Skip to main content
NCBI home page
Clinical Cardiology logoLink to Clinical Cardiology
. 2007 Jul 5;26(Suppl 3):39–44. doi: 10.1002/clc.4960261508

Connecting the role of C‐reactive protein and statins in cardiovascular disease

Paul M Ridker 1,✉
PMCID: PMC6653849  PMID: 12708638

Abstract

The observation that almost half of all myocardial infarctions and strokes occur in persons without elevated levels of low‐density lipoprotein cholesterol has prompted the study of factors other than hyperlipidemia that contribute to the development of atherosclerosis. A growing body of evidence indicates that inflammation plays a substantial role in plaque progression and rupture. Research interest has increasingly focused on biomarkers of inflammation as a means of predicting more accurately which patients are at high risk for cardiovascular disease (CVD). Clinical studies indicate that C‐reactive protein (CRP), a marker of systemic inflammation, independently predicts cardiovascular risk in healthy persons as well as in persons with established CVD and those with acute ischemia. 3‐Hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors, or statins, have been shown to reduce levels of CRP through mechanisms independent of their effects on lipid levels. Initial clinical studies also suggest that CRP levels may have utility in the targeting of statin therapy, particularly in primary prevention. These results need direct testing in large, prospective clinical trials to determine whether statin therapy will benefit persons without overt hyperlipidemia but with evidence of systemic inflammation. Confirmation of these preliminary findings, if incorporated into evidence‐based guidelines, may profoundly change the approach to diagnosis and treatment of CVD.

Keywords: biomarkers, C‐reactive protein, high‐density lipoprotein cholesterol, 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibition, hyperlipidemia, low‐density lipoprotein cholesterol, myocardial infarction, statin

Full Text

The Full Text of this article is available as a PDF (75.2 KB).

References

  • 1. Braunwald E: Shattuck Lecture—Cardiovascular medicine at the turn of the millennium: Triumphs, concerns, and opportunities. N Engl J Med 1997; 337: 1360–1369 [DOI] [PubMed] [Google Scholar]
  • 2. Castelli WP: Lipids, risk factors and ischaemic heart disease. Atherosclerosis 1996; 124 (suppl): S1–S9 [DOI] [PubMed] [Google Scholar]
  • 3. 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). J Am Med Assoc 2001; 285: 2486–2497 [DOI] [PubMed] [Google Scholar]
  • 4. Ross R: Atherosclerosis: An inflammatory disease. N Engl J Med 1999; 340: 115–126 [DOI] [PubMed] [Google Scholar]
  • 5. 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 [DOI] [PubMed] [Google Scholar]
  • 6. Scandinavian Simvastatin Survival Study Group : Randomised trial of cholesterol lowering in 4,444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383–1389 [PubMed] [Google Scholar]
  • 7. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr., for the AFCAPS/TexCAPS Research Group : Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. Results of AFCAPS/TexCAPS. J Am Med Assoc 1998; 279: 1615–1622 [DOI] [PubMed] [Google Scholar]
  • 8. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995; 333: 1301–1307 [DOI] [PubMed] [Google Scholar]
  • 9. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH: Plasma concentration of interleukin‐6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000; 101; 1767–1772 [DOI] [PubMed] [Google Scholar]
  • 10. Ridker PM, Buring JE, Rifai N: Soluble P‐selectin and the risk of future cardiovascular events. Circulation 2001; 103: 491–495 [DOI] [PubMed] [Google Scholar]
  • 11. Ridker PM, Hennekens CH, Roitman‐Johnson B, Stampfer MJ, Allen J: Plasma concentrations of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men. Lancet 1998; 351: 88–92 [DOI] [PubMed] [Google Scholar]
  • 12. Schonbeck U, Varo N, Libby P, Buring J, Ridker PM: Soluble CD40L and cardiovascular risk in women. Circulation 2001; 104: 2266–2268 [DOI] [PubMed] [Google Scholar]
  • 13. 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 [DOI] [PubMed] [Google Scholar]
  • 14. Koenig W, Sund M, Frohlich M, Fischer HG, Lowel H, Doring A, Hutchinson WL, Pepys MB, for the MRFIT Research Group : Relationship of C‐reactive protein and coronary heart disease in the MRFIT nested case‐control study. Am J Epidemiol 1996; 144: 537–547 8797513 [Google Scholar]
  • 15. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH: Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336: 973–979 [DOI] [PubMed] [Google Scholar]
  • 16. Tracy RP, Lemaitre RN, Psaty BM, Ives DG, Evans RW, Cushman M, Meilahn EN, Kuller LH: 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 [DOI] [PubMed] [Google Scholar]
  • 17. 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; 98: 731–733 [DOI] [PubMed] [Google Scholar]
  • 18. Koenig W, Sund M, Frohlich M, Fischer HG, Lowel H, Doring A, Hutchinson WL, Pepys MB: 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) Augsberg Cohort Study, 1984 to 1992. Circulation 1999; 99: 237–242 [DOI] [PubMed] [Google Scholar]
  • 19. Roivainen M, Viik‐Kajander M, Palosuo T, Toivanen P, Leinonen M, Saikku P, Tenkanen L, Manninen V, Hovi T, Manttari M: Infections, inflammation, and the risk of coronary heart disease. Circulation 2000; 101; 252–257 [DOI] [PubMed] [Google Scholar]
  • 20. Harris TB, Ferrucci L, Tracy RP, Corti MC, Wacholder S, Ettinger WH Jr, Heimovitz H, Cohen HJ, Wallace R: Associations of elevated interleukin‐6 and C‐reactive protein levels with mortality in the elderly. Am J Med 1999; 106: 506–512 [DOI] [PubMed] [Google Scholar]
  • 21. Danesh J, Whincup P, Walker M, Lennon L, Thomson A, Appleby P, Gallimore JR, Pepys MB: Low grade inflammation and coronary heart disease: Prospective study and updated meta‐analysis. Br Med J 2000; 321: 199–204 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Mendall MA, Strachan DP, Butland BK, Ballam L, Morris J, Sweetnam PM, Elwood PC: C‐reactive protein: Relation to total mortality, cardiovascular mortality and cardiovascular risk factors in men. Eur Heart J 2000; 21: 1584–1590 [DOI] [PubMed] [Google Scholar]
  • 22a. 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 [DOI] [PubMed] [Google Scholar]
  • 23. 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 [DOI] [PubMed] [Google Scholar]
  • 24. Lindmark E, Diderholm E, Wallentin L, Siegbahn A: Relationship between interleukin 6 and mortality in patients with unstable coronary artery disease: Effects of an early invasive or noninvasive strategy. J Am Med Assoc 2001; 286: 2107–2113 [DOI] [PubMed] [Google Scholar]
  • 25. Chew DP, Bhatt DL, Robbins MA, Penn MS, Schneider JP, Lauer MS, Topol EJ, Ellis SG: Incremental prognostic value of elevated baseline C‐reactive protein among established markers of risk in percutaneous coronary intervention. Circulation 2001; 28: 104: 992–997 [DOI] [PubMed] [Google Scholar]
  • 25a. Ridker PM, Buring JE, Cook NR, Rifai N: 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 [DOI] [PubMed] [Google Scholar]
  • 25b. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM: C‐reactive protein, interleukin‐6, and the risk of developing type 2 diabetes mellitus. JAMA 2001; 286: 327–334 [DOI] [PubMed] [Google Scholar]
  • 26. Libby P: Current concepts of the pathogenesis of the acute coronary syndromes. Circulation 2001; 17: 365–372 [DOI] [PubMed] [Google Scholar]
  • 27. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T, for the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators : Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: The MIRACL study: A randomized controlled trial. J Am Med Assoc 2001; 285; 1711–1718 [DOI] [PubMed] [Google Scholar]
  • 28. Stenestrand U, Wallentin L, for the Swedish Register of Cardiac Intensive Care (RIKS‐HIA) : Early statin treatment following acute myocardial infarction and 1‐year survival. J Am Med Assoc 2001; 285: 430–436 [DOI] [PubMed] [Google Scholar]
  • 29. Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E: Long‐term effects of pravastatin on plasma concentration of C‐reactive protein: The Cholesterol and Recurrent Events (CARE) investigators. Circulation 1999; 100: 230–235 [DOI] [PubMed] [Google Scholar]
  • 30. Albert M, Danielson E, Rifai N, Ridker PM, PRINCE Investigators: Effect of statin therapy on C‐reactive protein levels: The pravastatin inflammation/CRP evaluation (PRINCE): A randomized trial and cohort study. J Am Med Assoc 2001; 286: 64–70 [DOI] [PubMed] [Google Scholar]
  • 31. Ridker PM, Rifai N, Clearfield M, Downs JR, Weis SE, Miles S, Gotto AM Jr, for the Air Force/Texas Coronary Atherosclerosis Prevention Study Investigators : 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 [DOI] [PubMed] [Google Scholar]
  • 32. 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 [DOI] [PubMed] [Google Scholar]
  • 33. Jialal I, Stein D, Balis D, Grundy S, Adams‐Huet B, Devaraj S: Effect of hydroxymethyl glutaryl coenzyme A reductase inhibitor therapy on high sensitive C‐reactive protein levels. Circulation 2001; 103: 1933–1935 [DOI] [PubMed] [Google Scholar]
  • 34. Ridker PM, Rifai N, Pfeffer MA, Sacks FM, Moyé LA, Goldman S, Flaker GC, Braunwald E: 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 [DOI] [PubMed] [Google Scholar]
  • 34a. Ridker PM: Clinical application of C‐reactive protein for cardiovascular disease detection and prevention. Circulation 2003; 107: 363–369 [DOI] [PubMed] [Google Scholar]

Articles from Clinical Cardiology are provided here courtesy of Wiley

RESOURCES