C-Reactive Protein


Vol. 7 •Issue 11 • Page 29
C-Reactive Protein

Inflammatory marker or predictor of outcomes

Inflammation is the normal protective process by the human body in response to external or internal triggers. Over the past decade, many mysteries of the human inflammatory response have been unraveled, including the fact that numerous biochemical mediator substances are involved.

Each of these has an interactive role in the process that defines inflammation. Some of these substances have been studied for use as predictors of disease processes. One of these is C-reactive protein (CRP).

CRP in Inflammation

The process of atherosclerotic plaque development begins with risk factors that promote endothelial cell damage within the vessel wall, such as cigarette smoking, hypertension, atherogenic lipoproteins and hyperglycemia.1

These factors give rise to noxious stimuli that cause release of monocytes, which migrate to the subintimal space, transform into macrophages and, along with lipoproteins, create the fatty streak thought to be responsible for plaque formation. Further cell wall injury within the vessel attracts mast cells, macrophages and activated T cells, which adhere and increase plaque size.

Activated enzymes and other substances may weaken the atherosclerotic plaque cap, making it prone to rupture.1 The ruptured core exposes it to blood, which promotes thrombosis. Proinflammatory cytokines, various interleukins and tumor necrosis factor-alpha are bioactive substances involved throughout this process.

Proinflammatory substances and cytokines from adipose tissue stimulate liver hepatocytes to produce acute phase reactants such as C-reactive protein. This causes a rise in plasma CRP levels.2 CRP is a marker of inflammation and may contribute to the pathogenesis of an atherosclerotic lesion.3

It has been speculated that an elevated CRP level may be a marker of cardiovascular risk because of the relationship between adipose tissue, insulin resistance and dyslipidemia, hallmarks of the metabolic syndrome.2 Though CRP has been indicated in the inflammatory process, the value of elevated levels of this marker as a predictor of cardiac disease remains controversial.

CRP as a Disease Predictor

Cardiovascular disease continues to be the leading cause of death in the United States. The ability to accurately diagnose cardiac processes, from angina to ischemic heart disease, through the use of biochemical markers has not been perfected. Researchers continue to look for the one marker that can be used to predict cardiac disease and associated outcomes. No single marker alone has been shown to be definitive.

Recently, it has become a practice at some institutions to obtain blood samples for CRP levels in patients with symptoms of cardiac disease. Since elevated CRP levels may be due to acute or chronic inflammatory states, high sensitivity CRP (hs-CRP) assay tests are available to help determine risk of cardiac disease. In patients with acute myocardial injury, production of CRP levels occurs within 4-6 hours of symptoms and peaks in 48-72 hours.4

In 2003, the American Heart Association (AHA) in conjunction with the CDC issued a scientific statement related to the use of CRP and other inflammatory markers in predicting cardiovascular disease. The evidence available indicated it was reasonable to measure hs-CRP levels in adults with major risk factors to assess absolute risk for cardiac disease primary prevention strategies.1 The statement also concluded that hs-CRP levels may be useful in determining the likelihood of recurrent cardiac events, including death, myocardial infarction and restenosis after percutaneous coronary intervention in patients with stable coronary disease.1 The statement did not recommend widespread hs-CRP screening of adult populations for risk stratification.

The AHA/CDC statement denotes values of CRP to assist in risk determination. If the hs-CRP is less than 1.0 mg/L it can be postulated that a person is at low risk for developing cardiovascular disease. A hs-CRP level between 1.0 and 3.0 mg/L has been linked to an average risk, while a level greater than 3.0 mg/L has been associated with a high risk of developing cardiovascular disease.5 These results should be evaluated in the context of other risk factors related to cardiac disease.

Questions Still Remain

Research published after the AHA/CDC statement has questioned the utility of hs-CRP values in predicting cardiac disease. One study has shown that in regard to established high-risk factors, such as elevated cholesterol and cigarette smoking, CRP values are only moderate predictors of cardiac disease and add little to the predictive value of established risk factors.6

High hs-CRP levels have been correlated with large myocardial infarct size.4 Often, this is associated with higher mortality. Is it the infarct size alone or the hs-CRP level that determines mortality? Or is it the combination of the two values? The relationship between CRP levels and the degree of myocardial necrosis suggest these levels may reflect the inflammatory response to myocardial injury.

The use of CRP levels alone has not shown conclusive predictive value for cardiovascular disease or its sequela.

Evaluation of risk factors remains the standard for predicting cardiovascular disease. Non-modifiable risk factors such as age, gender and family history of cardiovascular events are important considerations when evaluating patients at risk. Modifiable risks and behaviors such as hypertension, diabetes, tobacco and alcohol use, inactivity, obesity and cholesterol management along with stress reduction techniques should be targeted in initial assessments. The greater the number of risk factors, including age adjustments, the greater the risk of developing cardiovascular disease. Primary prevention strategies addressing modifiable risks, education and behavioral changes are first-line therapies used to prevent cardiovascular events.

CRP Levels as Predictors of Mortality

One study associated higher CRP levels after myocardial injury to increases in 30-day mortality and the development of heart failure. But these values do not predict future recurrent infarction.4 High levels of CRP in patients with unstable angina may reflect atherosclerotic plaque instability. This has possible significance in assessing for future cardiac events. Serial CRP levels may be valuable in determining risk progression. With further research, CRP levels may be of importance in evaluating heart failure outcomes.

CRP values alone are markers of inflammation. Elevation of CRP levels should be evaluated in the face of acute illness and infectious processes. Future research reviewing its relationship to other inflammatory markers, risk factors and treatment strategies may hold more promising value in predicting cardiac disease. CRP in relation to age, gender and treatment strategies may be a more useful tool in determining progressive cardiovascular risk.

Alternative approaches in evaluating CRP may look at how to decrease levels of CRP and determine the effect on cardiovascular status. Use of multivitamin therapy has been shown to decrease CRP levels.7 Researchers are evaluating the effect of statin therapy on lowering CRP levels.

The clinical effect on cardiac risk determination and outcomes remains to be determined. Continued research on the utility of CRP levels in assessing risks, outcomes and mortality associated with cardiac events may guide future therapies to prevent heart disease.

References

1. Pearson, T., et al. (2003). Markers of inflammation and cardiovascular disease: Application to clinical and public health practice: A statement for healthcare professionals from the CDC and the American Heart Association. Circulation, 107(3), 499-511.

2. Tall, A.R. (2004). C-reactive protein reassessed. The New England Journal of Medicine, 350(14), 1450-1452.

3. Pai, J., et al. (2004). Inflammatory markers and the risk of coronary heart disease in men and women. The New England Journal of Medicine, 351(25), 2599-2610.

4. Sulieman, M., et al. (2003). Admission C-reactive protein levels and 30-day mortality in patients with acute myocardial infarction. American Journal of Medicine, 115(9), 695-701.

5. American Heart Association. (2005). Inflammation, heart disease and stroke: the role of CRP. Retrieved March 11, 2005 from the World Wide Web: http://www.americanheart.org/presenter.jhtml?identifier=4648

6. Danesh, J., et al. (2004). C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. The New England Journal of Medicine, 350(14), 1387-1397.

7. Church, T., et al. (2003). Reduction of c-reactive protein levels through use of a multivitamin. American Journal of Medicine, 115(9), 702-707.

Sue Durkin is a clinical nurse specialist in the critical care unit, Advocate Good Samaritan Hospital, Downers Grove, IL. She wishes to thank Barbara Gulczynski, APN, NP, CNS, for her review of this article.

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