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Prof. Mateja Kaja Jezovnik
Prof. Pavel Poredos ,
The C-reactive protein (CRP) has been shown to be a reliable marker of underlying systemic inflammation, a strong and independent predictor of future cardiovascular events in subjects with and without established cardiovascular disease. Determination of hs-CRP can assist physicians to evaluate cardiovascular risk and to monitor therapeutic interventions. The measurement of plasma CRP is reasonable for assessing absolute risk for coronary artery disease in primary prevention - particularly in intermediate risk individuals.
Inflammation plays an important role in the initiation and progression of atherosclerosis and the development of atherosclerotic events. Epidemiological and clinical studies have shown strong and consistent relationships between markers of inflammation and risk for cardiovascular CVD events (1, 2). The results of these studies have increased interest in the potential use of inflammatory biomarkers to help predict which individuals are at risk for future CVD events. The identification of markers may also serve as new targets of therapy in the management of atherothrombotic disease.
A number of biomarkers that appear to be linked to inflammation and atherogenesis have been identified, between them, CRP has attracted particular attention. Plasma CRP has : a long half-life, exhibits stable levels in individuals, has negligible circadian variation and it is easily measured.
As a downstream biomarker, CRP provides : a functional integration of overall upstream cytokine activation; it also exhibits activities that may initiate and stimulate progression of vascular disease, including the binding and activation of complement.
It has also been shown that high concentrations of plasma CRP : elevated levels of cell adhesion molecules and tissue factor, mediate low-density lipoproteins cholesterol (LDL-C) uptake by endothelial macrophages, induce recruitment of monocytes into blood vessel walls, and augment levels of monocyte chemoattractant protein-1 (3).
CRP has been shown to be a reliable measure of underlying systemic inflammation and a strong predictor of future cardiovascular events. These results stimulated interest for CRP measurement in CVD risk assessment in clinical practice.
Although most studies have shown that CRP is a strong and independent predictor of atherosclerotic risk, the recently reported Reykjavik Study showed a more moderate predictive capability of CRP (6). Baseline CRP levels were significantly higher in subjects who developed CHD during the study than in controls, however the odds ratio for CHD was only 1.92. This slightly different finding was most probably caused by the upper tertile cut-off point of CRP, used in this study –2.0 mg/L rather than 3.0mg/L as recommended by the Centers for Disease Control and Prevention and the American Heart Association (AHA) (7), and may underestimate the risk associated with CRP levels. Beyond primary prevention, multiple studies have found that : - hs-CRP levels in stable patients after myocardial infarction can predict recurrent infarction and cardiovascular death. - Elevated levels of CRP also predict recurrence of ischemic attack in patients undergoing elective or percutaneous intervention (8) and surgical revascularization (9). - Further, hs-CRP levels predict incident peripheral arterial disease (10) as well as incident and recurrent stroke (11).
CRP and therapeutic interventions
Different therapeutic interventions have been shown to reduce CRP levels:
- Diet and exercise-therapies proven to lower the risk of both heart disease and diabetes are associated with decreased hs-CRP in obese and modestly overweight patients (12). - Intensive lifestyle modifications that combine both caloric restriction and moderate-intensity physical exercise produce reductions of approximately 30 % (13). - Agents commonly used to treat diabetes, including insulin, metformin, and the peroxisome proliferator activated receptor - gamma agonists rosiglitazone and pioglitazone, also lower CRP (14). - Recent data from the PROVE IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) - TIMI 22 and the REVERSAL (reversal of Atherosclerosis with Lipitor) trials further suggest that hs-CRP levels achieved by statin therapy may rival LDL-C levels achieved with these agents (15). The greatest clinical benefit of statin therapy occurred among patients who lowered both LDL-C and hs-CRP. Post-hoc analyses of these data showed even greater risk reductions at hs-CRP levels <1 mg/l. In the REVERSAL trial treated coronary disease patients with the same statin agents as in PROVE IT atherosclerotic progression, as measured by intravascular ultrasound, showed primarily among individuals who lowered both LDL-C and hs-CRP (16).
Overall, data suggest that CRP may identify different patients to those identified by traditional risk factors and may have an adjunctive role in the global risk prediction of CVD.
The question arises if plasma hs-CRP screening of the entire adult population is reasonable and whether plasma hs-CRP measurement can identify individuals who are apparently at low risk and may benefit from treatment of risk factors like lipid-lowering therapy. Results from some studies support this hypothesis.
Although these data suggest that elevated CRP plasma levels defines the risk that warrants therapy among individuals who do not meet current criteria (determined by classical RF), definitive prospective evidence for a broader application in event reduction remains undetermined.
To answer this question, a large-scale (15.000 men and women), randomized clinical trial Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) – will evaluate the effects of statin therapy in subjects who have both plasma LDL-C levels below target level and plasma CRP levels that indicate increased risk of a CHD event. (18). The results of JUPITER should provide important information regarding the use of plasma CRP values to guide initiation of lipid-lowering therapy in a primary prevention population deemed to be at low cardiovascular risk by means of current criteria. According to present knowledge measurement of plasma hs-CRP is reasonable for assessing absolute risk for coronary disease primary prevention, particularly in intermediate – risk individuals. The currently recommended plasma hs-CRP cut points are <1.0 mg/L for low risk, 1.0 to 3.0 mg/L for average risk, and > 3.0 mg/L for high risk (3). It is expected that in the future CRP determination will serve as a useful tool for the identification of patients who will benefit the most from preventive measures.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
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*Dr P. Poredoš and Dr M. Kaja Jezovnik Ljubljana, Slovenia Past chairperson of the Working Group on Peripheral Circulation
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