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(Circulation. 1999;100:96-102.)
© 1999 American Heart Association, Inc.

Current Perspective

C-Reactive Protein as a Cardiovascular Risk Factor

More Than an Epiphenomenon?

Wim K. Lagrand, MD; Cees A. Visser, MD, PhD; Willem T. Hermens, PhD; Hans W. M. Niessen, MD, PhD; Freek W. A. Verheugt, MD, PhD; Gert-Jan Wolbink, MD, PhD; C. Erik Hack, MD, PhD

From the Departments of Cardiology (W.K.L., C.A.V.), Pathology (H.W.M.N.), and Internal Medicine (C.E.H.), Free University Hospital, Amsterdam; Cardiovascular Research Institute Maastricht (CARIM) (W.T.H.), University of Maastricht; the Department of Cardiology (F.W.A.V.), University Hospital Sint Radboud, Nijmegen; and CLB (G.-J.W., C.E.H.), Sanquin Blood Supply Foundation, Amsterdam, The Netherlands.

Correspondence to Wim K. Lagrand, Free University Hospital, Department of Cardiology, PO Box 7057, NL 1007 MB Amsterdam, The Netherlands. E-mail cardiol{at}azvu.nl

	Abstract

Top Abstract Introduction C-Reactive Protein CRP and Cardiovascular Disease Association Between CRP and... CRP-Mediated Inflammation in... Ligands for CRP in... Implications References

 
Background—Circulating levels of C-reactive protein (CRP) may constitute an independent risk factor for cardiovascular disease. How CRP as a risk factor is involved in cardiovascular disease is still unclear.

Methods and Results—By reviewing available studies, we discuss explanations for the associations between CRP and cardiovascular disease. CRP levels within the upper quartile/quintile of the normal range constitute an increased risk for cardiovascular events, both in apparently healthy persons and in persons with preexisting angina pectoris. High CRP responses after acute myocardial infarction indicate an unfavorable outcome, even after correction for other risk factors. This link between CRP and cardiovascular disease has been considered to reflect the response of the body to the inflammatory reactions in the atherosclerotic (coronary) vessels and adjacent myocardium. However, because CRP localizes in infarcted myocardium (with colocalization of activated complement), we hypothesize that CRP may directly interact with atherosclerotic vessels or ischemic myocardium by activation of the complement system, thereby promoting inflammation and thrombosis.

Conclusions—CRP constitutes an independent cardiovascular risk factor. Unraveling the molecular background of this association may provide new directions for prevention of cardiovascular events.

Key Words: cardiovascular diseases • myocardial infarction • inflammation • risk factors • physiology

	Introduction

Top Abstract Introduction C-Reactive Protein CRP and Cardiovascular Disease Association Between CRP and... CRP-Mediated Inflammation in... Ligands for CRP in... Implications References

 
Recent studies provide evidence that inflammation plays a role in the pathogenesis of cardiovascular disease.^{1 2 3} Some inflammatory or hemostatic markers actually constitute cardiovascular risk factors. In this respect, the acute phase reactant C-reactive protein (CRP) is of special interest: Baseline levels of CRP in apparently healthy persons or patients with stable angina pectoris constitute an independent risk factor for cardiovascular events,^{4 5 6 7 8} whereas the rise in CRP after acute myocardial infarction (AMI)^{9 10 11 12 13 14 15 16} or during unstable angina pectoris^{17 18 19 20} correlates with outcome.

The link between CRP and cardiovascular disease is thought to be indirect in that circulating CRP only reflects the extent of the acute phase reaction in response to nonspecific stimuli such as confounding risk factors, atherosclerosis, vascular injury, ischemia, and necrosis. However, several arguments are against this explanation that increased plasma levels of CRP are merely an epiphenomenon. First, chronic infections that cause a rise in circulating CRP also yield a higher risk for cardiovascular disease.^{21 22 23 24} Second, CRP is a cardiovascular risk factor even after correction for other risk factors.⁷ Finally, CRP can be found localized in inflamed tissues,²⁵ including atherosclerotic vessels²⁶ and infarcted myocardium.^{27 28} Here we review studies showing associations between CRP and cardiovascular disease and discuss possible explanations for these associations.

	C-Reactive Protein

Top Abstract Introduction C-Reactive Protein CRP and Cardiovascular Disease Association Between CRP and... CRP-Mediated Inflammation in... Ligands for CRP in... Implications References

 
Acute phase responses are induced by cytokines released from the jeopardized tissue.^{29 30} These cytokines stimulate the liver to synthesize acute phase proteins including CRP.³¹ Plasma CRP increases markedly during acute phase reactions.³² The physiological role of CRP is yet unknown. In vitro, CRP displays both anti-inflammatory and proinflammatory effects.^{33 34} The latter includes the ability of ligand-bound CRP to activate the complement system.³⁴

	CRP and Cardiovascular Disease

Top Abstract Introduction C-Reactive Protein CRP and Cardiovascular Disease Association Between CRP and... CRP-Mediated Inflammation in... Ligands for CRP in... Implications References

 
Regarding associations between circulating CRP and cardiovascular disease (see Table 1), diseases without (atherosclerosis and stable and unstable angina) or with myocardial tissue damage (AMI) should be distinguished. In the latter situation the acute phase response is triggered, at least in part, by myocardial necrosis, and variations in postinfarct rise of circulating CRP are analyzed. In contrast, in the former the acute phase response is not triggered (at least not by myocardial necrosis) and baseline levels of circulating CRP are studied. This explains why circulating CRP levels associated with increased risk or worse course vary from cutoff points of 0.3 mg/dL in unstable angina^{18 35} to 20 mg/dL in AMI.^{15 16}

View this table: [in this window] [in a new window]   Table 1. Studies Analyzing Associations Between CRP and Cardiovascular Disease

In cardiovascular disease without myocardial necrosis, plasma CRP correlates with the extent and severity of atherosclerosis^{36 37} and with hemostatic, lipid, and infectious risk factors for cardiovascular disease.⁵ Even after correction for these risk factors, high-normal CRP levels still predict an increased risk for development of symptomatic peripheral arterial disease³⁷ and the occurrence of coronary events in both stable¹⁹ and unstable^{18 19} angina pectoris and even in apparently healthy persons.⁷

AMI triggers an acute phase response resulting in a rise of circulating CRP levels, which correlates with infarct size.^{9 10 11 12} Though infarct size is a major denominator for long-term prognosis after AMI, short-term prognosis, in particular mortality during the first 6 months, is associated with CRP responses in thrombolysis-treated patients independent of infarct size.¹⁴ Hence baseline levels of CRP constitute an independent risk factor for coronary events in healthy persons as well as in patients with stable or unstable angina pectoris. The postinfarct rise of circulating CRP is associated with short-term clinical outcome in patients with AMI. We will now discuss potential mechanisms explaining these associations (Table 2).

View this table: [in this window] [in a new window]   Table 2. CRP as an Indirect Cardiovascular Risk Factor: Possible Explanations

	Association Between CRP and Cardiovascular Disease: Possible Explanations

Top Abstract Introduction C-Reactive Protein CRP and Cardiovascular Disease Association Between CRP and... CRP-Mediated Inflammation in... Ligands for CRP in... Implications References

 
CRP Reflects Inflammation of (Coronary) Vessels by Pathogenic Agents
CRP may increase in cardiovascular disease in response to infectious (viral, bacterial) agents inducing inflammatory reactions in the (coronary) vessels. Although this possibility cannot be excluded definitely, infectious agents in coronary vessels or myocardium have not been demonstrated convincingly thus far.²⁴ Notably, chronic infections elsewhere in the body^{21 22 23 24} are also associated with an increased risk for cardiovascular disease. Furthermore, the chronologic sequence of infection by pathogens and the initiation and progression of cardiovascular disease still remains to be elucidated.²⁴ These infections likely are associated with raised CRP levels. Hence, chronic infections may be associated with cardiovascular disease by a coinciding rise of plasma CRP due to elicitation of an acute phase response.⁵

CRP Reflects Inflammation Related to the Atherosclerotic Process
CRP levels have been considered to reflect the extent of inflammatory reactions in the atherosclerotic vessels.^{36 37} Thus, by virtue of its acute phase behavior, CRP is a marker for severity and progression of atherosclerotic processes in the vessels.³⁶ However, many patients with stable and with unstable angina pectoris have normal levels of acute phase proteins, implying that coronary atherosclerosis itself does not induce a full-blown acute phase response.^{17 18 19 20} Moreover, levels of other acute phase reactants do not show similar associations as reported for CRP. Haverkate et al¹⁹ reported that baseline CRP levels predict subsequent coronary events in both stable and unstable angina, whereas levels of serum amyloid A peptide do not. Acute phase proteins such as ₁-acid glycoprotein^{6 13} or ₁-antichymotrypsin¹³ are also not associated with cardiovascular disease. Some studies report that CRP levels correlate with the incidence of coronary events only when not adjusted for fibrinogen.^{4 20} However, in one of these studies, a rather insensitive assay for CRP was used that was unable to differentiate levels within the normal range.¹⁹ If baseline CRP reflects the extent of arteriosclerotic processes, levels would be expected to be higher in patients with angina pectoris than in apparently healthy persons, as was indeed found in a few small studies.^{38 39} However, median levels of CRP in the study of Mendall et al⁵ in apparently healthy individuals are remarkably similar to those reported by Haverkate et al¹⁹ in patients with stable angina pectoris (0.17 mg/dL). Finally, the possibility that CRP is linked to cardiovascular disease because it increases in response to clot formation superimposed on atherosclerotic lesions in the vessels is unlikely.⁴⁰

CRP Reflects Extent of (Myocardial) Ischemia
Myocardial ischemia without necrosis does not induce a rise of circulating CRP levels, as was demonstrated in patients with variant angina pectoris with documented episodes of myocardial ischemia.⁴¹ Hence the explanation that CRP simply reflects the extent of myocardial ischemia is not tenable.

CRP Reflects Extent of (Myocardial) Necrosis
Obviously, myocardial necrosis triggers a rise of circulating CRP. Thus the extent of necrosis in part determines the CRP response. In agreement herewith, CRP correlates with infarct size in conservatively treated patients with AMI.^{11 12} These correlations are less significant after early coronary recanalization in patients with AMI.¹² Recanalization of an infarct-related coronary artery improves prognosis after AMI as it decreases infarct size.⁴² It also attenuates the CRP response, suggesting that successful reperfusion may limit inflammation in infarcted myocardium,¹² though it also may induce reperfusion injury. Hence postinfarct CRP responses may simply reflect the extent of myocardial necrosis, although most studies do not correct for other possible confounders. However, this explanation does not fit with observations that CRP responses after AMI predict clinical outcome such as 6-month mortality, irrespective of infarct size.^{14 15 16} Thus CRP responses after AMI cannot simply reflect the extent of myocardial necrosis.

CRP Reflects Amount and Activity of Circulating Proinflammatory Cytokines
Local or circulating pro-inflammatory cytokines are detectable in atherosclerosis,⁴³ unstable angina,⁴⁴ or AMI³⁰ and correlate with plasma CRP levels.⁴⁵ Accordingly, cytokines may be the real risk factors, whereas plasma CRP reflects the release of these mediators. Although this possibility cannot be ruled out definitely, it does not explain the localization of CRP in inflamed tissues, including atherosclerotic vessels and infarcted myocardium.^{25 26 27 28} Rather, latter findings point to a contribution of CRP in the inflammatory processes ensuing in ischemic myocardium and atherosclerotic lesions.

Taken together, all explanations for the associations between CRP and cardiovascular disease, as discussed above, have in common that CRP levels are indirectly linked to the extent and severity of the atherosclerotic processes. None of these explanations consider that CRP may directly participate in the inflammatory reactions, contributing to tissue damage and clinical complications in cardiovascular disease.

	CRP-Mediated Inflammation in Cardiovascular Disease: A Hypothesis

Top Abstract Introduction C-Reactive Protein CRP and Cardiovascular Disease Association Between CRP and... CRP-Mediated Inflammation in... Ligands for CRP in... Implications References

 
Recently, we observed colocalization of CRP and activated complement fragments in infarcted (but not in normal) myocardium of patients who had died after AMI.²⁸ Furthermore, with the use of an assay that specifically detects CRP-induced complement activation,⁴⁶ patients with AMI were found to have increasing plasma levels of CRP-induced complement activation fragments (W.K. Lagrand, MD, et al, unpublished observations, 1997). Thus, after AMI, CRP contributes to inflammation in ischemic myocardium by activating complement. Notably, CRP²⁶ and activated complement⁴⁷ have also been found in human atherosclerotic vessels. Thus CRP may constitute a cardiovascular risk factor because it localizes in ischemic myocardium and atherosclerotic lesions, thereby promoting local complement activation.

Local activation of the classic pathway of complement by ischemic myocardium has been observed in various animal models for AMI.^{48 49} Inhibition of this activation attenuates the infiltration of neutrophils into the jeopardized myocardium and reduces infarct size.^{48 50 51 52} Also in humans, complement is activated by ischemic myocardium.^{28 48 53 54} Activated complement fragments may mediate vascular and myocardial damage through various mechanisms: stimulation, aggregation and degranulation of neutrophils;⁵⁵ enhancement of clotting by induction of tissue factor expression, and the formation of procoagulant microvesicles,^{56 57} or even direct damage of endothelial cells and cardiomyocytes by insertion of pores (C5b-9) into the cell membrane.^{53 54} Furthermore, activated complement may induce arrhythmia and provoke contractile dysfunction and vasoconstriction of the coronary vessels.⁵⁸ Thus part of the hemodynamic alterations and myocardial dysfunction after myocardial ischemia and infarction may result from local complement activation.⁵⁹

	Ligands for CRP in Cardiovascular Disease

Top Abstract Introduction C-Reactive Protein CRP and Cardiovascular Disease Association Between CRP and... CRP-Mediated Inflammation in... Ligands for CRP in... Implications References

 
Pivotal in CRP-mediated complement activation is binding of CRP to a ligand. Postulated ligands for CRP in atherosclerosis include lipoproteins.⁶⁰ CRP can bind to phosphatidylcholine vesicles containing lysophosphatidylcholine.^{61 62} Lysophospholipids are generated from phospholipids by phospholipase A₂ (PLA₂) enzymes and have been demonstrated in infarcted myocardium.⁶³ Therefore we postulate that lysophospholipids constitute the ligand for CRP in ischemic myocardium (see Figure).

View larger version (28K): [in this window] [in a new window]   Figure 1. Model to explain the proinflammatory effect of CRP. Lysophospholipids in the outer leaflet of flip-flopped cells, generated by cPLA2 or sPLA2, constitute ligands for CRP. During ischemia, phospholipids and lysophospholipids of inner and outer leaflet of the cell membrane exchange ("flip-flop"), resulting in a more equal distribution of (lyso)phospholipids among either leaflet, compared with the asymmetrical localization in normal cells. Ligand-bound CRP activates complement, which leads to further tissue damage and hemodynamic effects. Binding of CRP to phospholipids may occur at cells but also at microvesicles derived from flip-flopped cells.

PLA₂ enzymes hydrolyze phospholipids to yield lysophospholipids and free fatty acid. Mammals have various PLA₂ enzymes, including cytosolic (c)PLA₂ and secretory (s)PLA₂.⁶⁴ Plasma concentrations of the latter markedly increase during acute phase reactions.^{65 66} The inner and outer leaflet of the cell membrane of normal cells differ in phospholipid composition, sphingomyelin and phosphatidylcholine being present in the outer leaflet and phosphatidylserine and phosphatidylethanolamine mainly in the inner.⁶⁷ During apoptosis or ischemia this asymmetry is lost and the various phospholipids of outer and inner leaflets exchange ("flip-flop" of the membrane)^{67 68} (see Figure). Remarkably, sPLA₂ cannot hydrolyze the phospholipids in the outer leaflet of normal cells but easily hydrolyzes those of a flip-flopped cell.^{68 69 70} Thus ligands for CRP may be generated on flip-flopped cells by sPLA₂ (see Figure). Alternatively, lysophospholipids in the outer leaflet of the cell membrane may result from hydrolysis of phospholipids in the inner leaflet via activation of cPLA₂,^{63 64} followed by a flip-flop (see Figure). Finally, ischemic cells may generate microvesicles, which, on interaction with PLA₂ enzymes, also may constitute binding sites for CRP.^{69 70} Ligand-bound CRP activates the classic pathway of complement,³⁴ and this activation subsequently enhances inflammation and contributes to myocardial tissue damage or dysfunction (see Figure).

	Implications

Top Abstract Introduction C-Reactive Protein CRP and Cardiovascular Disease Association Between CRP and... CRP-Mediated Inflammation in... Ligands for CRP in... Implications References

 
Our hypothesis predicts that high CRP responses after AMI will lead to more intense CRP depositions and inflammatory reactions and hence tissue damage in the jeopardized myocardium (see Table 1). It also explains why high-normal or slightly increased baseline levels of plasma CRP constitute and predict an increased risk for cardiovascular events since in these cases one condition for CRP-mediated complement activation (ie, available CRP in plasma) is then fulfilled. The other condition is the presence of lysophospholipids and membrane flip-flop in the coronary vessels and affected ischemic myocardium (see Figure), which may result from short-term ischemic periods. Alternatively, variations in baseline plasma CRP of individuals may reflect differences in CRP responses elicited by appropriate stimuli, for example caused by genetic differences in the CRP gene yielding high and low responders, the former being at risk for cardiovascular disease.³⁸

Consequently, prevention of cardiovascular events in persons with high-normal or elevated plasma CRP levels may be achieved by anti-inflammatory agents like aspirin,⁷ reducing the synthesis of CRP (cytokine-antagonists?), preventing the binding of CRP to membranes (phosphorylcholine-like drugs?) or inhibiting CRP-induced activation of the classical complement pathway (C1-esterase-inhibitor?). Future studies should reveal whether these approaches are indeed efficacious.

	Acknowledgments

 
This study was financially supported by the Netherlands Heart Foundation, grant 93-119.

	References

Top Abstract Introduction C-Reactive Protein CRP and Cardiovascular Disease Association Between CRP and... CRP-Mediated Inflammation in... Ligands for CRP in... Implications References

 
1. Ross T. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801–809.[Medline] [Order article via Infotrieve]

2. Libby P. Molecular basis of the acute coronary syndromes. Circulation. 1995;91:2844–2850.[Free Full Text]

3. Ridker PM. C-reactive protein and risks of future myocardial infarction and thrombotic stroke. Eur Heart J. 1998;19:1–3.[Free Full Text]

4. Thompson SG, Kienast J, Pyke SDM, Haverkate F, van de Loo JCW. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med. 1995;332:635–641.[Abstract/Free Full Text]

5. Mendall MA, Patel P, Ballam L, Strachan D, Northfield TC. C-reactive protein and its relation to cardiovascular risk factors: a population based cross sectional study. BMJ. 1996;312:1061–1065.[Abstract/Free Full Text]

6. Kuller LH, Tracy RP, Shaten J, Meilahn EN. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Am J Epidemiol. 1996;144:537–547.[Abstract/Free Full Text]

7. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336:973–979.[Abstract/Free Full Text]

8. Tracy RP, Lemaitre RN, Psaty BM, Ives DG, Evans RW, Cushman M, Meilahn EN, Kuller LH. Relationship of C-reactive protein to risk of cardiovascular disease in the elderly. Arterioscler Thromb Vasc Biol. 1997;17:1121–1127.[Abstract/Free Full Text]

9. de Beer FC, Hind CRK, Fox KM, Allan RM, Maseri A, Pepys MB. Measurement of serum C-reactive protein concentration in myocardial ischaemia and infarction. Br Heart J. 1982;47:239–243.[Abstract/Free Full Text]

10. Pietilä K, Harmoinen A, Pöyhönen L, Koskinen M, Heikkila J, Ruosteenoja R. Intravenous streptokinase treatment and serum C-reactive protein in patients with acute myocardial infarction. Br Heart J. 1987;58:225–229.[Abstract/Free Full Text]

11. Pietilä K, Harmoinen A, Teppo A-M. Acute phase reaction, infarct size and in-hospital morbidity in myocardial infarction patients treated with streptokinase or recombinant tissue type plasminogen activator. Ann Med. 1991;23:529–535.[Medline] [Order article via Infotrieve]

12. Pietilä KO, Harmoinen AP, Hermens WT, Simoons ML, van de Werf F, Verstraete M. Serum C-reactive protein and infarct size in myocardial infarct patients with a closed versus an open infarct-related coronary artery after thrombolytic therapy. Eur Heart J. 1993;14:915–919.[Abstract/Free Full Text]

13. Casl MT, Surina B, Glojnaric-Spasic I, Pape E, Jagarinec N, Kranjcevic S. Serum amyloid A protein in patients with acute myocardial infarction. Ann Clin Biochem. 1995;32:196–200.

14. Pietilä KO, Harmoinen AP, Jokiniitty J, Pasternack AI. Serum C-reactive protein concentration in acute myocardial infarction and its relationship to mortality during 24 months of follow-up in patients under thrombolytic treatment. Eur Heart J. 1996;17:1345–1349.[Abstract/Free Full Text]

15. Ueda S, Ikeda U, Yamamoto K, Takahashi M, Nishinaga M, Nago N, Shimada K. C-reactive protein as a predictor of cardiac rupture after myocardial infarction. Am Heart J. 1996;131:857–860.[Medline] [Order article via Infotrieve]

16. Anzai T, Yoshikawa T, Shiraki H, Asakura Y, Akaishi M, Mitamura H, Ogawa S. C-reactive protein as a predictor of infarct expansion and cardiac rupture after a first Q wave acute myocardial infarction. Circulation. 1997;96:778–784.[Abstract/Free Full Text]

17. Berk BC, Weintraub WS, Alexander RW. Elevation of C-reactive protein in "active" coronary artery disease. Am J Cardiol. 1990;65:168–172.[Medline] [Order article via Infotrieve]

18. Liuzzo G, Biasucci LM, Gallimore JR, Grillo RL, Rebuzzi AG, Pepys MB, Maseri A. The prognostic value of C-reactive protein and serum amyloid A protein in severe unstable angina. N Engl J Med. 1994;331:417–424.[Abstract/Free Full Text]

19. 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;349:462–466.[Medline] [Order article via Infotrieve]

20. 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]

21. Jousilahti P, Vartiainen E, Tuomilehto J, Puska P. Symptoms of chronic bronchitis and the risk of coronary disease. Lancet. 1996;348:567–572.[Medline] [Order article via Infotrieve]

22. Patel P, Mendall MA, Carrington D, Strachan D, Leatham E, Molineaux N. Association of Helicobacter pylori and Chlamydia pneumoniae infections with coronary heart disease and cardiovascular risk factors. BMJ. 1995;311:711–714.[Abstract/Free Full Text]

23. Melnick JL, Adam E, DeBakey ME. Possible role of cytomegalovirus in atherogenesis. JAMA. 1990;263:2204–2207.[Abstract/Free Full Text]

24. Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: is there a link? Lancet. 1997;350:430–436.[Medline] [Order article via Infotrieve]

25. Gitlin JD, Gitlin JI, Gitlin D. Localization of C-reactive protein in synovium of patients with rheumatoid arthritis. Arthritis Rheum. 1977;20:1491–1499.[Medline] [Order article via Infotrieve]

26. Hatanaka K, Li XA, Masuda K, Yutani C, Yamamoto A. Immunohistochemical localization of C-reactive protein-binding sites in human atherosclerotic aortic lesions by a modified streptavidin-biotin-staining method. Pathol Int. 1995;45:635–641.[Medline] [Order article via Infotrieve]

27. Kushner I, Rakita I, Kaplan MH. Studies of acute-phase protein, II: localization of Cx-protein in heart in induced myocardial infarction in rabbits. J Clin Invest. 1963;42:286–292.

28. Lagrand WK, Niessen JWM, Wolbink GJ, Jaspars EH, Visser CA, Verheugt FWA, Meijer CJLM, Hack CE. C-reactive protein colocalizes with complement in human hearts during acute myocardial infarction. Circulation. 1997;95:97–103.[Abstract/Free Full Text]

29. Castell JV, Andus T, Kunz D, Heinrich PC. Interleukin-6: the major regulator of acute-phase protein synthesis in man and rat. Ann N Y Acad Sci. 1989;557:87–101.[Medline] [Order article via Infotrieve]

30. Neumann F-J, Ott I, Gawaz M, Richardt G, Holzapfel H, Jochum M, Schömig A. Cardiac release of cytokines and inflammatory responses in acute myocardial infarction. Circulation. 1995;92:748–755.[Abstract/Free Full Text]

31. Gauldie J, Richards C, Northemann W, Fey G, Baumann H. IFNb2/BSF2/IL-6 is the monocyte-derived HSF that regulates receptor specific acute phase gene regulation in hepatocytes. Ann N Y Acad Sci. 1989;557:46–59.[Medline] [Order article via Infotrieve]

32. Agrawal A, Kilpatrick JM, Volanakis JE. Structure and function of human C-reactive protein. In: Mackiewicz A, Kushner I, Baumann H, eds. Acute Phase Proteins. Molecular Biology, Biochemistry, and Clinical Applications. Boca Raton, Fla: CRC Press, Inc; 1993:79–92.

33. Heuertz RM, Piquette CA, Webster RO. Rabbits with elevated serum C-reactive protein exhibit diminished neutrophil infiltration and vascular permeability in C5a-induced alveolitis. Am J Pathol. 1993;142:319–328.[Abstract]

34. Volanakis JE. Complement activation by C-reactive protein complexes. Ann N Y Acad Sci. 1982;389:235–249.[Medline] [Order article via Infotrieve]

35. Biasucci LM, de Maat MPM, Meo A, van der Greef W, Summaria F, Quaranta G, Liuzzo G, Kluft C, Maseri A. Analysis of activation markers of coagulation, fibrinolysis and inflammation in unstable angina by probit transformation. Fibrinolysis. 1996;10(suppl 2):145–147.

36. Heinrich J, Schulte H, Schönfeld R, Köhler E, Assmann G. Association of variables of coagulation, fibrinolysis and acute-phase with atherosclerosis in coronary and peripheral arteries and those arteries supplying the brain. Thromb Haemost. 1995;73:374–378.[Medline] [Order article via Infotrieve]

37. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Plasma concentrations of C-reactive protein and risk of developing peripheral vascular disease. Circulation. 1998;97:425–428.[Abstract/Free Full Text]

38. de Maat MPM, de Bart ACW, Hennis BC, Meijer HP, Havelaar AC, Mulder PGH, Kluft C. Interindividual and intraindividual variability in plasma fibrinogen, TPA antigen, PAI activity, and CRP in healthy, young volunteers and patients with angina pectoris. Arterioscler Thromb Vasc Biol. 1996;16:1156–1162.[Abstract/Free Full Text]

39. Macy EM, Hayes TE, Tracy RP. Variability in the measurement of C-reactive protein in healthy subjects: implications for reference intervals and epidemiological applications. Clin Chem. 1997;43:52–58.[Abstract/Free Full Text]

40. Biasucci LM, Liuzzo G, Caligiura G, van de Greef W, Quaranta G, Monaco C, Rebuzzi AG, Kluft C, Maseri A. Episodic activation of the coagulation system in unstable angina does not elicit an acute phase response. Am J Cardiol. 1996;77:85–87.[Medline] [Order article via Infotrieve]

41. Liuzzo G, Biasucci LM, Rebuzzi AG, Gallimore R, Caligiuri G, Lanza GA, Quaranta G, Monaco C, Pepys MB, Maseri A. Plasma protein acute-phase response in unstable angina is not induced by ischemic injury. Circulation. 1996;94:2373–2380.[Abstract/Free Full Text]

42. GISSI. Long-term effects of intravenous thrombolysis in acute myocardial infarction: final report of the GISSI study. Lancet. 1987;2:871–874.[Medline] [Order article via Infotrieve]

43. Hansson GK. Immune and inflammatory mechanisms in the development of atherosclerosis. Br Heart J. 1993;69(suppl):S38–S41.

44. Biasucci LM, Vitelli A, Liuzzo G, Altamura S, Caligiuri G, Monaco C, Rebuzzi AG, Ciliberto G, Maseri A. Elevated levels of interleukin-6 in unstable angina. Circulation. 1996;94:874–877.[Abstract/Free Full Text]

45. Tilg H, Mair J, Herold M, Aulitzky WE, Lechleitner P, Dienstl F, Huber C. Acute phase response after myocardial infarction: correlation between serum levels of cytokines and C-reactive protein. Klin Wochenschr. 1990;68:1083.[Medline] [Order article via Infotrieve]

46. 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 Immunol. 1996;157:473–479.[Abstract]

47. Seifert PS, Kazatchkine MD. The complement system in atherosclerosis. Atherosclerosis. 1988;73:91–104.[Medline] [Order article via Infotrieve]

48. Kilgore KS, Friedrichs GS, Homeister JW, Lucchesi BR. The complement system in myocardial ischemia/reperfusion injury. Cardiovasc Res. 1994;28:437–444.[Free Full Text]

49. Pinckard RN, Olson MS, Giclas PC, Terry R, Boyer JT, O'Rourke RA. Consumption of classical complement components by heart subcellular membranes in vitro and in patients after acute myocardial infarction. J Clin Invest. 1975;56:740–750.

50. Buerke M, Murohara T, Lefer AM. Cardioprotective effects of a C1 esterase inhibitor in myocardial ischemia and reperfusion. Circulation. 1995;91:393–402.[Abstract/Free Full Text]

51. Maroko PR, Carpenter CB, Chiariello M, Fishbein MC, Radvany P, Kostman JD, Hale SL. Reduction by cobra venom factor of myocardial necrosis after coronary artery occlusion. J Clin Invest. 1978;61:661–670.

52. Weisman HF, Bartow T, Leppo MK, Marsh HC, Carson GR, Concino MF, Boyle MP, Roux KH, Weisfeldt ML, Fearon DT. Soluble human complement receptor type 1: in vivo inhibitor of complement suppressing post-ischemic myocardial inflammation and necrosis. Science. 1990;249:146–151.[Abstract/Free Full Text]

53. Hugo F, Hamdoch T, Mathey D, Schäfer H, Bhakdi S. Quantitative measurement of SC5b-9 and C5b-9(m) in infarcted areas of human myocardium. Clin Exp Immunol. 1990;81:132–136.[Medline] [Order article via Infotrieve]

54. Mathey D, Schofer J, Schäfer HJ, Hamdoch T, Joachim HC, Ritgen A, Hugo F, Bhakdi S. Early accumulation of the terminal complement-complex in the ischaemic myocardium after reperfusion. Eur Heart J. 1994;15:418–423.[Abstract/Free Full Text]

55. Engler RL, Schmid-Schonbein GW, Pavelec RS. Leukocyte capillary plugging in myocardial ischemia and reperfusion in the dog. Am J Pathol. 1983;111:98–111.[Abstract]

56. Carson SD, Johnson DR. Consecutive enzyme cascades: complement activation at the cell surface triggers increased tissue factor activity. Blood. 1990;762:361–367.

57. Hamilton KK, Hattori R, Esmon CT, Sims PJ. Complement proteins C5b-9 induce vesiculation of the endothelial plasma membrane and expose catalytic surface for the assembly of the prothrombinase enzyme complex. J Biol Chem. 1990;265:3809–3814.[Abstract/Free Full Text]

58. DelBalzo UH, Levi R, Polly MJ. Cardiac dysfunction caused by purified human C3a anaphylatoxins. Proc Natl Acad Sci U S A. 1985;82:886–890.[Abstract/Free Full Text]

59. Homeister JW, Satoh P, Lucchesi BR. Effects of complement activation in the isolated heart. Circ Res. 1992;71:303–319.[Abstract/Free Full Text]

60. Rowe IF, Soutar AK, Trayner IM, Thompson GR, Pepys MB. Circulating human C-reactive protein binds very low density lipoproteins. Clin Exp Immunol. 1984;58:237–244.[Medline] [Order article via Infotrieve]

61. Volanakis JE, Narkates AJ. Interaction of C-reactive protein with artificial phosphatidylcholine bilayers and complement. J Immunol. 1981;126:1820–1825.[Abstract]

62. Mori S, Nakata Y, Endo H. Involvements of fibronectin and lysophosphatidylcholine for selective binding of C-reactive protein. Cell Mol Biol. 1991;37:421–431.[Medline] [Order article via Infotrieve]

63. Van der Vusse GJ, van Bilsen M, Reneman RS. Ischemia and reperfusion induced alterations in membrane phospholipids: an overview. Ann N Y Acad Sci. 1994;723:1–14.

64. Glaser KB, Mobilio D, Chang JY, Senko N. Phospholipase A₂ enzymes: regulation and inhibition. Trends Pharmacol Sci. 1993;14:92–98.[Medline] [Order article via Infotrieve]

65. Crowl RM, Stoller TJ, Convoy RR, Stoner CR. Induction of phospholipase A₂ gene expression in human hepatoma cells by mediators of the acute phase response. J Biol Chem. 1991;266:2647–2651.[Abstract/Free Full Text]

66. Leong LLL, Sturm MJ, Ismail Y, Stephens CJ, Taylor RR. Plasma phospholipase A₂ activity in clinical acute myocardial infarction. Clin Exp Pharmacol Physiol. 1992;19:113–118.[Medline] [Order article via Infotrieve]

67. Zachowski A. Phospholipids in animal eukaryotic membranes: transverse asymmetry and movement. Biochem J. 1993;294:1–14.

68. Higgins CF. Flip-flop: the transmembrane translocation of lipids. Cell. 1994;79:393–395.[Medline] [Order article via Infotrieve]

69. Fourcade O, Simon M-F, Viodé C, Rugani N, Leballe F, Ragab A, Fournié B, Sarda L, Chap H. Secretory phospholipase A₂ generates the novel lipid mediator lysophosphatidic acid in membrane microvesicles shed from activated cells. Cell. 1995;80:919–927.[Medline] [Order article via Infotrieve]

70. Hack CE, Wolbink GJ, Schalkwijk C, Speijer H, Hermens WT, van den Bosch H. A role for secretory phospholipase A₂ and C-reactive protein in the removal of injured cells. Immunol Today. 1997;18:111–115.[Medline] [Order article via Infotrieve]

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				G. Engstrom, L. Janzon, G. Berglund, P. Lind, L. Stavenow, B. Hedblad, and F. Lindgarde Blood Pressure Increase and Incidence of Hypertension in Relation to Inflammation-Sensitive Plasma Proteins Arterioscler. Thromb. Vasc. Biol., December 1, 2002; 22(12): 2054 - 2058. [Abstract] [Full Text] [PDF]

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				L. Sternik, S. Samee, H. V. Schaff, K. J. Zehr, L. O. Lerman, D. R. Holmes, J. Herrmann, and A. Lerman C-Reactive Protein Relaxes Human Vessels In Vitro Arterioscler. Thromb. Vasc. Biol., November 1, 2002; 22(11): 1865 - 1868. [Abstract] [Full Text] [PDF]

				T.S. Church, C.E. Barlow, C.P. Earnest, J.B. Kampert, E.L. Priest, and S.N. Blair Associations Between Cardiorespiratory Fitness and C-Reactive Protein in Men Arterioscler. Thromb. Vasc. Biol., November 1, 2002; 22(11): 1869 - 1876. [Abstract] [Full Text] [PDF]

				R. P. Tracy Inflammation in Cardiovascular Disease: Cart, Horse or Both-Revisited Arterioscler. Thromb. Vasc. Biol., October 1, 2002; 22(10): 1514 - 1515. [Full Text] [PDF]

				K. Winbeck, H. Poppert, T. Etgen, B. Conrad, and D. Sander Prognostic Relevance of Early Serial C-Reactive Protein Measurements After First Ischemic Stroke Stroke, October 1, 2002; 33(10): 2459 - 2464. [Abstract] [Full Text] [PDF]

				C. H. Toh, J. Samis, C. Downey, J. Walker, L. Becker, N. Brufatto, L. Tejidor, G. Jones, W. Houdijk, A. Giles, et al. Biphasic transmittance waveform in the APTT coagulation assay is due to the formation of a Ca++-dependent complex of C-reactive protein with very-low-density lipoprotein and is a novel marker of impending disseminated intravascular coagulation Blood, September 18, 2002; 100(7): 2522 - 2529. [Abstract] [Full Text] [PDF]

				T. J. Wang, M. G. Larson, D. Levy, E. J. Benjamin, M. J. Kupka, W. J. Manning, M. E. Clouse, R. B. D'Agostino, P. W.F. Wilson, and C. J. O'Donnell C-Reactive Protein Is Associated With Subclinical Epicardial Coronary Calcification in Men and Women: The Framingham Heart Study Circulation, September 3, 2002; 106(10): 1189 - 1191. [Abstract] [Full Text] [PDF]

				P. L. McGeer and E. G. McGeer Innate Immunity, Local Inflammation, and Degenerative Disease Sci. Aging Knowl. Environ., July 24, 2002; 2002(29): re3 - 3. [Abstract] [Full Text] [PDF]

				J. Oh, R. Wunsch, M. Turzer, M. Bahner, P. Raggi, U. Querfeld, O. Mehls, and F. Schaefer Advanced Coronary and Carotid Arteriopathy in Young Adults With Childhood-Onset Chronic Renal Failure Circulation, July 2, 2002; 106(1): 100 - 105. [Abstract] [Full Text] [PDF]

				A. J.G. Hanley, K. Williams, M. P. Stern, and S. M. Haffner Homeostasis Model Assessment of Insulin Resistance in Relation to the Incidence of Cardiovascular Disease: The San Antonio Heart Study Diabetes Care, July 1, 2002; 25(7): 1177 - 1184. [Abstract] [Full Text] [PDF]

				R.J. de Winter, G.S. Heyde, K.T. Koch, J. Fischer, J.P. van Straalen, M. Bax, C.E. Schotborgh, K.J. Mulder, G.T. Sanders, J.J. Piek, et al. The prognostic value of pre-procedural plasma C-reactive protein in patients undergoing elective coronary angioplasty Eur. Heart J., June 2, 2002; 23(12): 960 - 966. [Abstract] [Full Text] [PDF]

				A. S.M. Shamsuzzaman, M. Winnicki, P. Lanfranchi, R. Wolk, T. Kara, V. Accurso, and V. K. Somers Elevated C-Reactive Protein in Patients With Obstructive Sleep Apnea Circulation, May 28, 2002; 105(21): 2462 - 2464. [Abstract] [Full Text] [PDF]

				A. Festa, R. D'Agostino Jr, R. P. Tracy, and S. M. Haffner Elevated Levels of Acute-Phase Proteins and Plasminogen Activator Inhibitor-1 Predict the Development of Type 2 Diabetes: The Insulin Resistance Atherosclerosis Study Diabetes, April 1, 2002; 51(4): 1131 - 1137. [Abstract] [Full Text] [PDF]

				C. D.A. Stehouwer, M.-A. Gall, J. W.R. Twisk, E. Knudsen, J. J. Emeis, and H.-H. Parving Increased Urinary Albumin Excretion, Endothelial Dysfunction, and Chronic Low-Grade Inflammation in Type 2 Diabetes: Progressive, Interrelated, and Independently Associated With Risk of Death Diabetes, April 1, 2002; 51(4): 1157 - 1165. [Abstract] [Full Text] [PDF]

				M. A Vickers, F. R Green, C. Terry, B. M Mayosi, C. Julier, M. Lathrop, P. J Ratcliffe, H. C Watkins, and B. Keavney Genotype at a promoter polymorphism of the interleukin-6 gene is associated with baseline levels of plasma C-reactive protein Cardiovasc Res, March 1, 2002; 53(4): 1029 - 1034. [Abstract] [Full Text] [PDF]

				A. Tchernof, A. Nolan, C. K. Sites, P. A. Ades, and E. T. Poehlman Weight Loss Reduces C-Reactive Protein Levels in Obese Postmenopausal Women Circulation, February 5, 2002; 105(5): 564 - 569. [Abstract] [Full Text] [PDF]

				R. Nijmeijer, W. K Lagrand, A. Baidoshvili, Y. T.P Lubbers, W. T. Hermens, C. J.L.M Meijer, C. A Visser, C.E. Hack, and H. W.M Niessen Secretory type II phospholipase A2 binds to ischemic myocardium during myocardial infarction in humans Cardiovasc Res, January 1, 2002; 53(1): 138 - 146. [Abstract] [Full Text] [PDF]

				A. O'Hare and K. Johansen Lower-Extremity Peripheral Arterial Disease among Patients with End-Stage Renal Disease J. Am. Soc. Nephrol., December 1, 2001; 12(12): 2838 - 2847. [Abstract] [Full Text] [PDF]

				M. Pirro, J. Bergeron, G. R. Dagenais, P.-M. Bernard, B. Cantin, J.-P. Despres, and B. Lamarche Age and Duration of Follow-up as Modulators of the Risk for Ischemic Heart Disease Associated With High Plasma C-Reactive Protein Levels in Men Arch Intern Med, November 12, 2001; 161(20): 2474 - 2480. [Abstract] [Full Text] [PDF]

				E. Rizos and D. P Mikhailidis Are high density lipoprotein (HDL) and triglyceride levels relevant in stroke prevention? Cardiovasc Res, November 1, 2001; 52(2): 199 - 207. [Abstract] [Full Text] [PDF]

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