Current Atherosclerosis Reports

, Volume 9, Issue 1, pp 33–41

Statins and biomarkers of inflammation



Clinical and epidemiologic studies convincingly demonstrate that increased levels of low-density lipoprotein cholesterol promote premature atherosclerosis. Several large clinical trials have demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) decrease cardiovascular events. The beneficial effects of statins may extend to mechanisms beyond cholesterol reduction. Evidence for the pleiotropic effects of statins is provided by recent clinical trials in which the benefit of statin drugs is manifest early in the course of lipid-lowering therapy, well before plaque regression could occur. Inflammation is pivotal in all stages of atherosclerosis, and C-reactive protein (CRP), the prototypic marker of inflammation, has emerged as a cardiovascular risk marker. Statins reduce CRP levels, and this reduction in most studies does not correlate to reduction in cholesterol. In addition, statins have beneficial effects on endothelial function, monocytemacrophages, and platelets. In this review we discuss the role of inflammation in atherosclerosis, the role of CRP as a risk marker, the clinical evidence implicating the anti-inflammatory effects of statins, and the cellular and molecular basis underlying the anti-inflammatory effects of statins.


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References and Recommended Reading

  1. 1.
    Gordon T, Kannel WB: Premature mortality from coronary heart disease: the Framingham Study. JAMA 1971, 215:1617–1625.PubMedCrossRefGoogle Scholar
  2. 2.
    Iso H, Jacobs DR Jr, Wentworth D, et al.: Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. N Engl J Med 1989, 320:904–910.PubMedCrossRefGoogle Scholar
  3. 3.
    Pedersen TR, Kjekshus J, Berg K, et al.: Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994, 344:1383–1389.CrossRefGoogle Scholar
  4. 4.
    LIPID Study Group: Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels: the Long-Term Intervention With Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1988, 339:1349–1357.Google Scholar
  5. 5.
    Sacks FM, Pfeffer MA, Moye LA, et al.: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels: Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996, 335:1001–1009.PubMedCrossRefGoogle Scholar
  6. 6.
    Shepherd J, Cobbe SM, Ford I, et al.: 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.PubMedCrossRefGoogle Scholar
  7. 7.
    Packard CJ: Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation 1998, 97:1440–1445.Google Scholar
  8. 8.
    Ridker PM, Rifai N, Pfefffer MA: 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
  9. 9.
    Kinlay S, Schwartz GG, Olsson AG, et al.: Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering Study Investigators. High-dose atorvastatin enhances the decline in inflammatory markers in patients with acute coronary syndromes in the MIRACL study. Circulation 2003, 108:1560–1566.PubMedCrossRefGoogle Scholar
  10. 10.
    Ridker PM, Cannon CP, Morrow D, et al.: Pravastatin or Atorvastatin Evaluation and Infection Therapy-Throm-bolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) Investigators. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005, 352:20–28.PubMedCrossRefGoogle Scholar
  11. 11.
    Nissen SE, Tuzcu EM, Schoenhagen P, et al.: Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) Investigators. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005, 352:29–38.PubMedCrossRefGoogle Scholar
  12. 12.
    Libby P: Inflammation in atherosclerosis. Nature 2002, 420:868–874.PubMedCrossRefGoogle Scholar
  13. 13.
    Jialal I, Devaraj S: Inflammation and atherosclerosis: the value of the high-sensitivity C-reactive protein assay as a risk marker. Am J Clin Pathol 2001, 116(Suppl):S108-S115.PubMedGoogle Scholar
  14. 14.
    Jialal I, Devaraj S: Role of C-reactive protein in the assessment of cardiovascular risk. Am J Cardiol 2003, 91:200–202.PubMedCrossRefGoogle Scholar
  15. 15.
    Rifai N, Ridker OM: HsCRP—a novel and promising marker of CHD. Clin Chem 2001, 47:403–411.PubMedGoogle Scholar
  16. 16.
    Verma S, Devaraj S, Jialal I: Is C-reactive protein an innocent bystander or proatherogenic culprit? C-reactive protein promotes atherothrombosis. Circulation 2006, 113:2135–2150.PubMedGoogle Scholar
  17. 17.
    Ridker PM, Glynn RJ, Hennekens CH: CRP adds to the predictive value of total and HDL cholesterol in determining risk of first MI. Circulation 1998, 97:2007–2011.PubMedGoogle Scholar
  18. 18.
    Ridker PM, Hennekens CH, Buring JE, et al.: CRP and other markers of inflammation in the prediction of CAD in women. N Engl J Med 2000, 342:836–843.PubMedCrossRefGoogle Scholar
  19. 19.
    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
  20. 20.
    Cushman M, Arnold AM, Psaty BM, et al.: C-reactive protein and the 10-year incidence of coronary heart disease in older men and women: the Cardiovascular Health Study. Circulation 2005, 112:25–31.PubMedCrossRefGoogle Scholar
  21. 21.
    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
  22. 22.
    Ridker PM, Rifai N, Pfeffer MA, et al.: Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation 1999, 100:230–235.PubMedGoogle Scholar
  23. 23.
    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
  24. 24.
    Jialal I, Stein D, Balis D, et al.: Effect of hydroxymethyl glutaryl coenzyme A reductase inhibitor therapy on high sensitive C-reactive protein levels. Circulation 2001, 103:1933–1935.PubMedGoogle Scholar
  25. 25.
    Miller M, Jialal I: Effects of simvastation (40 and 80 mg) on highly sensitive C-reactive protein in patients with combined hyperlipidemia. Am J Cardiol 2001, 89:468–469.CrossRefGoogle Scholar
  26. 26.
    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
  27. 27.
    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
  28. 28.
    Tan KC, Chow WS, Tam SC, et al.: Atorvastatin lowers C-reactive protein and improves endothelium-dependent vasodilation in type 2 diabetes mellitus. J Clin Endocrinol Metab 2002, 87:563–568.PubMedCrossRefGoogle Scholar
  29. 29.
    Van de Ree MS, Huisman MV, Princen HM, et al.: Strong decrease of hsCRP with high dose atorvastatin in patients with type 2 diabetes mellitus. Atherosclerosis 2003, 166:129–135.PubMedCrossRefGoogle Scholar
  30. 30.
    Horne BD, Muhlestein JB, Carlquist JF, et al.: Statin therapy, lipid levels, C-reactive protein and the survival of patients with angiographically severe CAD. J Am Coll Cardiol 2000, 36:1774–1780.PubMedCrossRefGoogle Scholar
  31. 31.
    Reisen WF, Engler H, Risch M, et al.: Short term effects of atorvastatin on CRP. Eur Heart J 2002, 23:794–799.CrossRefGoogle Scholar
  32. 32.
    van Wissen S, Trip MD, Smilde TJ, et al.: Differential hsCRP reduction in patients with familial hypercholesterolemia treated with aggressive or conventional statin therapy. Atherosclerosis 2002, 165:361–366.PubMedCrossRefGoogle Scholar
  33. 33.
    Taylor AJ, Kent SM, Flaherty PJ, et al.: ARBITER: Arterial biology for the investigation of treatment effects of reducing cholesterol. Circulation 2002, 106:2055–2060.PubMedCrossRefGoogle Scholar
  34. 34.
    Cortellaro M, Cofrancesco E, Boschetti C, et al.: Effects of fluvastatin and bezafibrate combination on plasma fibrinogen, tPA and CRP in CAD patients with mixed hyperlipidemia (FACT Study). Thromb Hemost 2000, 83:549–553.Google Scholar
  35. 35.
    de Lemos JA, Blazing MA, Wiviott SD, et al.: Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 2004, 292:1307–1316.PubMedCrossRefGoogle Scholar
  36. 36.
    Morrow DA, deLemos JA, Sabatine MS, et al.: Clinical relevance of C-reactive protein during follow-up of patients with acute coronary syndromes in the Aggrastat-to-Zocor Trial. Circulation 2006 114:281–288.PubMedCrossRefGoogle Scholar
  37. 37.
    Wilson SH, Simari RD, Best PJ, et al.: Simvastatin preserves coronary endothelial function in hypercholesterolemia in the absence of lipid lowering. Arterioscler Thromb Vasc Biol 2001, 21:122–128.PubMedGoogle Scholar
  38. 38.
    Sukhova GK, Williams JK, Libby P: Statins reduce inflammation in atheroma of nonhuman primates independent of effects on serum cholesterol. Arterioscler Thromb Vasc Biol 2002, 22:1452–1458.PubMedCrossRefGoogle Scholar
  39. 39.
    Dupuis J, Tardif JC, Cernacek P, et al.: Cholesterol reduction rapidly improves endothelial function after acute coronary syndromes. The RECIFE (reduction of cholesterol in ischemia and function of the endothelium) trial. Circulation 1999, 99:3227–3233.PubMedGoogle Scholar
  40. 40.
    Tamai O, Matsuoka H, Itabe H, et al.: Single LDL apheresis improves endothelium-dependent vasodilatation in hypercholesterolemic humans. Circulation 1997, 95:76–82.PubMedGoogle Scholar
  41. 41.
    Kinlay S, Libby P, Ganz P: Endothelial function and coronary artery disease. Curr Opin Lipidol 2001, 12:383–389.PubMedCrossRefGoogle Scholar
  42. 42.
    Egashira K, Hirooka Y, Kai H, et al.: Reduction in serum cholesterol with pravastatin improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia. Circulation 1994, 89:2519–2524.PubMedGoogle Scholar
  43. 43.
    Treasure CB, Klein JL, Weintraub WS, et al.: Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med 1995, 332:481–487.PubMedCrossRefGoogle Scholar
  44. 44.
    Fabian E, Varga A: Effect of simvastatin therapy on endothelial function of hypercholesteremic patients with syndrome X. Orv Hetil 2002, 143:2067–2071.PubMedGoogle Scholar
  45. 45.
    Liao JK: Beyond lipid lowering: the role of statins in vascular protection. Int J Cardiol 2002, 86:5–18.PubMedCrossRefGoogle Scholar
  46. 46.
    O’Driscoll G, Green D, Taylor RR: Simvastatin, an HMG-coenzyme: a reductase inhibitor, improves endothelial function within 1 month. Circulation 1997, 95:1126–1131.PubMedGoogle Scholar
  47. 47.
    Koh KK: Effects of statins on vascular wall: vasomotor function, inflammation, and plaque stability. Cardiovasc Res 2000, 47:648–657.PubMedCrossRefGoogle Scholar
  48. 48.
    Niwa S, Totsuka T, Hayashi S: Inhibitory effect of fluvastatin, an HMG-CoA reductase inhibitor, on the expression of adhesion molecules on human monocyte cell line. Int J Immunopharmacol 1996, 18:669–675.PubMedCrossRefGoogle Scholar
  49. 49.
    Weitz-Schmidt G, Welzenbach K, Brinkmann V, et al.: Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med 2001, 7:687–692.PubMedCrossRefGoogle Scholar
  50. 50.
    Serrano CV, Yoshida VM, Venturinelli ML, et al.: Effect of simvastatin on monocytes adhesion molecule expression in patients with hypercholesterolemia. Atherosclerosis 2001, 157:505–512.PubMedCrossRefGoogle Scholar
  51. 51.
    Weber C, Erl W, Weber PC: HMGCoA reductase inhibitors decrease CD11b expression and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia. J Am Coll Cardiol 1997, 30:1212–1217.PubMedCrossRefGoogle Scholar
  52. 52.
    Ferro D, Parrotto S, Basili S, et al.: Simvastatin inhibits the monocyte expression of proinflammatory cytokines in patients with hypercholesterolemia. J Am Coll Cardiol 2000, 36:427–431.PubMedCrossRefGoogle Scholar
  53. 53.
    Bustos C, Hernandez-Presa MA, Ortego M, et al.: HMG-CoA reductase inhibition by atorvastatin reduces neointimal inflammation in a rabbit model of atherosclerosis. J Am Coll Cardiol 1998, 32:2057–2064.PubMedCrossRefGoogle Scholar
  54. 54.
    Rezai Majd A, Maca T, Bucek RA, et al.: Simvastatin reduces expression of cytokines IL-6,IL-8 and MCP-1 in circulating monocytes from hypercholesterolemic patients. Arterioscler Thromb Vasc Biol 2002, 22:1194–1199.CrossRefGoogle Scholar
  55. 55.
    Colli S, Eligini S, Lalli M, et al.: Vastatins inhibit tissue factor in cultured human macrophages: a novel mechanism of protection against atherothrombosis. Arterioscler Thromb Vasc Biol 1997, 17:265–272.PubMedGoogle Scholar
  56. 56.
    Devaraj S, Chan E, Jialal I: Direct demonstration of the anti-inflammtory effects of simvastatin in patients with metabolic syndrome. J Clin Endocrinol Metab 2006, In press.Google Scholar
  57. 57.
    Mohiuddin I, Chai H, Lin PH, et al.: Nitrotyrosine and chlorotyrosine: clinical significance and biological functions in the vascular system. J Surg Res 2006, 133:143–149.PubMedCrossRefGoogle Scholar
  58. 58.
    Shishehbor MH, Aviles RJ, Brennan ML, et al.: Association of nitrotyrosine levels with cardiovascular disease and modulation by statin therapy. JAMA 2003, 289:1675–1680.PubMedCrossRefGoogle Scholar
  59. 59.
    Nicholls SJ, Hazen SL: Myeloperoxidase and cardiovascular disease. Arterioscler Thromb Vasc Biol 2005, 25:1102–1111.PubMedCrossRefGoogle Scholar
  60. 60.
    Shishehbor MH, Brennan ML, Aviles RJ, et al.: Statins promote potent systemic antioxidant effects through specific inflammatory pathways. Circulation 2003, 108:426–431.PubMedCrossRefGoogle Scholar
  61. 61.
    Caslake MJ, Packard CJ: Lipoprotein-associated phospholipase A2 as a biomarker for coronary disease and stroke. Nat Clin Pract Cardiovasc Med 2005, 2:529–535.PubMedCrossRefGoogle Scholar
  62. 62.
    O’Donoghue M, Morrow DA, Sabatine MS, et al.: Lipoprotein-associated phospholipase A2 and its association with cardiovascular outcomes in patients with acute coronary syndromes in the PROVEIT-TIMI 22 (PRavastatin Or atorVastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction) trial. Circulation 2006, 113:1745–1752.PubMedCrossRefGoogle Scholar
  63. 63.
    Rasmussen LM, Hansen PR, Nabipour MT, et al.: Diverse effects of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase on the expression of VCAM-1 and E-selectin in endothelial cells. Biochem J 2001, 369(Pt 2):363–370.CrossRefGoogle Scholar
  64. 64.
    Yoshida M, Sawada T, Ishii H, et al.: HMG-CoA reductase inhibitor modulates monocyte-endothelial cell interaction under physiological flow conditions in vitro: involvement of Rho GTPase-dependent mechanism. Arterioscler Thromb Vasc Biol 2001, 21:1165–1171.PubMedGoogle Scholar
  65. 65.
    Laufs U, La Fata V, Plutzky J, et al.: Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998, 97:1129–1135.PubMedGoogle Scholar
  66. 66.
    Dichtl W, Dulak J, Frick M, et al.: HMG-CoA reductase inhibitors regulate inflammatory transcription factors in human endothelial and vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2003, 23:58–63.PubMedCrossRefGoogle Scholar
  67. 67.
    Li AC, Binder CJ, Gutierrez A, et al.: Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha, beta/delta, and gamma. J Clin Invest 2004, 114:1564–1576.PubMedCrossRefGoogle Scholar
  68. 68.
    Zelvyte I, Dominaitiene R, Crisby M, et al.: Modulation of inflammatory mediators and PPARgamma and NFkappaB expression by pravastatin in response to lipoproteins in human monocytes in vitro. Pharmacol Res 2002, 45:147–154.PubMedCrossRefGoogle Scholar
  69. 69.
    Landrier JF, Thomas C, Grober J, et al.: Statin induction of liver fatty acid-binding protein (L-FABP) gene expression is peroxisome proliferator-activated receptor-alpha-dependent. J Biol Chem 2004, 279:45512–45518.PubMedCrossRefGoogle Scholar
  70. 70.
    Inoue I, Itoh F, Aoyagi S, et al.: Fibrate and statin synergistically increase the transcriptional activities of PPARalpha/RXRalpha and decrease the transactivation of NFkappaB. Biochem Biophys Res Commun 2002, 290:131–139.PubMedCrossRefGoogle Scholar
  71. 71.
    Ridker PM: JUPITER Study Group. 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 design of the JUPITER trial. Circulation 2003, 108:2292–2297.PubMedCrossRefGoogle Scholar

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© Current Medicine Group LLC 2007

Authors and Affiliations

  1. 1.VA Northern California Health System, Laboratory for Atherosclerosis and Metabolic ResearchUniversity of California Davis Medical CenterSacramentoUSA

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