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DOI: 10.1160/TH12-05-0341
Do we know enough about the immune pathogenesis of acute coronary syndromes to improve clinical practice?
Publication History
Received:
23 May 2012
Accepted after minor revision:
17 July 2012
Publication Date:
25 November 2017 (online)
Summary
Morbidities related to atherosclerosis, such as acute coronary syndromes (ACS) including unstable angina and myocardial infarction, remain leading causes of mortality. Unstable plaques are inflamed and infiltrated with macrophages and T lymphocytes. Activated dendritic cells interact with T cells, yielding predominantly Th1 responses involving interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α), while the role of interleukin 17 (IL-17) is questionable. The expansion of CD28nullCD4 or CD8 T cells as well as pattern recognition receptors activation (especially Toll-like receptors; TLR2 and TLR4) is characteristic for unstable plaque. Inflammation modifies platelet and fibrin clot characteristics, which are critical for ACS. Understanding of the inflammatory mechanisms of atherothrombosis, bridging inflammation, oxidative stress and immune regulation, will allow for the detection of subjects at risk, through the use of novel biomarkers and imaging techniques including intravascular ultrasound, molecular targeting, magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET). Moreover, understanding the specific inflammatory pathways of plaque rupture and atherothrombosis may allow for immunomodulation of ACS. Statins and anti-platelet drugs are anti-inflammatory, but importance of immune events in ACS warrants the introduction of novel, specific treatments directed either on cytokines, TLRs or inflammasomes. While the prime time for the introduction of immunologically inspired diagnostic tests and treatments for atherosclerosis have not come yet, we are closer than ever before to finally being able to benefit from this vast body of experimental and clinical evidence. This paper provides a comprehensive review of the role of the immune system and inflammation in ACS.
Note: The review process for this manuscript was fully handled by G. Y. H. Lip, Editor in Chief.
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References
- 1 Lutgens E, Binder CJ. Immunology of atherosclerosis. Thromb Haemost 2011; 106: 755-756.
- 2 Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature 2011; 473: 317-325.
- 3 Lob HE, Marvar PJ, Guzik TJ. et al. Induction of hypertension and peripheral inflammation by reduction of extracellular superoxide dismutase in the central nervous system. Hypertension 2010; 55: 277-283.
- 4 Guzik TJ, Hoch NE, Brown KA. et al. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med 2007; 204: 2449-2460.
- 5 Arbab-Zadeh A, Nakano M, Virmani R. et al. Acute coronary events. Circulation 2012; 125: 1147-1156.
- 6 Boden H, van der Hoeven BL, Karalis I. et al. Management of acute coronary syndrome: achievements and goals still to pursue. Novel developments in diagnosis and treatment. J Intern Med 2012; 271: 521-536.
- 7 Yusuf S, Hawken S, Ounpuu S. et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004; 364: 937-952.
- 8 Randi AM, Biguzzi E, Falciani F. et al. Identification of differentially expressed genes in coronary atherosclerotic plaques from patients with stable or unstable angina by cDNA array analysis. J Thromb Haemost 2003; 01: 829-835.
- 9 Razuvaev A, Ekstrand J, Folkersen L. et al. Correlations between clinical variables and gene-expression profiles in carotid plaque instability. Eur J Vasc Endovasc Surg 2011; 42: 722-730.
- 10 Liuzzo G, Baisucci LM, Gallimore JR. et al. Enhanced inflammatory response in patients with preinfarction unstable angina. J Am Coll Cardiol 1999; 34: 1696-1703.
- 11 Liuzzo G, Kopecky SL, Frye RL. et al. Perturbation of the T-cell repertoire in patients with unstable angina. Circulation 1999; 100: 2135-2139.
- 12 De Palma R, Del Galdo F, Abbate G. et al. Patients with acute coronary syndrome show oligoclonal T-cell recruitment within unstable plaque: evidence for a local, intracoronary immunologic mechanism. Circulation 2006; 113: 640-646.
- 13 Finn AV, Nakano M, Narula J. et al. Concept of vulnerable/unstable plaque. Arterioscler Thromb Vasc Biol 2010; 30: 1282-1292.
- 14 Gori AM, Cesari F, Marcucci R. et al. The balance between pro- and anti-inflammatory cytokines is associated with platelet aggregability in acute coronary syndrome patients. Atherosclerosis 2009; 202: 255-262.
- 15 Manthey HD, Zernecke A. Dendritic cells in atherosclerosis: functions in immune regulation and beyond. Thromb Haemost 2011; 106: 772-778.
- 16 Shah PK. Inflammation and plaque vulnerability. Cardiovasc Drugs Ther 2009; 23: 31-40.
- 17 van der Wal AC, Becker AE, van der Loos CM. 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.
- 18 Healy AM, Pickard MD, Pradhan AD. et al. Platelet expression profiling and clinical validation of myeloid-related protein-14 as a novel determinant of cardiovascular events. Circulation 2006; 113: 2278-2284.
- 19 Calabro P, Golia E, Ye h ET. CRP and the risk of atherosclerotic events. Semin Immunopathol 2009; 31: 79-94.
- 20 Wyss CA, Neidhart M, Altwegg L. et al. Cellular actors, Toll-like receptors, and local cytokine profile in acute coronary syndromes. Eur Heart J 2010; 31: 1457-1469.
- 21 Silvain J, Collet J P, Nagaswami C. et al. Composition of coronary thrombus in acute myocardial infarction. J Am Coll Cardiol 2011; 57: 1359-1367.
- 22 Yunoki K, Naruko T, Sugioka K. et al. Erythrocyte-rich thrombus aspirated from patients with ST-elevation myocardial infarction: association with oxidative stress and its impact on myocardial reperfusion. Eur Heart J 2012; 33: 1480-1490.
- 23 Liuzzo G, Goronzy JJ, Yang H. et al. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. Circulation 2000; 101: 2883-2888.
- 24 Cheng X, Yu X, Ding YJ. et al. The Th17/Treg imbalance in patients with acute coronary syndrome. Clin Immunol 2008; 127: 89-97.
- 25 Mor A, Luboshits G, Planer D. et al. Altered status of CD4(+)CD25(+) regulatory T cells in patients with acute coronary syndromes. Eur Heart J 2006; 27: 2530-2537.
- 26 Steppich BA, Moog P, Matissek C. et al. Cytokine profiles and T cell function in acute coronary syndromes. Atherosclerosis 2007; 190: 443-451.
- 27 Butcher M, Galkina E. Current views on the functions of interleukin-17A-producing cells in atherosclerosis. Thromb Haemost 2011; 106: 787-795.
- 28 Ozdogru I, Inanc MT, Eryol NK. et al. CD14+ monocyte levels in subgroups of acute coronary syndromes. Coron Artery Dis 2007; 18: 519-522.
- 29 Tsujioka H, Imanishi T, Ikejima H. et al. Impact of heterogeneity of human peripheral blood monocyte subsets on myocardial salvage in patients with primary acute myocardial infarction. J Am Coll Cardiol 2009; 54: 130-138.
- 30 Kashiwagi M, Imanishi T, Ozaki Y. et al. Differential expression of Toll-like receptor 4 and human monocyte subsets in acute myocardial infarction. Atherosclerosis 2012; 221: 249-253.
- 31 Ji QW, Guo M, Zheng JS. et al. Downregulation of T helper cell type 3 in patients with acute coronary syndrome. Arch Med Res 2009; 40: 285-293.
- 32 Herder C, Peeters W, Illig T. et al. RANTES/CCL5 and risk for coronary events: results from the MONICA/KORA Augsburg case-cohort, Athero-Express and CARDIoGRAM studies. PLoS One 2011; 06: e25734.
- 33 Winnik S, Klingenberg R, Matter CM. Plasma RANTES: a molecular fingerprint of the unstable carotid plaque?. Eur Heart J 2011; 32: 393-395.
- 34 Virmani R, Burke A P, Farb A. et al. Pathology of the vulnerable plaque. J Am Coll Cardiol 2006; 47: C13-18.
- 35 Waxman S, Ishibashi F, Muller JE. Detection and treatment of vulnerable plaques and vulnerable patients: novel approaches to prevention of coronary events. Circulation 2006; 114: 2390-2411.
- 36 Yla-Herttuala S, Bentzon JF, Daemen M. et al. Stabilisation of atherosclerotic plaques. Position paper of the European Society of Cardiology (ESC) Working Group on atherosclerosis and vascular biology. Thromb Haemost 2011; 106: 1-19.
- 37 Virmani R, Kolodgie FD, Burke A P. et al. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000; 20: 1262-1275.
- 38 Guzik TJ, Mangalat D, Korbut R. Adipocytokines - novel link between inflammation and vascular function?. J Physiol Pharmacol 2006; 57: 505-528.
- 39 Harrison DG, Guzik TJ, Lob HE. et al. Inflammation, immunity, and hypertension. Hypertension 2011; 57: 132-140.
- 40 Weber C, Noels H. Atherosclerosis: current pathogenesis and therapeutic options. Nat Med 2011; 17: 1410-1422.
- 41 Edfeldt K, Swedenborg J, Hansson GK. et al. Expression of toll-like receptors in human atherosclerotic lesions: a possible pathway for plaque activation. Circulation 2002; 105: 1158-1161.
- 42 Zacharias DG, Kim SG, Massat AE. et al. Humanin, a cytoprotective peptide, is expressed in carotid artherosclerotic plaques in humans. PLoS One 2012; 07: e31065.
- 43 Newby AC. Matrix metalloproteinase inhibition therapy for vascular diseases. Vascul Pharmacol 2012; 56: 232-244.
- 44 Libby P. Molecular and cellular mechanisms of the thrombotic complications of atherosclerosis. J Lipid Res 2009; 50 (Suppl) S352-357.
- 45 Schramm A, Matusik P, Osmenda G. et al. Targeting NADPH oxidases in vascular pharmacology. Vascul Pharmacol 2012; 56: 216-231.
- 46 Tavora FR, Ripple M, Li L. et al. Monocytes and neutrophils expressing myeloper-oxidase occur in fibrous caps and thrombi in unstable coronary plaques. BMC Cardiovasc Disord 2009; 09: 27.
- 47 Han SF, Liu P, Zhang W. et al. The opposite-direction modulation of CD4+CD25+ Tregs and T helper 1 cells in acute coronary syndromes. Clin Immunol 2007; 124: 90-97.
- 48 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.
- 49 de Boer OJ, van der Wal AC. FOXP3+ regulatory T cells in vulnerable atherosclerotic plaques. Int J Cardiol 2010; 145: 161.
- 50 Patel S, Chung SH, White G. et al. The ”atheroprotective“ mediators apolipoprotein A-I and Foxp3 are over-abundant in unstable carotid plaques. Int J Cardiol 2010; 145: 183-187.
- 51 Danzaki K, Matsui Y, Ikesue M. et al. Interleukin-17A deficiency accelerates unstable atherosclerotic plaque formation in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2012; 32: 273-280.
- 52 Zhao Z, Wu Y, Cheng M. et al. Activation of Th17/Th1 and Th1, but not Th17, is associated with the acute cardiac event in patients with acute coronary syndrome. Atherosclerosis 2011; 217: 518-524.
- 53 Dumitriu IE, Baruah P, Finlayson CJ. et al. High levels of costimulatory receptors OX40 and 4-1BB characterize CD4+CD28null T cells in patients with acute coronary syndrome. Circ Res 2012; 110: 857-869.
- 54 Vinh A, Chen W, Blinder Y. et al. Inhibition and genetic ablation of the B7/CD28 T-cell costimulation axis prevents experimental hypertension. Circulation 2010; 122: 2529-2537.
- 55 Yilmaz A, Lochno M, Traeg F. et al. Emergence of dendritic cells in rupture-prone regions of vulnerable carotid plaques. Atherosclerosis 2004; 176: 101-110.
- 56 Erbel C, Sato K, Meyer FB. et al. Functional profile of activated dendritic cells in unstable atherosclerotic plaque. Basic Res Cardiol 2007; 102: 123-132.
- 57 Niessner A, Sato K, Chaikof EL. et al. Pathogen-sensing plasmacytoid dendritic cells stimulate cytotoxic T-cell function in the atherosclerotic plaque through in-terferon-alpha. Circulation 2006; 114: 2482-2489.
- 58 Doring Y, Manthey HD, Drechsler M. et al. Auto-antigenic protein-DNA complexes stimulate plasmacytoid dendritic cells to promote atherosclerosis. Circulation 2012; 125: 1673-1683.
- 59 Van Vre EA, Ait-Oufella H, Tedgui A. et al. Apoptotic cell death and efferocytosis in atherosclerosis. Arterioscler Thromb Vasc Biol 2012; 32: 887-893.
- 60 Zheng Y, Gardner SE, Clarke MC. Cell death, damage-associated molecular patterns, and sterile inflammation in cardiovascular disease. Arterioscler Thromb Vasc Biol 2011; 31: 2781-2786.
- 61 Seneviratne AN, Sivagurunathan B, Monaco C. Toll-like receptors and macrophage activation in atherosclerosis. Clin Chim Acta 2012; 413: 3-14.
- 62 Kounis NG. Kounis syndrome (allergic angina and allergic myocardial infarction): a natural paradigm?. Int J Cardiol 2006; 110: 7-14.
- 63 Matusik P, Mazur P, Stepien E. et al. Architecture of intraluminal thrombus removed from abdominal aortic aneurysm. J Thromb Thrombolysis 2010; 30: 7-9.
- 64 Kato K, Matsubara T, Iida K. et al. Elevated levels of pro-inflammatory cytokines in coronary artery thrombi. Int J Cardiol 1999; 70: 267-273.
- 65 Sakai T, Inoue S, Takei M. et al. Activated inflammatory cells participate in thrombus size through tissue factor and plasminogen activator inhibitor-1 in acute coronary syndrome: Immunohistochemical analysis. Thromb Res 2011; 127: 443-449.
- 66 Libby P, Simon DI. Inflammation and thrombosis: the clot thickens. Circulation 2001; 103: 1718-1720.
- 67 Shebuski RJ, Kilgore KS. Role of inflammatory mediators in thrombogenesis. J Pharmacol Exp Ther 2002; 300: 729-735.
- 68 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.
- 69 Shiraki R, Inoue N, Kawasaki S. et al. Expression of Toll-like receptors on human platelets. Thromb Res 2004; 113: 379-385.
- 70 von Hundelshausen P, Weber KS, Huo Y. et al. RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium. Circulation 2001; 103: 1772-1777.
- 71 Ostrovsky L, King AJ, Bond S. et al. A juxtacrine mechanism for neutrophil adhesion on platelets involves platelet-activating factor and a selectin-dependent activation process. Blood 1998; 91: 3028-3036.
- 72 Ott I, Neumann FJ, Gawaz M. et al. Increased neutrophil-platelet adhesion in patients with unstable angina. Circulation 1996; 94: 1239-1246.
- 73 Sarma J, Laan CA, Alam S. et al. Increased platelet binding to circulating monocytes in acute coronary syndromes. Circulation 2002; 105: 2166-2171.
- 74 Campbell RA, Overmyer KA, Selzman CH. et al. Contributions of extravascular and intravascular cells to fibrin network formation, structure, and stability. Blood 2009; 114: 4886-4896.
- 75 Matusik P, Dubiel M, Wizner B. et al. Age-related gap in the management of heart failure patients. The National Project of Prevention and Treatment of Cardiovascular Diseases - POLKARD. Cardiol J 2012; 19: 146-152.
- 76 Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 2007; 81: 1-5.
- 77 Arslan F, de Kleijn D P, Pasterkamp G. Innate immune signaling in cardiac ischemia. Nat Rev Cardiol 2011; 08: 292-300.
- 78 Timmers L, Pasterkamp G, de Hoog VC. et al. The innate immune response in rep-erfused myocardium. Cardiovasc Res 2012; 94: 276-283.
- 79 Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol 2004; 04: 499-511.
- 80 Monassier JP. Reperfusion injury in acute myocardial infarction. From bench to cath lab. Part I: Basic considerations. Arch Cardiovasc Dis 2008; 101: 491-500.
- 81 Liao YH, Xia N, Zhou SF. et al. Interleukin-17A contributes to myocardial ischemia/reperfusion injury by regulating cardiomyocyte apoptosis and neutrophil infiltration. J Am Coll Cardiol 2012; 59: 420-429.
- 82 Leuschner F, Rauch PJ, Ueno T. et al. Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis. J Exp Med 2012; 209: 123-137.
- 83 Madjid M, Naghavi M, Litovsky S. et al. Influenza and cardiovascular disease: a new opportunity for prevention and the need for further studies. Circulation 2003; 108: 2730-2736.
- 84 Dong M, Liu T, Li G. Association between acute infections and risk of acute coronary syndrome: a meta-analysis. Int J Cardiol 2011; 147: 479-482.
- 85 Corrales-Medina VF, Madjid M, Musher DM. Role of acute infection in triggering acute coronary syndromes. Lancet Infect Dis 2010; 10: 83-92.
- 86 Clayton TC, Thompson M, Meade TW. Recent respiratory infection and risk of cardiovascular disease: case-control study through a general practice database. Eur Heart J 2008; 29: 96-103.
- 87 Tiirola T, Sinisalo J, Nieminen MS. et al. Chlamydial lipopolysaccharide is present in serum during acute coronary syndrome and correlates with CRP levels. Atherosclerosis 2007; 194: 403-407.
- 88 Shah PK. Plaque disruption and thrombosis: potential role of inflammation and infection. Cardiol Rev 2000; 08: 31-39.
- 89 Rosenfeld ME, Campbell LA. Pathogens and atherosclerosis: update on the potential contribution of multiple infectious organisms to the pathogenesis of atherosclerosis. Thromb Haemost 2011; 106: 858-867.
- 90 Epstein SE, Zhu J, Najafi AH. et al. Insights into the role of infection in atherogenesis and in plaque rupture. Circulation 2009; 119: 3133-3141.
- 91 Madjid M, Vela D, Khalili-Tabrizi H. et al. Systemic infections cause exaggerated local inflammation in atherosclerotic coronary arteries: clues to the triggering effect of acute infections on acute coronary syndromes. Te x Heart Inst J 2007; 34: 11-18.
- 92 Fitzgerald JR, Foster TJ, Cox D. The interaction of bacterial pathogens with platelets. Nat Rev Microbiol 2006; 04: 445-457.
- 93 Vallance P, Collier J, Bhagat K. Infection, inflammation, and infarction: does acute endothelial dysfunction provide a link?. Lancet 1997; 349: 1391-1392.
- 94 Davis MM, Taubert K, Benin AL. et al. Influenza vaccination as secondary prevention for cardiovascular disease: a science advisory from the American Heart Association/American College of Cardiology. Circulation 2006; 114: 1549-1553.
- 95 Lamontagne F, Garant M P, Carvalho JC. et al. Pneumococcal vaccination and risk of myocardial infarction. CMAJ 2008; 179: 773-777.
- 96 Lopez-Pedrera C, Perez-Sanchez C, Ramos-Casals M. et al. Cardiovascular risk in systemic autoimmune diseases: epigenetic mechanisms of immune regulatory functions. Clin Dev Immunol 2012; 2012: 9746-9748.
- 97 Shoenfeld Y, Gerli R, Doria A. et al. Accelerated atherosclerosis in autoimmune rheumatic diseases. Circulation 2005; 112: 3337-3347.
- 98 Bili A, Moss AJ, Francis CW. et al. Anticardiolipin antibodies and recurrent coronary events: a prospective study of 1150 patients. Thrombogenic Factors, and Recurrent Coronary Events Investigators. Circulation 2000; 102: 1258-1263.
- 99 Ridker PM, Everett BM. Letter by Ridker and Everett regarding article, ”The inflammatory hypothesis: any progress in risk stratification and therapeutic targets?“. Circulation 2007; 115: e475 author reply e476.
- 100 Wang TJ, Gona P, Larson MG. et al. Multiple biomarkers for the prediction of first major cardiovascular events and death. N Engl J Med 2006; 355: 2631-2639.
- 101 Liuzzo G, Biasucci LM, Trotta G. et al. Unusual CD4+CD28null T lymphocytes and recurrence of acute coronary events. J Am Coll Cardiol 2007; 50: 1450-1458.
- 102 Heeschen C, Dimmeler S, Hamm CW. et al. Soluble CD40 ligand in acute coronary syndromes. N Engl J Med 2003; 348: 1104-1111.
- 103 Packard CJ, O'Reilly DS, Caslake MJ. et al. Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. West of Scotland Coronary Prevention Study Group. N Engl J Med 2000; 343: 1148-1155.
- 104 Sawicki M, Sypniewska G, Kozinski M. et al. Diagnostic efficacy of myeloperoxidase for the detection of acute coronary syndromes. Eur J Clin Invest 2011; 41: 667-671.
- 105 Ferrante G, Nakano M, Prati F. et al. High levels of systemic myeloperoxidase are associated with coronary plaque erosion in patients with acute coronary syndromes: a clinicopathological study. Circulation 2010; 122: 2505-2513.
- 106 Matter CM, Stuber M, Nahrendorf M. Imaging of the unstable plaque: how far have we got?. Eur Heart J 2009; 30: 2566-2574.
- 107 Rudd JH, Warburton EA, Fryer TD. et al. Imaging atherosclerotic plaque inflammation with [18F]-fluorodeoxyglucose positron emission tomography. Circulation 2002; 105: 2708-2711.
- 108 Rudd JH, Narula J, Strauss HW. et al. Imaging atherosclerotic plaque inflammation by fluorodeoxyglucose with positron emission tomography: ready for prime time?. J Am Coll Cardiol 2010; 55: 2527-2535.
- 109 Dweck MR, Chow MW, Joshi NV. et al. Coronary Arterial 18F-Sodium Fluoride Uptake: A Novel Marker of Plaque Biology. J Am Coll Cardiol 2012; 59: 1539-1548.
- 110 Gaemperli O, Shalhoub J, Owen DR. et al. Imaging intraplaque inflammation in carotid atherosclerosis with 11C-PK11195 positron emission tomography/computed tomography. Eur Heart J 2012; 33: 1902-1910.
- 111 Corti R, Fuster V. Imaging of atherosclerosis: magnetic resonance imaging. Eur Heart J 2011; 32: 1709-19b.
- 112 Hermann S, Starsichova A, Waschkau B. et al. Non-FDG imaging of atherosclerosis: Will imaging of MMPs assess plaque vulnerability?. J Nucl Cardiol 2012; 19: 609-617.
- 113 Burtea C, Ballet S, Laurent S. et al. Development of a Magnetic Resonance Imaging Protocol for the Characterization of Atherosclerotic Plaque by Using Vascular Cell Adhesion Molecule-1 and Apoptosis-Targeted Ultrasmall Superpara-magnetic Iron Oxide Derivatives. Arterioscler Thromb Vasc Biol 2012; 32: 36-48.
- 114 Streitner I, Goldhofer M, Cho S. et al. Cellular imaging of human atherosclerotic lesions by intravascular electric impedance spectroscopy. PLoS One 2012; 07: e35405.
- 115 Meng X, Zhang K, Li J. et al. Statins Induce the Accumulation of Regulatory T Cells in the Atherosclerotic Plaque. Mol Med 2012; 18: 598-605.
- 116 Cyrus T, Sung S, Zhao L. et al. Effect of low-dose aspirin on vascular inflammation, plaque stability, and atherogenesis in low-density lipoprotein receptor-deficient mice. Circulation 2002; 106: 1282-1287.
- 117 Timmers L, Sluijter J P, Verlaan CW. et al. Cyclooxygenase-2 inhibition increases mortality, enhances left ventricular remodeling, and impairs systolic function after myocardial infarction in the pig. Circulation 2007; 115: 326-332.
- 118 Frutkin AD, Otsuka G, Stempien-Otero A. et al. TGF-[beta]1 limits plaque growth, stabilizes plaque structure, and prevents aortic dilation in apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol 2009; 29: 1251-1257.
- 119 Yang JM, Wang Y, Qi LH. et al. Combinatorial interference of toll-like receptor 2 and 4 synergistically stabilizes atherosclerotic plaque in apolipoprotein E-knock-out mice. J Cell Mol Med 2011; 15: 602-611.
- 120 Li Y, Si R, Feng Y. et al. Myocardial ischemia activates an injurious innate immune signaling via cardiac heat shock protein 60 and Toll-like receptor 4. J Biol Chem 2011; 286: 31308-31319.
- 121 Pellegrin M, Miguet-Alfonsi C, Bouzourene K. et al. Long-term exercise stabilizes atherosclerotic plaque in ApoE knockout mice. Med Sci Sports Exerc 2009; 41: 2128-2135.
- 122 Wallace EL, Abdel-Latif A, Charnigo R. et al. Meta-Analysis of Long-Term Outcomes for Drug-Eluting Stents Versus Bare-Metal Stents in Primary Percutaneous Coronary Interventions for ST-Segment Elevation Myocardial Infarction. Am J Cardiol 2012; 109: 932-940.
- 123 Kalesan B, Stefanini GG, Raber L. et al. Long-term comparison of everolimus-and sirolimus-eluting stents in patients with acute coronary syndromes. JACC Cardiovasc Interv 2012; 05: 145-154.
- 124 Serruys PW, Silber S, Garg S. et al. Comparison of zotarolimus-eluting and ever-olimus-eluting coronary stents. N Engl J Med 2010; 363: 136-146.
- 125 Alfonso F, Virmani R. New morphological insights on coronary plaque rupture: bridging the gap from anatomy to clinical presentation?. JACC Cardiov-asc Interv 2011; 04: 83-6.
- 126 Schoneveld AH, Oude Nijhuis MM, van Middelaar B. et al. Toll-like receptor 2 stimulation induces intimal hyperplasia and atherosclerotic lesion development. Cardiovasc Res 2005; 66: 162-169.
- 127 Arslan F, Smeets MB, O'Neill LA. et al. Myocardial ischemia/reperfusion injury is mediated by leukocytic toll-like receptor-2 and reduced by systemic administration of a novel anti-toll-like receptor-2 antibody. Circulation 2010; 121: 80-90.
- 128 Shishido T, Nozaki N, Yamaguchi S. et al. Toll-like receptor-2 modulates ventricular remodeling after myocardial infarction. Circulation 2003; 108: 2905-2910.
- 129 Vink A, Schoneveld AH, van der Meer JJ. et al. In vivo evidence for a role of tolllike receptor 4 in the development of intimal lesions. Circulation 2002; 106: 1985-1990.
- 130 Timmers L, Sluijter J P, van Keulen JK. et al. Toll-like receptor 4 mediates mal-adaptive left ventricular remodeling and impairs cardiac function after myocardial infarction. Circ Res 2008; 102: 257-264.
- 131 NeriSerneri GG, Prisco D, Martini F. et al. Acute T-cell activation is detectable in unstable angina. Circulation 1997; 95: 1806-1812.
- 132 Ammirati E, Cianflone D, Vecchio V. et al. Effector Memory T cells Are Associated With Atherosclerosis in Humans and Animal Models. J Am Heart Assoc 2012; 01: 27-41.
- 133 Giubilato S, Liuzzo G, Brugaletta S. et al. Expansion of CD4+CD28null T-lymphocytes in diabetic patients: exploring new pathogenetic mechanisms of increased cardiovascular risk in diabetes mellitus. Eur Heart J 2011; 32: 1214-1226.
- 134 Cirillo P, Golino P, Piscione F. et al. Transcoronary Th-17 lymphocytes and acute coronary syndromes: new evidence from the crime scene?. Int J Cardiol 2011; 153: 215-216.
- 135 Ammirati E, Cianflone D, Banfi M. et al. Circulating CD4+CD25hiCD127lo regulatory T-Cell levels do not reflect the extent or severity of carotid and coronary atherosclerosis. Arterioscler Thromb Vasc Biol 2010; 30: 1832-1841.
- 136 Ammirati E, Vermi AC, Cianflone D. et al. Expansion of T-cell receptor zeta dim effector T cells in acute coronary syndromes. Arterioscler Thromb Vasc Biol 2008; 28: 2305-2311.
- 137 Methe H, Brunner S, Wiegand D. et al. Enhanced T-helper-1 lymphocyte activation patterns in acute coronary syndromes. J Am Coll Cardiol 2005; 45: 1939-1945.
- 138 Liu LL, Lu JL, Chao PL. et al. Lower prevalence of circulating invariant natural killer T (iNKT) cells in patients with acute myocardial infarction undergoing primary coronary stenting. Int Immunopharmacol 2011; 11: 480-484.
- 139 Yilmaz A, Weber J, Cicha I. et al. Decrease in circulating myeloid dendritic cell precursors in coronary artery disease. J Am Coll Cardiol 2006; 48: 70-80.
- 140 Mazzone A, De Servi S, Ricevuti G. et al. Increased expression of neutrophil and monocyte adhesion molecules in unstable coronary artery disease. Circulation 1993; 88: 358-363.
- 141 Meisel SR, Shapiro H, Radnay J. et al. Increased expression of neutrophil and monocyte adhesion molecules LFA-1 and Mac-1 and their ligand ICAM-1 and VLA-4 throughout the acute phase of myocardial infarction: possible implications for leukocyte aggregation and microvascular plugging. J Am Coll Cardiol 1998; 31: 120-125.
- 142 Biasucci LM, D'Onofrio G, Liuzzo G. et al. Intracellular neutrophil myeloperox-idase is reduced in unstable angina and acute myocardial infarction, but its reduction is not related to ischemia. J Am Coll Cardiol 1996; 27: 611-616.
- 143 Wong CW, Luis S, Zeng I. et al. Eosinophilia and coronary artery vasospasm. Heart Lung Circ 2008; 17: 488-496.
- 144 Giugliano GR, Giugliano R P, Gibson CM. et al. Meta-analysis of corticosteroid treatment in acute myocardial infarction. Am J Cardiol 2003; 91: 1055-1059.
- 145 Azar RR, Rinfret S, Theroux P. et al. A randomized placebo-controlled trial to assess the efficacy of antiinflammatory therapy with methylprednisolone in unstable angina (MUNA trial). Eur Heart J 2000; 21: 2026-2032.
- 146 Sajadieh A, Wendelboe O, Hansen JF. et al. Nonsteroidal anti-inflammatory drugs after acute myocardial infarction. DAVIT Study Group. Danish Verapamil Infarction Trial. Am J Cardiol 1999; 83: 1263-1265 A9.
- 147 Altman R, Luciardi HL, Muntaner J. et al. Efficacy assessment of meloxicam, a preferential cyclooxygenase-2 inhibitor, in acute coronary syndromes without ST-segment elevation: the Nonsteroidal Anti-Inflammatory Drugs in Unstable Angina Treatment-2 (NUT-2) pilot study. Circulation 2002; 106: 191-195.
- 148 Mahaffey KW, Granger CB, Nicolau JC. et al. Effect of pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to fibrinolysis in acute myocardial infarction: the COMPlement inhibition in myocardial infarction treated with thromboLYtics (COMPLY) trial. Circulation 2003; 108: 1176-1183.
- 149 Granger CB, Mahaffey KW, Weaver WD. et al. Pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to primary percutaneous coronary intervention in acute myocardial infarction: the COMplement inhibition in Myo-cardial infarction treated with Angioplasty (COMMA) trial. Circulation 2003; 108: 1184-1190.
- 150 Armstrong PW, Granger CB, Adams PX. et al. Pexelizumab for acute ST-elev-ation myocardial infarction in patients undergoing primary percutaneous coronary intervention: a randomized controlled trial. J Am Med Assoc 2007; 297: 43-51.
- 151 Baran KW, Nguyen M, McKendall GR. et al. Double-blind, randomized trial of an anti-CD18 antibody in conjunction with recombinant tissue plasminogen activator for acute myocardial infarction: limitation of myocardial infarction following thrombolysis in acute myocardial infarction (LIMIT AMI) study. Circulation 2001; 104: 2778-2783.
- 152 Faxon D P, Gibbons RJ, Chronos NA. et al. The effect of blockade of the CD11/CD18 integrin receptor on infarct size in patients with acute myocardial infarction treated with direct angioplasty: the results of the HALT-MI study. J Am Coll Cardiol 2002; 40: 1199-1204.
- 153 Mertens P, Maes A, Nuyts J. et al. Recombinant P-selectin glycoprotein ligand-immunoglobulin, a P-selectin antagonist, as a n adjunc t to th ro mbolys is in acute myocardial infarction. The P-Selectin Antagonist Limiting Myonecrosis (PSALM) trial. Am Heart J 2006; 152: 125 e1-8.
- 154 Liu X, Huang Y, Hanet C. et al. Study of antirestenosis with the BiodivYsio dexamethasone-eluting stent (STRIDE): a first-in-human multicenter pilot trial. Catheter Cardiovasc Interv 2003; 60: 172-179.
- 155 Sakurai R, Inajima T, Kaneda H. et al. Sirolimus-eluting stents reduce long-term mortality compared with bare metal stents in ST-segment elevation myocardial infarction: A meta-analysis of randomized controlled trials. Int J Cardiol y2012. epub ahead of print.
- 156 Hannan EL, Samadashvili Z, Walford G. et al. Comparison of outcomes for patients receiving drug-eluting versus bare metal stents for non-ST-segment elevation myocardial infarction. Am J Cardiol 2011; 107: 1311-1318.
- 157 Windecker S, Serruys PW, Wandel S. et al. Biolimus-eluting stent with biodegradable polymer versus sirolimus-eluting stent with durable polymer for coronary revascularisation (LEADERS): a randomised non-inferiority trial. Lancet 2008; 372: 1163-1173.
- 158 Kim HK, Jeong MH, Ahn YK. et al. Comparison of outcomes between Zotarolimus- and sirolimus-eluting stents in patients with ST-segment elevation acute myocardial infarction. Am J Cardiol 2010; 105: 813-818.
- 159 Massberg S, Byrne RA, Kastrati A. et al. Polymer-free sirolimus- and probucol-eluting versus new generation zotarolimus-eluting stents in coronary artery disease: the Intracoronary Stenting and Angiographic Results: Test Efficacy of Sirolimus- and Probucol-Eluting versus Zotarolimus-eluting Stents (ISAR-TEST 5) trial. Circulation 2011; 124: 624-632.