Q J Med 2003; 96: 793-807
© 2003 Association of Physicians
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C-reactive protein and cardiovascular disease: new insights from an old molecule
From the Centre for Amyloidosis and Acute Phase Proteins, Department of Medicine, Royal Free and University College Medical School, Royal Free Campus, London, UK
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Summary |
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 Top Summary IntroductionCRP in health and...Structure and function of...CRP and cardiovascular diseaseReferences |
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The classical acute-phase protein, C-reactive protein (CRP), is an exquisitely sensitive systemic marker of disease with broad clinical utility for monitoring and differential diagnosis. Inflammation, the key regulator of CRP synthesis, plays a pivotal role in atherothrombotic cardiovascular disease. There is a powerful predictive association between raised serum CRP values and the outcome of acute coronary syndromes, and, remarkably, between even modestly increased CRP production and future atherothrombotic events in otherwise healthy individuals. Baseline CRP values also reflect metabolic states associated with atherothrombotic events. The presence of CRP within most atherosclerotic plaques and all acute myocardial infarction lesions, coupled with binding of CRP to lipoproteins and its capacity for pro-inflammatory complement activation, suggests that CRP may contribute to the pathogenesis and complications of cardiovascular disease. We review the biological properties of CRP, the association between CRP and cardiovascular disease, and the possibility that CRP may be a novel therapeutic target.
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Introduction |
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TopSummaryIntroductionCRP in health and...Structure and function of...CRP and cardiovascular diseaseReferences |
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The acute-phase response comprises the non-specific physiological and biochemical responses of endothermic animals to most forms of tissue damage, infection, inflammation, and neoplasia. In particular, the synthesis of a number of proteins is rapidly up-regulated, principally in hepatocytes, under the control of a cascade of cytokines, including interleukin-1 (IL-1), tumour necrosis factor-
(TNF-) and interleukin-6 (IL-6), originating at the site of pathology.1 Inflammation is a major feature of atherosclerotic plaques,2,3 and there is a strong association between antecedent or concurrent systemic inflammatory activity and the occurrence of atherothrombotic events, especially myocardial infarction.4,5 C-reactive protein (CRP), named for its capacity to precipitate the somatic C-polysaccharide of Streptococcus pneumoniae,6 was the first acute-phase protein to be described, and is an exquisitely sensitive systemic marker of inflammation and tissue damage.7 It is a member of the pentraxin family of plasma proteins, which are part of the lectin fold superfamily8 of calcium-dependent ligand-binding and lectin (carbohydrate-binding) proteins. Other acute-phase proteins include proteinase inhibitors, coagulation, complement and transport proteins, but the only molecule that displays the same remarkable sensitivity, speed, and dynamic range of responses as CRP is serum amyloid A protein (SAA) (Table 1). 7 In this review we summarize current knowledge of the clinical, physiological and pathological roles of CRP, particularly in the context of cardiovascular disease.
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CRP in health and disease |
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TopSummaryIntroductionCRP in health and...Structure and function of...CRP and cardiovascular diseaseReferences |
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In healthy volunteer blood donors, the median concentration of CRP is 0.8 mg/l,9 but following an acute-phase stimulus, values may increase by as much as 10 000-fold, with de novo hepatic synthesis starting very rapidly, serum concentrations beginning to rise by about 6 h, and peaking around 48 h after a single stimulus.10 In the general, ostensibly healthy population, the median baseline value is slightly higher and tends to increase with age, females having slightly higher circulating concentrations.11 In most, but not all diseases (Table 2), the circulating value of CRP much more accurately reflects on-going inflammation than do other biochemical parameters of inflammation, such as plasma viscosity or the erythrocyte sedimentation rate. This is because the plasma half-life of CRP is the same (about 19 h) under all conditions, and the sole determinant of the plasma concentration is therefore the synthesis rate, which, in turn, reflects the intensity of the pathological process(es) stimulating CRP production.12 In vivo turnover studies of human CRP in man did not demonstrate any detectable tissue deposition of CRP, even in inflamed or infected foci,12 and in animal studies the only significant cellular site of CRP clearance and catabolism was the hepatocyte.13
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Liver failure impairs CRP production, but no other intercurrent pathologies and very few drugs reduce CRP values, unless they also affect the underlying acute-phase stimulus. The CRP value is thus a very useful non-specific biochemical marker of inflammation, measurement of which contributes importantly to: (i) screening for organic disease; (ii) monitoring the response to treatment of inflammation and infection; and (iii) detecting intercurrent infection in the few specific diseases characterized by modest or absent acute-phase responses to those diseases themselves (Table 3).14,15 It is not known why systemic lupus erythematosus and the other conditions listed in Table 2 fail to elicit major CRP production, despite evident inflammation and tissue damage, nor why the CRP responses to intercurrent infection are apparently intact in such patients.16,17
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Structure and function of CRP |
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Phylogeny and function
The pentraxin family, named for its electron micrographic appearance, from the Greek penta (five) and ragos (berries),18 comprises CRP and serum amyloid P component (SAP) in man, and is highly conserved in evolution, with homologous proteins throughout the vertebrates and even in the phylogenetically distant arthropod, Limulus polyphemus, the horseshoe crab.19 SAP, named for its universal presence in amyloid deposits,20 is a constitutive, non-acute phase plasma glycoprotein in man and all other species studied, except the mouse, in which it is the major acute-phase protein.21 In contrast, mouse CRP is a trace protein, the concentration of which increases only modestly in the acute-phase response to a maximum of about 2 mg/l.22 No mouse CRP knockout has yet been made to our knowledge, and in vivo work on CRP function has largely been confined to mice transgenic for rabbit23 or human CRP.24 It is important to be aware that these artefactual heterologous systems may not provide physiologically relevant information. In particular, this is because, despite the evolutionary conservation of sequence, subunit organization and protein fold, there are major structural and functional differences between CRPs of different species, including glycosylation, capacity to activate autologous complement, and regulation of basal and acute phase synthesis.7 These differences necessitate extreme caution in extrapolating from animal models to man.
Human CRP is a calcium-dependent ligand-binding protein, which binds with highest affinity to phosphocholine (PC) residues, as well as a variety of other autologous and extrinsic ligands, and aggregates or precipitates the cellular, particulate or molecular structures bearing these ligands. Autologous ligands include native and modified plasma lipoproteins,25 damaged cell membranes,26 a number of different phospholipids and related compounds, small nuclear ribonucleoprotein particles,27,28 and apoptotic cells.29 Extrinsic ligands include many glycan, phospholipid and other components of micro-organisms, such as capsular and somatic components of bacteria, fungi and parasites, as well as plant products.30,31 When human CRP is ligand-bound, it is recognized by C1q and potently activates the classical complement pathway, engaging C3, the main adhesion molecule of the complement system, and the terminal membrane attack complex, C5-C9.32–35 Bound CRP may also provide secondary binding sites for factor H, and thereby regulate alternative pathway amplification and C5 convertases.36
The secondary effects of CRP that follow ligand binding resemble some of the key properties of antibodies, suggesting that under various circumstances CRP may contribute to host defence against infection, function as a pro-inflammatory mediator, and participate in physiological and pathophysiological handling of autologous constituents. The impaired CRP response in active systemic lupus16 and the spontaneous anti-nuclear autoimmunity of SAP knockout mice37 are compatible with pentraxins functioning to prevent autoimmunity.
Innate immunity
The conservation of the structure of CRP and of its calcium-dependent specific binding of ligands containing PC and related substances, together with the lack of any known deficiency or protein polymorphism, suggest that this protein must have had survival value. Microbial infection is a major driving force of change during evolution, and CRP has many features compatible with a role in innate immunity. The innate immune system discriminates self from non-self using a restricted number of pattern recognition receptors that recognize pathogen associated molecular patterns,38 and most micro-organisms that penetrate the body’s external barriers are recognized and cleared by cells and molecules which exhibit these broad specificities. If infectious organisms evade these mechanisms, the specific antigen receptor–bearing lymphocytes of the adaptive immune system come into play, and significant subsets of lymphocytes, even in previously unexposed animals, express germ-line-encoded specificity for immunogenic epitopes of pathogens. The T-cell-independent natural IgM antibodies produced by the progeny of these cells comprise a significant proportion of serum immunoglobulins at birth, and can both provide protection against some viral and bacterial infections,39 and play a role via complement activation in enhancing specific adaptive T-cell-dependent antibody production.40,41 The antigen-specific receptors of the natural antibody-producing lymphocytes often contain highly conserved sequences, and represent an ‘evolutionary memory’ bridging pattern recognition molecules and the phylogenetically more recent and sophisticated adaptive responses. Importantly, many of the natural antibodies encoded by non-mutated germline VH or VL genes react with a variety of self-determinants, including carbohydrates and glycolipids, as well as cross-reacting with bacterial or oncofetal antigens. They may thus have a significant role in handling autologous ligands as well as extrinsic antigens.
One important class of highly conserved natural antibodies expresses the so-called T15 idiotype, binds to PC as does CRP, and like CRP, protects against Streptococcus pneumoniae infection.42–44 PC is a component of many prokaryotes and is almost universally present in eukaryotes.45 In Streptococcus pneumoniae, PC is present in the somatic ribitol teichoic acid component and is associated with different sugar residues in a variety of other organisms, including other Streptococci, Clostridium, and Bacillus species, and H. influenzae.46,47 PC is also found in the external components of a variety of pathogenic protozoa, fungi, nematodes, and other intestinal parasites. PC is, of course, ubiquitous in the phospholipids of cellular membranes of higher animals, and importantly also in the circulating plasma lipoproteins that are intimately involved in the pathogenesis of atherosclerosis. The specific binding of CRP to low-density and very-low-density lipoproteins (LDL and VLDL) and to the membranes of damaged cells has long been recognised,25,48,49 and more recently it has been observed that CRP also binds to apoptotic cells in a Ca2+-dependent manner, enhancing their opsonization and phagocytosis by macrophages.29 Our original finding that native, non-aggregated, human CRP does not bind to native LDL48 has lately been confirmed and extended with the observation that native CRP does however bind to oxidized LDL; this, as well as the binding of CRP to apoptotic cells and to oxidized but not to non-oxidized phosphatidyl choline (PtC), is mediated by recognition of exposed PC residues.50 The spectrum of ligand recognition by CRP closely resembles that of EO6, an autoantibody to oxidized LDL, which is a T15 clono-specific anti-PC antibody with specific binding to PC on oxidized but not on native PtC.51 An important physiological role of CRP may thus be, as we have previously suggested, in the handling of autologous materials52 including oxidized PC-bearing phospholipids within oxidized LDL and on the plasma membranes of apoptotic cells. Similarly, pathophysiological effects of CRP may also be mediated via these interactions with autologous ligands.52 Intriguingly, the spectrum of autologous ligand recognition by CRP overlaps that of pathogenic anti-phospholipid autoantibodies.53
Structure
The human CRP molecule (Mr 115 135) is composed of five identical non-glycosylated polypeptide subunits (Mr 23 027) each containing 206 amino acid residues. The protomers are non-covalently associated in an annular configuration with cyclic pentameric symmetry.54 The CRP protomer has the characteristic ‘lectin fold’8 composed of a two-layered ß sheet with flattened jellyroll topology (Figure 1). Two calcium ions are bound 4Å apart by protein side-chains coming from loops at the concave face, termed the B face as this is the site of ligand binding. The other face (A) carries a single helix (Figure 1).
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The crystallographic structure of the CRP-PC complex, and indirect evidence from mutagenesis studies, show that the key residues in the ligand-binding pocket responsible for recognition of PC are Phe66 and Glu88.54–56 C1q, the recognition protein of the classical pathway, probably binds to complexed or aggregated CRP in a pocket at the open end of a cleft on the A faces of the protomers in the intact pentamer. Mutagenesis studies of CRP suggest that Asp112 and Tyr175 are important contact residues for C1q binding, that Glu88 influences the conformational change in C1q necessary for complement activation, and that Asn158 and His38 probably contribute to the correct geometry of the binding site.57
Genes and gene expression
The genes for both CRP and SAP are on chromosome 1, and the CRP gene consists of a coding sequence for a signal peptide of 18 residues and the first two amino acids of the native protein, followed by an intron of 278 bp and then the coding sequence for the remaining 204 residues.58,59 A single non-functional pseudogene with 50–80% region-specific homology is found close to the authentic CRP gene, and typical promoter sequences are located upstream of the cap region (104 nucleotides from the start of the signal peptide). Plasma CRP is produced by hepatocytes,60 although other sites for CRP synthesis and possibly secretion have been suggested.61–65 CRP may thus have local roles in particular micro-environments, as well as its functions effected via the systemic circulation. Increased CRP production is induced predominantly by the cytokine IL-6, but either IL-1 or TNF- may also contribute.66 Control of CRP expression is principally at the level of transcription, and in vitro studies in hepatocyte cell lines have identified some of the intra-cellular signalling pathways67,68 and also shown that secretion is more efficient during an acute-phase response.69
Healthy subjects tend to have rather stable, individual, baseline CRP concentrations,70 that are significantly (35–40%) heritable.71,72 Although no deficiency or protein polymorphisms of CRP have yet been identified, associations between CRP production and genetic polymorphisms in IL-173 and IL-674 have been suggested. In one large prospective cohort of apparently healthy men, plasma CRP concentrations were shown to be significantly reduced among carriers of a 1059G/C polymorphism in the human CRP gene (GC or CC) as compared with non-carriers (GG). However, there was no significant association with risk of arterial thrombosis.75 A polymorphic GT repeat in the intron of the CRP gene is reportedly associated with differences in baseline CRP concentrations in both normal individuals and in patients with systemic lupus erythematosus,76 and with susceptibility to invasive pneumococcal disease.77 If such polymorphisms, particularly in the CRP gene itself, can be shown to correlate reliably with both baseline CRP concentrations (and/or CRP production in the acute-phase response) and clinical outcome, the case for a pathogenetic role of CRP in inflammatory disease will be strengthened.
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CRP and cardiovascular disease |
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TopSummaryIntroductionCRP in health and...Structure and function of...CRP and cardiovascular diseaseReferences |
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The commercial availability of routine high-sensitivity assays for CRP has enabled a flood of studies demonstrating a powerful predictive relationship between increased CRP production, even within the range previously considered to be normal, and atherothrombotic events (Figures 2 and 3).78–87 Circulating CRP values correlate closely with other markers of inflammation, some of which show similar, albeit generally less significant, predictive associations.88,89 However CRP itself is particularly interesting with respect to cardiovascular biology and pathology, because not only does it bind selectively to LDL,48 especially oxidized and enzyme-modified LDL as found in atheromatous plaques,90 but it is actually deposited in the majority of such plaques91,92 and it has a range of pro-inflammatory properties that could potentially contribute to the pathogenesis, progression and complications of atheroma.14,52,93
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Tissue necrosis is a potent acute-phase stimulus, and following myocardial infarction, there is a major CRP response, the magnitude of which reflects the extent of myocardial necrosis.10,94 Furthermore, the peak CRP values at around 48 h after the onset, powerfully predict outcome after myocardial infarction.94–97 Importantly, CRP is deposited within all acute myocardial infarcts,98,99 and compelling experimental evidence now suggests that the CRP response not only reflects tissue damage in this context, but may also contribute significantly to the severity of ischaemic myocardial injury.100
The production of CRP following myocardial necrosis is the typical acute phase response to cell death and inflammation, mediated by the action on the liver of the cytokine cascade, especially IL-6, triggered by such events. However, the stimuli that trigger the low-grade up-regulation of CRP production that predicts coronary events in general populations,84–86 or the more substantial CRP values associated with poor prognosis in severe unstable angina79,101,102 or after angioplasty,103 are not clear. The association with future stroke as well as the outcome following stroke,104–106 along with the ability of CRP to powerfully predict outcome in chronic renal disease,107 also require explanation. Potential acute-phase stimuli may arise from inflammation within atheromatous lesions themselves, and thus reflect their extent and/or severity or instability. However, atherosclerotic burden per se as determined by coronary artery calcification, for example, does not necessarily correlate with CRP concentrations,108 although a recent analysis from the Framingham Heart Study did find an association between CRP and coronary calcification.109 The distinction between so called ‘disease markers’ and ‘process markers’ is important, particularly with respect to inflammation,5 not least because our concepts of the underlying disease processes continue to evolve. Hence, for example, the evidence that there is widespread activation of neutrophils across the coronary vascular beds of unstable angina patients,110 challenges the concept of a single vulnerable plaque in unstable coronary syndromes. Similarly, in the CAPTURE study (Chimeric c7E3 AntiPlatelet Therapy in Unstable angina REfractory to standard treatment trial), troponin T, but not CRP, was predictive of cardiac risk during the initial 72 h period, whereas CRP was an independent predictor of both cardiac risk and repeated coronary revascularization (coronary artery bypass graft surgery and percutaneous transluminal coronary angioplasty) during the 6 months of follow-up. At four year review, both elevated troponin T and CRP were associated with impaired outcome, independently of other established risk factors, but with a different time course. Elevated troponin was associated with increased procedure related risk, and elevated CRP with increased risk for subsequent events.111,112
Alternatively, increased production of CRP may reflect inflammation elsewhere in the body, although there is no strong correlation with serological evidence of the various chronic microbial infections, such as C. pneumoniae and H. pylori, that have been putatively linked with coronary heart disease.86 Indeed, within what was until recently accepted as the reference range for circulating CRP concentration, up to 5 or 10 mg/l,9 higher values have now been found to be strongly associated with increased body mass index,113 and also with many features of the insulin resistance or metabolic syndrome,114–116 up to and including frank diabetes mellitus.117 This may reflect in part the fact that adipocytes are the source of a substantial portion of baseline IL-6 production,118 but in general it suggests that some or even most of the inflammatory marker profile associated with increased atherothrombotic risk in the population at large, may not be triggered by inflammation or tissue damage in the classical sense. Rather it may be a sign of a particular metabolic state which happens also to be pro-atherogenic, or at least predisposing to atherothrombotic events. Indeed, CRP production predicts the development of type 2 diabetes independently of traditional risk factors.119 In insulin-resistant obese individuals, elevated CRP values fall in parallel with improvements in insulin resistance associated with weight loss, but the association between CRP and insulin resistance is independent of body mass.120 Oral contraceptive use121 and systemic, but not transdermal, post-menopausal hormone replacement therapy122–125 are also associated with significantly raised baseline CRP concentrations without any sign of tissue-damaging inflammation. Other associations with elevated baseline CRP values include periodontal disease, smoking, consumption of coffee, and stress.89,126 Also, lately, other conditions not classically viewed as involving inflammation have been associated with elevations in CRP concentration, for example, atrial fibrillation.127,128
Weight loss predictably leads to lower baseline CRP concentrations,129,130 as does moderate alcohol intake,131,132 and there is an association between exercise and reductions in CRP production.133,134 Of particular note is the class effect of HMG CoA-reductase inhibitors (statins), which reproducibly reduce CRP values, independent of their effects on lipid values.135–139 Such an effect may reflect direct hepatocyte interactions, and/or a reduction in atherosclerotic plaque inflammation.140 PPAR-alpha-activators notably directly suppress IL-1-induced but not IL-6-induced expression of CRP in cell culture.141
When prescribed in a primary preventative role, lovastatin reduces the future risk of cardiovascular events not only in patients with above median LDL cholesterol values, but also in patients with normal LDL and CRP concentrations greater than the median. Indeed the risk reduction was essentially the same in the two groups, suggesting that, in primary cardiovascular disease prevention programmes, statin therapy may be appropriately indicated not only by raised lipid values, but also by increased CRP concentrations.142,143 The predictive power for future cardiovascular disease, may even be stronger for CRP than for LDL cholesterol, and there is evidence that increased CRP values identify individuals at risk who are not detected, for example, by the Framingham risk score.144
However, it is critically important to recognize that the CRP response is non-specific and is triggered by many disorders unrelated to cardiovascular disease. In using CRP for cardiovascular risk assessment, it is therefore essential to clearly establish true baseline CRP values, not distorted by either trivial or serious intercurrent pathologies. At the individual level, as opposed to epidemiological studies, this requires at least a proper history and physical examination of the patient, and possibly also appropriate relevant investigations, together with two or three serial CRP measurements if the first result is in the higher risk range (
> 2.5 mg/l). Assessment of the utility and implications of measuring CRP, as well as other inflammatory markers, is currently a very topical issue.145
C-reactive protein and the pathogenesis of atherosclerosis
Our original identification of the possibility that CRP may contribute to the pathogenesis of atherosclerosis,25 has lately become the focus of much work in this field.146 The binding of CRP to lipids, especially lecithin (phosphatidyl choline), and to plasma lipoproteins, especially what was formerly called ß-lipoprotein, has been known for over 60 years, and the first suggestion of a possible relationship to atherosclerosis came when it was demonstrated that aggregated, but not native, non-aggregated, CRP selectively bound just LDL and some VLDL from whole serum. However, native CRP does bind to partially degraded, so-called modified LDL, as it is found in atheromatous plaques, and to oxidized LDL. Furthermore CRP is present in most such plaques examined ex vivo. This CRP could contribute to complement activation and thus inflammation in the plaques, and there is experimental evidence supporting a possible role of complement in atherogenesis.147,148 CRP has also been reported to stimulate tissue factor production by peripheral blood monocytes and could thereby have important pro-coagulant effects.149,150 However, this latter action of CRP has not been well defined or robustly controlled; for example, all the published work has been done with commercially sourced CRP of incompletely defined provenance and purity, and there have been few robust specificity controls. Nevertheless, if the phenomenon is reproducible it provides a possible direct link between increased CRP production and atherothrombotic events. Similarly, it has been claimed that CRP is recognized by a subset of cellular Fc(
) receptors151–154 and could thereby engage multiple processes of inflammation. However, robustly controlled studies, using recombinant and highly purified CRP and avoiding use of whole IgG anti-CRP antibodies, do not confirm such interactions with human cells.155,156
Endothelial dysfunction, a marker of atherosclerosis related to coronary events, is associated in epidemiological studies with markers of systemic inflammation including CRP production,157,158 and CRP has been reported to have direct effects on both inducible and constitutive endothelial nitric oxide synthesis.159–161 Expression of adhesion molecules in endothelial cell cultures is also reportedly increased by in vitro exposure to CRP,162–164 as are angiotensin type 1 receptors in vascular smooth muscle.165 The expression and activity of plasminogen activator inhibitor-1 by human aortic endothelial cells has also been claimed to be upregulated by CRP.166 CRP values are clearly related to the development, severity and progress of coronary artery disease in transplanted hearts, and immunohistochemical detection of arterial endothelial ICAM-1 was associated with elevated serum CRP concentrations.167 In other studies, addition of CRP to LDL in cell culture systems apparently stimulates the formation of foam cells, typical of atherosclerotic plaques.164,168,169 It is not known whether this reflects opsonization of the LDL particles by CRP or an effect of CRP on the phagocytic cells themselves.
All these experimental in vitro observations must be treated with great caution until the purity and integrity of the CRP used have been rigorously established and the specificity of the observed effects formally established, for example by the use of specific CRP absorbents, ligands, antibodies and inhibitors of binding. Furthermore in extrapolating results from in vitro models, it is critical to bear in mind key facts about human CRP, in particular its systemic distribution as a plasma protein and its 10 000-fold dynamic concentration range in the acute phase response. These properties would seem to make inherently unlikely some of the claims for CRP as a fine modulator of sophisticated cellular functions.
Myocardial infarction
Once arterial occlusion has occurred, and there is ischaemic tissue damage with cellular necrosis and ensuing local inflammation, the possible pathogenetic contribution of CRP is much clearer. Apart from the epidemiological association between higher peak CRP values and poor prognosis, there is robust immunohistochemical evidence of CRP deposition within all acute myocardial infarcts, co-localized with activated complement components.99 Although this suggests that CRP might have deleterious effects, investigation of such mechanisms in man will require a drug that selectively inhibits CRP effects in vivo. However, rat CRP does not activate rat complement, in contrast to human CRP, which potently activates rat as well, of course, as human complement.170 The rat model of myocardial infarction produced by coronary artery ligation could therefore be used to investigate specifically the complement-dependent pro-inflammatory role of human CRP in myocardial infarction. When rats undergoing coronary artery ligation received daily injections of pure human CRP, they became sicker than similarly operated rats receiving buffer alone or the closely related pentraxin SAP, which does not activate complement.100 Injection of human CRP into un-operated rats had no adverse effects. Some of the coronary-artery-ligated rats treated with human CRP died, and those surviving to day 5, when all animals were killed, had infarcts 40% larger than buffer or SAP-treated controls.100 This dramatic enhancement of infarct size by human CRP was completely abrogated by in vivo complement depletion of the rats using cobra venom factor, and hence was absolutely complement-dependent.100 Indeed, it has long been known that in vivo complement depletion markedly reduces inflammation and infarct size in this and similar animal models.171–174 We thus conclude that a substantial proportion of final myocardial infarction size following acute coronary occlusion is determined by complement mediated inflammation, and that human CRP, both in our rat model and very likely also in the clinical situation, is responsible for at least some of this complement activation.175
A target for therapy in cardiovascular disease?
There is compelling epidemiological and laboratory evidence that CRP is a sensitive marker of the inflammation and/or metabolic processes associated with atherothrombotic events, and some observations suggest that CRP may contribute to their pathogenesis. Availability of drugs to block CRP binding and its effects in vivo176 would provide a powerful tool for determining whether CRP is just a marker or does indeed participate in pathogenesis of atheroma and/or its complications. Such agents may also have cardioprotective effects in acute myocardial infarction. Existing knowledge of the structure and function of CRP, including its three-dimensional structure alone and complexed with ligands,54 coupled with experience in developing an inhibitor177 of the related protein, SAP, establishes an excellent platform for drug design.
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Acknowledgments |
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GMH is a MRC Clinical Training Fellow. The work of the Centre for Amyloidosis and Acute Phase Proteins is supported by grants from the Medical Research Council (UK), The Wellcome Trust, the Wolfson Foundation, and NHS Research and Development Funds. We thank Beth Jones for expert assistance in preparing the manuscript.
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Footnotes |
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Address correspondence to Dr G.M. Hirschfield or Professor M.B. Pepys, Centre for Amyloidosis and Acute Phase Proteins, Department of Medicine, Royal Free and University College Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF. e-mail: g.hirschfield{at}rfc.ucl.ac.uk or m.pepys{at}rfc.ucl.ac.uk
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