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Inflammation and atherosclerosis : Clinical utility of the C-reactive protein

An article from the e-journal of the ESC Council for Cardiology Practice

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.

Prevention


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.

Involvement of CRP in atherogenesis

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 and cardiovascular risk

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.

  • In the prospective Physicians’ Health Study it has been demonstrated that CRP levels predict the risk of cardiovascular events in apparently healthy men and women. Baseline CRP levels have been found to be higher among men who developed myocardial infarction or stroke than among those who remained free of CVD events (3, 4). Moreover, men in the quartile with the highest CRP values had three times more the risk of myocardial infarction compared with men in the lowest quartile, and the risk of stroke was approximately doubled. The risks were independent of traditional lipid and non lipid risk factors. In women, CRP levels have also been found to be highly predictive of future CVD risk.
  • In a prospective, case–control analysis from the Women’s Health Initiative (5), among women with no history of CVD, median baseline levels of CRP were significantly higher in women who subsequently suffered a CVD event than in women who remained free of CVD. CRP has been shown to have an independent prediction of the first cardiovascular event even after adjusting for classical risk factors.

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).

Clinical utility of CRP measurement

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 women's Health Study showed that an elevated plasma hs-CRP value was the best single marker and, when combined with the plasma total cholesterol - HDL-C ratio, provided an even more potent prediction of prospective risk and added prognostic information to measurement of plasma lipid levels (5).

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.

  • The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) included men and women without CHD who had average total and LDL-C plasma levels below-average HDL-C plasma levels (17). Treatment with lovastatin showed a risk reduction of 37 % for the first acute coronary event over 5 years. Participants were stratified by a high or low plasma total cholesterol–HDL-C ratio and plasma hs-CRP values. Compared with results of the placebo group, the statin group demonstrated marked event reduction in the group of participants with high values of CRP. In contrast, statin therapy had little effect on the rate of events in individuals with low ratio/low CRP values. Therefore individuals with low levels of LDL-cholesterol and concomitant elevation of CRP might benefit substantially from statin treatment.  These findings suggest that plasma CRP screening can indeed identify individuals at seemingly low risk calculated on the basis of classical risk factors who will nonetheless benefit from treatment of risk factors. Therefore, determination of CRP may provide additional information regarding which patients may benefit from statin treatment irrespective of cholesterol level.

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.

References


1. Ridker PM, Cushman M, Stampfer MJ, Tracy R, Hannekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336: 973-9.

2. Ballantyne CH, Nambi V. Markers of inflammation and their clinical significance. Atherosclerosis suppl 2005; 6: 21-9.

3. Libby P, Ridker PM. Inflammation and atherosclerosis: role of C-reactive protein in risk assessment. Am J Med 2004; 116: 9S-16S.

4. Ridker PM, Glym RJ, Hennekens CH. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation 1998; 97: 2007-11.

5. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 200; 342: 836-43.

6. Danesh J, Wheeler JG, Hirschfield GM et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 2004; 350: 1387-97.

7. Libby P, Willerson JT, Braunwald E. C-reactive protein and coronary heart disease. N Engl. J Med 2004; 351: 295-6.

8. de Winter RJ, Koch KT, van Straalen JP et al. C-reactive protein and coronary events following percutaneous coronary angioplasty. Am J Med 2003; 115: 85-90.

9. Milazzo D, Biasucci LM, Luciani N et al. Elevated levels of C-reactive protein before coronary artery bypass grafting, predict recurrence of ischemic events. Am J Cardiol 1999; 84: 459-61.

10. Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a) and standard cholesterol screening as predictors of peripheral arterial disease. JAMA 2001; 285: 2481-5.

11. Di Napoli M, Papa F. Inflammation, hemostatic markers and antithrombotic agents in relation to long-term risk of new cardiovascular events in first-ever ischemic stroke patients. Stroke 2002; 33: 1763-71.

12. Tchernof A, Nolan A, Sites CK, Ades PA, Poehlman ET. Weightloss reduces C-reactive protein levels in obese postmenopausal women. Circulation 2002; 105: 564-9.

13. Haffner S, Temprosa M, Crandall J et al. Intensive lifestyle intervention or metformin on inflammation and coagulation in participants with impaired glucose tolerance. Diabetes 2005; 54: 1566-72.

14. Haffner MI. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 2002; 106: 679-84.

15. Ridker PM, Cannon CP, Morrow D et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005; 352: 20-8.

16. Nissen SE, Tuzcu EM, Schoenhagen P et al. Statin therapy, LDL cholesterol, C-reactive protein and coronary artery disease. N Engl J Med 2005;  352: 29-38.

17. Ridker PM, Rifai N, Clearfield M et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med 2001; 344: 1959-65.

18. Ridker PM. Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and designs of the JUPITER trial. Circulation 2003; 108: 2292-7.

 

VolumeNumber:

Vol5 N°15

Notes to editor


*Dr P. Poredoš and Dr M. Kaja Jezovnik
Ljubljana, Slovenia
Past chairperson of the Working Group on Peripheral Circulation

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.