Examining the Role of and Treatment Directed at IL-1β in Atherosclerosis
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The purpose of this review was to examine the role of IL-1β in the inflammatory process central to the development of atherosclerosis and to discuss current clinical evidence for treatments targeting IL-1β in coronary artery disease.
IL-1β has been shown to modulate atherosclerotic plaque progression by upregulating the synthesis of adhesion molecules on endothelial cells, as well increasing activation and proliferation of vascular smooth muscle cells. Animal studies have further suggested that alterations in the balance between agonists and antagonists of IL-1β are important in promoting atherosclerosis. In humans, preliminary assessment of therapy targeting IL-1β noted early reductions in serum inflammatory biomarkers among those with systemic inflammatory or coronary artery disease. The CANTOS trial, a large randomized double-blind study found that canakinumab, a monoclonal antibody targeting IL-1β, reduced ischemic events in patients being treated for secondary prevention.
Cellular, animal, and now clinical studies have suggested a role for therapies aimed at IL-1β for treatment of CAD. However, given potential side effects and costs of these medications, further study is required to determine which patients may be most suited for treatment above current standard of care.
KeywordsInterleukin-1β Atherosclerosis Coronary artery disease Inflammation
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Conflict of Interest
Razi Khan, Eric Rheaume, and Jean-Claude Tardif declare no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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- 1.Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. American Heart Association statistics committee and stroke statistics subcommittee. Heart disease and stroke statistics–2015 update: a report from the American Heart Association. Circulation. 2015;131:e29–e322.PubMedGoogle Scholar
- 5.•• Bevilacqua MP, Pober JS, Wheeler ME, Cotran RS, Gimbrone MA Jr. Interleukin-1 activation of vascular endothelium. Effects on procoagulant activity and leukocyte adhesion. Am J Pathol. 1985;121:394 Major study describing in vivo effects of IL-1β on vascular endothelial cells. PubMedPubMedCentralGoogle Scholar
- 7.• Varghese GP, Folkersen L, Strawbridge RJ, Halvorsen B, Yndestad A, Ranheim T, et al. NLRP3 inflammasome expression and activation in human atherosclerosis. J Am Heart Assoc. 2016;5:e003031 Study comparing expression of inflammasome in atherosclerotic arteries and non-diseased arteries. Google Scholar
- 12.• Chamberlain J, Gunn J, Francis S, Holt C, Crossman D. Temporal and spatial distribution of interleukin-1β in balloon injured porcine coronary arteries. Cardiovasc Res. 1999;44:156–65 Study looking at IL-1β synthesis in porcine coronary arteries in response to arterial inflammation. CrossRefGoogle Scholar
- 24.• Roubille F, Busseuil D, Shi Y, Nachar W, Mihalache-Avram T, Mecteau M, et al. The interleukin-1β modulator gevokizumab reduces neointimal proliferation and improves reendothelialization in a rat carotid denudation model. Atherosclerosis. 2014;236:277–85 Study where use of monoclonal antibody targeting IL-1β mitigated neointimal thickening in response to arterial inflammation. CrossRefGoogle Scholar
- 25.• Granowitz EV, Poutsiaka DD, Cannon JG, Wolff SM, Dinarello CA, Santos AA, et al. Production of interleukin-1-receptor antagonist during experimental endotoxaemia. Lancet. 1991;338:1423–4 Study that proposes use of IL-1Ra as serum biomarker for inflammation rather than IL-1β. CrossRefGoogle Scholar
- 30•.. Biasucci LM, Liuzzo G, Fantuzzi G, Caligiuri G, Rebuzzi AG, Ginnetti F, et al. Increasing levels of interleukin (IL)-1Ra and IL-6 during the first 2 days of hospitalization in unstable angina are associated with increased risk of in-hospital coronary events. Circulation. 1999;99:2079–84 Study examining prognostic impact of changes in serum IL-1Ra levels in patients admitted with unstable angina. CrossRefGoogle Scholar
- 31••.. Schofer N, Ludwig S, Rübsamen N, Schnabel R, Lackner KJ, Ruprecht HJ, et al. Prognostic impact of Interleukin-1 receptor antagonist in patients with documented coronary artery disease. Int J Cardiol. 2018;257:24–9 Large observational study examining prognostic impact of serum IL-1Ra levels in patients with ACS and stable angina. CrossRefGoogle Scholar
- 39.Abbate A, Kontos MC, Grizzard JD, Biondi-Zoccai GGL, Van Tassell BW, Robati R, et al. Interleukin-1 blockade with anakinra to prevent adverse cardiac remodeling after acute myocardial infarction (Virginia Commonwealth University Anakinra Remodeling Trial [VCU-ART] Pilot study). Am J Cardiol. 2010;105:1371–1377. e1.CrossRefGoogle Scholar
- 40.Abbate A, Van Tassell BW, Biondi-Zoccai G, Kontos MC, Grizzard JD, Spillman DW, et al. Effects of interleukin-1 blockade with anakinra on adverse cardiac remodeling and heart failure after acute myocardial infarction [from the Virginia Commonwealth University-Anakinra remodeling trial (2)(VCU-ART2) pilot study]. Am J Cardiol. 2013;111:1394–400.CrossRefGoogle Scholar
- 41.Abbate A, Kontos MC, Abouzaki NA, Melchior RD, Thomas C, Van Tassell BW, et al. Comparative safety of interleukin-1 blockade with anakinra in patients with ST-segment elevation acute myocardial infarction (from the VCU-ART and VCU-ART2 pilot studies). Am J Cardiol. 2015;115:288–92.CrossRefGoogle Scholar
- 42.• Morton AC, Rothman AMK, Greenwood JP, Gunn J, Chase A, Clarke B, et al. The effect of interleukin-1 receptor antagonist therapy on markers of inflammation in non-ST elevation acute coronary syndromes: the MRC-ILA Heart Study. Eur Heart J. 2014;36:377–84 Trial examining the effect of IL-1β inhibition on inflammatory biomarkers in patients with recent MI. CrossRefGoogle Scholar
- 45•.. Ridker PM, MacFadyen JG, Thuren T, Everett BM, Libby P, Glynn RJ, et al. 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;390:1833–42 CANTOS substudy looking at IL-1β inhibition and lung cancer incidence and mortality. CrossRefGoogle Scholar
- 47•.. Ridker PM, MacFadyen JG, Everett BM, Libby P, Thuren T, Glynn RJ, et al. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet. 2018;391:319–28 CANTOS substudy examining response of inflammatory markers to IL-1β inhibition therapy. CrossRefGoogle Scholar