Atherosclerosis, once considered to result from a passive process of lipid accumulation, is now known to be an active process of cell activation, inflammation and thrombosis.1 Inflammation is the key mechanism in the pathogenesis of the different stages of atherosclerosis, from onset, progression of atheroma, plaque instability and rupture, and restenosis following angioplasty.2–4 The inflammatory process is exacerbated by the cardiovascular risk factors identified in epidemiological studies, particularly elevated LDL cholesterol.1 There is mounting evidence that modifying these risk factors reduces inflammation and thus helps prevent atherosclerotic events.5

However, the inflammatory process of atherosclerosis is difficult to measure directly. No imaging techniques can assess inflammatory changes, and arterial biopsy to monitor such alterations or therapeutic interventions is neither practical nor ethical. There is therefore a growing interest in biomarkers of inflammation, plasma proteins that can by quantified in peripheral blood.

C-reactive protein

In recent decades, over 30 epidemiological studies have shown that CPR is associated with cardiovascular risk.7 The molecule has characteristics that make it a particularly attractive subject of study: as a positive acute phase protein it is a marker of systemic inflammation that increases in response to various types of injury, particularly bacterial infections, that function as inflammatory stimuli.8 Its production in the liver is induced mainly by interleukin-6 (IL-6) and, unlike other acute phase markers, its levels are relatively stable, with no significant diurnal variation, and can thus be accurately measured.9 During the 1990s high-sensitivity techniques were developed to detect lower serum CRP levels than by previous laboratory methods (down to 0.3mg/l), known as high-sensitivity CRP (hs-CRP), and these techniques should be used when assessing the cardiovascular risk associated with the chronic vascular inflammation of atherosclerosis.There is growing evidence that CRP is not merely a marker of inflammation, but also plays an active role in atherogenesis (Figure 1).10,11 In 2003, Ishikawa et al. concluded that CRP is found inside atherosclerotic plaques and plays an important part in both plaque instability and post-angioplasty restenosis.10 Similarly, Inoue et al. demonstrated in 2005 that CRP is released by atherosclerotic plaques responsible for acute coronary syndromes (ACS).11 They also showed that there is a CRP gradient in the coronary circulation proximal and distal to the plaque and a transcardiac gradient (from coronary sinus to peripheral blood) that gradually increases after angioplasty, peaking at 48hours, suggesting a cardiac origin of CRP.11 CRP levels correlate directly with various cardiovascular risk factors, including body mass index, smoking, systolic blood pressure (BP), levels of triglycerides and total cholesterol, heart rate, fasting blood glucose and history of CAD or stroke, and inversely with HDL cholesterol and diastolic BP, in both children and adults.12–14

Figure 1.

C-reactive protein is not merely a marker of the atherosclerotic inflammatory process but also plays an active role in the pathogenesis of atherosclerosis.

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In vitro and in vivo studies have shown that CRP is not merely a marker of inflammation, but that it plays an active part in the development of the atherosclerotic plaque and subsequent plaque instability and thrombus formation. There has accordingly been extensive research into the relation between CRP and cardioprotective drugs. An analysis of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) showed that statin therapy as primary prevention directly lowers hs-CRP levels; individuals with high LDL cholesterol (irrespective of hs-CRP levels) and those with low LDL cholesterol but high hs-CRP were at greater risk of cardiovascular events during follow-up; the lovastatin group showed substantial benefit.64 In the PRINCE (PRavastatin Inflammation/CRP Evaluation) study, pravastatin reduced CRP levels in individuals with no prior history of cardiovascular disease.65

However, three meta-analyses of studies of statins in primary prevention concluded that they did not reduce total or coronary mortality in men or women,66–68 while in the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) study, in which many more women than men were enrolled, the reduction in events was significant only for men.69

The JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) study was a multicenter randomized double-blind trial in 17 802 apparently healthy individuals without hyperlipidemia (LDL cholesterol <130mg/dl) but hs-CRP >2mg/l, divided into two groups: rosuvastatin 20mg/day or placebo. Participants were followed for a mean of 1.9 years (maximum 5.0). Rosuvastatin reduced LDL cholesterol by 50% and CRP by 37%, and there were significantly fewer major cardiovascular events in the treatment group. The rate of the combined primary endpoint of stroke, MI, UA, coronary revascularization or cardiovascular death was 0.77 and 1.36 per 100 person/years of follow-up for the rosuvastatin and placebo groups, respectively (HR for the rosuvastatin group: 0.56; 95% confidence interval [CI]: 0.46–0.69; p<0.00001) (Figure 2).70 There was no significant difference in treatment effect between the sexes (42% in men and 46% in women).71

Figure 2.

Rosuvastatin significantly reduced the incidence of major cardiovascular events in apparently healthy individuals without hyperlipidemia (LDL <130mg/dl) but with elevated high-sensitivity C-reactive protein (>2mg/l).

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Adapted from Ridker et al.70

Two meta-analyses that included the JUPITER trial concluded that statin therapy reduced the relative risk of cardiovascular events and increased survival in both sexes.71,72

Some authors consider that preventive treatment with statins in patients with high hs-CRP and normal LDL cholesterol is cost-effective for those with Framingham risk score ≥10%.73,74 However, others argue that it is more cost-effective to begin statin therapy without assessing hs-CRP, on the assumption that the drug is safe and is beneficial even in patients with normal CRP.75

It is important to note that the population of the JUPITER trial, although apparently healthy, all had at least one cardiovascular risk factor, such as obesity or smoking. According to Rashid,76 the JUPITER results warrant further LDL cholesterol lowering than is currently targeted in primary prevention groups that have a pre-existing condition or lifestyle that elevates cardiovascular risk but still do not have a high global CVD risk as assessed with current algorithms. Lifestyle modifications (smoking cessation, normalization of body weight and dietary changes) should be achieved first before considering statin therapy. Assessment of hs-CRP can help identify this patient subgroup, who should begin preventive therapy early in an attempt to reduce the prevalence of cardiovascular disease.

With regard to secondary prevention, the findings of the Cholesterol And Recurrent Events (CARE) trial, a randomized study assessing the effect of pravastatin after MI, showed that although the relative risk of adverse coronary events was substantially reduced with statin therapy in patients with and without evidence of inflammation, the reduction was greater in those with evidence of inflammation as assessed by hs-CRP measurement (54% vs. 25%), even though lipid levels were similar in the two groups.48 This suggests that statins are particularly effective in patients with elevated hs-CRP. The PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) study demonstrated that intensive statin therapy reduces hs-CRP levels to less than 2mg/l, resulting in lower risk of MI and fatal coronary events, independently of reductions in LDL cholesterol (Figure 3).77 A subanalysis of the Aggrastat-to-Zocor study showed that hs-CRP levels 30 days and four months after MI are independently associated with long-term survival and that more aggressive statin therapy is likely to result in low CRP.78 The evidence in these studies of the pleiotropic effects of statins suggests that assessment of CRP levels can identify individuals who do not have elevated LDL cholesterol but nonetheless would benefit from statin therapy to reduce cardiovascular events (Table 3).

Figure 3.

Intensive pravastatin therapy in patients with acute coronary syndrome reduced high-sensitivity C-reactive protein to below 2mg/l, resulting in reduced risk of myocardial infarction and fatal coronary events, independently of reductions in LDL cholesterol.

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Adapted from Ridker et al.77

In the Physician's Health Study, the use of aspirin was associated with a significantly larger reduction in risk of MI in men in the highest quartile of hs-CRP levels than in those in the lowest quartile (55.7% vs. 13.9%).16 However, few studies have assessed the direct effect of aspirin on CRP levels; one small randomized trial studied the effect of low-dose aspirin in healthy volunteers but did not detect any effect on CRP.79

In 2003, the American Heart Association and the US Centers for Disease Control and Prevention published guidelines on the use of markers of inflammation in cardiovascular risk assessment,87 and in 2009 the National Academy of Clinical Biochemistry published guidelines on emerging biomarkers for primary prevention of cardiovascular disease.88

According to these guidelines, hs-CRP should not be measured in the general population to determine cardiovascular risk, but can be used in risk stratification of adults at intermediate risk for CAD (10–20% risk at 10 years), to help decide whether to begin primary prevention with statins. hs-CRP levels should be expressed in mg/l and patients should be classified as low risk (<1.0mg/l), intermediate risk (1.0–3.0mg/l), or high risk (>3.0mg/l). If the concentration is <3mg/l, measurement does not need to be repeated. If the value is >3mg/l, it should be repeated at least two weeks later when there is no evidence of active systemic inflammation; the lower of the two results should be used. Values of >10mg/l suggest a very strong acute phase response and, if not of cardiovascular cause, require further etiological investigation.

Therapy (statins or aspirin) based on hs-CRP levels should be at the discretion of the clinician, since its benefit is still uncertain, and little evidence supports the use of serial testing for hs-CRP as a means to monitor therapy in primary prevention. Individuals with persistently high levels should improve their lifestyles (e.g. weight loss, regular exercise, dietary modification and smoking cessation), irrespective of their LDL cholesterol levels.

In 2009, the Canadian Cardiovascular Society also published new guidelines on primary cardiovascular prevention,89 which recommend that in individuals with intermediate cardiovascular risk according to conventional risk scores, hs-CRP should be assessed as well as LDL and HDL cholesterol in order to improve risk stratification. The European Atherosclerosis Society has yet to pronounce on this issue. By contrast, the 2007 European guidelines on cardiovascular disease prevention state that incorporation of CRP and other emerging risk factors into prediction of cardiovascular risk may be premature and is therefore not recommended.90

In February 2010, the US Food and Drug Administration approved rosuvastatin for prevention of cardiovascular events in women aged over 60 and in men aged over 50 with hs-CRP >2mg/l and another conventional risk factor, even without hyperlipidemia.91

Both European and American guidelines consider that in patients with documented CAD hs-CRP measurement may be useful as an independent marker for assessing likelihood of death, MI or restenosis after PCI.87,92 However, secondary preventive interventions and application of ACS treatment guidelines should not be dependent on hs-CRP levels.

It should be noted that in 2010, a study by Hemingway et al. evaluating the quality of research into the prognostic value of CRP in stable CAD concluded that the 83 studies analyzed suffered from a variety of biases and that any link between hs-CRP and prognosis is so weak that it cannot be used as the basis for clinical recommendations.93

There is growing evidence that hs-CRP is an important marker of cardiovascular risk and is linked to the pathophysiology of atherosclerosis, providing additional value in primary and secondary prevention. Despite the limitations to its use in routine clinical practice, particularly interindividual variability, the available data indicate that selective determination of hs-CRP is useful in individuals with intermediate cardiovascular risk (10–20% risk at 10 years) in order to optimize risk stratification and clinical management.

The authors have no conflicts of interest to declare.