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Cardiovascular Series

The Value of C-reactive Protein in the Clinical Assessment of Cardiovascular Disease Risk

Stephen Brunton, MD

Mortality from CVD and stroke has declined over the last decade, largely due to improvements in therapy and secondary prevention.1,2 However, CVD remains a leading cause of morbidity and mortality. This situation is likely to be exacerbated by the alarming increase in the incidence of obesity3 and the decline in physical activity,4 which are both precursors to hypertension, dyslipidemia, type 2 diabetes, and the metabolic syndrome.

Cholesterol screening is often used to determine risk, but this approach fails to identify almost 50% of the 1.3 million individuals who develop myocardial infarction (MI) in the United States annually—especially those with normal to moderately elevated serum cholesterol concentrations.5

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INFLAMMATION IN CARDIOVASCULAR DISEASE

Atherosclerosis is more than the accumulation of lipids within the artery walls. It is a chronic inflammatory response to arterial injury. It can start early in life, and progress slowly and silently for decades.6 Indeed, the earliest manifestation of the condition—the so-called –fatty streak”—is common in young infants and children6; this inflammatory lesion consisting of monocyte-derived macrophages and T lymphocytes can ultimately develop into an arterial plaque.

All stages of the atherosclerotic disease process comprise an inflammatory response to injury, from initiation to growth and subsequent complications associated with plaque rupture (Figure 1). This process is promoted by cigarette smoking, hypertension, atherogenic lipids, and hyperglycemia. With ongoing inflammation, the macrophages increase and, on ingestion of oxidized lipids, become foam cells. When saturated with lipids, these cells are activated, leading to the release of hydrolytic enzymes, cytokines, growth factors, and procoagulant substances. These factors further damage the vasculature by inducing the proliferation and migration of vascular smooth-muscle cells. Over many such cycles, the lesions enlarge, change structure, and eventually form a fibromuscular cap. At the very least, these advanced plaques lead to reduced vascular compliance and subsequent hypertension, renal failure, or peripheral arterial disease (PAD). At worst, the plaque may rupture, causing a potentially fatal MI or ischemic stroke.

Figure is not available.

FIGURE 1. Progression of atherosclerosis over the lifespan.

A number of circulating serum markers have been identified that provide a window on atherosclerosis by reflecting the degree of inflammatory activity.7 These include proinflammatory risk factors/ markers such as oxidized low-density lipoprotein cholesterol (LDL-C), adhesion molecules, and cytokines. One such cytokine, interleukin-6 (IL-6), induces the expression of hepatic genes encoding for acute-phase reactantsãincluding CRP, which is produced in response to low-grade systemic inflammation.

In a recent study directly comparing the predictive value of 12 putative risk factors (including cholesterol), CRP was found to be the single strongest marker of risk for future CVD (Figure 2).8,9 High-sensitivity CRP (hs-CRP) was able to distinguish between high- and low-risk patients, even in those with a –safe” LDL-C level < 130 mg/dL.8-10

Figure is not available.

FIGURE 2. Relative risk and associated 95% confidence intervals for future cardiovascular events associated with lipid and inflammatory risk factors.9*.

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C-REACTIVE PROTEIN AND RISK ASSESSMENT

Evidence indicates that elevated CRP concentrations reflect an increased tendency toward plaque rupture.6,11 Indeed, hs-CRP consistently predicts new coronary events in patients with unstable angina and acute MI.12,13 High CRP levels are an indicator of stenosis in patients with chronic stable angina,14 and of restenosis after percutaneous coronary intervention.15 They can also predict prognosis and recurrent events following stroke,16 PAD,17 and chronic heart failure.18

In addition, increased CRP levels may predict de novo atherosclerosis, and are associated with an elevated subclinical atherosclerosis burden that contributes to increased cardiovascular events. In the Womenês Health Study, hs-CRP levels were measured at baseline in 27,939 apparently healthy women who were then followed over a 9-year period for the first occurrence of cardiovascular events.19 The predictive value of hs-CRP for CVD was linear over the full range of values, and across the full range of Framingham Risk Scores.

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PRIMARY PREVENTION

The hs-CRP level has independent prognostic value for future cardiovascular events, including MI, stroke, sudden cardiovascular death, and PAD (Figure 3).8,10,20-23 A meta-analysis comparing individuals in the lower tertile of hs-CRP values with those in the upper tertile showed a relative odds ratio (OR) for major coronary events of 2.1, with a 95% confidence interval (CI) of 1.4 to 3.3.24 Similar results were obtained in the Reykjavik Study, with an OR for coronary heart disease (CHD) of 1.4 for the upper tertile versus the lower tertile of CRP values.25

Figure is not available.

FIGURE 3. Prospective studies of hs-CRP as a risk factor for future CVD in apparently healthy populations. Squares represent relative risk estimates, and lines represent 95% confidence intervals for individuals in the top quartile compared with those in the bottom quartile.35

Importantly, CRP retains an independent association with incident coronary events even after adjusting for age, hyperlipidemia, smoking, body mass index, diabetes, history of hypertension, exercise level, and family history.26 However, CRP was found to be inferior to total cholesterol level, current smoking, and systolic blood pressure as a predictor of CHD.25 Furthermore, CRP measurement added only marginally to the predictive value of these established risk factors.25

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C-REACTIVE PROTEIN MEASUREMENT

Of the inflammatory markers associated with CVD, CRP is the most conducive for use in clinical practice. It is easily and inexpensively measured with widely available, standardized, high-sensitivity assays that show good interassay precision (coefficient of variability for the hs-CRP assay of < 10%, range of 0.3 to 10 mg/L).27

C-reactive protein levels are affected by lifestyle choices, concurrent disease, and pharmacotherapy. Higher CRP concentrations are recorded with smoking, excess weight, hypertension, dyslipidemia, the metabolic syndrome, or type 2 diabetes (Table 1).27 Conversely, CRP values can be effectively reduced by weight loss,28 exercise,29 and treatment with statins30 or peroxisome proliferators-activated receptor-α/γ agonists.31 As statin therapy appears to lower CRP in a cholesterol-independent fashion,30 monitoring inflammatory markers may improve utilization of statin therapy, particularly in primary prevention. A prospective study—the Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin—is currently investigating the effects of rosuvastatin in the primary prevention of cardiovascular events in 15,000 individuals with normal LDL-C and elevated CRP levels.

Table is not available.

TABLE 1. Patient Characteristics Associated With an Increase/Decrease in C-reactive Protein Levels27

C-reactive protein levels may also be affected by age and gender.32-34 There is conflicting evidence regarding the effects of ethnicity. The National Health and Nutrition Examination Survey32 concluded that race had no substantial effect on CRP levels, but the Womenês Health Study (WHS) showed that median CRP levels are significantly higher among black women than among their white, Hispanic, and Asian counterparts.33 This study measured CRP levels in 25,541 women, of whom approximately 4% were nonwhite, and intergroup differences were attenuated but not completely negated by correction for other CVD risk factors. As with cholesterol testing, an average of two separate CRP measurements is required to classify risk level (Table 2).27 Optimally, the measurements should be taken 2 weeks apart in fasting or nonfasting metabolically stable patients with no overt signs of inflammation or infection. C-reactive protein differs from other plasma markers of CHD risk, in that it is an acute-phase reactant that rises up to 1,000-fold in response to injury or inflammation, returning to baseline within 7 to 10 days. It is therefore recommended that any hs-CRP level > 10 mg/L should be discarded, and that the test should be repeated at least 14 days later to allow acute inflammatory conditions to resolve (Table 2).27

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INTERPRETING THE RESULTS

The American Heart Association (AHA) and the US Centers for Disease Control and Prevention (CDC) have established CRP ranges for CVD risk that correspond approximately to tertiles of hs-CRP (Table 3).27 The high-risk category confers a 2-fold increase in relative risk (RR) for cardiovascular events compared with the low-risk group.27

Table is not available.

TABLE 3. Risk Categories Based on C-reactive Protein Level27

The predictive value of hs-CRP increases considerably when combined with plasma cholesterol measurements. The WHS8 and Physicianês Health Study10 found that when participants were stratified according to hs-CRP and the total cholesterol:high-density lipoprotein cholesterol (TC:HDL-C) ratio, the RR for a coronary event in the highest quintile of both markers combined was 9-fold higher than in the lowest. Consequently, a new risk assessment algorithm has been proposed to assess relative cardiovascular risk based on initial determinations of TC:HDL-C and hs-CRP quintiles (Table 4).35

Table is not available.

TABLE 4. Relative Risk Estimates of Future Coronary Events in Women Based on Marker Quintile35*

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IMPLICATIONS

The best potential application for hs-CRP testing may be in patients with the metabolic syndrome and others at intermediate risk—ie, 10% to 20% risk of CHD over 10 years (Table 2). Identification of an additional risk predictor may help to dictate further evaluation (eg, imaging, exercise testing) or therapy (eg, hyperlipidemic, antiplatelet, or cardioprotective agents).

The risk reduction associated with CRP-lowering interventions (eg, aspirin) is greatest in individuals with elevated CRP levels,10 allowing for targeted primary prevention. The CDC and AHA27 recently endorsed the optional use of hs-CRP to identify patients without known CVD who may be at higher absolute risk than indicated by other major risk factors. As CRP levels are sensitive to changes in lifestyle (eg, smoking cessation, dietary modification, exercise, weight loss), testing may also motivate patients to improve their lifestyles or comply with drug therapies.

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CONCLUSION

Although generally considered a dyslipidemic condition, inflammatory mechanisms play a prominent role in all stages of atherosclerosis. Analysis of hs-CRP is one of the most accurate ways to assess the risk of MI in otherwise healthy women, with a predictive value exceeding that of even LDL-C. In patients at intermediate cardiovascular risk, this additional predictor can help to determine the nature and aggressiveness of primary prevention measures.

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ACKNOWLEDGEMENT

Dr Brunton has received educational sponsorship from AstraZeneca. Editorial support was provided by The Future Forum Secretariat, London, England.

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Stephen Brunton, MD, is director, faculty development, Cabarrus Family Medicine Residency, Charlotte, NC.

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