Inflammatory markers in coronary artery disease: Pathophysiological mechanisms, prognostic and Therapeutic implications

Current Cardiology Reviews

Volumn 2, Issue 3, 2006, Pages 173-184

  Ikonomidis, Ignatios ^a   Stamatelopoulos, Kimon ^a   Lekakis, John ^a   Kremastinos, Dimitrios Th ^a  

^a UNIVERSITY OF ATHENS   (Greece)

Author keywords

Aspirin; C reactive protein; Inflammation; Macrophage colony stimulating factor; Prognosis

Indexed keywords

ACETYLSALICYLIC ACID; ACETYLSALICYLIC ACID 3 (NITROXYMETHYL)PHENYL ESTER; ANTIBIOTIC AGENT; BACTERIAL VACCINE; C REACTIVE PROTEIN; COLONY STIMULATING FACTOR; CYCLOOXYGENASE 2 INHIBITOR; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; ENALAPRIL; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; INTERLEUKIN 10; INTERLEUKIN 6; MONOCYTE CHEMOTACTIC PROTEIN 1; PERINDOPRIL; PROSTACYCLIN; QUINAPRIL; THROMBOPLASTIN; TRANSFORMING GROWTH FACTOR BETA1; WARFARIN;

ACUTE DISEASE; ANTIINFLAMMATORY ACTIVITY; ATHEROGENESIS; CHLAMYDIASIS; CHRONIC DISEASE; CLINICAL TRIAL; CORONARY ARTERY ATHEROSCLEROSIS; CORONARY ARTERY DISEASE; CORONARY ARTERY THROMBOSIS; CORONARY RISK; CYTOKINE PRODUCTION; CYTOKINE RELEASE; DOWN REGULATION; FOAM CELL; HEART LEFT VENTRICLE FAILURE; HEART MUSCLE ISCHEMIA; HUMAN; INCIDENCE; INTRAVASCULAR ULTRASOUND; MACROPHAGE; MONOCYTE; NONHUMAN; PATHOPHYSIOLOGY; PREDICTION; PRIMARY PREVENTION; PRIORITY JOURNAL; PROGNOSIS; PROTEIN BLOOD LEVEL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN TARGETING; REVIEW; RISK ASSESSMENT; RISK FACTOR; RISK REDUCTION; SECONDARY PREVENTION; THROMBOCYTE ACTIVATION; TREATMENT OUTCOME; VACCINATION;

EID: 33747210964     PISSN: 15733947     EISSN: None     Source Type: Journal    
DOI: 10.2174/157340306778019397     Document Type: Review

References (166)

1. Ross R. Atherosclerosis - An inflammatory disease. N Engl J Med 1999; 340: 115-126.
2. Mehra VC, Ramgolam VS, Bender JR. Cytokines in cardiovascular disease. J Leucocyte Biol 2005; 78
3. Haverkate F, Thompson SG, Pyke SD, Gallimore JR, Pepys MB. Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Lancet 1997; 349: 462-466.
4. Danesh J, Whincup P, Walker M, et al. Low-grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ 2001; 2: 172-180.
5. Danesh J, Wheeler JG, Hirschfield GM, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 2004; 350; 1287-1297.
6. Pai JK, Pischon T, Ma J, et al. Inflammatory markers and the risk of coronary heart disease in men and women. N Engl J Med 2004; 351: 2599-2610.
7. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005; 352: 20-28.
8. Ridker Pm, Rifai N, Stampfer MJ, et al. Plasma concentration of IL-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000; 101: 1767-72.
9. 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.
10. Zebrack JS, Anderson JL, Maycock CA, et al. Usefulness of high sensitivity C-reactive protein in predicting long-term risk of death or acute myocardial infarction in patients with unstable or stable angina pectoris or acute myocardial infarction. Am J Cardiol 2002; 89: 145-149.
11. Rallidis LS, Zolidaki MG, Manioudaki HS, et al. Prognostic value of C-reactive protein, fibrinogen, interleukin 6 and macrophage colony stimulating factor in severe unstable angina. Clin Cardiol 2002; 25: 461-466.
12. Saitoh A, Kishiba H, Tsukada Y, et al. Clinical significance of increased plasma concentration of MCSF in patients with angina pectoris. J Am Coll Cardiol 2000; 35: 655-665.
13. Skalen K, Gustafsson M, Rydberg E, et al. Subendothelial retension of atherogenic lipoproteins in early atherosclerosis. Nature 2002; 417: 750-754.
14. Witzum JL, Berliner JA. Oxidized phospholipids and isoprostanes in atherosclerosis. Curr Opin Lipidol 1998; 9: 441-448.
15. Hulthe J, Wilkstrand J, Fagerberg B. Relation between C-reactive protein and intima-media thickness in the carotid and femoral arteries and to antibodies against oxidized low-density lipoprotein in healthy men: the Atherosclerosis and Insulin Resistance (AIR) study. Clin Sci (Lond) 2001; 100: 371-378.
16. Kol A, Libby P. The mechanisms by which infectious agents may contribute to atherosclerosis and its clinical manifestations. Trends Cardiovasc Med 1998; 8: 191-199.
17. Zhang L, Ma Y, Zhang J, Cheng J, Du J. A new cellular signaling mechanism for angiotensin II activation of NF-kappaB: An Ikap-paB-independent, RSK-mediated phosphorylation of p65. Arteriosel Thromb Vasc Biol 2005; 25: 1148-1153.
18. Collins T, Cybulsky MI. NFkB: pivotal mediator or innocent bystander in atherogenesis? J Clin Invest 2001; 107: 255-264.
19. Clinton S, Under wood R, Sherman M, Kufe D, Libby P. Macrophage-colony stimulating factor gene expression in vascular cells in experimental and human atherosclerosis. Am J Pathol 1992; 140: 301-316.
20. Rajavashisth TB, Andalibi A, Territo MC, et al. Induction of endothelial cell expression of granulocyte and macrophage colony stimulating factors by modified low-density lipoproteins. Nature (Lond) 1990; 344: 254-257.
21. Steinbrecher UP, Parthasarathy S, Leake DS, et al. Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. Proc Natl Acad Sci USA 1986; 81: 3883-3887.
22. Faure E, Thomas I, Xu H, et al. Bacterial lipopolysaccharide and IFN-γ induce Toll-like receptor 2 and Toll-like receptor 4 expression in human endothelial cells: role of NFkB activation. J Immunol 2001; 166: 2018-24.
23. Febbraio M, Hajar DP, Silverstein RI. CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism. J Clin Invest 2001; 108: 785-791.
24. Roth P, Stanley ER. The biology of CSF-1 and its receptor. Current topics in Microbiology and Immunology. Berlin: Sonneg-Verlag, 1992, vol. 181, p 141-158.
25. Vidal-Vanachlocha F, Fantuzzi G, Mentoza, et al. IL-18 induces IL-1 β-dependent hepatic melanoma metastasis via vascular cell adhesion molecule-1. Proc Natl Acad Sci USA 2000; 97: 734-739.
26. Osborn I, Hession C, Tizard R, et al. Direct expression cloning of vascular cell adhesion molecule 1, a cytokine induced endothelial protein that binds to lymphocytes. Cell 1989; 59: 1203-1211.
27. Blankenberg S, Barbaux S, Tiret L. Adhesion molecules and atherosclerosis. Atherosclerosis 2003; 170: 191-203.
28. Cushing SD, Berlinger JA, Valente AJ, et al. Minimally modified low density lipoprotein induces monocyte chemotactic protein -1 in human endothelial cells and smooth muscle cells. Proc Natl Acad Sci USA 1990; 87: 5134-5138.
29. Shyy J, Wickham LL, Hagan JP, et al. Human Monocyte colony-stimulating factor stimulates gene expression of Monocyte chemotactic protein 1 and increases the adhesion of monocytes to endothelial monolayers. J Clin Invest 1993; 92: 1745-1751.
30. Frangogiannis NG, Mendoza LH, Ren G, et al. MCSF expression is induced in healing myocardial infarcts and may regulate monocyte and endothelial cell phenotype. Am J Physiol Heart Circ Physiol 2003; 285: H483-92
31. Hansson GK. Inflammation, atherosclerosis and coronary artery disease. N Engl J Med 2005; 352: 1685-1695.
32. Feiser L, Mukhopadhyay S, Gordon S, et al. Scavenger receptors in innate immunity. Curr Opin Immunol 2002; 14: 123-8.
33. Ishibashi S, Inaba T, Shimano H, et al. Monocyte colony stimulating factor enhances cholesterol uptake and degradation of acetylated low density lipoproteins and cholesterol esterification in human monocyte derived macrophages. J Biol Chem 1990; 265: 14109-14117.
34. Janeway CA Jr, Medzhitov R. Innate immune recognition. Annu Rev Immunol. 2002; 20: 197-216.
35. Bauer J, Ganter U, Geiger T, et al. Regulation of interleukin 6 expression in cultured human blood monocytes and monocyte derived macrophages. Blood 1988; 72: 1134-1140.
36. Bataille R, Klein B. C-reactive protein levels as a direct indicator of interleukin 6 levels in humans in vivo. Arthritis Reum 1992; 35: 982-984.
37. Ikonomidis I, Andreotti F, Economou E, et al. Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin. Circulation 1999; 100: 793-798.
38. Jabs WJ, Theissing E, Nitschke M, et al. Local generation of C-reactive protein in diseased coronary artery venous bypass grafts and normal vascular tissue. Circulation 2003; 108: 1428-31.
39. Yasojima K, Schwab C, McGeer EG, McGeer PL. Generation of C-reactive protein and complement components in atherosclerotic plaques. Am J Pathol 2001; 158: 1039-51.
40. Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation 2000; 102: 2165-2168.
41. Zwaka TP, Hombach V, Torzawski J. C-reactive protein-mediated low density lipoprotein uptake by macrophages implications for atherosclerosis. Circulation 2001; 111: 1194-1197.
42. Hansson GK, Holm J, Jonasson L. Detection of activated T lymphocytes in the human atherosclerotic plaque. Am J Pathol 1989; 135: 169-175.
43. Xu Q. Role of the heat shock proteins in atherosclerosis. Arterioscler Thromb Vasc Biol 2002; 22: 1547-1459.
44. Frostegård J, Ulfgren AK, Nyberg P, et al. Cytokine expression in advanced human atherosclerotic plaques: dominance of proinflammatory (Th1) and macrophage-stimulating cytokines. Atherosclerosis 1999; 145: 33-43.
45. Hsieh C, Macatonia SE, Tripp CS, Wolf SF, O'Garra A, Murphy KM. Development of Th1 CD4 T cells through IL-12 produced by Listeria-induced macrophages. Science 1993; 260: 547-9.
46. D'Andrea A, Aste-Amezaga M, Valiante NM, Ma X, Kubin M, Trinchieri G. Interleukin 10 (IL-10) inhibits human lymphocyte interferon-g production by suppressing natural killer cell stimulatory factor: IL-12 synthesis in accessory cells. J Exp Med 1993; 178: 1041-8.
47. Frostegard J, Ulfgren AK, Nyberg P, et al. Cytokine expression in advanced human atherosclerotic plaques: dominance of proinflammatory (Th1) and macrophage-stimulating cytokines. Atherosclerosis 1999; 145, 33-43.
48. Mach F, Schonbeck U, Sukhova GK, et al. Functional CD40 ligand is expressed on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for CD40-CD40 ligand signaling in atherosclerosis. Proc. Natl. Acad. Sci. USA 1997; 94: 1931-1936.
49. Schonbeck U, Libby P. CD40 signaling and plaque instability. Circ. Res. 2001; 89: 1092-1103.
50. Szabo SJ, Sullivan BM, Peng SL, Glimcher LH. Molecular mechanisms regulating Th1 immune responses. Annu Rev Immunol 2003; 21: 713-58.
51. Robertson AKL, Rudling M, Zhou X, Gorelik L, Flavell RA, Hansson GK. Disruption of TGF-beta signaling in T cells accelerates atherosclerosis. J Clin Invest 2003; 112: 1342-50.
52. Kojima, S., Harpel, P. C. and Rifkin, D. B. Lipoprotein (a) inbibits the generation of transforming growth factur beta: an endogenous inhibitor of smooth muscle cell migration. J. Cell Biol.; 1991; 113: 1439-1445.
53. Grainger DJ, Mosedale DE, Metcalfe JC, Böttinger EP. Dietary fat and reduced levels of TGFb1 act synergistically to promote activation of the vascular endothelium and formation of lipid lesions. J Cell Sci 2000; 113, 2355-2361.
54. Grainger DJ, Kemp PR, Witchell CM, Weissberg PL, Metcalfe JC. Transforming growth factor beta decreases the rate of proliferation of rat vascular smooth muscle cells by extending the G2 phase of the cell cycle and delays the rise in cyclic AMP before entry into M phase. Biochem. J 1994; 299: 227-235.
55. Amento E, Ehsani N, Libby P. Cytokines and growth factors positively and negatively regulate interstitial collagen gene expression in human vascular smooth muscle cells. Arterioscler. Thromb. 1991; 11: 1223-1230.
56. Yesner LM, Huh HY, Pearse SF, et al. Regulation of monocyte CD36 and thrombospondin expression by soluble mediators. Arterioscler Thromb Vasc Biol 1996; 16: 1019-1025.
57. Silverstein RL, Nachman RL. Thrombospondin binds to monocytemacrophages and mediates platelet monocyte adhesion. J Clin Invest 1987; 79: 867-874.
58. Orlandi M, Bartolini G, Minghetti L, et al. Prostaglandin and thromboxane biosynthesis in isolated platelet-free monocytes. III. The induction of cycloxygenase by colony stimulating factor -1. Prostaglandins Leukot Essent Fatty Acids 1989; 36: 101-106.
59. Raines EW, Rosenfeld ME, Ross R. The role of macrophages. In: Fuster V, Ross R, Topol EJ, eds. Atherosclerosis and Coronary Artery Disease. Philadelphia, Lippincott Raven Publishers 1996: 539-555.
60. Bombeli T, Schwartz BR, Harlan JM. Adhesion of activated platelets to endothelial cells: evidence for a GPIIbIIIa-dependent bridging mechanism and novel roles for endothelial intercellular adhesion molecule 1 (ICAM-1), avb3 integrin, and GPIba. J Exp Med 1998; 187: 329-39.
61. Myllarniemi K Calderon L, Lemstrom K, Buchdunger E, Hayry P. Inhibition of platelet-derived growth factor receptor tyrosine kinase inhibits vascular smooth muscle cell migration and proliferation. FASEB J. 1997; 11, 1119-1126.
62. Jones CB, Sane DC, Herrington DM. Matrix metalloproteinases: a review of their structure and role in acute coronary syndrome. Cardiovasc Res 2003; 59: 812-23.
63. Liu J, Sukhova GK, Sun JS, Xu WH, Libby P, Shi GP. Lysosomal cysteine proteases in atherosclerosis. Arterioscler Thromb Vasc Biol 2004; 24: 1359-66.
64. Uzui H, Harpf A, Liu M, et al. Increased expression of membrane type 3-matrix metalloproteinase in human atherosclerotic plaque: role of activated macrophages and inflammatory cytokines. Circulation 2002; 106: 3024-3030.
65. Fabunmi RP, Baker AH, Murray EJ, Booth RF, Newby AC. Divergent regulation by growth factors and cytokines of 95 kDa and 72 kDa gelatinases and tissue inhibitors or metalloproteinases-1, -2, and -3 in rabbit aortic smooth muscle cells. Biochem. J. 1996; 315: 335-342.
66. Lacraz S, Nicod L, Galve-de Rochemonteix B, Baumberger C, Dayer JM, Welgus HG. Suppression of metalloproteinase biosynthesis in human alveolar macrophages by interleukin-4. J. Clin.Invest. 1992; 90, 392-398.
67. Rajavashisth TB, Xu XP, Jovinge S, et al. Membrane type 1 matrix metalloproteinase expression in human atherosclerotic plaques: evidence for activation by proinflammatory mediators. Circulation 1999; 99: 3103-3109.
68. Doherty TM, Asotra K, Pei D, et al. Therapeutic developments in matrix metalloproteinase inhibition. Expert Opinion Therapeutic Patents. 2002; 12: 665-708.
69. Geng YJ, Wu Q, Muszynski M, Hansson GK, Libby P. Apoptosis of vascular smooth muscle cells induced by in vitro stimulation with interferon-γ, tumor necrosis factor-α and interleukin-1β Arterioscler. Thromb. Vasc. Biol. 1996; 16: 19-27.
70. Fukuo K, Suhara T, Nakahashi T, et al. Activated T cells induce up-regulation of Fas antigen in cultured endothelial cells. Heart Vessels 1997(Suppl. 12): 81-83.
71. Seshiah PN, Kereiakes DJ, Vasudevan SS, et al. Activated monocytes induce smooth muscle cell death. The role of macrophage colony stimulating factor and cell contact. Circulation 2002; 105: 174-178.
72. Blaschke F, Bruemmer D, Yin F, et al. C-reactive protein induces apoptosis in human coronary vascular smooth muscle cells. Circulation 2004; 110: 579-597.
73. Tremoli E, Camera M, Toschi V, Colli S. Tissue factor in atherosclerosis. Atherosclerosis 1999; 144: 273-283
74. Nemerson Y, Giesen PL. Some thoughts about localization and expression of tissue factor. Blood Coagulation Fibrinol 1998; 9: S45-S47.
75. Lyberg T, Stanley ER, Prydz H. Colony stimulating factor-1 induces thromboplastin activity in routine macrophages and human monocytes.J Cell Physiol 1987; 132: 367-370.
76. Narahara N, Enden T, Wiiger K Prydz H. Polar expression of tissue factor in human umbilical vein endothelial cell. Arteriorscler Thromb 1994; 14: 1815-1820
77. Mach F, Schoenbeck U, Bonnefoy JY, Pober J, Libby P. Activation of monocyte/macrophage functions related to acute atheroma complication by ligation of CD40. Induction of collagenase, stromelysin and tissue factor. Circulation 1997; 96: 396-399.
78. Otto I. Tissue factor in acute coronary syndromes. Semin Vasc Med 2003; 3: 185-192.
79. Nishiyama K, Ogawa H, Yasue H, et al. Simultaneous elevation of the levels of circulating monocyte chemoattractant protein-1 and tissue factor in acute coronary syndromes. Jpn Circ J 1998; 62: 710-712.
80. Venugopal SK, Devaraj S, Jialal I. C-Reactive Protein Decreases Prostacyclin Release From Human Aortic Endothelial Cells. Circulation 2003; 108: 1676
81. Wang CH, Li SH, Weisel RD, et al. C-reactive protein upregulates angiotensin I receptors in vascular smooth muscle cells. Circulation 2003; 107: 1783-1790
82. 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.
83. Cermak J, Key NS, Bach RR, et al. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor. Blood 1993; 82: 513-515.
84. Li SH, Szmitko PE, Weisel RD, et al. C-reactive protein upregulates complement-inhibitory factors in endothelial cells. Circulation 2004; 109: 834-836
85. Verma S, Szmitko PE, Yeh ETH. C-reactive protein: structure affects function. Circulation 2004; 109: 1914-1917
86. Zouridakis E, Avanzas P, Arroyo-Espliguero R, Fredericks S, Kaski JC. Markers of inflammation and rapid coronary artery disease progression in patients with stable angina pectoris Circulation. 2004; 110(13):1747-53.
87. Pasceri V, Cheng JS, Willerson JT, Yeh ET, Chang J. Modulation of C-reactive protein-mediated monocyte chemoattractant protein-1 induction in human endothelial cells by anti-atherosclerosis drugs. Circulation 2001; 103: 2531-4.
88. Bassuk S, Rifai N, Ridker P. High-Sensitivity C-Reactive Protein: Clinical Importance. Curr Probl Cardiol 2004; 29: 439-493.
89. Nakagomi A, Freedman SB, Geczy CL. Interferon gamma and lipopolysaccharide potentiate monocyte tissue factor induction by C-reactive protein: relationship with age sex and hormone replacement treatment. Circulation 2000; 101: 1785-1791.
90. Liuzzo G, Biasucci LM, Gallimore JR, et al. The prognostic value of C-reactive protein and serum amyloid A protein in severe unstable angina. N Engl J Med 1994; 331: 417-24.
91. Kuller LH, Tracy RP, Shaten J, Meilahn EN. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Am J Epidemiol 1996; 144: 537-47.
92. Sakkinen P, Abbott RD, Curb JD, Rodriguez BL, Yano K, Tracy RP. C-reactive protein and myocardial infarction. J Clin Epidemiol 2002; 55: 445-51.
93. Albert CM, Ma J, Rifai N, Stampfer MJ, Ridker PM. Prospective study of C-reactive protein, homocysteine, and plasma lipid levels as predictors of sudden cardiac death. Circulation 2002; 105: 2595-9.
94. Crea F, Monaco C, Lanza GA, et al. Inflammatory predictors of mortality in the Scandinavian Simvastatin Survival Study. Clin Cardiol 2002; 25: 461-466.
95. Saini A, Liu YJ, Cohen DJ, Ooi BS. Hyperglycemia augments macrophage growth response to colony stimulating factor-1. Metabolism 1996; 45: 1125-1129.
96. Tappia PS, Troughton KL, Langley-Evans SC, Grimble RF. Cigarette smoking influences cytokine production and antioxidant defences. Clin Sci (Lond) 1995; 88: 485-489.
97. Reynolds GD, Vance RP. C-Reactive protein immunohistochemical localisation in normal and atherosclerotic human aortas. Arch Pathol Lab Med 1987; 111: 265-269.
98. 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. Air Force/Texas Coronary Atherosclerosis Prevention Study Investigators. N Engl J Med. 2001; 344: 1959-1965.
99. 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: 1557-65.
100. Albert MA, Glynn RJ, Ridker P. Plasma Concentration of C-Reactive Protein and the Calculated Framingham Coronary Heart Disease Risk Score. Circulation. 2003; 108: 161-165.
101. Ridker P. the 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: 2292-97.
102. Heeschen C, Hamm CW, Bruemmer J, Simoons ML. Predictive value of C-reactive protein and troponin T in patients with unstable angina: a comparative analysis. CAPTURE Investigators. Chimeric c7E3 Anti-Platelet Therapy in Unstable angina REfractory to standard treatment trial. J Am Coll Cardiol. 2000; 35: 1535-1542.
103. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005; 352: 29-38.
104. Ridker PM, Cook NR. Clinical utility of very high and very low levels of C-reactive protein across the full range of Framingham risk scores. Circulation 2004; 109: 1955-9.
105. Ridker PM, Buring JE, Cook NP, 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: 391-7.
106. Ballantyne CM, Hoogeveen RC, Bang H, et al. Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) Study. Circulation 2004; 109: 837-42.
107. Koenig W, Lowel H, Baumert J, Meisinger C. C-reactive protein modulates risk prediction based on the Framingham Score: Implications for future risk assessment: Results from a large cohort study in Southern Germany. Circulation 2004; 109: 1349-53.
108. Ikonomidis I, Lekakis J, Revels I, Andreotti F, Nihoyannopoulos P. Increased circulating C-reactive protein and macrophage-colony stimulating factor are complementary predictors of long-term outcome in patients with chronic coronary artery disease. Ear Heart J 2005; 26: 1618-24.
109. Seino Y, Ikeda U, Ikeda M, et al. Interleukin 6 gene transcripts are expressed in human atherosclerotic lesions. Cytokine. 1994; 6: 87-91.
110. Castell JV, Andus T, Kunz D, Heinrich PC. Interleukin 6: the major regulator of acute phase protein in man and rat. Ann N Y Acad Sci 1989; 557: 87-101.
111. Bataille R, Klein B. C-reactive protein levels as a direct indicator of interleukin 6 levels in humans in vivo. Arthritis Rheum. 1992; 35: 982-984.
112. Biasucci LM, Vitelli A, Liuzzo D, et al. Elevated levels of interleukin-6 in unstable angina. Circulation. 1996; 94: 874-877.
113. Tashiro H, Simokawa H, Yamamoto K, Momomar M, Tada H, Taheshita A. Altered plasma levels of cytokines in patients with ischaemic heart disease. Coron Artery Dis. 1997; 8: 143-147.
114. Kukielka GL, Smith CW, Manning AM, Youker KA, Michael LH, Entman ML. Induction of Intreleukin-6 synthesis in the myocardium. Potential role in post-perfusion inflammatory injury. Circulation 1995; 92: 1866-1875.
115. Chong AJ, Pohlman Th, Hampton CR, Shimamoto A, Mackman N, Verrier ED. Tissue factor and thrombin mediate myocardial ischaemia-reperfusion injury. Ann Thorac Surg 2003; 75: S649-55.
116. Finkel MS, Hoffman RA, Shen L, Oddis CV, Simmons RL, Hattler BG. Interleukin 6 as a mediator of stunned myocardium. Am J Cardiol 1993; 71: 1231-32.
117. Deng MC, Erren M, Lutgen A, et al. Interleukin 6 correlates with hemodynamic impairement during dobutamine administration in chronic heart failure. Int J Cardiol 1996; 57: 129-134.
118. Ikonomidis I,, Athanassopoulos G, Lekakis J, et al. Myocardial Ischaemia induces interleukin 6 and tissue factor production in patients with coronary artery disease. A dobutamine stress echocardiography study. Circulation 2005; 112: 3272-9.
119. Cesari M, Penninx BW, Newman AB, et al. Inflammatory markers and onset of cardiovascular events: results from the Health ABC study. Circulation 2003; 108: 2317-22.
120. 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: 980-7.
121. Moreno PR, Falk E, Palacios IF, Newell JB, Fuster V, Fallon JT. Macrophage infiltration in acute coronary syndromes: implications for plaque rupture. Circulation 1994; 90: 775-778.
122. Ikonomidis I, Andreotti F, Nihoyannopoulos P. Reduction of dailylife ischaemia by aspirin in patients with angina: underlying link between thromboxane A2 and macrophage colony stimulating factor. Heart 2004; 90: 389-393.
123. Tashiro H, Simokawa H, Yamamoto K, et al. Monocyte-related cytokines in acute myocardial infarction. Am Heart J. 1995: 130: 446-452.
124. Rallidis LS, Zolindaki MG, Pentzeridis PC, Poulopoulos KP, Velissaridou AH, Apostolou TS. Raised concentrations of macrophage colony stimulating factor in severe unstable angina beyond the acute phase are strongly predictive of long term outcome. Heart 2004; 90: 25-29
125. Rosenfeld ME, Yla-Herttualla S, Lipton BA, Ord VA, Witztum JL, Steinberg D. Macrophage colony stimulating factor mRNA and protein in atherosclerotic lesions of rabbits and humans. Am J Pathol 1992; 140: 291-300.
126. Khreiss T, Jozsef L, Potempa LA, Filep JG. Conformational rearrangement in C-reactive protein is required for proinflammatory actions on human endothelial cells. Circulation 2004; 109: 2016-2022.
127. Zebrack JS, Muhlstein JB, Horne BD, Anderson JL. C-Reactive protein and angiographic coronary artery disease: independent and additive predictors of risk in patients with angina. J Am Coll Cardiol 2002; 39: 632-637.
128. Grainger DJ, Kemp PR, Liu AC, et al. Activation of transforming growth factor-β is inhibited in transgenic apolipoprotein (a) mice. Nature 1994; 370: 460-62.
129. Grainger DJ, Metcalfe JC. A pivotal role for TGF-beta in atherogenesis? Biol Rev Comb Philos Soc 1995; 70: 571-96.
130. Grainger DJ, Kemp PR, Metcalfe JC, et al. The serum concentration of active transforming growth factor-beta is severely depressed in advanced atherosclerosis. Nat Med 1995; 1: 74-9.
131. Tashiro H, Shimokawa H, Sadamatu K, Yamamoto K. Prognostic significance of plasma concentrations of transforming growth factor-b in patients with coronary artery disease. Coronary Artery Disease 2002, 13: 139-143
132. Sabatine MS, Morrow DA, de Lemos JA, et al. Multimarker approach to risk stratification in non-ST elevation acute coronary syndromes: simultaneous assessment of troponin I, C-reactive protein, and B-type natriuretic peptide. Circulation 2002; 105: 1760-3.
133. Koukkunen H, Penttila K, Kemppainen A, et al. C-reactive protein, fibrinogen, interleukin-6 and tumour necrosis factor-alpha in the prognostic classification of unstable angina pecturis Ann Med. 2001 33(1):37-47
134. Grayston JT, Kronmal RA, Jackson LA, et al for the ACES Investigators. Azithromycin for the Secondary Prevention of Coronary Events. N Engl J Med 2005; 352: 1637-45.
135. Cannon C. P., Braunwald E., McCabe C. H., et al, the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Antibiotic Treatment of Chlamydia pneumoniae after Acute Coronary Syndrome. N Engl J Med 2005; 352: 1646-1654.
136. Nilsson J, Hansson GK, Shah PK. Immunomodulation of atherosclerosis: implications for vaccine development. Arterioscler Thromb Vase Biol 2005; 25: 19-28.
137. Bhagat K, Vallance P. Inflammatory cytokines impair endothelial dependent dilatation in human veins in vivo. Circulation 1997; 96: 3042-3047.
138. Gaetano G, Cerletti C, Deiana E, Latini R. Pharmacology of platelet inhibition in humans: implications of the salicylate-aspirin interaction. Circulation, 1985; 72: 1185-1193.
139. Ikonomidis I, Lekakis I, Vamvakou G, Andreotti F, Nihoyannopoulos P. Cigarette smoking is associated with increased circulating proinflammatory and procoagulant markers in patients with chronic coronary artery disease: Effects of aspirin treatment. Am Heart J. 2005 May; 149(5): 832-9.
140. Solheim S, Amesen H, Eikvar L, Hurlen M, Seljeflot I. Influence of aspirin on inflammatory markers in patients after acute myocardial infarction. Am J Cardiol 2003; 92: 843-845.
141. Patrono C, Davi G, Giabattoni G. Thromboxane biosynthesis and metabolism in relation to cardiovascular risk factors. Trends Cardiovasc Med 1992; 2: 15-20
142. Neri Serneri GG, Gensini GF, Poggesi L, et al. The role of extra platelet thromboxane A2 in unstable angina investigated with dual thromboxane A2 inhibitor: importance of activated monocytes Coron Artery Dis 1994; 5: 137-45.
143. Cambria-Kiely JA, Gandhi PJ. Possible mechanisms of aspirin resistance. J Thromb Thrombolysis 2002; 13: 49-56.
144. Croock R, Grainger DJ, Irerson N, Salomone OA, Leatham EW, Kaski JC. Aspirin elevates circulating transforming growth factor-b in patients with chronic stable angina. Circulation. 1996; 94: 8(suppl): 463. Abstract.
145. Feldman M, Jialal I, Devaraj S, Cryer B. Effects of low-dose aspirin on serum C-reactive protein and thromboxane B2 concentrations: a placebo-controlled study using a highly sensitive C-reactive protein assay. J Am Coll Cardiol 2001; 37: 2036-41.
146. Feng D, Tracy RP, Lipinska I, Murillo J, McKenna C, Tofler GH. Effect of short-term aspirin use on C-reactive protein. J Thromb Thrombolysis 2000; 9: 37-41.
147. 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: 973-9.
148. Fiorucci S, Mencarelli A, Meneguzzi A, et al. Co-administration of nitric oxide-aspirin (NCX-4016) and aspirin prevents platelet and monocyte activation and protects against gastric damage induced by aspirin in humans. J Am Coll Cardiol 2004; 44(3): 635-41.
149. Mukhferjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001; 286: 954-959.
150. Drazen JM. COX-2 inhibitors- A lesson in unexpected problems. N Engl J Med 2005; 352: 1131-2.
151. Schönbeck U, Sukhova KG, Graber P, et al. Augmented expression of cyclooxygenase-2 in human atherosclerotic lesions. Am J Pathol. 1999; 155: 1281-1291.
152. Burleigh ME, Babaev VR, Oates JA, et al. Cyclooxygenase-2 promotes early atherosclerotic lesion formation in LDL receptor deficient mice. Circulation. 2002; 105: 1816-1823.
153. Cheng Y, Austin SC, Rocca B, et al. Role of prostacyclin in the cardiovascular response to thromboxane A2. Science 2002; 296: 539-541.
154. Altman R, Laciardi HL, Muntaner J, Del Rio F, Berman SG, Lopez R, et al. Efficacy assessment of meloxicam, a preferential cyclooxygenase-2 inhibitor, in acute coronary syndromes without ST-segment elevation. The NSAID in unstable angina treatment-2 (NUT-2) Pilot Study. Circulation. 2002; 106: 191-195.
155. Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Arterioscler Thromb Vasc Biol 2001; 21: 1712-9.
156. Crisby M, Nordin-Fredriksson G, Shah PK, Yano J, Zhu J, Nilsson J. Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization. Circulation 2001; 103: 926-33.
157. Di Napoli P, Taccardi A, Oliver M, De Caterina. R. Statins and stroke: evidence for cholesterol-independent effects. Eur Heart J 2002; 23: 399 1908-21.
158. Stefanadis C, Toutouzas K, Vavuranakis E. Statin treatment is associated with reduced thermal heterogeneity in human atherosclerotic plaques. Eur Heart J 2002; 23: 1664-9.
159. Arnaud C, Burger F, Steffens S, et al. Statins Reduce Interleukin-6-Induced C-Reactive Protein in Human Hepatocytes. New Evidence for Direct Antiinflammatory Effects of Statins. Arterioscler Thromb Vase Biol 2005; 25: 1231-6.
160. 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: 839-44.
161. Soejima H, Ogawa H, Yasue H, et al. Angiotensin-converting enzyme inhibition reduces monocyte chemoattractant protein-1 and 0 tissue factor levels in patients with myocardial infarction. J Am Coll Cardiol 1999; 34: 983-988
162. Tsikouris JP, Suarez JA, Simoni JS, Ziska M, Meyerrose GE. Exploring the effects of ACE inhibitor tissue penetration on vascular inflammation following acute myocardial infarction. Cor Artery Dis 2004; 15: 211-7
163. Sadamatsu K, Shimokawa H, Tashiro H, Yamamoto K. Long-term treatment with enelapril reduces plasma concentrations of macrophage colony stimulating factor in patients with coronary artery disease. Heart 2001; 86: 457-58.
164. Kurosaki K, Ikeda U, Murakami Y, Takahasi M, Shimada K. Inhibition of the renin-angiotensin system: no effect on circulating mascrophage colony-stimulating factor levels in acute myocardila infarction. J CardiovascPharmacol 2003; 42: 37-41.
165. Yusuf S, Pepine CJ, Garces C, et al. Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions. Lancet 1992; 340: 1173-1178
166. Fox KM; EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, doubleblind, placebo-controlled,