Role of interleukin 1 in the development of atherosclerosis

Atherosclerosis is now considered as chronic inflammatory vascular disease connected to «pathological» activation of innate and adaptive immunity, characterized by lipid deposition, leukocyte infiltration and proliferation of vascular smooth muscle cells. Subclinical (low grade) inflammation plays fundamental role at all stages of atherosclerotic process progression and determines cardiovascular catastrophes development and mortality. Proinflammatory cytokines including interleukin (IL) 1, IL6, tumor necrosis factor α (TNFα), IL17, IL18, IL27, IL33, IL37 tightly interacting within cytokine network occupy an important place among numerous mediators participating in immunopathogenesis of atherosclerosis and rheumatoid arthritis. IL1β playing an important role in the development of many acute and chronic immunoinflammatory diseases attracts particular attention. IL1β significance in the development of atherosclerosis is determined by many mechanisms including procoagulant activity, enhancement of monocytes and leucocytes adhesion to vascular endothelium, vascular smooth muscle cells growth and others. Fundamental role of inflammation in the development of atherosclerosis is well proved in investigations of anti-atherosclerotic effect of canakinumab. Randomized placebo-controlled trial CANTOS (Canakinumab ANti-inflammatory Thrombosis Otcomes Study) assessing efficacy of canakinumab as new tool for secondary prophylaxis cardiovascular complications in general population of patients with severe atherosclerotic vascular damage. CANTOS results in combination with accumulated in rheumatology data on cardiovascular effects of anti-inflammatory drugs are of great importance for personification of approach to secondary prophylaxis of caused by atherosclerosis cardiovascular complications. They also contribute to the development of inflammatory theory of atherosclerosis pathogenesis in the whole.

atherosclerosis, rheumatoid arthritis, gout, cytokines, interleukin 1, canakinumab, colchicine

1. Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med. 1999;340:S419-20. doi: 10.1016/S0002-8703(99)70266-8

2. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352:1685-95. doi: 10.1056/NEJMra043430

3. Libby P, Ridker PM, Hansson GK. Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol. 2009;54:2129-38. doi: 10.1016/j.jacc.2009.09.009

4. Fatkhullina AR, Peshkova IO, Koltsova EK. The Role of Cytokines in the Development of Atherosclerosis. Biochemistry (Moscow). 2016;81(11):1358-70. doi: 10.1134/S0006297916110134

5. Van Tassel BW, Toldo S, Mezzaroma E, Abbate A. Targeting interleukin-1 in heart disease. Circulation. 2013;128:1910-23. doi: 10.1161/CIRCULATION.113.003199

6. Libby PJ. A Interleukin-1 Beta as a Target for Atherosclerosis Therapy: Biological Basis of CANTOS and Beyond. J Amer Coll Cardiol. 2017;31;70(18):2278-89. doi: 10.1016/j.jacc.2017.09.028

7. Ridker PM. From C-reactive protein to interleukin-6 to interleukin-1: Moving upstream to identify novel targets for atheroprotection. Circ Res. 2016;118(1):145-56. doi: 10.1161/CIRCRESAHA.115.306656

8. Ray M, Autieri MV. Regulation of pro- and anti-atherogenic cytokines. Cytokines. 2017 Dec 6. pii: S1043-4666(17)30289-2. doi: 10.1016/j.cyto.2017.09.031

9. Reis A, Siegat NM, de Leon J. Interkeukin-6 in atherosclerosis: atherogenic or atheroprotective. Clin Lipidol. 2017;12:14023.

10. Van der Heijden T, Bot I, Kuiper J. The IL-12 cytokine family in cardiovascular diseases. Cytokine. 2017. pii: S1043-4666(17)30315- 0. doi: 10.1016/j.cyto.2017.10.010

11. Damen MSMA, Popa CD, Netea MG, et al. Interleukin-32 in chronic inflammatory conditions is associated with a higher risk of cardiovascular diseases. Atherosclerosis. 2017;264:83-91. doi: 10.1016/j.atherosclerosis.2017.07.005

12. Robert M, Miossec P. Effects of interleukin 17 on the cardiovascular system. Autoimmun Rev. 2017;16:984-91. doi: 10.1016/j.autrev.2017.07.009

13. Zhuang X, Wu B, Li J, et al. The emerging role of interleukin-37 in cardiovascular diseases. Immun Inflamm Dis. 2017;5(3):373-9. doi: 10.1002/iid3.159

14. Dinarello CA. An expanding role for interleukin-1 blockade from gout to cancer. Mol Med. 2014;20 Suppl 1:S43-S58. doi: 10.2119/molmed.2014.00232

15. Nasonov EL, Eliseev MS. Role of interleukin 1 in the development of human diseases. NauchnoPrakticheskaya Revmatologiya = Rheumatology Science and Practice. 2016;54(1):60-77 (In Russ.). doi: 10.14412/1995-4484-2016-60-77

16. Schett G, Dayer JM, Manger B. Interleukin-1 function and role in rheumatic disease. Nat Rev Rheumatol. 2016;12(1):14-24. doi: 10.1038/nrrheum.2016.166

17. Karasawa T, Takahashi M. Role of NLRP3 inflammasomes in atherosclerosis. J Atheroscler Thromb. 2017;24(5):443-51. doi: 10.5551/jat.RV17001 18. Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015;15:448-57. doi: 10.1038/ni1117-1271b

18. Popkova TV, Novikov DS, Nasonov EL. Interleukin 6 and cardiovascular pathology in rheumatoid arthritis. NauchnoPrakticheskaya Revmatologiya = Rheumatology Science and Practice. 2011;49(4):64-72 (In Russ.). doi: 10.14412/1995-4484-2011-63

19. Pokharel Y, Sharma PP, Qintar M, et al. High-sensitivity C-reactive protein levels and health status outcomes after myocardial infarction. Atherosclerosis. 2017;266:16-23. doi: 10.1016/j.atherosclerosis.2017.09.019

20. Wang A, Liu J, Li C, et al. Cumulative exposure to high-sensitivity C-reactive protein predicts the risk of cardiovascular disease. J Am Heart Assoc. 2017;6:e005610. doi: 10.1161/JAHA.117.005610 22. Ridker PM. A test in context. High-sensitive C-reactive protein. J Amer Coll Cardiol. 2016;67:712-23. doi: 10.1016/j.jacc.2015.11.037

21. Braunwald E. Creating controversy where none exists: the important role of C-reactive protein in the CARE, AFCAPS/TexCAPS, PROVE IT, REVERSAL, A to Z, JUPITER, HEART PROTECTION, and ASCOT trials. Eur Heart J. 2012;33:430-2. doi: 10.1093/eurheartj/ehr310

22. Bohula EA, Giugliano RP, Cannon CP, et al. Achievement of dual low-density lipoprotein cholesterol and high-sensitivity C-reactive protein targets more frequent with the addition of ezetimibe to simvastatin and associated with better outcomes in IMPROVE-IT. Circulation. 2015;132:1224-33. doi: 10.1161/CIRCULATIONAHA.115.018381

23. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371:2488-98. doi: 10.1056/NEJMoa1408617

24. Genovese G, Kähler AK, Handsaker RE, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371:2477-87. doi: 10.1056/NEJMoa1409405

25. Fuster JJ, MacLauchlan S, Zuriaga MA, et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science. 2017;355(6327):842-7. doi: 10.1126/science.aag1381

26. Fuster JJ, Walsh K. Somatic Mutations and Clonal Hematopoiesis: Unexpected Potential New Drivers of Age-Related Cardiovascular Disease. Circ Res. 2018;122(3):523-32. doi: 10.1161/CIRCRESAHA.117.3121

27. Jaiswal S, Natarajan P, Silver AJ, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med. 2017;377:111-21. doi: 10.1056/NEJMoa1701719

28. Sano S, Oshima K, Wang Y, et al. Tet2-Mediated Clonal Hematopoiesis Accelerates Heart Failure Through a Mechanism Involving the IL-1β/NLRP3 Inflammasome. J Am Coll Cardiol. 2018;71(8):875-86. doi: 10.1016/j.jacc.2017.12.037

29. Ridker PM, Thuren T, Zalewski A, Libby P. Interleukin-1β inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J. 2011;162:597-605. doi: 10.1016/j.ahj.2011.06.012

30. Ridker PM, Howard CP, Walter V, et al. Effects of interleukin-1β inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: a phase IIb randomized, placebo-controlled trial. Circulation. 2012;126:2739-48. doi: 10.1161/CIRCULATIONAHA.112.122556

31. Ridker PM, Everett BM, Thuren T, et al; CANTOS Trial Group. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017;377:1119-31. doi: 10.1056/NEJMoa1707914

32. Ridker PM, MacFadyen JG, Thuren T, et al; CANTOS Trial Group. Effect of interleukin-1β 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. doi: 10.1016/S0140-6736(17)32247-X

33. Ridker PM, MacFadyen JG, Everett BM, et al; CANTOS Trial Group. 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. doi: 10.1016/S0140-6736(17)32814-3

34. Ridker PM. Residual inflammatory risk: addressing the obverse side of the atherosclerosis prevention coin. Eur Heart J. 2016;37:1720-2. doi: 10.1093/eurheartj/ehw024

35. Nissen SE, Tuzcu EM, Schoenhagen P, et al: Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med. 2005;352:29-38. doi: 10.1056/NEJMoa042000

36. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883-99. doi: 10.1016/j.cell.2010.01.025

37. Rock KL, Kataoka H, Lai J-J. Uric acid as a danger signal in gout and its comorbidities. Nat Rev Rheumatol. 2013;9:13-23. doi: 10.1038/nrheum.2012/143

38. Andres M, Quintanilla MA, Sivera F, et al. Silent Monosodium Urate Crystal Deposits Are Associated With Severe Coronary Calcification in Asymptomatic Hyperuricemia: An Exploratory Study. Arthritis Rheum. 2017;68(6):1531-9. doi: 10.1002/art.39581

39. Bardin T, Richette P. Impact of comorbidities on gout and hyperuricaemia: an update on prevalence and treatment options. BMC Med. 2017;15(1):123. doi: 10.1186/s12916-017-0890-9

40. Solomon D, Glynn RJ, MacFadyen JG, et al. Serum urate, gout, and cardiovascular disease in a randomized controlled trial of canakinumab: a CANTOS secondary analysis. Ann Rheum Dis. 2018;56. doi: 10.1136/annrheumdis-2018.1567

41. Anders HJ. Of Inflammasomes and Alarmins: IL-1β and IL-1α in Kidney Disease. J Am Soc Nephrol. 2016;27(9):2564-75. doi: 10.1681/ASN.2016020177

42. Ridker PM, MacFadyen JG, Glynn RJ, et al. Inhibition of Interleukin-1β by Canakinumab and Cardiovascular Outcomes in Patients With Chronic Kidney Disease. Amer J Coll Cardiol. 2018;71(21):2405-14. doi: 10.1016/j.jacc.2018.03.490

43. Herder C, Dalmas E, Boni-Schnetzler M, Donath MY. The IL-1 pathway in type 2 diabetes and cardiovascular complications. Trends Endocrinol Metasb. 2015;26:551-63. doi: 10.1016/j.tem.2015.08.001

44. Rissanen A, Howard CP, Botha J, Thuren T; Global Investigators. Effect of anti-IL-1β antibody (canakinumab) on insulin secretion rates in impaired glucose tolerance or type 2 diabetes: results of a randomized, placebo-controlled trial. Diabetes Obes Metab. 2012;14:1088-96. doi: 10.1111/j.1463-1326.2012.01637.x

45. Hensen J, Howard CP, Walter V, Thuren T. Impact of interleukin1β antibody (canakinumab) on glycaemic indicators in patients with type 2 diabetes mellitus: results of secondary endpoints from a randomized, placebo-controlled trial. Diabetes Metab. 2013;39:524-31. doi: 10.1016/j.diabet.2013.07.003

46. Stahel M, Becker M, Graf N, Michels S. Systemic interleukin 1β inhibition in proliferative diabetic retinopathy: A Prospective Open-Label Study Using Canakinumab. Retina. 2016;36(2):385- 91. doi: 10.1097/IAE.0000000000000701

47. Choudhury RP, Birks JS, Mani V, et al. Arterial Effects of Canakinumab in Patients With Atherosclerosis and Type 2 Diabetes or Glucose Intolerance. J Am Coll Cardiol. 2016;68(16):1769-80. doi: 10.1016/j.jacc.2016.07.768

48. Cabrera SM, Wang X, Chen YG, et al; Canakinumab Study Group, Mandrup-Poulsen T; AIDA Study Group, Hessner MJ. Interleukin-1 antagonism moderates the inflammatory state associated with Type 1 diabetes during clinical trials conducted at disease onset. Eur J Immunol. 2016;46(4):1030-46. doi: 10.1002/eji.201546005

49. Everett BM, Donath MY, Pradhan AD, et al. Anti-Inflammatory Therapy with Canakinumab for the Prevention and Management of Diabetes. J Am Coll Cardiol. 2018. doi: 10.1016/j.jacc.2018.03.002

50. Eliseev MS, Zhelyabina OV, Markelova EI, Novikova DS, Vladimirov SA, Korsakova YuO, Aleksandrova EN, Novikov AA, Nasonov EL. Assessment of cardiovascular risk from the use of an interleukin-1 inhibitor in patients with severe tophaceous gout. Sovremennaya Revmatologiya = Modern Rheumatology Journal. 2016;10(1):7-14 (In Russ.). doi: 10.14412/1996-7012-2016-1-7-14

51. Leung YY, Hui LLY, Kraus VB. Colchicine – update on mechanisms of action and therapeutic uses. Semin Arthritis Rheum. 2015;45(3):341-50. doi: 10.1016/j.semarthrit.2015.06.013

52. Crittenden DB, Lehmann RA, Schneck L, et al. Colchicine use is associated with decreased prevalence of myocardial infarction in patients with gout. J Rheumatol. 2012;39:1458-64. doi: 10.3899/jrheum.111533

53. Solomon DH, Liu CC, Kuo IH, et al. Effects of colchicine on risk of cardiovascular events and mortality among patients with gout: a cohort study using electronic medical records linked with Medicare claims. Ann Rheum Dis. 2016;75(9):1674-9. doi: 10.1136/annrheumdis-2015-207984

54. Demidowich AP, Davis AI, Dedhia N, Yanovski JA. Colchicine to decrease NLRP3-activated inflammation and improve obesityrelated metabolic dysregulation. Med Hypotheses. 2016;92:67-73. doi: 10.1016/j.mehy.2016.04.039

55. Martinez GJ, Robertson S, Barraclough J, et al. Colchicine Acutely Suppresses Local Cardiac Production of Inflammatory Cytokines in Patients With an Acute Coronary Syndrome. J Am Heart Assoc. 2015;4:e002128. doi: 10/1161/JAHA.115.002128

56. Robertson S, Martinez GJ, Payet CA, et al. Colchicine therapy in acute coronary syndrome patients acts on caspase-1 to suppress NLRP3 inflammasome monocyte activation. Clin Sci (London). 2016;130(14):1237-46. doi: 10.1042/CS20160090

57. Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Lowdose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol. 2013;61:404-10. doi: 10.1016/j.jacc.2012.10.027

58. Vaidya K, Arnott C, Martinez GJ, et al. Colchicine Therapy and Plaque Stabilization in Patients With Acute Coronary Syndrome: A CT Coronary Angiography Study. JACC Cardiovasc Imaging. 2017 Oct 14. pii: S1936-878X(17)30791-X. doi: 10.1016/j.jcmg.2017.08.013

59. Deftereos S, Giannopoulos G, Angelidis C, et al. AntiInflammatory Treatment With Colchicine in Acute Myocardial Infarction: A Pilot Study. Circulation. 2015;132:1395-403. doi: 10.1161/CIRCULATIONAHA.115.017611

60. Tousoulis D, Oikonomou E, Economou EK, et al. Inflammatory cytokines in atherosclerosis: current therapeutic approaches. Eur Heart J. 2016;37:1723-32. doi: 10.1093/eurheartj/ehv759

61. Nasonov EL, Popkova TV. Anti-inflammatory therapy for atherosclerosis: Contribution to and lessons of rheumatology. NauchnoPrakticheskaya Revmatologiya = Rheumatology Science and Practice. 2017;55(5):465-73 (In Russ.). doi: 10.14412/1995-4484-2017-465-473

62. Savola P, Lundgren S, Kerä nen MAI, et al. Clonal hematopoiesis in patients with rheumatoid arthritis. Blood Cancer J. 2018;26;8(8):69. doi: 10.1038/s41408-018-0107-2