Inflammation and coagulation in atherosclerosis

Summary

Cardiovascular diseases remain to be the leading cause of death in Western societies. Despite major findings in vascular biology that lead to a better understanding of the pathomechanisms involved in atherosclerosis, treatment of the disease has only changed slightly within the last years. A big body of evidence suggests that atherosclerosis is a chronic inflammatory disease of the vessel wall. Accumulation and peroxidation of LDL-particles within the vessel wall trigger a strong inflammatory response, causing macrophage and T-cell accumulation within the vessel wall. Additionally, B-cells and specific antibodies against LDL-particles, as well as the complement system are implicated in atherogenesis. Besides data from clinical trials and autopsy studies it was the implementation of mouse models of atherosclerosis and the emerging field of direct genmodification that lead to a thorough description of the pathophysiological mechanisms involved in the disease and created overwhelming evidence for a participation of the immune system. Recently, the cross-talk between coagulation and inflammation in atherogenesis has gained attention. Serious limitations and disparities in the pathophysiology of atherosclerosis in mice and men complicated the translation of experimental data into clinical practice. Despite these limitations, new anti-inflammatory medical therapies in cardiovascular disease are currently being tested in clinical trials.

Zusammenfassung

Kardiovaskuläre Erkrankungen sind noch immer die häufigste Todesursache in der westlichen Welt. Trotz neuer Erkenntnisse aus der vaskulären Biologie, die zu einem besseren Verständnis der Pathomechanismen in der Atherosklerose geführt haben, hat sich die Therapie der Erkrankung in den vergangenen Jahren nicht wesentlich geändert. Die Atherosklerose wird heute als chronisch inflammatorische Erkrankung der Gefäßwand betrachtet. Zelluläre und humorale Bestandteile des Immunsystems, z. B. Makrophagen und T-Zellen, aber auch B-Zellen und spezifische Antikörper gegen akkumulierende LDL-Partikel in der Gefäßwand spielen eine wichtige Rolle in der Pathophysiologie dieser Erkrankung. Neben Daten aus klinischen Beobachtungswie auch aus Autopsiestudien, war vor allem die Möglichkeit gezielter Genmodifikation und die Etablierung geeigneter Tiermodelle ausschlaggebend für die detaillierte Beschreibung entzündlicher Prozesse in der Atherogenese.

Das Zusammenspiel zwischen Koagulation und Inflammation in der Atherogenese hat in letzter Zeit wieder mehr Aufmerksamkeit erlangt. Limitationen des Mausmodells und Unterschiede in der Pathophysiologie der Erkrankung in Tier und Mensch erschwerten bisher die Umsetzung der experimentellen Daten im klinischen Alltag. Trotz dieser Limitationen befinden sich heute mehrere gezielt anti-inflammatorische medikamentöse Therapien in klinischer Prüfung.

Keywords

Inflammation - atherosclerosis - CRP

Schlüsselwörter

Inflammation - Entzündung - Atherosklerose - CRP

• References

• 1 Minino AM, Murphy SL, Xu J, Kochanek KD. Deaths: final data for 2008. Natl Vital Stat Rep 2011; 59: 1-126.
• 2 Go AS, Mozaffarian D, Roger VL. et al. Heart disease and stroke statistics – 2013 update: a report from the American Heart Association. Circulation 2013; 127: e6-e245.
• 3 Ross R, Harker L. Hyperlipidemia and atherosclerosis. Science 1976; 193: 1094-1100.
• 4 Ross R, Glomset JA. The pathogenesis of atherosclerosis (first of two parts). N Engl J Med 1976; 295: 369-377.
• 5 Ross R, Glomset JA. The pathogenesis of atherosclerosis (second of two parts). N Engl J Med 1976; 295: 420-425.
• 6 Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med 1999; 340: 115-126.
• 7 Libby P, Ridker PM, Hansson GK. Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol 2009; 54: 2129-2138.
• 8 Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature 2011; 473: 317-325 #
• 9 Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol 2011; 12: 204-212.
• 10 Demyanets S, Huber K, Wojta J. Inflammation and the cardiovascular system. Eur Surg 2011; 43: 78-89.
• 11 Ridker PM. Testing the inflammatory hypothesis of atherothrombosis: scientific rationale for the cardiovascular inflammation reduction trial (CIRT). J Thromb Haemost 2009; 07 (Suppl. 01) 332-339.
• 12 Ridker PM, Thuren T, Zalewski A, Libby P. Interleukin-1beta inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J 2011; 162: 597-605.
• 13 Skalen K, Gustafsson M, Rydberg E. et al. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature 2002; 417: 750-754.
• 14 Bochkov VN, Mechtcheriakova D, Lucerna M. et al. Oxidized phospholipids stimulate tissue factor expression in human endothelial cells via activation of ERK/EGR-1 and Ca⁺⁺/NFAT. Blood 2002; 99: 199-206.
• 15 Galkina E, Ley K. Vascular adhesion molecules in atherosclerosis. Arterioscler Thromb Vasc Biol 2007; 27: 2292-2301.
• 16 Cybulsky MI, Gimbrone Jr MA. Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science 1991; 251: 788-791.
• 17 Lundberg AM, Hansson GK. Innate immune signals in atherosclerosis. Clin Immunol 2010; 134: 5-24.
• 18 Schwartz SM, Galis ZS, Rosenfeld ME, Falk E. Plaque rupture in humans and mice. Arterioscler Thromb Vasc Biol 2007; 27: 705-713.
• 19 Arbab-Zadeh A, Nakano M, Virmani R, Fuster V. Acute coronary events. Circulation 2012; 125: 1147-1156.
• 20 Finn AV, Nakano M, Narula J. et al. Concept of vulnerable/unstable plaque. Arterioscler Thromb Vasc Biol 2010; 30: 1282-1292.
• 21 Kranzhofer R, Schmidt J, Pfeiffer C. et al. Angiotensin induces inflammatory activation of human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 1999; 19: 1623-1629.
• 22 Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol 2012; 32: 2045-2051.
• 23 Kzhyshkowska J, Neyen C, Gordon S. Role of macrophage scavenger receptors in atherosclerosis. Immunobiology 2012; 217: 492-502.
• 24 Tall AR. Cholesterol efflux pathways and other potential mechanisms involved in the athero-protective effect of high density lipoproteins. J Intern Med 2008; 263: 256-273.
• 25 Salagianni M, Galani IE, Lundberg AM. et al. Tolllike receptor 7 protects from atherosclerosis by constraining “inflammatory” macrophage activation. Circulation 2012; 126: 952-962.
• 26 Cole JE, Navin TJ, Cross AJ. et al. Unexpected protective role for Toll-like receptor 3 in the arterial wall. Proc Natl Acad Sci USA 2011; 108: 2372-2377.
• 27 Seneviratne AN, Sivagurunathan B, Monaco C. Toll-like receptors and macrophage activation in atherosclerosis. Clin Chim Acta 2012; 413: 3-14.
• 28 Bjorkbacka H, Kunjathoor VV, Moore KJ. et al. Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nat Med 2004; 10: 416-421.
• 29 Grundtman C, Kreutmayer SB, Almanzar G. et al. Heat shock protein 60 and immune inflammatory responses in atherosclerosis. Arterioscler Thromb Vasc Biol 2011; 31: 960-968.
• 30 Lichtman AH, Binder CJ, Tsimikas S, Witztum JL. Adaptive immunity in atherogenesis: new insights and therapeutic approaches. J Clin Invest 2013; 123: 27-36.
• 31 Rajamaki K, Lappalainen J, Oorni K. et al. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS One 2010; 05: e11765.
• 32 Duewell P, Kono H, Rayner KJ. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2010; 464: 1357-1361.
• 33 Hansson GK, Klareskog L. Pulling down the plug on atherosclerosis: cooling down the inflammasome. Nat Med 2011; 17: 790-791.
• 34 Speidl WS, Kastl SP, Huber K, Wojta J. Complement in atherosclerosis: friend or foe?. J Thromb Haemost 2011; 09: 428-440.
• 35 Frauenknecht V, Schroeder V. Complement--a phylogenetically old system as a new player in the development of atherosclerosis. Hämostaseologie 2012; 32: 276-285.
• 36 Seifert PS, Hugo F, Hansson GK, Bhakdi S. Prelesional complement activation in experimental atherosclerosis. Terminal C5b-9 complement deposition coincides with cholesterol accumulation in the aortic intima of hypercholesterolemic rabbits. Lab Invest 1989; 60: 747-754.
• 37 Speidl WS, Kastl SP, Hutter R. et al. The complement component C5a is present in human coronary lesions in vivo and induces the expression of MMP-1 and MMP-9 in human macrophages in vitro. FASEB J 2011; 25: 35-44.
• 38 Kastl SP, Speidl WS, Kaun C. et al. In human macrophages the complement component C5a induces the expression of oncostatin M via AP-1 activation. Arterioscler Thromb Vasc Biol 2008; 28: 498-503.
• 39 Laine P, Pentikainen MO, Wurzner R. et al. Evidence for complement activation in ruptured coronary plaques in acute myocardial infarction. Am J Cardiol 2002; 90: 404-408.
• 40 Distelmaier K, Adlbrecht C, Jakowitsch J. et al. Local complement activation triggers neutrophil recruitment to the site of thrombus formation in acute myocardial infarction. Thromb Haemost 2009; 102: 564-572.
• 41 Shagdarsuren E, Bidzhekov K, Mause SF. et al. C5a receptor targeting in neointima formation after arterial injury in atherosclerosis-prone mice. Circulation 2010; 122: 1026-1036.
• 42 Wu G, Hu W, Shahsafaei A. et al. Complement regulator CD59 protects against atherosclerosis by restricting the formation of complement membrane attack complex. Circ Res 2009; 104: 550-558.
• 43 Speidl WS, Exner M, Amighi J. et al. Complement component C5a predicts future cardiovascular events in patients with advanced atherosclerosis. Eur Heart J 2005; 26: 2294-2299.
• 44 Muscari A, Bozzoli C, Puddu G. et al. Association of serum C3 levels with the risk of myocardial infarction. Am J Med 1995; 98: 357-364.
• 45 Engstrom G, Hedblad B, Janzon L, Lindgarde F. Complement C3 and C4 in plasma and incidence of myocardial infarction and stroke: a populationbased cohort study. Eur J Cardiovasc Prev Rehabil 2007; 14: 392-397.
• 46 Lindberg S, Pedersen SH, Mogelvang R. et al. Soluble form of membrane attack complex independently predicts mortality and cardiovascular events in patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention. Am Heart J 2012; 164: 786-792.
• 47 Speidl WS, Exner M, Amighi J. et al. Complement component C5a predicts restenosis after superficial femoral artery balloon angioplasty. J Endovasc Ther 2007; 14: 62-69.
• 48 Speidl WS, Katsaros KM, Kastl SP. et al. Coronary late lumen loss of drug eluting stents is associated with increased serum levels of the complement components C3a and C5a. Atherosclerosis 2010; 208: 285-289.
• 49 Passlick B, Flieger D, Ziegler-Heitbrock HW. Identification and characterization of a novel monocyte subpopulation in human peripheral blood. Blood 1989; 74: 2527-2534.
• 50 Zawada AM, Rogacev KS, Schirmer SH. et al. Monocyte heterogeneity in human cardiovascular disease. Immunobiology 2012; 217: 1273-1284.
• 51 Belge KU, Dayyani F, Horelt A. et al. The proinflammatory CD14+CD16+DR++ monocytes are a major source of TNF. J Immunol 2002; 168: 3536-3542.
• 52 Szaflarska A, Baj-Krzyworzeka M, Siedlar M. et al. Antitumor response of CD14+/CD16+ monocyte subpopulation. Exp Hematol 2004; 32: 748-755.
• 53 Ziegler-Heitbrock L, Ancuta P, Crowe S. et al. Nomenclature of monocytes and dendritic cells in blood. Blood 2010; 116: e74-e80.
• 54 Geissmann F, Manz MG, Jung S. et al. Development of monocytes, macrophages, and dendritic cells. Science 2010; 327: 656-661.
• 55 Geissmann F, Gordon S, Hume D. et al. Unravelling mononuclear phagocyte heterogeneity. Nat Rev Immunol 2010; 10: 453-460.
• 56 Woollard KJ. Immunological aspects of atherosclerosis. Clin Sci 2013; 125: 221-235.
• 57 Swirski FK, Libby P, Aikawa E. et al. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest 2007; 117: 195-205.
• 58 Tacke F, Alvarez D, Kaplan TJ. et al. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J Clin Invest 2007; 117: 185-194.
• 59 Poitou C, Dalmas E, Renovato M. et al. CD14dimCD16+ and CD14+CD16+ monocytes in obesity and during weight loss: relationships with fat mass and subclinical atherosclerosis. Arterioscler Thromb Vasc Biol 2011; 31: 2322-2330.
• 60 Rogacev KS, Ulrich C, Blomer L. et al. Monocyte heterogeneity in obesity and subclinical atherosclerosis. Eur Heart J 2010; 31: 369-376.
• 61 Rothe G, Gabriel H, Kovacs E. et al. Peripheral blood mononuclear phagocyte subpopulations as cellular markers in hypercholesterolemia. Arterioscler Thromb Vasc Biol 1996; 16: 1437-1447.
• 62 Rothe G, Herr AS, Stohr J. et al. A more mature phenotype of blood mononuclear phagocytes is induced by fluvastatin treatment in hypercholesterolemic patients with coronary heart disease. Atherosclerosis 1999; 144: 251-261.
• 63 Schlitt A, Heine GH, Blankenberg S. et al. CD14+CD16+ monocytes in coronary artery disease and their relationship to serum TNF-alpha levels. Thromb Haemost 2004; 92: 419-424.
• 64 Imanishi T, Ikejima H, Tsujioka H. et al. Association of monocyte subset counts with coronary fibrous cap thickness in patients with unstable angina pectoris. Atherosclerosis 2010; 212: 628-635.
• 65 Kashiwagi M, Imanishi T, Tsujioka H. et al. Association of monocyte subsets with vulnerability characteristics of coronary plaques as assessed by 64-slice multidetector computed tomography in patients with stable angina pectoris. Atherosclerosis 2010; 212: 171-176.
• 66 Rogacev KS, Seiler S, Zawada A. et al. CD14++CD16+ monocytes and cardiovascular outcome in patients with chronic kidney disease. Eur Heart J 2011; 32: 84-92.
• 67 Heine GH, Ulrich C, Seibert E. et al. CD14(++)CD16+ monocytes but not total monocyte numbers predict cardiovascular events in dialysis patients. Kidney Int 2008; 73: 622-629.
• 68 Rogacev KS, Cremers B, Zawada AM. et al. CD14++CD16+ monocytes independently predict cardiovascular events: a cohort study of 951 patients referred for elective coronary angiography. J Am Coll Cardiol 2012; 60: 1512-1520.
• 69 Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 2012; 122: 787-795.
• 70 Mantovani A, Garlanda C, Locati M. Macrophage diversity and polarization in atherosclerosis: a question of balance. Arterioscler Thromb Vasc Biol 2009; 29: 1419-1423.
• 71 Niessner A, Sato K, Chaikof EL. et al. Pathogensensing plasmacytoid dendritic cells stimulate cytotoxic T-cell function in the atherosclerotic plaque through interferon-alpha. Circulation 2006; 114: 2482-2489.
• 72 Niessner A, Weyand CM. Dendritic cells in atherosclerotic disease. Clin Immunol 2010; 134: 25-32.
• 73 Alberts-Grill N, Denning TL, Rezvan A, Jo H. The role of the vascular dendritic cell network in atherosclerosis. Am J Physiol Cell Physiol 2013; 315: C1-C21.
• 74 Gupta S, Pablo AM, Jiang X. et al. IFN-gamma potentiates atherosclerosis in ApoE knock-out mice. J Clin Invest 1997; 99: 2752-2761.
• 75 Whitman SC, Ravisankar P, Daugherty A. IFNgamma deficiency exerts gender-specific effects on atherogenesis in apolipoprotein E−/− mice. J Interferon Cytokine Res 2002; 22: 661-670.
• 76 Lee TS, Yen HC, Pan CC, Chau LY. The role of interleukin 12 in the development of atherosclerosis in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 1999; 19: 734-742.
• 77 Whitman SC, Ravisankar P, Daugherty A. Interleukin-18 enhances atherosclerosis in apolipoprotein E(−/−) mice through release of interferongamma. Circ Res 2002; 90: E34-38.
• 78 King VL, Szilvassy SJ, Daugherty A. Interleukin-4 deficiency decreases atherosclerotic lesion formation in a site-specific manner in female LDL receptor−/− mice. Arterioscler Thromb Vasc Biol 2002; 22: 456-461.
• 79 King VL, Cassis LA, Daugherty A. Interleukin-4 does not influence development of hypercholesterolemia or angiotensin II-induced atherosclerotic lesions in mice. Am J Pathol 2007; 171: 2040-2047.
• 80 Cardilo-Reis L, Gruber S, Schreier S. et al. Interleukin-13 protects from atherosclerosis and modulates plaque composition by skewing the macrophage phenotype. EMBO Mol Med 2012; 04: 1072-1086.
• 81 Demyanets S, Konya V, Kastl SP. et al. Interleukin-33 induces expression of adhesion molecules and inflammatory activation in human endothelial cells and in human atherosclerotic plaques. Arterioscler Thromb Vasc Biol 2011; 31: 2080-2089.
• 82 Miller AM, Xu D, Asquith DL. et al. IL-33 reduces the development of atherosclerosis. J Exp Med 2008; 205: 339-346.
• 83 Erbel C, Chen L, Bea F. et al. Inhibition of IL-17A attenuates atherosclerotic lesion development in apoE-deficient mice. J Immunol 2009; 183: 8167-8175.
• 84 Taleb S, Romain M, Ramkhelawon B. et al. Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis. J Exp Med 2009; 206: 2067-2077.
• 85 Ait-Oufella H, Salomon BL, Potteaux S. et al. Natural regulatory T cells control the development of atherosclerosis in mice. Nat Med 2006; 12: 178-180.
• 86 Caligiuri G, Nicoletti A, Poirier B, Hansson GK. Protective immunity against atherosclerosis carried by B cells of hypercholesterolemic mice. J Clin Invest 2002; 109: 745-753.
• 87 Ait-Oufella H, Herbin O, Bouaziz JD. et al. B cell depletion reduces the development of atherosclerosis in mice. J Exp Med 2010; 207: 1579-1587.
• 88 Tsiantoulas D, Gruber S, Binder CJ. B-1 cell immunoglobulin directed against oxidation-specific epitopes. Front Immunol 2012; 03: 415.
• 89 Binder CJ. Natural IgM antibodies against oxidation-specific epitopes. J Clin Immunol 2010; 30 (Suppl. 01) S56-S60.
• 90 Binder CJ, Horkko S, Dewan A. et al. Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nat Med 2003; 09: 736-743.
• 91 Lewis MJ, Malik TH, Ehrenstein MR. et al. Immunoglobulin M is required for protection against atherosclerosis in low-density lipoprotein receptor-deficient mice. Circulation 2009; 120: 417-426.
• 92 Ravandi A, Boekholdt SM, Mallat Z. et al. Relationship of IgG and IgM autoantibodies and immune complexes to oxidized LDL with markers of oxidation and inflammation and cardiovascular events: results from the EPIC-Norfolk Study. J Lipid Res 2011; 52: 1829-1836.
• 93 Griffin DO, Holodick NE, Rothstein TL. Human B1 cells in umbilical cord and adult peripheral blood express the novel phenotype CD20+ CD27+ CD43+ CD70. J Exp Med 2011; 208: 67-80.
• 94 Sage AP, Tsiantoulas D, Baker L. et al. BAFF receptor deficiency reduces the development of atherosclerosis in mice--brief report. Arterioscler Thromb Vasc Biol 2012; 32: 1573-1576.
• 95 Liuzz G, Goronzy JJ, Yang H. et al. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. Circulation 2000; 101: 2883-2888.
• 96 Afek A, George J, Gilburd B. et al. Immunization of low-density lipoprotein receptor deficient (LDLRD) mice with heat shock protein 65 (HSP-65) promotes early atherosclerosis. J Autoimmun 2000; 14: 115-121.
• 97 Maron R, Sukhova G, Faria AM. et al. Mucosal administration of heat shock protein-65 decreases atherosclerosis and inflammation in aortic arch of low-density lipoprotein receptor-deficient mice. Circulation 2002; 106: 1708-1715.
• 98 Klingenberg R, Lebens M, Hermansson A. et al. Intranasal immunization with an apolipoprotein B-100 fusion protein induces antigen-specific regulatory T cells and reduces atherosclerosis. Arterioscler Thromb Vasc Biol 2010; 30: 946-952.
• 99 Fredrikson GN, Hedblad B, Berglund G. et al. Identification of immune responses against aldehyde-modified peptide sequences in apoB associated with cardiovascular disease. Arterioscler Thromb Vasc Biol 2003; 23: 872-878.
• 100 Ameli S, Hultgardh-Nilsson A, Regnstrom J. et al. Effect of immunization with homologous LDL and oxidized LDL on early atherosclerosis in hypercholesterolemic rabbits. Arterioscler Thromb Vasc Biol 1996; 16: 1074-1079.
• 101 Nilsson J, Bjorkbacka H, Fredrikson GN. Apolipoprotein B100 autoimmunity and atherosclerosis – disease mechanisms and therapeutic potential. Curr Opin Lipidol 2012; 23: 422-428.
• 102 Lahoute C, Herbin O, Mallat Z, Tedgui A. Adaptive immunity in atherosclerosis: mechanisms and future therapeutic targets. Nat Rev Cardiol 2011; 08: 348-358.
• 103 Mallat Z, Taleb S, Ait-Oufella H, Tedgui A. The role of adaptive T cell immunity in atherosclerosis. J Lipid Res 2009; (Suppl. 50) S364-S369.
• 104 Hermansson A, Ketelhuth DF, Strodthoff D. et al. Inhibition of T cell response to native low-density lipoprotein reduces atherosclerosis. J Exp Med 2010; 207: 1081-1093.
• 105 Fredrikson GN, Andersson L, Soderberg I. et al. Atheroprotective immunization with MDAmodified apo B-100 peptide sequences is associated with activation of Th2 specific antibody expression. Autoimmunity 2005; 38: 171-179.
• 106 Fredrikson GN, Hedblad B, Berglund G. et al. Association between IgM against an aldehydemodified peptide in apolipoprotein B-100 and progression of carotid disease. Stroke 2007; 38: 1495-1500.
• 107 Schiopu A, Frendeus B, Jansson B. et al. Recombinant antibodies to an oxidized low-density lipoprotein epitope induce rapid regression of atherosclerosis in apobec-1(−/−)/low-density lipoprotein receptor(−/−) mice. J Am Coll Cardiol 2007; 50: 2313-2318.
• 108 Lipinski S, Bremer L, Lammers T. et al. Coagulation and inflammation. Molecular insights and diagnostic implications. Hämostaseologie 2011; 31: 94-104.
• 109 Jackson SP. Arterial thrombosis – insidious, unpredictable and deadly. Nat Med 2011; 17: 1423-1436.
• 110 Furman MI, Barnard MR, Krueger LA. et al. Circulating monocyte-platelet aggregates are an early marker of acute myocardial infarction. J Am Coll Cardiol 2001; 38: 1002-1006.
• 111 Loeffen R, Spronk HM, ten Cate H. The impact of blood coagulability on atherosclerosis and cardiovascular disease. J Thromb Haemost 2012; 10: 1207-1216.
• 112 Borissoff JI, Spronk HM, ten Cate H. The hemostatic system as a modulator of atherosclerosis. N Engl J Med 2011; 364: 1746-1760.
• 113 Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013; 13: 34-45.
• 114 Rautou PE, Vion AC, Amabile N. et al. Microparticles, vascular function, and atherothrombosis. Circ Res 2011; 109: 593-606.
• 115 Ye Z, Liu EH, Higgins JP. et al. Seven haemostatic gene polymorphisms in coronary disease: metaanalysis of 66,155 cases and 91,307 controls. Lancet 2006; 367: 651-658.
• 116 Biere-Rafi S, Tuinenburg A, Haak BW. et al. Factor VIII deficiency does not protect against atherosclerosis. J Thromb Haemost 2012; 10: 30-37.
• 117 Borissoff JI, Spronk HM, Heeneman S, ten Cate H. Is thrombin a key player in the ‘coagulationatherogenesis’ maze?. Cardiovasc Res 2009; 82: 392-403.
• 118 Kastl SP, Speidl WS, Katsaros KM. et al. Thrombin induces the expression of oncostatin M via AP-1 activation in human macrophages: a link between coagulation and inflammation. Blood 2009; 114: 2812-2818.
• 119 Borissoff JI, Heeneman S, Kilinc E. et al. Early atherosclerosis exhibits an enhanced procoagulant state. Circulation 2010; 122: 821-830.
• 120 Lee IO, Kratz MT, Schirmer SH. et al. The effects of direct thrombin inhibition with dabigatran on plaque formation and endothelial function in apolipoprotein E-deficient mice. J Pharmacol Exp Ther 2012; 343: 253-257.
• 121 Bea F, Kreuzer J, Preusch M. et al. Melagatran reduces advanced atherosclerotic lesion size and may promote plaque stability in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2006; 26: 2787-2792.
• 122 Steg PG, James SK, Atar D. et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012; 33: 2569-2619.
• 123 Merlini PA, Bauer KA, Oltrona L. et al. Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation 1994; 90: 61-68.
• 124 Chintala M, Strony J, Yang B. et al. SCH 602539, a protease-activated receptor-1 antagonist, inhibits thrombosis alone and in combination with cangrelor in a Folts model of arterial thrombosis in cynomolgus monkeys. Arterioscler Thromb Vasc Biol 2010; 30: 2143-2149.
• 125 Tricoci P, Huang Z, Held C. et al. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med 2012; 366: 20-33.
• 126 Morrow DA, Braunwald E, Bonaca MP. et al. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med 2012; 366: 1404-1413.
• 127 Rothberg MB, Celestin C, Fiore LD. et al. Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit. Ann Intern Med 2005; 143: 241-250.
• 128 Wallentin L, Wilcox RG, Weaver WD. et al. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial. Lancet 2003; 362: 789-797.
• 129 Mega JL, Braunwald E, Wiviott SD. et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012; 366: 9-19.
• 130 Daugherty A. Mouse models of atherosclerosis. Am J Med Sci 2002; 323: 3-10.
• 131 Breslow JL. Mouse models of atherosclerosis. Science 1996; 272: 685-688.
• 132 Bentzon JF, Falk E. Atherosclerotic lesions in mouse and man: is it the same disease?. Curr Opin Lipidol 2010; 21: 434-440.
• 133 Nussenblatt RB, Bielekova B, Childs R. et al. National Institutes of Health Center for Human Immunology Conference, September 2009. Ann NY Acad Sci 2010; 1200 (Suppl. 01) E1-E23.
• 134 Ridker PM, Cushman M, Stampfer MJ. et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336: 973-979.
• 135 Speidl WS, Graf S, Hornykewycz S. et al. Highsensitivity C-reactive protein in the prediction of coronary events in patients with premature coronary artery disease. Am Heart J 2002; 144: 449-455.
• 136 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: 417-424.
• 137 Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. JAMA 2007; 297: 611-619.
• 138 Speidl WS, Zeiner A, Nikfardjam M. et al. An increase of C-reactive protein is associated with enhanced activation of endogenous fibrinolysis at baseline but an impaired endothelial fibrinolytic response after venous occlusion. J Am Coll Cardiol 2005; 45: 30-34.
• 139 Kaptoge S, Di Angelantonio E, Pennells L. et al. C-reactive protein, fibrinogen, and cardiovascular disease prediction. N Engl J Med 2012; 367: 1310-1320.
• 140 Ridker PM, Kastelein JJ, Genest J, Koenig W. C-reactive protein and cholesterol are equally strong predictors of cardiovascular risk and both are important for quality clinical care. Eur Heart J 2013; 34: 1258-1261.
• 141 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.
• 142 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.
• 143 Morrow DA, de Lemos 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.
• 144 Ridker PM, Danielson E, Fonseca FA. et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359: 2195-2207.
• 145 Ridker PM, Howard CP, Walter V. et al. Effects of interleukin-1beta inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: a phase IIb randomized, placebo-controlled trial. Circulation 2012; 126: 2739-2748.