Inflammation and Arterial Thrombosis 21 dian LDL value in AFCAPS/TexCAPS; such patients had a number-to-needed- to-treat of 42, a level considered not only cost-effective but cost-saving. However, lovastatin therapy was also effective in reducing the risk of first-ever coronary events among study participants with low levels of LDL cholesterol who had above-average levels of CRP. Specifically, the magnitude of risk reduction asso- ciated with statin use for those with above-average CRP levels but normal lipid levels was almost identical to that observed among those with above-median cholesterol levels. Moreover, among such patients who had elevated levels of CRP but normal lipid levels, the event rate was just as high as that observed among those with overt hyperlipidemia. For these individuals, the number- needed-to-treat was also very low (NNT ϭ 48). By contrast, lovastatin appeared to have no effect in participants in AFCAPS/TexCAPS who had below-average LDL levels and below-average CRP levels. As might be expected, the absolute event rate was very low in this group, who had normal to low lipid levels and no evidence of inflammation. In this low-risk population defined by both LDL and CRP, the NNT was exceptionally large and statin utility cost-ineffective. Finally, like the PRINCE study, the AFCAPS/TexCAPS CRP substudy showed that lovastatin reduced CRP levels in a lipid-independent manner, this time at 1- year follow-up. When viewed together, data from the PRINCE study (196) and the AFCAPS/TexCAPS CRP substudy (200) confirm that elevated levels of CRP are a potent independent predictor of heart attack and stroke, and that combining CRP with cholesterol levels provides an improved tool for global risk prediction. Moreover, both of these large studies demonstrate clearly that statin therapy leads to approximately 15% reductions in CRP levels. Last, although hypothesis-gener- ating, the AFCAPS/TexCAPS CRP substudy also suggests that statins may sig- nificantly reduce vascular risk even in individuals who do not have overt hyperlip- idemia. IV. SUMMARY Pathological and experimental data suggest that atherosclerosis is an inflamma- tory disease. In support of the clinical extension of these observations, prospec- tive epidemiological data provide consistent evidence of an association between sensitive markers of systemic inflammation and the risk of future cardiovascular events. In particular, high-sensitivity testing for CRP identifies apparently healthy individuals who are at higher risk for vascular events at 5 or more years after blood sampling, as well as individuals with stable and unstable coronary disease who are more likely to suffer recurrent atherothrombosis. The predictive capacity of hs-CRP is independent of information offered by traditional vascular risk fac- tors, other novel markers of thrombotic risk, as well as other key participants in 22 Morrow and Ridker the inflammatory cascade. Clinical studies indicate that the risk associated with elevation of inflammatory markers may be modified by established preventive therapies in cardiovascular disease. Experimental data suggest that common therapies such as aspirin and HMG-CoA reductase inhibitors may act in part through modulating inflammatory processes or mediators that may be central to atherothrombosis (109,188). Taken together, these data support the possibility that anti-inflammatory therapies may come to play a role in the prevention and treatment of cardiovascular disease and that inflammatory markers such as hs- CRP may prove clinically useful in targeting therapy to those patients who will derive the greatest benefit. REFERENCES 1. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999; 340:115– 126. 2. Morrow DA, Ridker PM. Inflammation in cardiovascular disease. In: Topol E, ed. Textbook of Cardiovascular Medicine Updates. Cedar Knolls: Lippincott Wil- liams & Wilkins, 1999:1–12. 3. Morrow DA, Ridker PM. C-reactive protein, inflammation, and coronary risk. Med Clin North Am 2000; 84:149–161. 4. Stary HC. Evolution and progression of atherosclerotic lesions in coronary arteries of children and young adults. Arteriosclerosis 1989; 9:19–32. 5. Davies MJ. A macro and micro view of coronary vascular insult in ischemic heart disease. Circulation 1990; 82:38–46. 6. Gimbrone MA, Jr. Culture of vascular endothelium. Prog Hemost Thromb 1976; 3:1–28. 7. Liao F, et al. Genetic evidence for a common pathway mediating oxidative stress, inflammatory gene induction, and aortic fatty streak formation in mice. J Clin Invest 1994; 94:877–884. 8. Gong KW, et al. Effect of active oxygen species on intimal proliferation in rat aorta after arterial injury. J Vasc Res 1996; 33:42–46. 9. Glagov S, et al. Hemodynamics and atherosclerosis. Insights and perspectives gained from studies of human arteries. Arch Pathol Lab Med 1988; 112:1018– 1031. 10. Steinberg D. Antioxidants and atherosclerosis. A current assessment. Circulation 1991; 84:1420–1425. 11. Libby P, Egan D, Skarlatos S. Roles of infectious agents in atherosclerosis and restenosis: an assessment of the evidence and need for future research. Circulation 1997; 96:4095–4103. 12. Benditt EP, Barrett T, McDougall JK. Viruses in the etiology of atherosclerosis. Proc Natl Acad Sci U S A 1983; 80:6386–6389. 13. Lemstrom K, et al. Cytomegalovirus antigen expression, endothelial cell prolifera- Inflammation and Arterial Thrombosis 23 tion, and intimal thickening in rat cardiac allografts after cytomegalovirus infection. Circulation 1995; 92:2594–2604. 14. Harker LA, et al. Homocystine-induced arteriosclerosis. The role of endothelial cell injury and platelet response in its genesis. J Clin Invest 1976; 58:731–741. 15. Quinn MT, et al. Oxidatively modified low density lipoproteins: a potential role in recruitment and retention of monocyte/macrophages during atherogenesis. Proc Natl Acad Sci U S A 1987; 84:2995–2998. 16. Nagel T, et al. Shear stress selectively upregulates intercellular adhesion mole- cule-1 expression in cultured human vascular endothelial cells. J Clin Invest 1994; 94:885–891. 17. Cybulsky MI, Gimbrone MA, Jr. Endothelial expression of a mononuclear leuko- cyte adhesion molecule during atherogenesis. Science 1991; 251:788–791. 18. Osborne L, et al. Direct expression cloning of vascular cell adhesion molecule 1, a cytokine-induced protein that binds to lymphocytes. Cell 1989; 59:1203– 1211. 19. Poston RN, et al. Expression of intercellular adhesion molecule-1 in atherosclerotic plaques. Am J Pathol 1992; 140:665–673. 20. Nakashima Y, et al. Upregulation of VCAM-1 and ICAM-1 at atherosclerosis- prone siteson the endothelium in the ApoE-deficient mouse. Arterioscler Thromb Vasc Biol 1998; 18:842–851. 21. Osborne L. Leukocyte adhesion to endothelium in inflammation. Cell 1990; 62: 3–6. 22. Navab M, et al. Monocyte adhesion and transmigration in atherosclerosis. Coronary Artery Dis 1994; 5:198–204. 23. Valente AJ, et al. Mechanisms in intimal monocyte-macrophage recruitment. A special role for monocyte chemotactic protein-1. Circulation 1992; 86:20–25. 24. Nelken NA, et al. Monocyte chemoattractant protein-1 in human atheromatous plaques. J Clin Invest 1991; 88:1121–1127. 25. Wang JM, et al. Expression of monocyte chemotactic protein and interleukin-8 by cytokine-activated human vascular smooth muscle cells. Arterioscler Thromb 1991; 11:1166–1174. 26. Cushing SD, et al. Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc Natl Acad Sci U S A 1990; 87:5134–5138. 27. Rajavashisth TB, et al. Induction of endothelial cell expression of granulocyte and macrophage colony-stimulating factors by modified low-density lipoproteins. Na- ture 1990; 344:254–257. 28. Jonasson L, et al. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis 1986; 6:131–138. 29. Mitchinson MJ, Ball RY. Macrophages and atherogenesis. Lancet 1987; 2:146– 148. 30. Yla-Herttuala S, et al. Expression of monocyte chemoattractant protein 1 in macro- phage-rich areas of human and rabbit atherosclerotic lesions. Proc Natl Acad Sci U S A 1991; 88:5252–5256. 31. Aqel NM, et al. Monocytic origin of foam cells in human atherosclerotic plaques. Atherosclerosis 1984; 53:265–271. 24 Morrow and Ridker 32. Yla-Herttuala S, et al. Evidence for the presence of oxidatively modified low den- sity lipoprotein in atherosclerotic lesions of rabbit and man. J Clin Invest 1989; 84:1086–1095. 33. Steinberg D, et al. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989; 320:915–924. 34. Mantovani A, Bussolino F, Dejana E. Cytokine regulation of endothelial cell func- tion. FASEB J 1992; 6:2591–2599. 35. Raines EW, Dower SK, Ross R. Interleukin-1 mitogenic activity for fibroblasts and smooth muscle cells is due to PDGF-AA. Science 1989; 243:393–396. 36. Libby P, Friedman GB, Salomon RN. Cytokines as modulators of cell proliferation in fibrotic diseases. Am Rev Respir Dis 1989; 140:1114–1117. 37. Seino Y, et al. Interleukin 6 gene transcripts are expressed in human atherosclerotic lesions. Cytokine 1994; 6:87–91. 38. Rus HG, Vlaicu R, Niculescu F. Interleukin-6 and interleukin-8 protein and gene expression in human arterial atherosclerotic wall. Atherosclerosis 1996; 127:263– 271. 39. Sukovich DA, et al. Expression of interleukin-6 in atherosclerotic lesions of male ApoE-knockout mice: inhibition by 17beta-estradiol. Arterioscler Thromb Vasc Biol 1998; 18:1498–1505. 40. Old LJ. Tumor necrosis factor (TNF). Science 1985; 230:630–632. 41. Libby P, et al. Endotoxin and tumor necrosis factor induce interleukin-1 gene ex- pression in adult human vascular endothelial cells. Am J Pathol 1986; 124:179– 185. 42. Schwartz SM, Reidy MA. Common mechanisms of proliferation of smooth muscle in atherosclerosis and hypertension. Hum Pathol 1987; 18:240–247. 43. Libby P, Warner SJ, Friedman GB. Interleukin 1: a mitogen for human vascular smooth muscle cells that induces the release of growth-inhibitory prostanoids. J Clin Invest 1988; 81:487–498. 44. Winkles JA, et al. Human vascular smooth muscle cells both express and respond to heparin-binding growth factor I (endothelial cell growth factor). Proc Natl Acad Sci U S A 1987; 84:7124–7128. 45. Libby P, et al. Production of platelet-derived growth factor-like mitogen by smooth-muscle cells from human atheroma. N Engl J Med 1988; 318:1493–1498. 46. Ip JH, et al. Syndromes of accelerated atherosclerosis: role of vascular injury and smooth muscle cell proliferation. J Am Coll Cardiol 1990; 15:1667–1687. 47. Ikeda U, et al. Interleukin 6 stimulates growth of vascular smooth muscle cells in a PDGF-dependent manner. Am J Physiol 1991; 260:H1713–1717. 48. Ross R, et al. Localization of PDGF-B protein in macrophages in all phases of atherogenesis. Science 1990; 248:1009–1012. 49. Shimokado K, et al. A significant part of macrophage-derived growth factor con- sists of at least two forms of PDGF. Cell 1985; 43:277–286. 50. Meier B, et al. Human fibroblasts release reactive oxygen species in response to interleukin-1 or tumour necrosis factor-alpha. Biochem J 1989; 263:539–545. 51. Rosenfeld ME, Ross R. Macrophage and smooth muscle cell proliferation in ath- erosclerotic lesions of WHHL and comparably hypercholesterolemic fat-fed rab- bits. Arteriosclerosis 1990; 10:680–687. Inflammation and Arterial Thrombosis 25 52. Libby P. Molecular bases of the acute coronary syndromes. Circulation 1995; 91: 2844–2850. 53. Lendon CL, et al. Atherosclerotic plaque caps are locally weakened when macro- phages density is increased. Atherosclerosis 1991; 87:87–90. 54. Henney AM, et al. Localization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization. Proc Natl Acad Sci U S A 1991; 88:8154–8158. 55. Bini A, et al. Identification and distribution of fibrinogen, fibrin, and fibrin(ogen) degradation products in atherosclerosis. Use of monoclonal antibodies. Arterioscle- rosis 1989; 9:109–121. 56. Davies MJ, Thomas AC. Plaque fissuring—the cause of acute myocardial in- farction, sudden ischaemic death, and crescendo angina. Br Heart J 1985; 53:363– 373. 57. Davies M. Thrombosis and coronary atherosclerosis. In: Julian D, Kublen W, Nor- ris R, Swan H, Collen D, Verstraete M, eds. Thrombolysis in Cardiovascular Dis- ease. New York: Marcel Dekker; 1989:25–43. 58. Roberts WC, Buja LM. The frequency and significance of coronary arterial thrombi and other observations in fatal acute myocardial infarction: a study of 107 necropsy patients. Am J Med 1972; 52:425–443. 59. Fuster V, et al. Atherosclerotic plaque rupture and thrombosis. Evolving concepts. Circulation 1990; 82:47–59. 60. Serruys PW, et al. Is transluminal coronary angioplasty mandatory after successful thrombolysis? Quantitative coronary angiographic study. Br Heart J 1983; 50:257– 265. 61. Hackett D, Davies G, Maseri A. Pre-existing coronary stenoses in patients with first myocardial infarction are not necessarily severe. Eur Heart J 1988; 9:1317– 1323. 62. Ambrose JA, et al. Angiographic progression of coronary artery disease and the development of myocardial infarction. J Am Coll Cardiol 1988; 12:56–62. 63. Little WC, et al. Can coronary angiography predict the site of a subsequent myocar- dial infarction in patients with mild-to-moderate coronary artery disease? Circula- tion 1988; 78:1157–1166. 64. Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation 1995; 92:657– 671. 65. Constantinides P. Plaque fissuring in human coronary thrombosis. J Atheroscler Res 1966; 6:1–17. 66. Falk E. Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis. Characteristics of coronary atherosclerotic plaques underlying fatal oc- clusive thrombi. Br Heart J 1983; 50:127–134. 67. Ambrose JA, et al. Coronary angiographic morphology in myocardial infarction: a link between the pathogenesis of unstable angina and myocardial infarction. J Am Coll Cardiol 1985; 6:1233–1238. 68. Fuster V. Lewis A. Conner Memorial Lecture. Mechanisms leading to myocardial infarction: insights from studies of vascular biology. Circulation 1994; 90:2126– 2146. 69. Lee RT, et al. Mechanical deformation promotes secretion of IL-1 alpha and IL-1 receptor antagonist. J Immunol 1997; 159:5084–5088. 26 Morrow and Ridker 70. Falk E. Why do plaques rupture? Circulation 1992; 86:30–42. 71. Loree HM, et al. Effects of fibrous cap thickness on peak circumferential stress in model atherosclerotic vessels. Circ Res 1992; 71:850–858. 72. van der Wal AC, et al. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 1994; 89:36–44. 73. Moreno PR, et al. Macrophage infiltration in acute coronary syndromes. Implica- tions for plaque rupture. Circulation 1994; 90:775–778. 74. Richardson PD, Davies MJ, Born GV. Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques. Lancet 1989; 2:941– 944. 75. Miyao Y, et al. Elevated plasma interleukin-6 levels in patients with acute myocar- dial infarction. Am Heart J 1993; 126:1299–1304. 76. Pannitteri G, et al. Interleukins 6 and 8 as mediators of acute phase response in acute myocardial infarction. Am J Cardiol 1997; 80:622–625. 77. Biasucci LM, et al. Elevated levels of interleukin-6 in unstable angina. Circulation 1996; 94:874–877. 78. Marx N, et al. Induction of cytokine expression in leukocytes in acute myocardial infarction. J Am Coll Cardiol 1997; 30:165–170. 79. Neumann FJ, et al. Cardiac release of cytokines and inflammatory responses in acute myocardial infarction. Circulation 1995; 92:748–755. 80. Amento EP, et al. Cytokines and growth factors positively and negatively regulate interstitial collagen gene expression in human vascular smooth muscle cells. Arte- rioscler Thromb 1991; 11:1223–1230. 81. Hansson GK, et al. Immune mechanisms in atherosclerosis. Arteriosclerosis 1989; 9:567–578. 82. Rekhter MD, et al. Type I collagen gene expression in human atherosclerosis. Lo- calization to specific plaque regions. Am J Pathol 1993; 143:1634–1648. 83. Warner SJ, Friedman GB, Libby P. Regulation of major histocompatibility gene expression in human vascular smooth muscle cells. Arteriosclerosis 1989; 9:279– 288. 84. Galis ZS, et al. Cytokine-stimulated human vascular smooth muscle cells synthe- size a complement of enzymes required for extracellular matrix digestion. Circ Res 1994; 75:181–189. 85. Saren P, Welgus HG, Kovanen PT. TNF-alpha and IL-1beta selectively induce expression of 92-kDa gelatinase by human macrophages. J Immunol 1996; 157: 4159–4165. 86. Mach F, et al. Activation of monocyte/macrophage functions related to acute ather- oma complication by ligation of CD40: induction of collagenase, stromelysin, and tissue factor. Circulation 1997; 96:396–399. 87. Rajavashisth TB, et al. Membrane type 1 matrix metalloproteinase expression in human atherosclerotic plaques: evidence for activation by proinflammatory media- tors. Circulation 1999; 99:3103–3109. 88. Moreau M, et al. Interleukin-8 mediates downregulation of tissue inhibitor of met- alloproteinase-1 expression in cholesterol-loaded human macrophages: relevance to stability of atherosclerotic plaque. Circulation 1999; 99:420–426. Inflammation and Arterial Thrombosis 27 89. Galis ZS, et al. Increased expression of matrix metalloproteinases and matrix de- grading activity in vulnerable regions of human atherosclerotic plaques. J Clin In- vest 1994; 94:2493–2503. 90. van der Wal AC, Becker AE. Atherosclerotic plaque rupture—pathologic basis of plaque stability and instability. Cardiovasc Res 1999; 41:334–344. 91. Fuster V, et al. Insights into the pathogenesis of acute ischemic syndromes. Circula- tion 1988; 77:1213–1220. 92. Lee RT, et al. Structure-dependent dynamic mechanical behavior of fibrous caps from human atherosclerotic plaques. Circulation 1991; 83:1764–1770. 93. Lin CS, et al. Morphodynamic interpretation of acute coronary thrombosis, with special reference to volcano-like eruption of atheromatous plaque caused by coro- nary artery spasm. Angiology 1988; 39:535–547. 94. Annex BH, et al. Differential expression of tissue factor protein in directional ather- ectomy specimens from patients with stable and unstable coronary syndromes. Cir- culation 1995; 91:619–622. 95. Moreno PR, et al. Macrophages, smooth muscle cells, and tissue factor in unstable angina. Implications for cell-mediated thrombogenicity in acute coronary syn- dromes. Circulation 1996; 94:3090–3097. 96. Wilcox JN, et al. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci U S A 1989; 86:2839–2843. 97. Neri Serneri G, et al. Transient intermittent lymphocyte activation is responsible for the instability of angina. Circulation 1992; 86:790–797. 98. Camerer E, et al. Cell biology of tissue factor, the principal initiator of blood coagu- lation. Thromb Res 1996; 81:1–41. 99. Hirsh PD, et al. Release of prostaglandins and thromboxane into the coronary circu- lation in patients with ischemic heart disease. N Engl J Med 1981; 304:685–691. 100. Fitzgerald DJ, et al. Platelet activation in unstable coronary disease. N Engl J Med 1986; 315:983–989. 101. Willerson JT, et al. Specific platelet mediators and unstable coronary artery lesions. Experimental evidence and potential clinical implications. Circulation 1989; 80: 198–205. 102. Shimokawa H, et al. Chronic treatment with interleukin-1 beta induces coronary intimal lesions and vasospastic responses in pigs in vivo. The role of platelet- derived growth factor. J Clin Invest 1996; 97:769–776. 103. Kohchi K, et al. Significance of adventitial inflammation of the coronary artery in patients with unstable angina: results at autopsy. Circulation 1985; 71:709– 716. 104. Braunwald E. Shattuck Lecture—cardiovascular medicine at the turn of the millen- nium: triumphs, concerns, and opportunities. N Engl J Med 1997; 337:1360–1369. 105. Manson JE, et al. Primary Prevention of Myocardial Infarction. New York: Oxford University Press, 1997. 106. Ridker PM, Haughie P. Prospective studies of C-reactive protein as a risk factor for cardiovascular disease. J Invest Med 1998; 46:391–395. 107. Ridker P. Fibrinolytic and inflammatory markers for arterial occlusion: the evolv- ing epidemiology of thrombosis and hemostasis. Thromb Haemost 1997; 78:53– 59. 28 Morrow and Ridker 108. Harris TB, et al. Associations of elevated interleukin-6 and C-reactive protein lev- els with mortality in the elderly. Am J Med 1999; 106:506–512. 109. Ikonomidis I, et al. Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin. Circulation 1999; 100:793–798. 110. Hwang SJ, et al. Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atheroscle- rosis Risk In Communities (ARIC) study. Circulation 1997; 96:4219–4225. 111. Ridker PM, et al. Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men. Lancet 1998; 351:88–92. 112. Aukrust P, et al. Enhanced levels of soluble and membrane-bound CD40 ligand in patients with unstable angina. Possible reflection of T lymphocyte and platelet involvement in the pathogenesis of acute coronary syndromes. Circulation 1999; 100:614–620. 113. Kai H, et al. Peripheral blood levels of matrix metalloproteases-2 and -9 are elevated in patients with acute coronary syndromes. J Am Coll Cardiol 1998; 32:368–372. 114. Pepys MB, Baltz ML. Acute phase proteins with special reference to C-reactive protein and related proteins (pentaxins) and serum amyloid A protein. Adv Immu- nol 1983; 34:141–212. 115. Macy E, Hayes T, Tracy R. Variability in the measurement of C-reactive protein in healthy subjects: implications for reference interval and epidemiologic applica- tions. Clin Chem 1997; 43:52–58. 116. Ledue TB, et al. Analytical evaluation of particle-enhanced immunonephelometric assays for C-reactive protein, serum amyloid A and mannose-binding protein in human serum. Ann Clin Biochem 1998; 35:745–753. 117. Wilkins J, et al. Rapid automated high sensitivity enzyme immunoassay of C- reactive protein. Clin Chem 1998; 44:1358–1361. 118. Rifai N, Tracy RP, Ridker PM. Clinical efficacy of an automated high-sensitivity C-reactive protein assay. Clin Chem 1999; 45:2136–2141. 119. Berk BC, Weintraub WS, Alexander RW. Elevation of C-reactive protein in ‘‘ac- tive’’ coronary artery disease. Am J Cardiol 1990; 65:168–172. 120. Pietila K, et al. C-reactive protein in subendocardial and transmural myocardial infarcts. Clin Chem 1986; 32:1596–1597. 121. Mendall MA, et al. C reactive protein and its relation to cardiovascular risk factors: a population based cross sectional study. Br Med J 1996; 312:1061–1065. 122. Ridker PM. Evaluating novel cardiovascular risk factors: can we better predict heart attacks? Ann Intern Med 1999; 130:933–937. 123. Tracy RP, et al. Lifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects. Arterioscler Thromb Vasc Biol 1997; 17:2167–2176. 124a. Kennon S, et al. The effect of aspirin on C-reactive protein as a marker of risk in unstable angina. J Am Coll Cardiol 2001; 37:1266–1270. 124b. Feldman M, et al. Effects of low-dose aspirin on serum C-reactive protein and thromboxane B2 concentrations: A placebo controlled study using a highly sensi- tive C-reactive protein assay. J Am Coll Cardiol 2001; 37:2036–2041. 125. Ridker PM, et al. Prospective study of C-reactive protein and the risk of future Inflammation and Arterial Thrombosis 29 cardiovascular events among apparently healthy women. Circulation 1998; 98: 731–733. 126. Koenig W, 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) Augsberg Cohort Study, 1984 to 1992. Circulation 1999; 99:237–242. 127. Tracy RP, 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. 128. Ridker PM, 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. 129. Danesh J, et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. Br Med J 2000; 321:199–204. 130. Roivainen M, et al. Infections, inflammation, and the risk of coronary heart disease. Circulation 2000; 101:252–257. 130a. Ridker PM. High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention cardiovascular disease. Circulation 2001; 103:1813–1818. 131. Kuller LH, et al. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Multiple Risk Factor Intervention Trial. Am J Epidemiol 1996; 144:537–547. 132. Haverkate F, et al. Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action on Thrombosis and Disa- bilities Angina Pectoris Study Group. Lancet 1997; 349:462–466. 133. Liuzzo G, et al. The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina. N Engl J Med 1994; 331:417–424. 134. Morrow DA, et al. C-Reactive protein is a potent predictor of mortality indepen- dently and in combination with troponin T in acute coronary syndromes. J Am Coll Cardiol 1998; 31:1460–1465. 135. Ridker PM, 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. 136. Steering Committee of the Physicians’ Health Study Research G. Final report on the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med 1989; 321:129–135. 137a. Ridker PM, et al. Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease. Circulation 1998; 97:425–428. 137b. Ridker PM, et al. Novel risk factors for systemic atherosclerosis. A comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cho- lesterol screening as predictors of peripheral arterial disease. JAMA 2001; 285: 2481–2485. 138. Ridker P, Glynn R, Hennekens C. 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. 139. Cushman M, et al. Effect of postmenopausal hormones on inflammation-sensitive 30 Morrow and Ridker proteins: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Study. Cir- culation 1999; 100:717–722. 140. Cushman M, et al. Hormone replacement therapy, inflammation, and hemostasis in elderly women. Arterioscler Thromb Vasc Biol 1999; 19:893–899. 141. Ridker PM, et al. Hormone replacement therapy and increased plasma concentra- tion of C-reactive protein. Circulation 1999; 100:713–716. 142. Hulley S, et al. Randomized trial of estrogen plus progestin for secondary preven- tion of coronary heart disease in postmenopausal women. Heart and Estrogen/Pro- gestin Replacement Study (HERS) Research Group. JAMA 1998; 280:605–613. 143. Kushner I, Broder ML, Karp D. Control of the acute phase response. Serum C- reactive protein kinetics after acute myocardial infarction. J Clin Invest 1978; 61: 235–242. 144. de Beer FC, et al. Measurement of serum C-reactive protein concentration in myo- cardial ischaemia and infarction. Br Heart J 1982; 47:239–243. 145. Voulgari F, et al. Serum levels of acute phase and cardiac proteins after myocardial infarction, surgery, and infection. Br Heart J 1982; 48:352–356. 146. Ikeda U, et al. Serum interleukin 6 levels become elevated in acute myocardial infarction. J Mol Cell Cardiol 1992; 24:579–584. 147. Anzai T, et al. C-reactive protein as a predictor of infarct expansion and cardiac rupture after a first Q-wave acute myocardial infarction. Circulation 1997; 96:778– 784. 148. Ferreiros ER, et al. Independent prognostic value of elevated C-reactive protein in unstable angina. Circulation 1999; 100:1958–1963. 149. Toss H, et al. Prognostic influence of increased fibrinogen and C-reactive protein levels in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. Circulation 1997; 96:4204–4210. 150. Rebuzzi A, et al. Incremental prognostic value of serum levels of troponin T and C-reactive protein on admission in patients with unstable angina pectoris. Am J Cardiol 1998; 82:715–719. 151. Benamer H, et al. Comparison of the prognostic value of C-reactive protein and tropo- nin I in patients with unstable angina pectoris. Am J Cardiol 1998; 82:845–850. 152. Oltrona L, et al. C-reactive protein elevation and early outcome in patients with unstable angina pectoris. Am J Cardiol 1997; 80:1002–1006. 153. Biasucci L, et al. Elevated levels of C-reactive protein at discharge in patients with unstable angina predict recurrent instability. Circulation 1999; 99:855–860. 154. Pietila KO, et al. Serum C-reactive protein concentration in acute myocardial in- farction and its relationship to mortality during 24 months of follow-up in patients under thrombolytic treatment. Eur Heart J 1996; 17:1345–1349. 155. Pietila K, et al. Intravenous streptokinase treatment and serum C-reactive protein in patients with acute myocardial infarction. Br Heart J 1987; 58:225–229. 156. Pietila K, et al. Serum C-reactive protein and infarct size in myocardial infarct patients with a closed versus an open infarct-related coronary artery after thrombo- lytic therapy. Eur Heart J 1993; 14:915–919. 157. Pietila K, et al. Comparison of peak serum C-reactive protein and hydroxybutyrate dehydrogenase levels in patients with acute myocardial infarction treated with al- teplase and streptokinase. Am J Cardiol 1997; 80:1075–1077. [...]... (events/pt/yr) 740 .2 5 32. 6 20 7.6 50.8 155 131 24 16 0 .21 0 .25 0. 12 0.31 3 12 278 36 3 32 44.8 52 52 0 5 0 0.17 0.19 0.00 0.015 0 ASA dose varied between 80 and 325 mg/day Source: Modified from Refs 14, 16, 17, 29 , 30 54 Crowther and Ginsberg 3 Diagnostic Pathway A congenital or acquired hypercoagulable state should be suspected in all patients presenting with unusual forms of thrombosis or in whom thrombosis. .. 2 Plasma Folate and Homocysteine Concentrations Before and After Folic Acid Fortification (Framingham Offspring Study Participants not Taking Vitamin B Supplements) Characteristic Plasma folate Ͻ 3 ng/mL (%) Baseline Follow-up Fasting total homocysteine Ͼ 13 µmol/L (%) Baseline Follow-up Study group a (n ϭ 24 8) Control group (n ϭ 553) 22 .0 (17.3 26 .7) b 1.7 (0.0–5.4) 25 .3 (22 .1 28 .4) 20 .7 (18.3 23 .2) ... Homocysteine and Vascular Disease Risk 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 47 to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study Circulation 1998; 98 :20 4 Rimm EB, Willett WC, Hu FB, Sampson L, Colditz GA, Manson JE, Hennekens C, Stampfer MJ Folate and vitamin B 6 from diet and supplements in relation to risk of... prevention of thromboembolism, high-intensity warfarin (target INR Ͼ 2. 8) has been evaluated in five settings: (1) patients with tissue heart valves (27 ); (2) patients with acute deep vein thrombosis (28 ); (3) patients with APLA (16 ,29 ,30); (4) patients with previous stroke (31); and (5) patients with coronary artery disease (26 ) High-intensity warfarin was not more effective than standard-intensity warfarin... synthesize tissue factor Blood 1993; 82: 513– 520  32 177 178 179 180 181 1 82 183 184 185 186 187 188 189 190 191 1 92 193 Morrow and Ridker Zouki C, et al Prevention of in vitro neutrophil adhesion to endothelial cells through shedding of L-selectin by C-reactive protein and peptides derived from Creactive protein J Clin Invest 1997; 100: 522 – 529 Wolbink GJ, et al CRP-mediated activation of complement in... interleukin-6 in baboons Euro Cyto Netw 1994; 5 :27 5– 28 1 Stouthard JM, et al Interleukin-6 stimulates coagulation, not fibrinolysis, in humans Thromb Haemost 1996; 76:738–7 42 Biasucci LM, et al Increasing levels of interleukin (IL )-1 Ra and IL-6 during the first 2 days of hospitalization in unstable angina are associated with increased risk of in-hospital coronary events Circulation 1999; 99 :20 79 20 84 Ridker... women; positively associated with age; and inversely associated with vitamin B 12 and folate Reference ranges were developed for American adults, and, as an example, the 95th percentile of homocysteine range was 12. 9 µmol/L in men and 10 .2 µmol/L in women 40 to 59 years of age (8) 38 Wilson Figure 2 Relations between homocysteine levels and plasma levels of vitamin B 12 and folate (From Ref 6.) Naturally... total and HDL cholesterol in determining risk of first myocardial infarction Circulation 1998; 97 :20 07 20 11 Rifai N, Ridker P A Proposed cardiovascular risk assessment algorithm employing high-sensitivity C-reactive protein and lipid screening Clin Chem 20 01; 47 :28 – 30 Vaughan CJ, Murphy MB, Buckley BM Statins do more than just lower cholesterol Lancet 1996; 348:1079–10 82 Ridker PM, et al Long-term... for beta -2 glycoprotein-1, a circulating plasma glycoprotein Anticardiolipin antibodies are likely associated 49 50 Crowther and Ginsberg with titer-dependent increases in the risk of thrombosis and recurrent pregnancy loss ACA, and to a lesser extent lupus anticoagulants, may demonstrate specificity for certain anionic phospholipids, in particular phosphatidylserine, phosphatidylinositol, and phosphatidylcholine... (14, 16,17), and in patients with an ACA, the risk of thromboembolism is higher in those with a previous history of thromboembolism than in those without such a history ( 12) This increased risk of recurrent thromboembolism has also been reported in patients with stroke (18 20 ), with venous thromboembolism (14), and with other types of thromboembolism (16,17) In summary, patients with APLA, particularly . group a Control group Characteristic (n ϭ 24 8) (n ϭ 553) Plasma folate Ͻ 3 ng/mL (%) Baseline 22 .0 (17.3 26 .7) b 25 .3 (22 .1 28 .4) Follow-up 1.7 (0.0–5.4) 20 .7 (18.3 23 .2) Fasting total homocysteine Ͼ 13. Inflammation and Arterial Thrombosis 21 dian LDL value in AFCAPS/TexCAPS; such patients had a number-to-needed- to-treat of 42, a level considered not only cost-effective but cost-saving. However, lovastatin. molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atheroscle- rosis Risk In Communities (ARIC) study. Circulation 1997; 96: 421 9– 422 5. 111.