Inflammation, atherosclerosis, and coronary artery disease.

ecent research has shown that inflammation plays a key role in coronary artery disease (CAD) and other manifestations of atherosclerosis. Immune cells dominate early atherosclerotic lesions, their effector molecules accelerate progression of the lesions, and activation of inflammation can elicit acute coronary syndromes. This review highlights the role of inflammation in the pathogenesis of atherosclerotic CAD. It will recount the evidence that atherosclerosis, the main cause of CAD, is an inflammatory disease in which immune mechanisms interact with metabolic risk factors to initiate, propagate, and activate lesions in the arterial tree. A decade ago, the treatment of hypercholesterolemia and hypertension was expected to eliminate CAD by the end of the 20th century. Lately, however, that optimistic prediction has needed revision. Cardiovascular diseases are expected to be the main cause of death globally within the next 15 years owing to a rapidly increasing prevalence in developing countries and eastern Europe and the rising incidence of obesity and diabetes in the Western world. 1 Cardiovascular diseases cause 38 percent of all deaths in North America and are the most common cause of death in European men under 65 years of age and the second most common cause in women. These facts force us to revisit cardiovascular disease and consider new strategies for prediction, prevention, and treatment.

[1]  J. Nilsson CRP--marker or maker of cardiovascular disease? , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[2]  R. Kronmal,et al.  Azithromycin for the secondary prevention of coronary events. , 2005, The New England journal of medicine.

[3]  A. Skene,et al.  Antibiotic treatment of Chlamydia pneumoniae after acute coronary syndrome. , 2005, The New England journal of medicine.

[4]  Paul Schoenhagen,et al.  Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. , 2005, The New England journal of medicine.

[5]  C. Lines,et al.  Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. , 2005, The New England journal of medicine.

[6]  L. Glimcher,et al.  T-bet deficiency reduces atherosclerosis and alters plaque antigen-specific immune responses. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[7]  M. Pfeffer,et al.  C-reactive protein levels and outcomes after statin therapy. , 2005, The New England journal of medicine.

[8]  M. Ehrenstein,et al.  Statins for atherosclerosis--as good as it gets? , 2005, The New England journal of medicine.

[9]  P. Shah,et al.  Immunomodulation of atherosclerosis: implications for vaccine development. , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[10]  Yuzhi Zhang,et al.  Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosis-susceptible and -resistant regions of human vasculature. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[11]  T. V. van Berkel,et al.  Blocking endothelial adhesion molecules: a potential therapeutic strategy to combat atherogenesis , 2004, Current opinion in lipidology.

[12]  C. Söderberg-Nauclér,et al.  Human Cytomegalovirus Inhibits Cytokine-Induced Macrophage Differentiation , 2004, Journal of Virology.

[13]  D. Broide,et al.  IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis. , 2004, The Journal of clinical investigation.

[14]  P. Libby,et al.  Lysosomal Cysteine Proteases in Atherosclerosis , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[15]  Richard T. Lee,et al.  Th2-predominant inflammation and blockade of IFN-gamma signaling induce aneurysms in allografted aortas. , 2004, The Journal of clinical investigation.

[16]  B. Hedblad,et al.  Fatality of Future Coronary Events Is Related to Inflammation-Sensitive Plasma Proteins: A Population-Based Prospective Cohort Study , 2004, Circulation.

[17]  M. Margaglione,et al.  Low-grade inflammation may play a role in the etiology of the metabolic syndrome in patients with coronary heart disease: the HIFMECH study. , 2004, Metabolism: clinical and experimental.

[18]  R. Madhok,et al.  Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial , 2004, The Lancet.

[19]  Vilmundur Gudnason,et al.  C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. , 2004, The New England journal of medicine.

[20]  K. Moore,et al.  Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways , 2004, Nature Medicine.

[21]  F. Mach,et al.  Antagonism of RANTES Receptors Reduces Atherosclerotic Plaque Formation in Mice , 2004, Circulation research.

[22]  H. Ljunggren,et al.  CD1d-dependent Activation of NKT Cells Aggravates Atherosclerosis , 2004, The Journal of experimental medicine.

[23]  S. Szabo,et al.  Molecular mechanisms regulating Th1 immune responses. , 2003, Annual review of immunology.

[24]  R. Flavell,et al.  Disruption of TGF-β signaling in T cells accelerates atherosclerosis , 2003 .

[25]  E. Topol,et al.  Prognostic value of myeloperoxidase in patients with chest pain. , 2003, The New England journal of medicine.

[26]  N. Leitinger Oxidized phospholipids as modulators of inflammation in atherosclerosis , 2003, Current opinion in lipidology.

[27]  J. Witztum,et al.  Oxidized low density lipoprotein and innate immune receptors , 2003, Current opinion in lipidology.

[28]  D. Herrington,et al.  Matrix metalloproteinases: a review of their structure and role in acute coronary syndrome. , 2003, Cardiovascular research.

[29]  Christopher M O'Connor,et al.  Azithromycin for the secondary prevention of coronary heart disease events: the WIZARD study: a randomized controlled trial. , 2003, JAMA.

[30]  S. Akira,et al.  Reduced atherosclerosis in interleukin-18 deficient apolipoprotein E-knockout mice. , 2003, Cardiovascular research.

[31]  S. Frøland,et al.  Interleukin-7–Mediated Inflammation in Unstable Angina: Possible Role of Chemokines and Platelets , 2003, Circulation.

[32]  Qingbo Xu,et al.  Cross-Reactive B-Cell Epitopes of Microbial and Human Heat Shock Protein 60/65 in Atherosclerosis , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[33]  J. Witztum,et al.  Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL , 2003, Nature Medicine.

[34]  P. Shah,et al.  Inhibition of Atherosclerosis in ApoE-Null Mice by Immunization with ApoB-100 Peptide Sequences , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[35]  P. Arner The adipocyte in insulin resistance: key molecules and the impact of the thiazolidinediones , 2003, Trends in Endocrinology & Metabolism.

[36]  P. Shah,et al.  Effect of short-term treatment with azithromycin on recurrent ischaemic events in patients with acute coronary syndrome in the Azithromycin in Acute Coronary Syndrome (AZACS) trial: a randomised controlled trial , 2003, The Lancet.

[37]  I. Charo,et al.  Decreased atherosclerosis in CX3CR1-/- mice reveals a role for fractalkine in atherogenesis. , 2003, The Journal of clinical investigation.

[38]  Peter Libby,et al.  Chlamydia pneumoniae as an emerging risk factor in cardiovascular disease. , 2002, JAMA.

[39]  Kazuo Haze,et al.  Neutrophil Infiltration of Culprit Lesions in Acute Coronary Syndromes , 2002, Circulation.

[40]  S. Youssef,et al.  The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease , 2002, Nature.

[41]  P. Libby,et al.  Stabilization of atherosclerotic plaques: New mechanisms and clinical targets , 2002, Nature Medicine.

[42]  M. Gawaz,et al.  A Critical Role of Platelet Adhesion in the Initiation of Atherosclerotic Lesion Formation , 2002, The Journal of experimental medicine.

[43]  Jacob George,et al.  Oral tolerance with heat shock protein 65 attenuates Mycobacterium tuberculosis-induced and high-fat-diet-driven atherosclerotic lesions. , 2002, Journal of the American College of Cardiology.

[44]  P. Ridker,et al.  Inflammatory bio‐markers and cardiovascular risk prediction , 2002, Journal of internal medicine.

[45]  A. Sposito,et al.  Statin Therapy in Acute Coronary Syndromes: Mechanistic Insight Into Clinical Benefit , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[46]  Qingbo Xu Role of heat shock proteins in atherosclerosis. , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[47]  P. Libby,et al.  Mucosal Administration of Heat Shock Protein-65 Decreases Atherosclerosis and Inflammation in Aortic Arch of Low-Density Lipoprotein Receptor-Deficient Mice , 2002, Circulation.

[48]  J. Borén,et al.  Subendothelial retention of atherogenic lipoproteins in early atherosclerosis , 2002, Nature.

[49]  A. Daugherty,et al.  IFN-gamma deficiency exerts gender-specific effects on atherogenesis in apolipoprotein E-/- mice. , 2002, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[50]  M. Fishbein,et al.  Overexpression of Interleukin-10 by Activated T Lymphocytes Inhibits Atherosclerosis in LDL Receptor–Deficient Mice by Altering Lymphocyte and Macrophage Phenotypes , 2002, Circulation research.

[51]  J. Witztum Splenic immunity and atherosclerosis: a glimpse into a novel paradigm? , 2002, The Journal of clinical investigation.

[52]  G. Hansson,et al.  Protective immunity against atherosclerosis carried by B cells of hypercholesterolemic mice. , 2002, The Journal of clinical investigation.

[53]  G. Hansson,et al.  Expression of Toll-Like Receptors in Human Atherosclerotic Lesions: A Possible Pathway for Plaque Activation , 2002, Circulation.

[54]  S. Gordon,et al.  Scavenger receptors in innate immunity. , 2002, Current opinion in immunology.

[55]  J. Liao,et al.  Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[56]  A. Tedgui,et al.  Interleukin-18/Interleukin-18 Binding Protein Signaling Modulates Atherosclerotic Lesion Development and Stability , 2001, Circulation research.

[57]  E. Falk,et al.  Dietary Supplementation With Methionine and Homocysteine Promotes Early Atherosclerosis but Not Plaque Rupture in ApoE-Deficient Mice , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[58]  S. Marx,et al.  Bench to bedside: the development of rapamycin and its application to stent restenosis. , 2001, Circulation.

[59]  L. Lindbom,et al.  Importance of Primary Capture and L-Selectin–Dependent Secondary Capture in Leukocyte Accumulation in Inflammation and Atherosclerosis in Vivo , 2001, The Journal of experimental medicine.

[60]  G. Hansson,et al.  In vivo downregulation of T helper cell 1 immune responses reduces atherogenesis in apolipoprotein E-knockout mice. , 2001, Circulation.

[61]  V. Emery,et al.  Viral infections and their impact on chronic renal allograft dysfunction. , 2001, Transplantation.

[62]  G. Hansson,et al.  Chlamydia pneumoniae Infection Does Not Induce or Modify Atherosclerosis in Mice , 2001, Circulation.

[63]  M. Burnett,et al.  Cytomegalovirus infection increases development of atherosclerosis in Apolipoprotein-E knockout mice. , 2001, Atherosclerosis.

[64]  P. Libby,et al.  Macrophage myeloperoxidase regulation by granulocyte macrophage colony-stimulating factor in human atherosclerosis and implications in acute coronary syndromes. , 2001, The American journal of pathology.

[65]  P. Shah,et al.  Pravastatin Treatment Increases Collagen Content and Decreases Lipid Content, Inflammation, Metalloproteinases, and Cell Death in Human Carotid Plaques: Implications for Plaque Stabilization , 2001, Circulation.

[66]  Anders Hamsten,et al.  LDL Immunization Induces T-Cell–Dependent Antibody Formation and Protection Against Atherosclerosis , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[67]  F. Mach,et al.  Statins as a newly recognized type of immunomodulator , 2000, Nature Medicine.

[68]  A. Becker,et al.  Unstable atherosclerotic plaques contain T-cells that respond to Chlamydia pneumoniae. , 2000, Cardiovascular research.

[69]  M. Kurrer,et al.  Linking immune-mediated arterial inflammation and cholesterol-induced atherosclerosis in a transgenic mouse model. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[70]  A. Siegbahn,et al.  Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. , 2000, The New England journal of medicine.

[71]  A. Maseri,et al.  Evidence for Antigen-Driven T-Cell Response in Unstable Angina , 2000, Circulation.

[72]  G Olivetti,et al.  PTX3, A prototypical long pentraxin, is an early indicator of acute myocardial infarction in humans. , 2000, Circulation.

[73]  R. Frye,et al.  Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. , 2000, Circulation.

[74]  P. Ridker,et al.  C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. , 2000, The New England journal of medicine.

[75]  A. Quyyumi,et al.  Effects of total pathogen burden on coronary artery disease risk and C-reactive protein levels. , 2000, The American journal of cardiology.

[76]  Cecilia Soderberg-Naucler,et al.  The Human Cytomegalovirus Chemokine Receptor US28 Mediates Vascular Smooth Muscle Cell Migration , 1999, Cell.

[77]  M. Bureau,et al.  Protective role of interleukin-10 in atherosclerosis. , 1999, Circulation research.

[78]  K. Forfang,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. , 1999, Circulation.

[79]  U. Andersson,et al.  Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines. , 1999, Atherosclerosis.

[80]  S Marx,et al.  Inhibition of intimal thickening after balloon angioplasty in porcine coronary arteries by targeting regulators of the cell cycle. , 1999, Circulation.

[81]  G. Zhong,et al.  The atherogenic effects of chlamydia are dependent on serum cholesterol and specific to Chlamydia pneumoniae. , 1999, The Journal of clinical investigation.

[82]  R. Gaynor,et al.  The anti-inflammatory agents aspirin and salicylate inhibit the activity of IκB kinase-β , 1998, Nature.

[83]  I. Charo,et al.  Decreased lesion formation in CCR2−/− mice reveals a role for chemokines in the initiation of atherosclerosis , 1998, Nature.

[84]  P. Libby,et al.  Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. , 1998, Molecular cell.

[85]  W. Koenig,et al.  Activation of human aortic smooth-muscle cells is inhibited by PPARα but not by PPARγ activators , 1998, Nature.

[86]  R. Ross,et al.  Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in the ApoE-deficient mouse. , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[87]  P. Libby,et al.  Activation of monocyte/macrophage functions related to acute atheroma complication by ligation of CD40: induction of collagenase, stromelysin, and tissue factor. , 1997, Circulation.

[88]  A. Tall,et al.  IFN-gamma potentiates atherosclerosis in ApoE knock-out mice. , 1997, The Journal of clinical investigation.

[89]  Alan D. Lopez,et al.  Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study , 1997, The Lancet.

[90]  P. Ridker,et al.  Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. , 1997, The New England journal of medicine.

[91]  A. Rebuzzi,et al.  Plasma protein acute-phase response in unstable angina is not induced by ischemic injury. , 1996, Circulation.

[92]  P. Kovanen,et al.  TNF-alpha and IL-1beta selectively induce expression of 92-kDa gelatinase by human macrophages. , 1996, Journal of immunology.

[93]  M J Davies,et al.  Stability and instability: two faces of coronary atherosclerosis. The Paul Dudley White Lecture 1995. , 1996, Circulation.

[94]  G. Ciliberto,et al.  Elevated levels of interleukin-6 in unstable angina. , 1996, Circulation.

[95]  L. Demer,et al.  Cross-regulatory roles of interleukin (IL)-12 and IL-10 in atherosclerosis. , 1996, The Journal of clinical investigation.

[96]  W D Wagner,et al.  A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. , 1995, Arteriosclerosis, thrombosis, and vascular biology.

[97]  P. Constantinides Infiltrates of activated mast cells at the site of coronary atheromatous erosion or rupture in myocardial infarction. , 1995, Circulation.

[98]  Michael Ginsberg,et al.  Decreased atherosclerosis in mice deficient in both macrophage colony-stimulating factor (op) and apolipoprotein E. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[99]  V. Fuster,et al.  Coronary plaque disruption. , 1995, Circulation.

[100]  Y. Bobryshev,et al.  Ultrastructural recognition of cells with dendritic cell morphology in human aortic intima. Contacting interactions of Vascular Dendritic Cells in athero-resistant and athero-prone areas of the normal aorta. , 1995, Archives of histology and cytology.

[101]  J. Witztum,et al.  T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[102]  E. Miller,et al.  Immunization of low density lipoprotein (LDL) receptor-deficient rabbits with homologous malondialdehyde-modified LDL reduces atherogenesis. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[103]  A. Rebuzzi,et al.  The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina. , 1994, The New England journal of medicine.

[104]  V. Fuster,et al.  Macrophage Infiltration in Acute Coronary Syndromes: Implications for Plaque Rupture , 1994, Circulation.

[105]  W D Wagner,et al.  A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[106]  G. Hansson,et al.  Immune mechanisms in atherosclerosis. , 1994, Coronary artery disease.

[107]  P. Libby,et al.  Cytokines and growth factors positively and negatively regulate interstitial collagen gene expression in human vascular smooth muscle cells. , 1991, Arteriosclerosis and thrombosis : a journal of vascular biology.

[108]  M. Cybulsky,et al.  Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. , 1991, Science.

[109]  G. Gabbiani,et al.  Interferon gamma inhibits both proliferation and expression of differentiation-specific alpha-smooth muscle actin in arterial smooth muscle cells , 1989, The Journal of experimental medicine.

[110]  G. Hansson,et al.  Detection of activated T lymphocytes in the human atherosclerotic plaque. , 1989, The American journal of pathology.

[111]  J. Mehta,et al.  Neutrophil function in ischemic heart disease. , 1989, Circulation.

[112]  A. Maseri,et al.  Pre-existing coronary stenoses in patients with first myocardial infarction are not necessarily severe. , 1988, European heart journal.

[113]  M. Nieminen,et al.  SEROLOGICAL EVIDENCE OF AN ASSOCIATION OF A NOVEL CHLAMYDIA, TWAR, WITH CHRONIC CORONARY HEART DISEASE AND ACUTE MYOCARDIAL INFARCTION , 1988, The Lancet.

[114]  G. Hansson,et al.  Cyclosporin A inhibits smooth muscle proliferation in the vascular response to injury. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[115]  G. Bondjers,et al.  Regional Accumulations of T Cells, Macrophages, and Smooth Muscle Cells in the Human Atherosclerotic Plaque , 1986, Arteriosclerosis.

[116]  L. Wilhelmsen,et al.  Fibrinogen as a risk factor for stroke and myocardial infarction. , 1984, The New England journal of medicine.

[117]  A. Siegelaub,et al.  The leukocyte count as a predictor of myocardial infarction. , 1974, The New England journal of medicine.

[118]  R. Flavell,et al.  Disruption of TGF-beta signaling in T cells accelerates atherosclerosis. , 2003, The Journal of clinical investigation.

[119]  J. Michel,et al.  Interleukin-10 Deficiency Increases Atherosclerosis, Thrombosis, and Low-density Lipoproteins in Apolipoprotein E Knockout Mice , 2003, Molecular medicine.

[120]  C. Janeway,et al.  Innate immune recognition. , 2002, Annual review of immunology.

[121]  W. Koenig,et al.  Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators. , 1998, Nature.

[122]  J. D. Smith,et al.  Mouse models of atherosclerosis. , 1998, Laboratory animal science.

[123]  A. Becker,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. , 1994, Circulation.