Current Atherosclerosis Reports

, Volume 5, Issue 5, pp 341–349

C-reactive protein and risk of cardiovascular disease: Evidence and clinical application

  • Paul M. Ridker
  • Shari S. Bassuk
  • Peter P. Toth
Article

Abstract

Prospective epidemiologic data consistently show that elevated C-reactive protein (CRP) levels are associated with an increased risk of subsequent cardiovascular events in apparently healthy populations, and accumulating laboratory research is uncovering possible mechanisms by which CRP may influence the development of atherothrombotic disease. CRP is a stronger predictor of cardiovascular disease than is low-density lipoprotein (LDL) cholesterol. CRP adds prognostic information at all levels of the calculated Framingham risk score and at all levels of severity of the metabolic syndrome. Commercially available high-sensitivity assays suitable for use in clinical settings allow for the routine assessment of CRP as a useful adjunct in cardiovascular risk screening. When such assays are used, CRP levels of less than 1, 1 to 3, and greater than 3 mg/L differentiate patients at low, moderate, and high risk, respectively, for future cardiovascular events. Persons with high CRP but normal LDL cholesterol comprise a high-risk group frequently overlooked in clinical practice. Knowledge of their high-risk status may improve these patients’ compliance with recommended lifestyle changes that are likely to improve prognosis. Preliminary data suggest that individuals with elevated CRP but low LDL cholesterol may benefit from pharmacologic interventions, including statin therapy. Large-scale trials are underway to assess the net efficacy and public health impact of this approach to the primary prevention of myocardial infarction and stroke.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Geng YJ, Libby P: Progression of atheroma: a struggle between death and procreation. Arterioscler Thromb Vasc Biol 2002, 22:1370–1380.PubMedCrossRefGoogle Scholar
  2. 2.
    Libby P, Ridker PM, Maseri A: Inflammation and atherosclerosis. Circulation 2002, 105:1135–1143.PubMedCrossRefGoogle Scholar
  3. 3.
    Ridker PM: Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 2003, 107:363–369.PubMedCrossRefGoogle Scholar
  4. 4.
    Pasceri V, Cheng JS, Willerson JT, et al.: Modulation of C-reactive protein-mediated monocyte chemoattractant protein-1 induction in human endothelial cells by anti-atherosclerosis drugs. Circulation 2001, 103:2531–2534.PubMedGoogle Scholar
  5. 5.
    Pasceri V, Willerson JT, Yeh ET: Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation 2000, 102:2165–2168.PubMedGoogle Scholar
  6. 6.
    Zwaka TP, Hombach V, Torzewski J: C-reactive protein-mediated low density lipoprotein uptake by macrophages: implications for atherosclerosis. Circulation 2001, 103:1194–1197.PubMedGoogle Scholar
  7. 7.
    Wang CH, Li SH, Weisel RD, et al.: C-reactive protein upregulates angiotensin type 1 receptors in vascular smooth muscle. Circulation 2003, 107:1783–1790.PubMedCrossRefGoogle Scholar
  8. 8.
    Venugopal SK, Devaraj S, Yuhanna I, et al.: Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells. Circulation 2002, 106:1439–1441.PubMedCrossRefGoogle Scholar
  9. 9.
    Verma S, Wang CH, Li SH, et al.: A self-fulfilling prophecy: C-reactive protein attenuates nitric oxide production and inhibits angiogenesis. Circulation 2002, 106:913–919.PubMedCrossRefGoogle Scholar
  10. 10.
    Fichtlscherer S, Rosenberger G, Walter DH, et al.: Elevated C-reactive protein levels and impaired endothelial vasoreactivity in patients with coronary artery disease. Circulation 2000, 102:1000–1006.PubMedGoogle Scholar
  11. 11.
    Devaraj S, Xu DY, Jialal I: C-reactive protein increases plasminogen activator inhibitor-1 expression and activity in human aortic endothelial cells: implications for the metabolic syndrome and atherothrombosis. Circulation 2003, 107:398–404.PubMedCrossRefGoogle Scholar
  12. 12.
    Verma S, Li SH, Badiwala MV, et al.: Endothelin antagonism and interleukin-6 inhibition attenuate the proatherogenic effects of C-reactive protein. Circulation 2002, 105:1890–1896.PubMedCrossRefGoogle Scholar
  13. 13.
    Bhakdi S, Torzewski M, Klouche M, et al.: Complement and atherogenesis: binding of CRP to degraded, nonoxidized LDL enhances complement activation. Arterioscler Thromb Vasc Biol 1999, 19:2348–2354.PubMedGoogle Scholar
  14. 14.
    Torzewski J, Torzewski M, Bowyer DE, et al.: C-reactive protein frequently colocalizes with the terminal complement complex in the intima of early atherosclerotic lesions of human coronary arteries. Arterioscler Thromb Vasc Biol 1998, 18:1386–1392.PubMedGoogle Scholar
  15. 15.
    Yasojima K, Schwab C, McGeer EG, et al.: Generation of C-reactive protein and complement components in atherosclerotic plaques. Am J Pathol 2001, 158:1039–1051.PubMedGoogle Scholar
  16. 16.
    Ouchi N, Kihara S, Arita Y, et al.: Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages. Circulation 2001, 103:1057–1063.PubMedGoogle Scholar
  17. 17.
    Ouchi N, Kihara S, Funahashi T, et al.: Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue. Circulation 2003, 107:671–674.PubMedCrossRefGoogle Scholar
  18. 18.
    Blake GJ, Ridker PM: C-reactive protein and other inflammatory risk markers in acute coronary syndromes. J Am Coll Cardiol 2003, 41:37S-42S.PubMedCrossRefGoogle Scholar
  19. 19.
    Kuller LH, Tracy RP, Shaten J, et al.: Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Am J Epidemiol 1996, 144:537–547.PubMedGoogle Scholar
  20. 20.
    Ridker PM, Cushman M, Stampfer MJ, et al.: Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997, 336:973–979.PubMedCrossRefGoogle Scholar
  21. 21.
    Ridker PM, Cushman M, Stampfer MJ, et al.: Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease. Circulation 1998, 97:425–428.PubMedGoogle Scholar
  22. 22.
    Tracy RP, Lemaitre RN, Psaty BM, et al.: Relationship of C-reactive protein to risk of cardiovascular disease in the elderly. Results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler Thromb Vasc Biol 1997, 17:1121–1127.PubMedGoogle Scholar
  23. 23.
    Harris TB, Ferrucci L, Tracy RP, et al.: Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med 1999, 106:506–512.PubMedCrossRefGoogle Scholar
  24. 24.
    Koenig W, Sund M, Frohlich M, et al.: C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation 1999, 99:237–242.PubMedGoogle Scholar
  25. 25.
    Danesh J, Whincup P, Walker M, et al.: Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ 2000, 321:199–204.PubMedCrossRefGoogle Scholar
  26. 26.
    Gussekloo J, Schaap MC, Frohlich M, et al.: C-reactive protein is a strong but nonspecific risk factor for fatal stroke in elderly persons. Arterioscler Thromb Vasc Biol 2000, 20:1047–1051.PubMedGoogle Scholar
  27. 27.
    Mendall MA, Strachan DP, Butland BK, et al.: C-reactive protein: relation to total mortality, cardiovascular mortality and cardiovascular risk factors in men. Eur Heart J 2000, 21:1584–1590.PubMedCrossRefGoogle Scholar
  28. 28.
    Packard CJ, O’Reilly DS, Caslake MJ, et al.: Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. West of Scotland Coronary Prevention Study Group. N Engl J Med 2000, 343:1148–1155.PubMedCrossRefGoogle Scholar
  29. 29.
    Ridker PM, Hennekens CH, Buring JE, et al.: C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000, 342:836–843.PubMedCrossRefGoogle Scholar
  30. 30.
    Roivainen M, Viik-Kajander M, Palosuo T, et al.: Infections, inflammation, and the risk of coronary heart disease. Circulation 2000, 101:252–257.PubMedGoogle Scholar
  31. 31.
    Lowe GD, Yarnell JW, Rumley A, et al.: C-reactive protein, fibrin D-dimer, and incident ischemic heart disease in the Speedwell study: are inflammation and fibrin turnover linked in pathogenesis? Arterioscler Thromb Vasc Biol 2001, 21:603–610.PubMedGoogle Scholar
  32. 32.
    Ridker PM: High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation 2001, 103:1813–1818.PubMedGoogle Scholar
  33. 33.
    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, 344:1959–1965.PubMedCrossRefGoogle Scholar
  34. 34.
    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, 285:2481–2485.PubMedCrossRefGoogle Scholar
  35. 35.
    Rost NS, Wolf PA, Kase CS, et al.: Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham Study. Stroke 2001, 32:2575–2579.PubMedGoogle Scholar
  36. 36.
    Folsom AR, Aleksic N, Catellier D, et al.: C-reactive protein and incident coronary heart disease in the Atherosclerosis Risk In Communities (ARIC) study. Am Heart J 2002, 144:233–238.PubMedCrossRefGoogle Scholar
  37. 37.
    Ridker PM, Rifai N, Rose L, et al.: 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.PubMedCrossRefGoogle Scholar
  38. 38.
    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.PubMedCrossRefGoogle Scholar
  39. 39.
    Albert CM, Ma J, Rifai N, et al.: Prospective study of C-reactive protein, homocysteine, and plasma lipid levels as predictors of sudden cardiac death. Circulation 2002, 105:2595–2599.PubMedCrossRefGoogle Scholar
  40. 40.
    Sakkinen P, Abbott RD, Curb JD, et al.: C-reactive protein and myocardial infarction. J Clin Epidemiol 2002, 55:445–451.PubMedCrossRefGoogle Scholar
  41. 41.
    Curb JD, Abbott RD, Rodriguez BL, et al.: C-reactive protein and the future risk of thromboembolic stroke in healthy men. Circulation 2003, 107:2016–2020.PubMedCrossRefGoogle Scholar
  42. 42.
    Wilson PW, D’Agostino RB, Levy D, et al.: Prediction of coronary heart disease using risk factor categories. Circulation 1998, 97:1837–1847.PubMedGoogle Scholar
  43. 43.
    Albert MA, Danielson E, Rifai N, et al.: Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA 2001, 286:64–70.PubMedCrossRefGoogle Scholar
  44. 44.
    Ridker PM, Glynn 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, 97:2007–2011.PubMedGoogle Scholar
  45. 45.
    Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001, 285:2486–2497.CrossRefGoogle Scholar
  46. 46.
    Ridker PM, Buring JE, Cook NR, et al.: C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14,719 initially healthy American women. Circulation 2003, 107:391–397.PubMedCrossRefGoogle Scholar
  47. 47.
    Pradhan AD, Manson JE, Rifai N, et al.: C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001, 286:327–334.PubMedCrossRefGoogle Scholar
  48. 48.
    Freeman DJ, Norrie J, Caslake MJ, et al.: C-reactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study. Diabetes 2002, 51:1596–1600.PubMedCrossRefGoogle Scholar
  49. 49.
    Barzilay JI, Abraham L, Heckbert SR, et al.: The relation of markers of inflammation to the development of glucose disorders in the elderly: the Cardiovascular Health Study. Diabetes 2001, 50:2384–2389.PubMedCrossRefGoogle Scholar
  50. 50.
    Thorand B, Lowel H, Schneider A, et al.: C-reactive protein as a predictor for incident diabetes mellitus among middle-aged men: results from the MONICA Augsburg cohort study, 1984–1998. Arch Intern Med 2003, 163:93–99.PubMedCrossRefGoogle Scholar
  51. 51.
    Wanner C, Zimmerman J, Schwedler S, et al.: Inflammation and cardiovascular risk in dialysis patients. Kidney Int 2002, 61:S99-S102.CrossRefGoogle Scholar
  52. 52.
    Blake GJ, Ridker PM: C-reactive protein, subclinical atherosclerosis, and risk of cardiovascular events. Arterioscler Thromb Vasc Biol 2002, 22:1512–1513.PubMedCrossRefGoogle Scholar
  53. 53.
    Burke AP, Tracy RP, Kolodgie F, et al.: Elevated C-reactive protein values and atherosclerosis in sudden coronary death: association with different pathologies. Circulation 2002, 105:2019–2023.PubMedCrossRefGoogle Scholar
  54. 54.
    Ford ES, Giles WH, Myers GL, et al.: Population distribution of high-sensitivity C-reactive protein among US men: findings from National Health and Nutrition Examination Survey 1999–2000. Clin Chem 2003, 49:686–690.PubMedCrossRefGoogle Scholar
  55. 55.
    Herrington DM, Brosnihan KB, Pusser BE, et al.: Differential effects of E and droloxifene on C-reactive protein and other markers of inflammation in healthy postmenopausal women. J Clin Endocrinol Metab 2001, 86:4216–4222.PubMedCrossRefGoogle Scholar
  56. 56.
    Ridker PM, Rifai N, Pfeffer MA, et al.: Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1999, 100:230–235.PubMedGoogle Scholar
  57. 57.
    Rifai N, Buring JE, Lee IM, et al.: Is C-reactive protein specific for vascular disease in women? Ann Intern Med 2002, 136:529–533.PubMedGoogle Scholar
  58. 58.
    Blake GJ, Ridker PM, Kuntz KM: Projected life-expectancy gains with statin therapy for individuals with elevated C-reactive protein levels. J Am Coll Cardiol 2002, 40:49–55.PubMedCrossRefGoogle Scholar
  59. 59.
    Esposito K, Pontillo A, Di Palo C, et al.: Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial. JAMA 2003, 289:1799–804.PubMedCrossRefGoogle Scholar
  60. 60.
    Bazzano LA, He J, Muntner P, et al.: Relationship between cigarette smoking and novel risk factors for cardiovascular disease in the United States. Ann Intern Med 2003, 138:891–897.PubMedGoogle Scholar
  61. 61.
    Ridker PM, Rifai N, Lowenthal SP: Rapid reduction in C-reactive protein with cerivastatin among 785 patients with primary hypercholesterolemia. Circulation 2001, 103:1191–1193.PubMedGoogle Scholar
  62. 62.
    Kinlay S, Timms T, Clark M, et al.: Comparison of effect of intensive lipid lowering with atorvastatin to less intensive lowering with lovastatin on C-reactive protein in patients with stable angina pectoris and inducible myocardial ischemia. Am J Cardiol 2002, 89:1205–1207.PubMedCrossRefGoogle Scholar
  63. 63.
    Ridker PM, Rifai N, Pfeffer MA, et al.: Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1998, 98:839–844.PubMedGoogle Scholar
  64. 64.
    Ridker PM: Should statin therapy be considered for patients with elevated C-reactive protein? The need for a definitive clinical trial. Eur Heart J 2001, 22:2135–2137.PubMedCrossRefGoogle Scholar
  65. 65.
    Chew DP, Bhatt DL, Robbins MA, et al.: Effect of clopidogrel added to aspirin before percutaneous coronary intervention on the risk associated with C-reactive protein. Am J Cardiol 2001, 88:672–674.PubMedCrossRefGoogle Scholar
  66. 66.
    Lincoff AM, Kereiakes DJ, Mascelli MA, et al.: Abciximab suppresses the rise in levels of circulating inflammatory markers after percutaneous coronary revascularization. Circulation 2001, 104:163–167.PubMedGoogle Scholar
  67. 67.
    Haffner SM, Greenberg AS, Weston WM, et al.: Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 2002, 106:679–684.PubMedCrossRefGoogle Scholar
  68. 68.
    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.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2003

Authors and Affiliations

  • Paul M. Ridker
    • 1
  • Shari S. Bassuk
    • 1
  • Peter P. Toth
    • 1
  1. 1.Center for Cardiovascular Disease PreventionBrigham and Women’s HospitalBostonUSA

Personalised recommendations