In summary, we agree with Lagrand and colleagues that complement activation might constitute an important pathophysiologic mechanism through which CRP could be directly involved in the pathogenesis of atherosclerosis. We feel, however, that at present direct evidence for such a pro-inflammatory effect of CRP is much less well established than its strong, consistent role as a marker for increased cardiovascular risk in apparently healthy subjects as well as in patients with manifest atherosclerosis.

References

  1. Griselli M, Herbert J, Hutchinson WL et al. C-reactive protein and complement are important mediators of tissue damage in acute myocardial infarction. J Exp Med1999; 190: 1733–1739[Abstract/Free Full Text]
  2. Lagrand WK, Niessen HWM, Wolbink GJ et al. C-reactive protein colocalizes with complement in human hearts during acute myocardial infarction. Circulation1997; 95: 97–103[Abstract/Free Full Text]
  3. Bhakdi S, Torzewski M, Klouche M, Hemmes M. Complement and atherogenesis: Binding of CRP to degraded, nonoxidized LDL enhances complement activation. Arterioscler Thromb Vasc Biol1999; 19: 2348–2354[Abstract/Free Full Text]
  4. Torzewski J, Rist C, Bienek M, Kaya Z, Koenig W, Hombach V. C-reactive protein and atherogenesis—C-reactive protein is chemotactic for monocytes in vitro and its accumulation in the arterial intima precedes monocyte infiltration in early atherogenesis. Eur Heart J1999; 20[Suppl]: 73 (Abstract)
  5. Zhang YX, Cliff WJ, Schoefl GI, Higgins G. Coronary C-reactive protein distribution: its relation to development of atherosclerosis. Atherosclerosis1999; 145: 375–379[ISI][Medline]