title: Anti-inflammatory therapies for cardiovascular disease.
abstract: Atherothrombosis is no longer considered solely a disorder of lipoprotein accumulation in the arterial wall. Rather, the initiation and progression of atherosclerotic lesions is currently understood to have major inflammatory influences that encompass components of both the innate and acquired immune systems. Promising clinical data for 'upstream' biomarkers of inflammation such as interleukin-6 (IL-6) as well as 'downstream' biomarkers such as C-reactive protein, observations regarding cholesterol crystals as an activator of the IL-1β generating inflammasome, and recent Mendelian randomization data for the IL-6 receptor support the hypothesis that inflammatory mediators of atherosclerosis may converge on the central IL-1, tumour necrosis factor (TNF-α), IL-6 signalling pathway. On this basis, emerging anti-inflammatory approaches to vascular protection can be categorized into two broad groups, those that target the central IL-6 inflammatory signalling pathway and those that do not. Large-scale Phase III trials are now underway with agents that lead to marked reductions in IL-6 and C-reactive protein (such as canakinumab and methotrexate) as well as with agents that impact on diverse non-IL-6-dependent pathways (such as varespladib and darapladib). Both approaches have the potential to benefit patients and reduce vascular events. However, care should be taken when interpreting these trials as outcomes for agents that target IL-6 signalling are unlikely to be informative for therapies that target alternative pathways, and vice versa. As the inflammatory system is redundant, compensatory, and crucial for survival, evaluation of risks as well as benefits must drive the development of agents in this class.
authors.affiliation: Division of Cardiovascular Medicine, Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, 900 Commonwealth Avenue, Boston, MA, 02215 USA Division of Preventive Medicine, Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, 900 Commonwealth Avenue, Boston, MA, 02215 USA pridker@partners.org.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Ridker
authors.affiliation: Cardiology, University Heart Center, University Hospital Zurich and Center for Molecular Cardiology, Campus Schlieren, University Zurich, Zurich, Switzerland.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
mesh_terms: D056704:Adaptive Immunity / Q000502:physiology; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000975:Antioxidants / Q000627:therapeutic use; D050197:Atherosclerosis / Q000188:drug therapy*; D002097:C-Reactive Protein / Q000502:physiology; D002352:Carrier Proteins / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors; D003078:Colchicine / Q000627:therapeutic use; D006801:Humans; D006886:Hydroxychloroquine / Q000627:therapeutic use; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D020024:Leukotriene Antagonists / Q000627:therapeutic use; D008075:Lipoproteins, HDL / Q000187:drug effects; D008727:Methotrexate / Q000627:therapeutic use; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D064801:Phospholipase A2 Inhibitors / Q000627:therapeutic use; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D015843:Serpins / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D037761:Sirtuins / Q000627:therapeutic use; D013927:Thrombosis / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000502:physiology; D014611:Vaccination / Q000379:methods; D000093242:Interleukin-6 Inhibitors
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D002097:C-Reactive Protein; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D003078:Colchicine; D006886:Hydroxychloroquine; D007375:Interleukin-1; D015850:Interleukin-6; D020024:Leukotriene Antagonists; D008075:Lipoproteins, HDL; D008727:Methotrexate; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D064801:Phospholipase A2 Inhibitors; D017472:Receptors, Interleukin-1; D015843:Serpins; D037761:Sirtuins; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C453881:NLRP3 protein, human
keywords: Atherosclerosis; C reactive protein; Canakinumab; Colchicine; Darapladib; Inflammasome; Inflammation; Interleukin-6; Methotrexate; Salsalate