Advertisement

BioDrugs

, Volume 32, Issue 2, pp 111–118 | Cite as

Interleukin-1 Blockade in Cardiovascular Diseases: From Bench to Bedside

  • Leo F Buckley
  • Antonio Abbate
Leading Article

Abstract

Interleukin-1 (IL-1) is the prototypical pro-inflammatory cytokine that occupies an apical place in the inflammatory cascade and also modulates cardiac function, functioning as a soluble cardiodepressant factor. Preclinical research over the past 4 decades has shown that blocking IL-1 processing or activity favorably affects cardiomyocyte survival and cardiac function in experimental animal models, paving the way for clinical studies in patients with heart disease. The promising results of phase II clinical trials of IL-1 blockade in patients with acute myocardial infarction and heart failure have been followed by a successful phase III trial in patients with prior acute myocardial infarction. Three IL-1 blockers with different mechanism of action are currently available for clinical use, although currently none have an indication for heart disease. We herein review the bench-to-bedside clinical translation of IL-1 targeting strategies and discuss the potential use of IL-1 blockade in patients with heart disease.

Notes

Compliance with Ethical Standards

Funding

No funding was received for the preparation of this manuscript.

Conflict of interest

Dr Abbate has received research support and consultant fees from Novartis, Swedish Orphan Biovitrum and Olatec. Dr Buckley reports no conflicts of interest.

References

  1. 1.
    Ford ES, Ajani UA, Croft JB, Critchley JA, Labarthe DR, Kottke TE, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980-2000. N Engl J Med. 2007;356(23):2388–98.CrossRefPubMedGoogle Scholar
  2. 2.
    American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2017 update: a report from the American Heart Association. Circulation. 2017;135(10):e146–603.CrossRefGoogle Scholar
  3. 3.
    Medzhitov R. Origin and physiological roles of inflammation. Nature. 2008;454(7203):428–35.CrossRefPubMedGoogle Scholar
  4. 4.
    Ridker PM. Residual inflammatory risk: addressing the obverse side of the atherosclerosis prevention coin. Eur Heart J. 2016;37(22):1720–2.CrossRefPubMedGoogle Scholar
  5. 5.
    Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol. 2012;32(9):2045–51.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336(14):973–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Ridker PM, Danielson E, Fonseca FAH, Genest J, Gotto AM, Kastelein JJP, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195–207.CrossRefPubMedGoogle Scholar
  8. 8.
    Dinarello CA. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood. 2011;117(14):3720–33.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Van Tassell BW, Toldo S, Mezzaroma E, Abbate A. Targeting interleukin-1 in heart disease. Circulation. 2013;128(17):1910–23.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Toldo S, Mezzaroma E, Mauro AG, Salloum F, Van Tassell BW, Abbate A. The inflammasome in myocardial injury and cardiac remodeling. Antioxid Redox Signal. 2015;22(13):1146–61.CrossRefPubMedGoogle Scholar
  11. 11.
    Toldo S, Abbate A. The NLRP3 inflammasome in acute myocardial infarction. Nat Rev Cardiol. 2017.  https://doi.org/10.1038/nrcardio.2017.161. [Epub ahead of print].
  12. 12.
    Libby P. Interleukin-1 beta as a target for atherosclerosis therapy: biological basis of CANTOS and Beyond. J Am Coll Cardiol. 2017;70:2278–89.CrossRefPubMedGoogle Scholar
  13. 13.
    Weber A, Wasiliew P, Kracht M. Interleukin-1 (IL-1) pathway. Sci Signal. 2010;3(105):cm1.PubMedGoogle Scholar
  14. 14.
    O’Brien LC, Mezzaroma E, Van Tassell BW, Marchetti C, Carbone S, Abbate A, et al. Interleukin-18 as a therapeutic target in acute myocardial infarction and heart failure. Mol Med. 2014;20(1):221–9.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Kakkar R, Lee RT. ST2 and adrenomedullin in heart failure. Heart Fail Clin. 2009;5:515–27.CrossRefPubMedGoogle Scholar
  16. 16.
    Shimokawa H, Ito A, Fukumoto Y, Kadokami T, Nakaike R, Sakata M, et al. Chronic treatment with interleukin-1?? induces coronary intimal lesions and vasospastic responses in pigs in vivo: the role of platelet-derived growth factor. J Clin Invest. 1996;97(3):769–76.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Isoda K, Sawada S, Ishigami N, Matsuki T, Miyazaki K, Kusuhara M, et al. Lack of interleukin-1 receptor antagonist modulates plaque composition in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2004;24(6):1068–73.CrossRefPubMedGoogle Scholar
  18. 18.
    Devlin CM, Kuriakose G, Hirsch E, Tabas I. Genetic alterations of IL-1 receptor antagonist in mice affect plasma cholesterol level and foam cell lesion size. Proc Natl Acad Sci USA. 2002;99(9):6280–5.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Libby P, Warner SJ, Friedman GB. Interleukin 1: a mitogen for human vascular smooth muscle cells that induces the release of growth-inhibitory prostanoids. J Clin Invest. 1988;81(2):487–98.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Chamberlain J, Evans D, King A, Dewberry R, Dower S, Crossman D, et al. Interleukin-1beta and signaling of interleukin-1 in vascular wall and circulating cells modulates the extent of neointima formation in mice. Am J Pathol. 2006;168(4):1396–403.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Chamberlain J, Francis S, Brookes Z, Shaw G, Graham D, Alp NJ, et al. Interleukin-1 regulates multiple atherogenic mechanisms in response to fat feeding. PLoS One. 2009;4(4):e5073.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Bevilacqua MP, Pober JS, Majeau GR, Cotran RS, Gimbrone MA. Interleukin 1 (IL-1) induces biosynthesis and cell surface expression of procoagulant activity in human vascular endothelial cells. J Exp Med. 1984;160(2):618–23.CrossRefPubMedGoogle Scholar
  23. 23.
    Bevilacqua MP, Pober JS, Wheeler ME, Cotran RS, Gimbrone MA. Interleukin 1 acts on cultured human vascular endothelium to increase the adhesion of polymorphonuclear leukocytes, monocytes, and related leukocyte cell lines. J Clin Invest. 1985;76(5):2003–11.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Bhaskar V, Yin J, Mirza AM, Phan D, Vanegas S, Issafras H, et al. Monoclonal antibodies targeting IL-1 beta reduce biomarkers of atherosclerosis in vitro and inhibit atherosclerotic plaque formation in Apolipoprotein E-deficient mice. Atherosclerosis. 2011;216(2):313–20.CrossRefPubMedGoogle Scholar
  25. 25.
    Castell JV, Gómez-lechón MJ, David M, Fabra R, Trullenque R, Heinrich PC. Acute-phase response of human hepatocytes: regulation of acute-phase protein synthesis by interleukin-6. Hepatology. 1990;12(5):1179–86.CrossRefPubMedGoogle Scholar
  26. 26.
    Libby P, Ordovas JM, Auger KR, Robbins AH, Birinyi LK, Dinarello CA. Endotoxin and tumor necrosis factor induce interleukin-1 gene expression in adult human vascular endothelial cells. Am J Pathol. 1986;124(2):179–85.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Choudhury RP, Birks JS, Mani V, Biasiolli L, Robson MD, L’Allier PL, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377:1119–31.CrossRefPubMedGoogle Scholar
  29. 29.
    Ridker PM, Howard CP, Walter V, Everett B, Libby P, Hensen J, 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(23):2739–48.CrossRefPubMedGoogle Scholar
  30. 30.
    Ridker PM, MacFadyen JG, Everett BM, Libby P, Thuren T, Glynn RJ. 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(10118):319–28.CrossRefPubMedGoogle Scholar
  31. 31.
    Abbate A, Salloum FN, Van Tassell BW, Vecile E, Toldo S, Seropian I, et al. Alterations in the interleukin-1/interleukin-1 receptor antagonist balance modulate cardiac remodeling following myocardial infarction in the mouse. PLoS One. 2011;6(11):e27923.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Abbate A, Salloum FN, Vecile E, Das A, Hoke NN, Straino S, et al. Anakinra, a recombinant human interleukin-1 receptor antagonist, inhibits apoptosis in experimental acute myocardial infarction. Circulation. 2008;117(20):2670–83.CrossRefPubMedGoogle Scholar
  33. 33.
    Sager HB, Heidt T, Hulsmans M, Dutta P, Courties G, Sebas M, et al. Targeting interleukin-1β reduces leukocyte production after acute myocardial infarction. Circulation. 2015;132(20):1880–90.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Toldo S, Mezzaroma E, Van Tassell BW, Farkas D, Marchetti C, Voelkel NF, et al. Interleukin-1β blockade improves cardiac remodelling after myocardial infarction without interrupting the inflammasome in the mouse. Exp Physiol. 2013;98(3):734–45.CrossRefPubMedGoogle Scholar
  35. 35.
    Harouki N, Nicol L, Remy-Jouet I, Henry JP, Dumesnil A, Lejeune A, et al. The IL-1β antibody gevokizumab limits cardiac remodeling and coronary dysfunction in rats with heart failure. JACC Basic Transl Sci. 2017;2(4):418–30.CrossRefGoogle Scholar
  36. 36.
    Seropian IM, Toldo S, Van Tassell BW, Abbate A. Anti-inflammatory strategies for ventricular remodeling following ST-segment elevation acute myocardial infarction. J Am Coll Cardiol. 2014;63(16):1593–603.CrossRefPubMedGoogle Scholar
  37. 37.
    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(10):1371–7.CrossRefPubMedGoogle Scholar
  38. 38.
    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(10):1394–400.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    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(3):288–92.CrossRefPubMedGoogle Scholar
  40. 40.
    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. 2015;36:377–84.CrossRefPubMedGoogle Scholar
  41. 41.
    Abbate A, Dinarello CA. Anti-inflammatory therapies in acute coronary syndromes: is IL-1 blockade a solution? Eur Heart J. 2015;36(6):337–9.CrossRefPubMedGoogle Scholar
  42. 42.
    Kacimi R, Long CS, Karliner JS. Chronic hypoxia modulates the interleukin-1beta-stimulated inducible nitric oxide synthase pathway in cardiac myocytes. Circulation. 1997;96(6):1937–43.CrossRefPubMedGoogle Scholar
  43. 43.
    Gulick T, Chung MK, Pieper SJ, Lange LG, Schreiner GF. Interleukin 1 and tumor necrosis factor inhibit cardiac myocyte beta-adrenergic responsiveness. Proc Natl Acad Sci USA. 1989;86:6753–7.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Chung MK, Gulick TS, Rotondo RE, Schreiner GF, Lange LG. Mechanism of cytokine inhibition of beta-adrenergic agonist stimulation of cyclic AMP in rat cardiac myocytes. Impairment of signal transduction. Circ Res. 1990;67(3):753–63.CrossRefPubMedGoogle Scholar
  45. 45.
    Liu SJ, Zhou W, Kennedy RH. Suppression of beta-adrenergic responsiveness of L-type Ca2 + current by IL-1beta in rat ventricular myocytes. Am J Physiol. 1999;276(1 Pt 2):H141–8.PubMedGoogle Scholar
  46. 46.
    El Khoury N, Mathieu S, Fiset C. Interleukin-1β Reduces L-type Ca 2 + Current through Protein Kinase Cϵ Activation in Mouse Heart. J Biol Chem. 2014;289(32):21896–908.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    McTiernan CF, Lemster BH, Frye C, Brooks S, Combes A, Feldman AM. Interleukin-1 beta inhibits phospholamban gene expression in cultured cardiomyocytes. Circ Res. 1997;81(4):493–503.CrossRefPubMedGoogle Scholar
  48. 48.
    Combes A, Frye CS, Lemster BH, Brooks SS, Watkins SC, Feldman AM, et al. Chronic exposure to interleukin 1β induces a delayed and reversible alteration in excitation-contraction coupling of cultured cardiomyocytes. Pflugers Arch Eur J Physiol. 2002;445(2):246–56.CrossRefGoogle Scholar
  49. 49.
    Tatsumi T, Matoba S, Kawahara A, Keira N, Shiraishi J, Akashi K, et al. Cytokine-induced nitric oxide production inhibits mitochondrial energy production and impairs contractile function in rat cardiac myocytes. J Am Coll Cardiol. 2000;35(5):1338–46.CrossRefPubMedGoogle Scholar
  50. 50.
    Van Tassell BW, Arena RA, Toldo S, Mezzaroma E, Azam T, Seropian IM, et al. Enhanced interleukin-1 activity contributes to exercise intolerance in patients with systolic heart failure. PLoS One. 2012;7(3):e33438.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Van Tassell BW, Seropian IM, Toldo S, Mezzaroma E, Abbate A. Interleukin-1β induces a reversible cardiomyopathy in the mouse. Inflamm Res. 2013;62(7):637–40.CrossRefPubMedGoogle Scholar
  52. 52.
    Toldo S, Mezzaroma E, Bressi E, Marchetti C, Carbone S, Sonnino C, et al. Interleukin-1β blockade improves left ventricular systolic/diastolic function and restores contractility reserve in severe ischemic cardiomyopathy in the mouse. J Cardiovasc Pharmacol. 2014;64(1):1–6.CrossRefPubMedGoogle Scholar
  53. 53.
    Thaik CM, Calderone A, Takahashi N, Colucci WS. Interleukin-1 beta modulates the growth and phenotype of neonatal rat cardiac myocytes. J Clin Invest. 1995;96(2):1093–9.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Francis GS, Bartos JA, Adatya S. Inotropes. J Am Coll Cardiol. 2014;63(20):2069–78.CrossRefPubMedGoogle Scholar
  55. 55.
    Van Tassell BW, Canada J, Carbone S, Trankle C, Buckley L, Oddi Erdle C, et al. Interleukin-1 blockade in recently decompensated systolic heart failure: results from the recently decompensated heart failure Anakinra Response Trial (REDHART). Circ Heart Fail. 2017;10(11):e004373.CrossRefPubMedGoogle Scholar
  56. 56.
    Mann DL. Innate immunity and the failing heart: the cytokine hypothesis revisited. Circ Res. 2015;356(25):2644–5.Google Scholar
  57. 57.
    Van Tassell BW, Buckley LF, Carbone S, Trankle CR, Canada JM, Dixon DL, et al. Interleukin-1 blockade in heart failure with preserved ejection fraction: rationale and design of the Diastolic Heart Failure Anakinra Response Trial 2 (D-HART2). Clin Cardiol. 2017;40(9):626–32.CrossRefPubMedGoogle Scholar
  58. 58.
    Mertens M, Ja S. Anakinra for rheumatoid arthritis (Review). Cochrane database Syst Rev. 2009;21(1):CD005121.Google Scholar
  59. 59.
    Vallabhaneni S, Chiller TM. Fungal infections and new biologic therapies. Curr Rheumatol Rep. 2016;18:29.CrossRefPubMedGoogle Scholar
  60. 60.
    Schiff MH, Kremer JM, Jahreis A, Vernon E, Isaacs JD, van Vollenhoven RF. Integrated safety in tocilizumab clinical trials. Arthritis Res Ther. 2011;13(5):R141.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Gualtierotti R, Ingegnoli F, Griffini S, Grovetti E, Meroni PL, Cugno M. Prothrombotic biomarkers in patients with rheumatoid arthritis: the beneficial effect of IL-6 receptor blockade. Clin Exp Rheumatol. 2016;34(3):451–8.PubMedGoogle Scholar
  62. 62.
    Kleveland O, Kunszt G, Bratlie M, Ueland T, Broch K, Holte E, et al. Effect of a single dose of the interleukin-6 receptor antagonist tocilizumab on inflammation and troponin T release in patients with non-ST-elevation myocardial infarction: a double-blind, randomized, placebo-controlled phase 2 trial. Eur Heart J. 2016;37(30):2406–13.CrossRefPubMedGoogle Scholar
  63. 63.
    Testa M, Yeh M, Lee P, Fanelli R, Loperfido F, Berman JW, et al. Circulating levels of cytokines and their endogenous modulators in patients with mild to severe congestive heart failure due to coronary artery disease or hypertension. J Am Coll Cardiol. 1996;28(4):964–71.CrossRefPubMedGoogle Scholar
  64. 64.
    Deswal A, Petersen NJ, Feldman AM, Young JB, White BG, Mann DL. Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the Vesnarinone trial (VEST). Circulation. 2001;103(16):2055–9.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Cardiovascular Medicine and Department of Pharmacy ServicesBrigham and Women’s HospitalBostonUSA
  2. 2.VCU Pauley Heart CenterVirginia Commonwealth UniversityRichmondUSA

Personalised recommendations