Inflammation and Atherosclerosis
2017; Lippincott Williams & Wilkins; Volume: 136; Issue: 20 Linguagem: Inglês
10.1161/circulationaha.117.030484
ISSN1524-4539
Autores Tópico(s)Inflammasome and immune disorders
ResumoHomeCirculationVol. 136, No. 20Inflammation and Atherosclerosis Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBInflammation and AtherosclerosisThe End of a Controversy Göran K. Hansson, MD, PhD Göran K. HanssonGöran K. Hansson Department of Medicine, Solna and Center for Molecular Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden. Originally published15 Sep 2017https://doi.org/10.1161/CIRCULATIONAHA.117.030484Circulation. 2017;136:1875–1877Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2017: Previous Version 1 Does inflammation matter in coronary artery disease? Is it a driving force in atherosclerosis or merely an epiphenomenon? Is there space for novel therapies besides those targeting cholesterol? The CANTOS trial (Canakinumab Anti-inflammatory Thrombosis Outcomes Study), which was presented at the European Society of Cardiology meeting in Barcelona a few weeks ago, provides answers to these important questions. Indeed, the results of this trial open up a new avenue for cardiovascular prevention.Atherosclerosis, the underlying pathology in most cases of myocardial infarction, ischemic stroke, and ischemic gangrene, is a disease of complex genesis that has remained controversial for decades. Clinical and experimental studies have provided unequivocal evidence for an etiologic role of cholesterol and also offered strong support for a pathogenic role of inflammation.1By targeting cholesterol, blood pressure, and cigarette smoking, cardiovascular prevention has become one of the great success stories in medicine. We have witnessed a reduction in the incidence of myocardial infarction by ≈40% in large parts of the world during the past 2 decades, and a substantial part of this decrease can be ascribed to preventive medicine.1 Cholesterol-lowering statin therapy reduces the incidence of major adverse cardiovascular events by 25% to 50% in individuals with elevated low-density lipoprotein cholesterol and has become standard therapy for a large segment of the population in the Western world.The success of statins made us wonder whether we could realistically expect any further improvement in cardiovascular prevention. This attitude gained further support when it was found that statins also have anti-inflammatory properties. Although residual risk after myocardial infarction remains high, many clinicians and investigators did not see any reason for further development of cardiovascular prevention. The results of the CANTOS study demand a reassessment of the situation.2CANTOS is a randomized, double-blind secondary prevention trial in 10 061 patients with prior myocardial infarction and elevated levels of the inflammation marker, high-sensitive C-reactive protein (>2 mg/L).2 In all, 80% of the study participants were treated for hypertension, 40% had diabetes mellitus, and >90% were on statin therapy. They were randomized into 4 groups that received canakinumab, a human monoclonal antibody to the inflammatory cytokine, interleukin (IL)-1β at 3 different dosages, or placebo.Canakinumab is currently used clinically in some rare autoinflammatory conditions and as a second line of treatment in rheumatoid diseases. As expected, canakinumab reduced high-sensitive C-reactive protein levels; it had no substantial effect on plasma lipids.2The primary end point of the study was the first occurrence of myocardial infarction, stroke, or cardiovascular death. Canakinumab reduced this end point significantly, from 4.5 per 100 person-years in the placebo group to 3.9 in the groups receiving ≥150 mg antibody per dose.2 This translated to a 15% relative reduction in risk. The effect was similar in the 300 mg per dose group, whereas the group receiving 50 mg per dose did not obtain any benefit. This finding suggests that a threshold somewhere between 50 and 150 mg must be reached to achieve protection.Serious side effects were rare and consisted mainly of infections.2 However, the mere fact that fatal infections were higher in groups receiving active treatment (0.31% versus 0.18% in the placebo group) warrants careful monitoring of infections in future studies and applications of canakinumab.Canakinumab treatment groups displayed remarkable effects on fatal cancer, with a major reduction in lung cancer.3 Further studies will be required to replicate these data.The results of the CANTOS study provide strong support for the hypothesis that atherosclerosis is an inflammatory disease. When CANTOS results are added to all the experimental and clinical data accumulated over decades, a clear picture emerges (Figure). The disease process is elicited when low-density lipoprotein accumulates in areas of disturbed flow in the artery, and therefore hypercholesterolemia and hypertension both act on the initiation of atherosclerosis. The pathological process that ensues is one of chronic inflammation, accompanied by repair processes, and eventually leads to thrombosis. In short, atherosclerosis is an inflammatory disease elicited by cholesterol accumulation in the artery.Download figureDownload PowerPointFigure. Role of inflammation in pathogenesis of atherothrombosis. LDL indicates low-density lipoprotein.IL-1β, the target of canakinumab, is produced as a proform in the macrophage and converted to active cytokine by the proteolytic enzyme, caspase-1.4 This enzyme is often linked to a proteolytic machine, the Nucleotide-Binding Oligomerization Domain, Leucine Rich Repeat And Pyrin Domain Containing 3 (NLRP3) inflammasome, which contains a pattern recognition receptor that is activated by certain crystals, including cholesterol microcrystals. When the macrophage accumulates large amounts of cholesterol through the uptake of modified low-density lipoprotein particles, cholesterol microcrystals precipitate in the cytosol. This causes inflammasome activation and IL-1β secretion.1,4 Therefore, the NLRP3 inflammasome links cholesterol accumulation to inflammation.IL-1β targets vascular cells, causing activation of leukocyte adhesion molecules, cytokines, and cyclooxygenase-2.4 IL-1β also facilitates adaptive immunity through its effect on T cells. Therefore, the overall effect of canakinumab is likely because of several downstream steps in innate and adaptive immunity.4Lowering cholesterol and blood pressure is now standard practice in cardiovascular medicine. Among patients in the CANTOS study, >90% were on statins, which have dual effects on lipids and inflammation. Therefore, most patients already obtained some degree of anti-inflammatory protection. The added benefit of IL-1β blockade was a 15% reduced event rate, on top of the ≈40% protection known to be achieved with statins. The magnitude of protection obtained with canakinumab was similar to that of the anti-PCSK9 antibody, evolocumab, in the recent FOURIER study.5 It is notable that FOURIER and CANTOS enrolled similar secondary prevention patient populations and demonstrated identical 15% relative risk reductions for evolocumab and canakinumab, respectively. Treating residual inflammatory risk appears, therefore, to be important in patients receiving statins. Such patients, with elevated high-sensitive C-reactive protein, will benefit from canakinumab therapy according to CANTOS.It would be interesting to know the extent of protection conferred by canakinumab alone, but it is unlikely that regulatory authorities will allow a secondary prevention trial in which cholesterol risk is not treated. Primary prevention trials would also be of great interest and should be particularly important for individuals with a high inflammatory burden.The results from CANTOS will undoubtedly encourage new drug development. Being an antibody, canakinumab requires parenteral injections and carries a certain, albeit small risk for adverse immune reactions. It would be desirable to develop small anti-inflammatory molecules for oral administration, and it also remains to be seen whether IL-1β is the only suitable target for control of vascular inflammation.4In conclusion, the CANTOS trial establishes beyond doubt that inflammation is a treatable pathogenic mechanism in atherosclerosis. It identifies IL-1β as a useful therapy target and will certainly encourage further clinical studies and drug development of anti-inflammatory compounds for cardiovascular prevention.DisclosuresNone.FootnotesThe opinions in this article are not necessarily those of the editors or of the American Heart Association.Circulation is available at http://circ.ahajournals.org.Correspondence to: Göran K. Hansson, MD, PhD, Department of Medicine, Solna and Center for Molecular Medicine, L8:03, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden. E-mail [email protected]References1. Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis.Nature. 2011; 473:317–325. doi: 10.1038/nature10146.CrossrefMedlineGoogle Scholar2. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ; CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease.N Engl J Med. 2017; 377:1119–1131. doi: 10.1056/NEJMoa1707914.CrossrefMedlineGoogle Scholar3. Ridker PM, MacFadyen JG, Thuren T, Everett BM, Libby P, Glynn RJ and Group CT. Effect of interleukin-1beta inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial.Lancet. 2017; 390:1833–1842. doi: 10.1016/S0140-6736(17)32247-X.CrossrefMedlineGoogle Scholar4. Bäck M, Hansson GK. Anti-inflammatory therapies for atherosclerosis.Nat Rev Cardiol. 2015; 12:199–211. doi: 10.1038/nrcardio.2015.5.CrossrefMedlineGoogle Scholar5. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR; FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease.N Engl J Med. 2017; 376:1713–1722. doi: 10.1056/NEJMoa1615664.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Kazandzhieva K, Mammadova-Bach E, Dietrich A, Gudermann T and Braun A (2022) TRP channel function in platelets and megakaryocytes: basic mechanisms and pathophysiological impact, Pharmacology & Therapeutics, 10.1016/j.pharmthera.2022.108164, 237, (108164), Online publication date: 1-Sep-2022. Gisterå A, Ketelhuth D, Malin S and Hansson G (2022) Animal Models of Atherosclerosis–Supportive Notes and Tricks of the Trade, Circulation Research, 130:12, (1869-1887), Online publication date: 10-Jun-2022. 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November 14, 2017Vol 136, Issue 20 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.117.030484PMID: 28916641 Originally publishedSeptember 15, 2017 Keywordsatherothrombosisinflammationclinical trialinterleukin-1atherosclerosismyocardial infarctionPDF download Advertisement SubjectsCardiovascular DiseaseInflammationSecondary Prevention
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