You’ve already learned about traditional risk factors for cardiovascular disease. In this edition of Know Her Heart, you’ll learn about the role of the inflammatory marker C-reactive protein (CRP) in risk assessment and about factors that influence CRP levels, such as race, sex, use of hormone replacement therapy, and exercise.

What Can CRP Tell You About Her Heart?
Elevated CRP is a marker of inflammation that can arise from a number of causes, including autoimmune conditions (rheumatoid arthritis, Reiter’s syndrome, lupus, polymyalgia rheumatica), lymphoma, and bacterial, viral, fungal, or parasitic infections. Increasingly, CRP level is being recognized as a predictor of cardiovascular disease.1-5 In recent years, studies have demonstrated that elevated CRP levels are a strong independent marker for cardiovascular disease in women.2-4

The Centers for Disease Control and Prevention (CDC) and the American Heart Association (AHA) support the use of CRP testing if the results of the test will guide considerations for further evaluation or therapy (SOR: C).6 Their clinical practice recommendations state that CRP testing may benefit patients without known cardiovascular disease but whose major cardiovascular risk factors put them at a 10% to 20% risk of coronary heart disease (CHD) over 10 years (intermediate risk).6 CRP levels should be evaluated in conjunction with traditional risk factors (obesity, diabetes, hyperlipidemia, cigarette smoking), rather than as an alternative measure for risk assessment.6



Significantly Elevated Risk

  • In a study of women 45 years or older with no prior history of disease, those with the highest levels of CRP had a more than 5-times increased risk for cardiovascular disease than those with the lowest CRP levels.2
  • In another study of apparently healthy women, those with CRP levels greater than or equal to 7.3 mg/L were at more than 7-fold increased risk for suffering a myocardial infarction or stroke.3
  • Of 12 markers measured in healthy postmenopausal women, CRP level was a strong predictor of risk for cardiovascular events—even stronger than cholesterol levels.4

Sex, Race, and CRP Levels

Recently, it has been reported that significant race and gender differences exist in the population distribution of elevated CRP levels1:

African American women—a population found to be at greater cardiovascular risk than other groups7—had the highest prevalence of elevated CRP levels (58%).1


Modulating CRP Levels: HRT and Exercise

Studies have demonstrated an association between hormone replacement therapy (HRT) and elevated CRP levels.8 However, the clinical importance of this association is still being examined.

  • Among women receiving HRT, those with the highest CRP levels had a 2-fold higher risk for CHD events than those with the lowest CRP levels.8
  • Among women with comparable baseline CRP levels, risk was similar between those taking and not taking HRT.8
Exercise appears to have an attenuating effect on CRP levels in women who are using HRT9:

  • HRT-related elevations in CRP were present in sedentary women but not in those who engage in regular exercise.
  • CRP levels were approximately 65% lower in physically active women compared with sedentary women, regardless of HRT status.


CRP Testing and Clinical Practice

According to CDC/AHA recommendations, CRP testing of intermediate-risk patients, when used in conjunction with an assessment of traditional risk factors, can provide “additional information to guide considerations of further evaluation (eg, imaging, exercise testing) or therapy (eg, drug therapies with lipid-lowering, antiplatelet, or cardioprotective agents)…”6

  • Women with elevated CRP levels may require diagnostic testing for CHD, which is commonly done with electrocardiography or myocardial perfusion imaging (MPI).

    • Exercise is the preferred method of inducing stress for MPI; however, a number of cross-sectional studies have noted an inverse association between physical activity and CRP levels.10-12 If patients are unable to exercise sufficiently for testing, they may be candidates for pharmacologic stress testing.13
  • Measuring CRP levels can be useful when considering pharmacologic therapy for women with a low-to-moderate risk lipid profile. CRP levels can help distinguish between high and low risk of cardiovascular events among women with low-density lipoprotein cholesterol (LDL-C) less than 130 mg/dL.4 This has the important implication that CRP testing may improve identification of women who will benefit from statin therapy for primary prevention, regardless of LDL-C levels.



References
1. Khera A, McGuire DK, Murphy SA, et al. Race and gender differences in C-reactive protein levels. J Am Coll Cardiol. 2005;46:464-469. 2. Rifai N, Buring JE, Lee I-M, Manson JE, Ridker PM. Is C-reactive protein specific for vascular disease in women? Ann Intern Med. 2002;136:529-533. 3. Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation. 1998:731-733. 4. 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. 2000;342:836-843. 5. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347:1557-1565. 6. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107:499-511. 7. American Heart Association. Heart Disease and Stroke Statistics—2006 Update. Dallas, Tex: American Heart Association; 2006. 8. Pradhan AD, Manson JE, Rossouw JE, et al. Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: prospective analysis from the Women’s Health Initiative observational study. JAMA. 2002;288:980-987. 9. Stauffer BL, Hoetzer GL, Smith DT, DeSouza CA. Plasma C-reactive protein is not elevated in physically active postmenopausal women taking hormone replacement therapy. J Appl Physiol. 2004;96:143-148. 10. Taaffe DR, Harris TB, Ferrucci L, Rowe J, Seeman TE. Cross-sectional and prospective relationships of interleukin-6 and C-reactive protein with physical performance in elderly persons: MacArthur studies of successful aging. J Gerontol A Biol Sci Med Sci. 2000;55A:M709-M715.. 11. Geffken DF, Cushman M, Burke GL, Polak JF, Sakkinen PA, Tracy RP. Association between physical activity and markers of inflammation in a healthy elderly population. Am J Epidemiol. 2001;153:242-250. 12. Ford ES. Does exercise reduce inflammation? Physical activity and C-reactive protein among U.S. adults. Epidemiology. 2002;13:561-568. 13. Gulati M, McBride PE. Functional capacity and cardiovascular assessment: submaximal exercise testing and hidden candidates for pharmacologic stress. Am J Cardiol. 2005;96(suppl):11J-19J.