Abstract
Atherothrombosis is the common link between clinical manifestations of arterial vascular disease including ischemic stroke and acute coronary syndromes, such as unstable angina and acute myocardial infarction. Our understanding of the common pathologic mechanisms underlying these conditions has significantly increased during the past ten years, yet atherothrombosis as the “root cause” of a large proportion of cardiovascular and cerebrovascular diseases is largely underappreciated. Although the classical risk factors of dyslipidemia, smoking, diabetes, hypertension, obesity, and sedentary lifestyle are widely recognized as being associated with a heightened risk of vascular disease, inflammation of the vascular system during the past decade has become increasingly regarded as the principal underlying mechanism in the development of clinical atherothrombotic disease. In addition, platelet-derived inflammatory mediators play an essential role in the pathogenesis of cardiovascular disease, being involved at all stages of plaque development until their eventual rupture and subsequent formation of a platelet-rich thrombus. Mounting evidence supports the role of both localized and systemic inflammation in these events. Platelets are central to vascular inflammatory processes. Thus, inflammation can stimulate local thrombosis and thrombosis can amplify inflammation. Consequently, antiplatelet therapy for the prevention of serious vascular events may provide a double benefit via an anti-inflammatory action of the antiplatelet agent in modifying plaque formation and stability and antiplatelet activity that inhibits platelet aggregation and thrombus formation from occurring following plaque rupture.
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References
CVD Prevention and Control: Missed opportunities. World Health Organization website: http://www.who.int/cardiovascular_diseases/prevention_control/en/ [accessed February 2, 2005]
Drouet L (2002) Atherothrombosis as a systemic disease. Cerebrovasc Dis 13(Suppl 1):1–6
Ross R (1999) Atherosclerosis—an inflammatory disease. N Engl J Med 340:115–126
Manzi S, Meilahn EN, Rairie JE, Conte CG, Medsger TA Jr, Jansen-McWilliams L, D’Agostino RB, Kuller LH (1997) Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol 145:408–415
Prior P, Symmons DP, Scott DL, Brown R, Hawkins CF (1984) Cause of death in rheumatoid arthritis. Br J Rheumatol 23:92–99
Moreno PR, Falk E, Palacios IF, Newell JB, Fuster V, Fallen JT (1994) Macrophage infiltration in acute coronary syndromes. Implications for plaque rupture. Circulation 90:775–778
Bhatt DL, Topol EJ (2003) Scientific advances in antiplatelet therapy. Nat Rev Drug Discov 2:15–28
Andre P, Nannizzi-Alaimo L, Prasad SK, Phillips DR (2002) Platelet-derived CD40L: the switch-hitting player of cardiovascular disease. Circulation 106:896–899
Coppinger JA, Cagney G, Toomey S, Kislinger T, Belton O, McRedmond JP, Cahill DJ, Emili A, Fitzgerald DJ, Maguire PB (2004) Characterization of the proteins released from activated platelets leads to localization of novel platelet proteins in human atherosclerotic lesions. Blood 103:2096–2104
Wagner DD, Burger PC (2003) Platelets in inflammation and thrombosis. Arterioscler Thromb Vasc Biol 23:2131–2137
Schonbeck U, Sukhova GK, Shimizu K, Mach F, Libby P (2000) Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice. Proc Natl Acad Sci USA 97:7458–7463
Lutgens E, Cleutjens KB, Heeneman S, Koteliansky VE, Burkly LC, Daemen MJ (2000) Both early and delayed anti-CD40L antibody treatment induces a stable plaque phenotype. Proc Natl Acad Sci USA 97:7464–7469
Henn V, Slupsky JR, Grafe M, Anagnostopoulos I, Forster R, Muller-Berghaus G, Kroczek RA (1998) CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 391:591–594
Schonbeck U, Libby P (2001) CD40 signaling and plaque instability. Circ Res 89:1092–1103
May AE, Kalsch T, Massberg S, Herouy Y, Schmidt R, Gawaz M (2002) Engagement of glycoprotein IIb/IIIa (alpha(IIb)beta3) on platelets upregulates CD40L and triggers CD40L-dependent matrix degradation by endothelial cells. Circulation 106:2111–2117
van Kooten C, Banchereau J (2000) CD40–CD40 ligand. J Leukoc Biol 67:2–17
Adawi A, Zhang Y, Baggs R, Finkelstein J, Phipps RP (1998) Disruption of the CD40–CD40 ligand system prevents an oxygen-induced respiratory distress syndrome. Am J Pathol 152:651–657
Durie FH, Fava RA, Foy TM, Aruffo A, Ledbetter JA, Noelle RJ (1993) Prevention of collagen-induced arthritis with an antibody to gp39, the ligand for CD40. Science 261:1328–1330
Shah SH, Newby LK (2003) C-reactive protein: a novel marker of cardiovascular risk. Cardiol Rev 11:169–179
Antithrombotic Trialists’ Collaboration (2002) Collaborative meta-analysis of randomised trials of antiplatelet therapy for the prevention of death, myocardial infarction, and stroke in high risk patients. Br Med J 324:71–86
Takeda T, Hoshida S, Nishino M, Tanouchi J, Otsu K, Hori M (2003) Relationship between effects of statins, aspirin and angiotensin II modulators on high-sensitive C-reactive protein levels. Atherosclerosis 169:155–158
Chew DP, Bhatt DL, Robbins MA, Mukherjee D, Roffi M, Schneider JP, Topol EJ, Ellis SG (2001) Effect of clopidogrel added to aspirin before percutaneous coronary intervention on the risk associated with C-reactive protein. Am J Cardiol 88:672–674
Hermann A, Rauch BH, Braun M, Schror K, Weber AA (2001) Platelet CD40 ligand (CD40L)—subcellular localization, regulation of expression, and inhibition by clopidogrel. Platelets 12:74–82
Blake GJ, Ridker PM (2001) Novel clinical markers of vascular wall inflammation. Circ Res 89:763–771
Rosenson RS, Koenig W (2003) Utility of inflammatory markers in the management of coronary artery disease. Am J Cardiol 92:10i–18i
Ridker PM, Rifai N, Pfeffer MA, Sacks FM, Moye LA, Goldman S, Flaker GC, Braunwald E (1998) Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. Circulation 98:839–844
Ridker PM, Rifai N, Clearfield M, Downs JR, Weis SE, Miles JS, Gotto AM Jr, Air Force/Texas Coronary Atherosclerosis Prevention Study Investigators (2001) Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med 344:1959–1965
Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH, Pfeffer MA, Braunwald E, (2005) Pravastatin or Atorvastatin Evaluation, Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) Investigators C-reactive protein levels and outcomes after statin therapy. N Engl J Med 352:20–28
Nissen SE, Tuzcu EM, Schoenhagen P, Crowe T, Sasiela WJ, Tsai J, Orazem J, Magorien RD, O’Shaughnessy C, Ganz P, Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) Investigators (2005) Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 352:29–38
Varo N, Vicent D, Libby P, Nuzzo R, Calle-Pascual AL, Bernal MR, Fernandez-Cruz A, Veves A, Jarolim P, Varo JJ, Goldfine A, Horton E, Schonbeck U (2003) Elevated plasma levels of the atherogenic mediator soluble CD40 ligand in diabetic patients: a novel target of thiazolidinediones. Circulation 107:2664–2669
Sidhu JS, Cowan D, Kaski JC (2003) The effects of rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist, on markers of endothelial cell activation, C-reactive protein, and fibrinogen levels in non-diabetic coronary artery disease patients. J Am Coll Cardiol 42:1757–1763
Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd, Criqui M, Fadl YY, Fortmann SP, Hong Y, Myers GL, Rifai N, Smith SC Jr, Taubert K, Tracy RP, Vinicor F, Centers for Disease Control, Prevention; American Heart Association (2003) 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 107:499–511
Rohde LE, Hennekens CH, Ridker PM (1999) Survey of C-reactive protein and cardiovascular risk factors in apparently healthy men. Am J Cardiol 84:1018–1022
Yasojima K, Schwab C, McGeer EG, McGeer PL (2001) Generation of C-reactive protein and complement components in atherosclerotic plaques. Am J Pathol 158:1039–1051
Lagrand WK, Niessen HW, Wolbink GJ, Jaspars LH, Visser CA, Verheugt FW, Meijer CJ, Hack CE (1997) C-reactive protein colocalizes with complement in human hearts during acute myocardial infarction. Circulation 95:97–103
Cermak J, Key NS, Bach RR, Balla J, Jacob HS, Vercellotti GM (1993) C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor. Blood 82:513–520
Ballou SP, Lozanski G (1992) Induction of inflammatory cytokine release from cultured human monocytes by C-reactive protein. Cytokine 4:361–368
Pasceri V, Willerson JT, Yeh ET (2000) Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation 102:2165–2168
Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH (1998) Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation 98:731–733
Danesh J, Wheeler JG, Hirschfield GM, Eda S, Eiriksdottir G, Rumley A, Lowe GD, Pepys MB, Gudnason V (2004) C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 350:1387–1397
Jialal I, Devaraj S, Venugopal SK (2004) C-reactive protein: risk marker or mediator in atherothrombosis? Hypertension 44:6–11
Cha JK, Jeong MH, Jang JY, Bae HR, Lim YJ, Kim JS, Kim SH, Kim JW (2003) Serial measurement of surface expressions of CD63, P-selectin and CD40 ligand on platelets in atherosclerotic ischemic stroke. A possible role of CD40 ligand on platelets in atherosclerotic ischemic stroke. Cerebrovasc Dis 16:376–382
Harding SA, Sarma J, Josephs DH, Cruden NL, Din JN, Twomey PJ, Fox KA, Newby DE (2004) Upregulation of the CD40/CD40 ligand dyad and platelet-monocyte aggregation in cigarette smokers. Circulation 109:1926-1929
Blankenberg S, Tiret L, Bickel C, Peetz D, Cambien F, Meyer J, Rupprecht HJ, AtheroGene Investigators (2002) lnterleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation 106:24–30
Ridker PM, Buring JE, Rifai N (2001) Soluble P-selectin and the risk of future cardiovascular events. Circulation 103:491–495
Brennan ML, Penn MS, Van Lente F, Nambi V, Shishehbor MH, Aviles RJ, Goormastic M, Pepoy ML, McErlean ES, Topol EJ, Nissen SE, Hazen SL (2003) Prognostic value of myeloperoxidase in patients with chest pain. N Engl J Med 349:1595–1604
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Steinhubl, S.R., Newby, L.K., Sabatine, M. et al. Platelets and Atherothrombosis: An Essential Role for Inflammation in Vascular Disease — A Review. Int J Angiol 14, 211–217 (2005). https://doi.org/10.1007/s00547-005-2021-2
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DOI: https://doi.org/10.1007/s00547-005-2021-2