The European Society of Cardiology
Identifying patients at risk of coronary vascular disease: the potential role of inflammatory markers
Gaubius Laboratory, TNO Institute of Prevention and Health, Leiden, The Netherlands
* Correspondence: Gaubius Laboratory, TNO Institute of Prevention and Health, Leiden, The Netherlands. Tel.: +31-715-181-497; fax: +31-715-181-904
kluft{at}euronet.nl
Abstract
Inflammation is intimately involved in the pathogenesis of cardiovascular disease (CVD). The measurement of inflammatory markers may be a potent method for identifying individuals with increased inflammation at risk of future cardiovascular events. High-sensitivity C-reactive protein (hs-CRP), one marker of inflammation, is a strong independent predictor of CVD and can be used to identify individuals at increased risk who would otherwise be missed if standard lipid measurements only were used. Furthermore, CRP may actively participate in the pathogenic progression of atherosclerotic disease by activating complement, inducing synthesis of tissue factor, influencing nitric oxide levels, and enhancing foam cell uptake of low-density lipoprotein cholesterol. Simple, inexpensive methods for measuring hs-CRP are commercially available, making the measurement of CRP levels feasible in clinical settings. Together, these data suggest that the ability to accurately predict CVD risk may be significantly increased by including CRP measurements in risk assessment models. In addition, the identification of increased inflammation suggests that rational therapy should be applied and favours treatments with anti-inflammatory action.
Key Words: Cardiovascular disease • C-reactive protein • Inflammation • Inflammatory markers • Risk factor assessment • Statins
Introduction
Even with increasingly stringent lifestyle guidelines, and the use of pharmacological approaches to reduce plasma cholesterol levels, cardiovascular disease (CVD) remains the major cause of morbidity and mortality worldwide. An abundance of data has shown the relationship between elevated cholesterol and increased risk of morbidity and mortality from CVD;1–4 however, approximately half of all coronary events occur in people with below-average cholesterol levels. In current strategies of cardiovascular risk assessment, lipid testing is routinely included, but it is apparent that serum cholesterol levels alone are insufficient to accurately predict cardiovascular risk in all people.
Atherosclerosis is the underlying cause of most CVD, starting early in life and progressing slowly and silently for decades before being complicated with acute myocardial infarction (MI), stroke or angina pectoris. The development of atherosclerosis involves a complex and self-reinforcing interaction between lipid accumulation and modification, the endothelium, smooth muscle cells and macrophages, inflammatory cytokines and various blood elements. Laboratory and epidemiological data indicate that inflammation plays a major role in this process.5,6
Since inflammation is associated with atherosclerosis, the measurement of inflammatory markers may be a powerful method for identifying increased inflammatory activity and predicting future cardiovascular events in individuals. Such markers include liver proteins, such as high-sensitivity-C-reactive protein (hs-CRP), serum amyloid A (SAA), secretory phospholipase A2 and fibrinogen; cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-
); and vascular markers, such as soluble intercellular adhesion molecule-1 (sICAM-1). Indeed, to date, these variables have been identified as prospective risk markers of CVD, and together provide a consistent message of the involvement of inflammation in cardiovascular risk. Of these markers, CRP is found to be the best predictor of the probability and severity of future coronary events (Fig. 1).6,7
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The role of local vascular inflammation is substantiated by measurements of local temperatures that are increased due to inflammation, in particular in patients with MI and unstable angina pectoris (UAP). These data on vascular temperature correlate with CRP (Fig. 2).8
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). Luminal arterial temperature differed significantly among patients with AMI, UAP and SAP. Reprinted from the Journal of Molecular and Cellular Cardiology, vol. 32, Stefanadis C, Diamantopoulos L, Dernellis J, et al., Heat production of atherosclerotic plaques and inflammation assessed by the acute phase proteins in acute coronary syndromes, pp. 43–52; 2000, with permission from Elsevier.In healthy persons, CRP is found only in relatively low amounts, with a median concentration of approximately 1 mg/l, while values can exceed 400 mg/l during the acute-phase response.9 The recent development of high-sensitivity assays allows clinicians to detect low-grade inflammation in apparently healthy people, as well as in those with established disease.6,10
CRP levels correlate with both chronic and acute disease states. For example, baseline levels of hs-CRP in apparently healthy persons more accurately predict the risk of first MI or stroke than conventional lipid risk markers.6,7,11–13 Increases in hs-CRP following acute MI, or in patients with UAP, are directly correlated with clinical outcome. In patients with stable angina pectoris (SAP), baseline hs-CRP levels constitute an independent risk factor for cardiovascular events.13
CRP as a marker for CVD risk
The increasing importance of inflammation as a component of the pathogenic progression of atherosclerotic disease and the acute process of events is underscored by the growth in research devoted to this topic. Much of this research has focused on the role of CRP as a predictor of cardiovascular risk.14
Prospective studies have shown that hs-CRP predicts future cardiovascular morbidity and mortality in individuals with known CVD. The European Concerted Action on Thrombosis and disabilities (ECAT) angina pectoris study, which followed 2121 men and women with SAP and UAP for up to 2 years, found that elevated hs-CRP levels predicted coronary events. For each standard deviation increase in hs-CRP there was a 45% increase in the relative risk (RR) of fatal or nonfatal MI (95% confidence interval [95% CI], 1.13–1.83%).7,15 In the Cholesterol And Recurrent Events (CARE) trial, which enrolled patients with a prior history of MI, hs-CRP levels were higher among patients who subsequently developed recurrent nonfatal MI or a fatal coronary event (RR=1.77; 95% CI, 1.1–2.9%).16
CRP is also an indicator of CVD risk in individuals with no evidence of disease. For example, results from the Multiple Risk Factor Intervention Trial (MRFIT) demonstrated that hs-CRP levels were strongly correlated with future CHD mortality among smokers (RR=4.3; 95% CI, 1.7–10.8%).17 Similarly, in the Physicians Health Study (PHS), baseline hs-CRP levels were significantly higher among men who subsequently experienced MI (RR=2.9; 95% CI, 1.8–4.6%; 
) or ischaemic stroke (RR=1.9; 95% CI, 1.1–32.3%; 
) than among men without future coronary events.18 Unlike the MRFIT study, this relationship was present in both smokers and non-smokers. A study conducted in 7735 men in the UK showed that participants in the highest tertile of hs-CRP levels had a 4-fold higher risk of developing CHD than men in the bottom third (RR=3.46; 95% CI, 2.59–4.62%).10 This relationship holds true for women as well as men: the Women's Health Study (WHS) found that the risk of future vascular events increased with each quartile of CRP (
for trend=0.0001).19 Women with levels in the highest quartile were five times more likely to undergo a vascular event than those in the lowest quartile (RR=4.8; 95% CI, 2.3–10.1%; 
) and had a 7-fold increased risk of MI or stroke (RR=7.3; 95% CI, 2.7–19.9%; ).19 A meta-analysis, including groups with pre-existing vascular disease and population studies, has shown the consistency of the role of CRP as marker of risk for CVD.10
Hormone replacement therapy (HRT) has been shown to increase hs-CRP in postmenopausal women, which may account for part of the effect of gender on CRP in this age group. The effect can be ascribed to oestrogen20, and the effects of oestrogen in general may be stronger in individuals with pre-existing elevated levels; high CRP might be a contraindication for oestrogen use.21
In the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial, 4 different HRTs caused a rapid, sustained and significant increase in CRP concentrations (
).22 A cross-sectional study of 493 healthy postmenopausal women found that those taking HRT had CRP levels 2-fold higher than those not taking HRT (0.27 versus 0.14 mg/dl; ).23 In the Heart and Estrogen/progestin Replacement Study follow-up (HERS II), there was a higher risk of cardiovascular events in the HRT treatment group than in the group given placebo during the first year of treatment.24,25 However, during additional years of follow-up there was no significant difference in the rate of cardiovascular events in the HRT group.
CRP as a tool in CVD risk assessment
For a marker to be an effective instrument in the assessment of disease risk, specific guidelines must be set that can be used to stratify individuals into different risk groups. It is useful in epidemiological research to stratify CRP levels into quartiles or quintiles; risk estimates can then be made by between-group comparisons. Analyses performed on apparently healthy men and women found that for each quintile increase in CRP, the adjusted RR of suffering a future cardiovascular event increased 26% for men (95% CI, 11–44%; 
) and 33% for women (95% CI, 13–56%; ).11,12,26
Apart from models incorporating multiple risk factors, such as the formulas from Framingham and Procam, CVD risk assessment approaches frequently use lipid levels as the sole predictive measure. Notably, models incorporating both hs-CRP and lipid parameters have a significantly greater ability to predict risk than models using lipids alone. For example, in PHS the predictive value of both hs-CRP and total cholesterol (TC) in forecasting future MI was significantly greater than that of a model using TC only (
). Likewise, models incorporating hs-CRP significantly improved risk prediction compared with models based only on the TC:high-density lipoprotein (HDL)-cholesterol ratio (
), or on TC and HDL-cholesterol ().18
In WHS, hs-CRP was superior to low-density lipoprotein (LDL)-cholesterol as a predictor of future cardiovascular events (RR=4.4; 95% CI, 2.2–8.9% versus RR=2.4; 95% CI, 1.3–4.6%, respectively) (Fig. 1).26 Furthermore, risk models incorporating both hs-CRP and the TC:HDL-cholesterol ratio were significantly better predictors of risk than models using the lipid ratio alone (). In addition, hs-CRP levels identified women with relatively low LDL-cholesterol levels (
130 mg/dl) as having an elevated risk of future MI, stroke and coronary revascularization.27
Data from PHS and WHS were used to calculate the RR associated with quintiles of hs-CRP and TC:HDL-cholesterol ratio.7 When participants in PHS were stratified according to quintile of hs-CRP and quintile of TC:HDL-cholesterol ratio, men in the highest quintile of both risk groups were approximately nine times more likely to experience a cardiovascular event than men in the lowest quintiles. In WHS, the RR of developing CVD was more than 8-fold greater for women in the highest quintiles of hs-CRP and TC:HDL-cholesterol ratio than for women in the lowest quintiles.7,18,26 Since the RR values for men and women are similar, a single algorithm can be used to predict the risk of future coronary events in both populations (Table 1).
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These data demonstrate that the combination of lipid and CRP data results in meaningful risk prediction strategies. The combination of CRP with more complex algorithms requires further evaluation about added value and ease of use. It can be remarked that the use of CRP as a risk marker also includes the identification of a disease mechanism and goes beyond risk prediction in suggesting a causal (anti-inflammatory) treatment.
Potential mechanisms of action of CRP in promotion of CVD
Ligand-bound CRP is a potent activator of the classical complement pathway, which leads to enhanced inflammation and exacerbation of myocardial tissue damage and dysfunction. CRP and complement have been found co-localized in infarcted, but not normal, myocardium of patients who died after acute MI.13 The critical role of complement activation in the enhancement of myocardial damage by CRP following ischaemic injury was clearly demonstrated by Griselli and colleagues.28 Complement is not activated by rat CRP, but is by human CRP. Injection of human, but not rat, CRP into rats after ligation of the coronary artery markedly enhanced tissue damage and reproducibly increased infarct size by approximately 40%. In vivo complement depletion, even when initiated 2 hours after ligation, caused a dramatic reduction in infarct size.
Activation of the complement pathway may mediate vascular and myocardial damage through a variety of mechanisms: stimulation, aggregation and degranulation of neutrophils, formation of procoagulant microvessels, and direct damage of endothelial cells and cardiomyocytes by insertion of pores. Additionally, activated complement may promote coronary vasoconstriction and cause arrhythmias.13
Independent of complement activation, CRP may also participate in CVD progression by increasing the expression and bioactivity of tissue factor (TF). The CRP-induced increase in TF expression, predominantly in monocytes/macrophages, is associated with an increase in procoagulant activity, which may contribute to the development of intravascular coagulation and thrombosis.29
CRP may promote CVD by increasing expression of intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1). Increases in ICAM-1 and VCAM-1 levels enhance progression of vascular disease by promoting leukocyte adhesion to the intima. In addition, high levels of CRP suppress the production of nitric oxide (NO) by reducing endogenous NO synthase (eNOS) mRNA expression, protein levels and enzyme activity. Since NO promotes vasodilation and inhibits smooth muscle cell proliferation, LDL-cholesterol oxidation, platelet adhesion and aggregation, and adhesion of monocytes to the arterial endothelium, a reduction in the bioactivity of eNOS and subsequent shortage of NO would be expected to enhance the progression of CVD.30
Therefore, in persons with elevated CRP, drugs that lower CRP plasma levels, such as aspirin and statins, or agents that reduce CRP synthesis or inhibit its binding to membranes and ligands, may reduce CVD risk.11,16,28
Liuzzo et al.21 demonstrated that baseline levels of CRP in patients before percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG) predict the magnitude of the increase in plasma CRP following the intervention (Fig. 3). These data imply that the inflammatory response to acute situations is associated with chronic levels of inflammation. This supports a direct role for CRP in promotion of CVD as discussed above. The combination of a relationship between chronic levels of CRP and the size of the inflammatory response in acute situations with a causal role of CRP in CVD may explain the strong association between CRP and acute events, and provides a possible explanation for the superiority of CRP among the inflammatory markers.
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Assessment of CRP levels
CRP is found in relatively low amounts in healthy individuals, with a `normal' range up to 5 mg/l, but values may increase as much as 1000-fold during the acute-phase response.6,9,31 Several characteristics of CRP make it an effective marker for predicting CVD risk: it is stable in vitro and in vivo; it is a response factor reacting to a chronic stimulus; it has no circadian variations; and there are several high-sensitivity assays commercially available or in development.6,12,35 However, temporary reactions to day-to-day stimuli, trauma or clinical and sub-clinical disease may cause a temporary increase in plasma CRP concentrations.
Current data suggest that the cut-off values that separate high-risk and low-risk individuals appear to be higher in CVD patients than in persons without known CVD.14 In patients undergoing coronary angioplasty or bypass surgery, those with CRP levels above 3 mg/l should be considered at high risk for ischaemic complications.6 In patients with CRP levels 
5 mg/l immediately following a coronary procedure, an additional measurement is warranted after 72 hours. If levels remain elevated, the patient should be considered at extremely high risk for future ischaemic events and restenosis.6
However, there are limitations to using CRP as an independent risk marker for CVD. First, CRP is an acute-phase protein and as such is highly sensitive to trauma, surgery and acute infection; therefore, CRP levels are not necessarily related to atherosclerotic inflammation. Second, oral contraceptives have a large impact on CRP values. Women taking oestrogen have higher CRP levels than age-matched men and women not on hormone therapy. The mechanism of this increase is unclear and it is not known whether oestrogen-induced elevation of CRP poses a similar cardiovascular risk as elevation of CRP when not using oestrogens. It should be noted that recent data indicate that the effect of oestrogen on CVD risk is more neutral than beneficial and that combination of oral HRT and statins is beneficial relative to oral HRT alone.24,25,31–33
If CRP is used as an independent predictor of CVD in primary prevention, a single low measure (below a consensus threshold) is usually sufficient to identify a person as being at low risk. Alcohol consumption is the only known cause of false low CRP levels.34 A single high measurement should be followed by one additional assessment within 2 weeks, in order to exclude temporary outliers and to obtain a representative value; however, multiple samples might occasionally be required to achieve this goal.35 A recent publication provides a full account of information needed for a practical approach to CRP assessment in individuals.35 It is argued that the easiest approach is to use a single threshold measurement; however, a consensus for this threshold has yet to be determined. Table 2 briefly summarizes the assessment strategy for a tentative threshold of 3 mg/l. When CRP values are used to separate persons into low-, medium- and high-risk groups at least 2 blood measurements are required and the mean CRP value should be used, as this will give a more reliable classification.
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To improve evaluation of risk, CRP values should be used in conjunction with other measures, including TC, LDL-cholesterol, HDL-cholesterol levels and the TC:HDL-cholesterol or LDL-cholesterol:HDL-cholesterol ratio.
Beyond lipid lowering – the effects of statins on inflammation
Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the enzyme that catalyses the rate-limiting step in cholesterol synthesis. Data from several studies suggest that the effects of statins on inflammation may contribute to the efficacy of these agents in the primary and secondary prevention of CHD events.16,36,37
Several studies have shown that statin therapy is associated with significant reductions in CRP levels and diminished risk of cardiovascular events, particularly in subjects with high baseline hs-CRP concentrations.36,38–42 Although statins are currently used only in patients with elevated lipid levels and high risk, statin therapy may have collateral anti-inflammatory benefits in persons without hyperlipidaemia. Studies in individuals with low or normal lipid levels but elevated CRP found that statins lowered CRP and reduced the rate of coronary events.36,41 Thus, evaluation of hs-CRP concentrations may also be a useful method for targeting statin therapy for primary prevention in these patients.
Furthermore, the use of statins in combination with oestrogen replacement therapy may reduce cardiovascular risk associated with oestrogen-induced increases in CRP. A study comparing the effect of combination oestrogen and statin therapies on CRP levels found that co-administration of oral oestrogens and a statin resulted in a significantly smaller increase in CRP than administration of oestrogens alone (
).24 This may be of clinical importance because, by attenuating the increase in CRP, statins may reduce the risk of future cardiovascular events that may be associated with oral oestrogens.
Conclusion
An abundance of data, only a small fraction of which is outlined above, suggests that inflammation has a major role in both the initiation and progression of atherosclerosis and the pathogenic cascade that induces and follows an acute event. In particular, CRP appears to be a relevant marker and also a player in both processes.
As a sensitive acute phase protein, CRP levels have proved to be a superior measure of the inflammatory status of atherosclerotic disease. Indeed, the results of multiple studies suggest that CRP levels correlate with the presence of active and vulnerable plaques, an important qualitative aspect of atherosclerotic disease related to risk of events.
Thus, CRP levels have been shown to accurately and independently predict the risk of CV events in patients across the range of lipid levels. Data from these studies should be incorporated into multivariate models of CVD risk to assist physicians in identifying, monitoring and treating all patients, including those with average to below-average lipid levels. Improved risk assessment may be of clinical utility because relatively simple interventions such as exercise, diet restriction, weight loss and drug therapy can substantially reduce the risk of CVD. Moreover, inflammation can more rationally be targeted with treatments proven to reduce the inflammatory status of the atherosclerotic vessel wall.
No less important is the role of CRP and inflammation in the progression and clinical outcome of acute events. As an activator of the complement pathway, an inducer of TF and a modulator of NO synthesis, CRP enhances and exacerbates the natural response to these events. As such, CRP may be an ideal target of investigation for current and future therapeutic strategies in the acute care setting.
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