Advertisement

Molecular Medicine

, Volume 20, Issue 1, pp 221–229 | Cite as

Interleukin-18 as a Therapeutic Target in Acute Myocardial Infarction and Heart Failure

  • Laura C. O’Brien
  • Eleonora Mezzaroma
  • Benjamin W. Van Tassell
  • Carlo Marchetti
  • Salvatore Carbone
  • Antonio Abbate
  • Stefano Toldo
Review Article

Abstract

Interleukin 18 (IL-18) is a proinflammatory cytokine in the IL-1 family that has been implicated in a number of disease states. In animal models of acute myocardial infarction (AMI), pressure overload, and LPS-induced dysfunction, IL-18 regulates cardiomyocyte hypertrophy and induces cardiac contractile dysfunction and extracellular matrix remodeling. In patients, high IL-18 levels correlate with increased risk of developing cardiovascular disease (CVD) and with a worse prognosis in patients with established CVD. Two strategies have been used to counter the effects of IL-18:IL-18 binding protein (IL-18BP), a naturally occurring protein, and a neutralizing IL-18 antibody. Recombinant human IL-18BP (r-hIL-18BP) has been investigated in animal studies and in phase I/II clinical trials for psoriasis and rheumatoid arthritis. A phase II clinical trial using a humanized monoclonal IL-18 antibody for type 2 diabetes is ongoing. Here we review the literature regarding the role of IL-18 in AMI and heart failure and the evidence and challenges of using IL-18BP and blocking IL-18 antibodies as a therapeutic strategy in patients with heart disease.

Notes

Acknowledgment

A Abbate and BW Van Tassell are supported by research grants from the American Heart Association and the National Institutes of Health. E Mezzaroma and S Toldo are supported by American Heart Association postdoctoral grants.

References

  1. 1.
    Van Tassell BW, et al. (2012) Enhanced interleukin-1 activity contributes to exercise intolerance in patients with systolic heart failure. PloS One. 7:e33438.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Go AS, et al. (2013) Heart disease and stroke tatistics—2013 update: a report from the American Heart Association. Circulation. 127:e6–e245.Google Scholar
  3. 3.
    Seropian IM, Toldo S, Van Tassell BW, Abbate A. (2014) Anti-inflammatory strategies for ventricular remodeling following ST-segment elevation acute myocardial infarction. J. Amer. Coll. Cardiol. 63:1593–603.CrossRefGoogle Scholar
  4. 4.
    Gullestad L, et al. (2012) Inflammatory cytokines in heart failure: mediators and markers. Cardiology. 122:23–35.CrossRefPubMedGoogle Scholar
  5. 5.
    Kalogeropoulos AP, Georgiopoulou VV, Butler J. (2012) From risk factors to structural heart disease: the role of inflammation. Heart Fail. Clin. 8:113–23.CrossRefPubMedGoogle Scholar
  6. 6.
    Dinarello CA, Pomerantz BJ. (2001) Proinflammatory cytokines in heart disease. Blood Purif. 19:314–21.CrossRefGoogle Scholar
  7. 7.
    Mann DL. (2002) Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ. Res. 91:988–98.CrossRefGoogle Scholar
  8. 8.
    Prabhu SD. (2004) Cytokine-induced modulation of cardiac function. Circ. Res. 95:1140–53.CrossRefPubMedGoogle Scholar
  9. 9.
    Nakamura K, Okamura H, Wada M, Nagata K, Tamura T. (1989) Endotoxin-induced serum factor that stimulates gamma interferon production. Infec. Immun. 57:590–5.Google Scholar
  10. 10.
    Munder M, Mallo M, Eichmann K, Modolell M. (1998) Murine macrophages secrete interferon gamma upon combined stimulation with interleukin (IL)-12 and IL-18: A novel pathway of autocrine macrophage activation. J. Exp. Med. 187:2103–8.CrossRefGoogle Scholar
  11. 11.
    Okamura H, et al. (1995) Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature. 378:88–91.CrossRefPubMedGoogle Scholar
  12. 12.
    Ahn HJ, et al. (1997) A mechanism underlying synergy between IL-12 and IFN-gamma-inducing factor in enhanced production of IFN-gamma. J. Immunol. 159:2125–2131.PubMedGoogle Scholar
  13. 13.
    Bazan JF, Timans JC, Kastelein RA. (1996) A newly defined interleukin-1? Nature. 379:591.CrossRefPubMedGoogle Scholar
  14. 14.
    Artlett CM. (2012) The role of the NLRP3 inflammasome in fibrosis. Open Rheumatol. J. 6:80–6.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Mezzaroma E, et al. (2011) The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse. Proc. Nat. Acad. Sci. U. S. A. 108:19725–30.CrossRefGoogle Scholar
  16. 16.
    Gu Y. (1997) Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme. Science. 275:206–9.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Ghayur T, et al. (1997) Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production. Nature. 386:619–23.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Puren AJ, Fantuzzi G, Dinarello CA. (1999) Gene expression, synthesis, and secretion of interleukin 18 and interleukin 1beta are differentially regulated in human blood mononuclear cells and mouse spleen cells. Proc. Nat. Acad. Sci. U. S. A. 96:2256–61.CrossRefGoogle Scholar
  19. 19.
    Lamkanfi M, Dixit VM. (2012) Inflammasomes and their roles in health and disease. Annu. Rev. Cell. Dev. Biol. 28:137–61.CrossRefPubMedGoogle Scholar
  20. 20.
    Toldo S, et al. (2013) Interleukin-1beta immunoneu-tralization improves cardiac remodeling after myocardial infarction without interrupting the inflammasome in the mouse. Exp. Physiol. 98:734–45.Google Scholar
  21. 21.
    Kawaguchi M, et al. (2011) Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. Circulation. 123:594–604.CrossRefPubMedGoogle Scholar
  22. 22.
    Takahashi M. (2014) NLRP3 Inflammasome as a novel player in myocardial infarction. Int. Heart J. 55:101–5.CrossRefPubMedGoogle Scholar
  23. 23.
    Saxena A, et al. (2013) IL-1 induces proinflammatory leukocyte infiltration and regulates fibroblast phenotype in the infarcted myocardium. J. Immunol. 191:4838–48.CrossRefPubMedGoogle Scholar
  24. 24.
    Sugawara S, et al. (2001) Neutrophil proteinase 3-mediated induction of bioactive IL-18 secretion by human oral epithelial cells. J. Immunol. 167:6568–75.CrossRefPubMedGoogle Scholar
  25. 25.
    Joosten LA, et al. (2009) Inflammatory arthritis in caspase 1 gene-deficient mice: contribution of proteinase 3 to caspase 1-independent production of bioactive interleukin-1beta. Arthritis Rheum. 60:3651–62.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Omoto Y, et al. (2006) Human mast cell chymase cleaves pro-IL-18 and generates a novel and biologically active IL-18 fragment. J. Immunol. 177:8315–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Omoto Y, et al. (2010) Granzyme B is a novel interleukin-18 converting enzyme. J. Dermatol. Sci. 59:129–35.CrossRefPubMedGoogle Scholar
  28. 28.
    Dinarello CA. (2011) Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood. 117:3720–32.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Robertson SE, et al. (2006) Expression and alternative processing of IL-18 in human neutrophils. Eur. J. Immunol. 36:722–31.Google Scholar
  30. 30.
    Bellora F, et al. (2012) M-CSF induces the expression of a membrane-bound form of IL-18 in a subset of human monocytes differentiating in vitro toward macrophages. Eur. J. Immunol. 42:1618–26.CrossRefPubMedGoogle Scholar
  31. 31.
    Dinarello CA. (2012) Membrane interleukin-18 revisits membrane IL-1alpha in T-helper type 1 responses. Eur. J. Immunol. 42:1385–7.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Akita K, et al. (1997) Involvement of caspase-1 and caspase-3 in the production and processing of mature human interleukin 18 in monocytic THP.1 cells. J. Biol. Chem. 272:26595–603.CrossRefPubMedGoogle Scholar
  33. 33.
    Torigoe K, et al. (1997) Purification and characterization of the human interleukin-18 receptor. J. Biol. Chem. 272:25737–42.CrossRefPubMedGoogle Scholar
  34. 34.
    Born TL, Thomassen E, Bird TA, Sims JE. (1998) Cloning of a novel receptor subunit, AcPL, required for interleukin-18 signaling. J. Biol. Chem. 273:29445–50.CrossRefPubMedGoogle Scholar
  35. 35.
    Parnet P, Garka KE, Bonnert TP, Dower SK, Sims JE. (1996) IL-1Rrp is a novel receptor-like molecule similar to the type I interleukin-1 receptor and its homologues T1/ST2 and IL-1R AcP. J. Biol. Chem. 271:3967–70.CrossRefPubMedGoogle Scholar
  36. 36.
    Boraschi D, et al. (2011) IL-37: a new anti-inflammatory cytokine of the IL-1 family. Eur. Cytokine Net. 22:127–47.Google Scholar
  37. 37.
    Nold MF, etal. (2010) IL-37 is a fundamental inhibitor of innate immunity. Nat. Immunol. 11:1014–22.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Riva F, etal. (2012) TIR8/SIGIRR is an interleukin-1 receptor/toll like receptor family member with regulatory functions in inflammation and immunity. Front Immunol. 3:322.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Lee JK, et al. (2004) Differences in signaling pathways by IL-1beta and IL-18. Proc. Natl. Acad. Sci. U. S. A. 101:8815–20.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Adachi O, et al. (1998) Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity. 9:143–50.CrossRefPubMedGoogle Scholar
  41. 41.
    Kanakaraj P, et al. (1999) Defective interleukin (IL)-18-mediated natural killer and T helper cell type 1 responses in IL-1 receptor-associated kinase (IRAK)-deficient mice. J. Exp. Med. 189:1129–38.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Kojima H, et al. (1998) Interleukin-18 activates the IRAK-TRAF6 pathway in mouse EL-4 cells. Biochem. Biophys. Res. Comm. 244:183–6.CrossRefPubMedGoogle Scholar
  43. 43.
    Wyman TH, et al. (2002) Physiological levels of in-terleukin-18 stimulate multiple neutrophil functions through p38 MAP kinase activation. J. Leukoc. Biol. 72:401–9.PubMedGoogle Scholar
  44. 44.
    Novick D, et al. (1999) Interleukin-18 binding protein: a novel modulator of the Th1 cytokine response. Immunity. 10:127–36.CrossRefPubMedGoogle Scholar
  45. 45.
    Kim SH, et al. (2000) Structural requirements of six naturally occurring isoforms of the IL-18 binding protein to inhibit IL-18. Proc. Nat. Acad. Sci. U. S. A. 97:1190–5.CrossRefGoogle Scholar
  46. 46.
    Mallat Z, et al. (2001) Expression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability. Circulation. 104:1598–603.CrossRefPubMedGoogle Scholar
  47. 47.
    Hong SN, et al. (2013) Atherosclerotic biomarkers and aortic atherosclerosis by cardiovascular magnetic resonance imaging in the Framingham Heart Study. J. Am. Heart Assoc. 2:e000307.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Blankenberg S. (2002) Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation. 106:24–30.CrossRefPubMedGoogle Scholar
  49. 49.
    Jefferis BJ, et al. (2011) Interleukin 18 and coronary heart disease: prospective study and systematic review. Atherosclerosis. 217:227–33.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Hartford M, et al. (2010) Interleukin-18 as a predictor of future events in patients with acute coronary syndromes. Arterioscler. Thromb. Vasc. Biol. 30:2039–46.CrossRefPubMedGoogle Scholar
  51. 51.
    Blankenberg S, et al. (2003) Interleukin-18 and the risk of coronary heart disease in European men: the Prospective Epidemiological Study of Myocardial Infarction (PRIME). Circulation. 108:2453–9.CrossRefPubMedGoogle Scholar
  52. 52.
    Kaptoge S, et al. (2013) Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis. Europ. Heart J. 35:578–89.CrossRefGoogle Scholar
  53. 53.
    Seta Y, et al. (2000) Interleukin 18 in acute myocardial infarction. Heart. 84:668.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Mallat Z, et al. (2004) Evidence for altered interleukin 18 (IL)-18 pathway in human heart failure. FASEB J. 18:1752–4.CrossRefGoogle Scholar
  55. 55.
    Gangemi S, et al. (2003) Increased circulating Interleukin-18 levels in centenarians with no signs of vascular disease: another paradox of longevity? Exp. Gerontol. 38:669–72.CrossRefPubMedGoogle Scholar
  56. 56.
    Chandrasekar B, Mummidi S, Claycomb WC, Mestril R, Nemer M. (2005) Interleukin-18 is a pro-hypertrophic cytokine that acts through a phosphatidylinositol 3-kinase-phosphoinositide-dependent kinase-1-Akt-GATA4 signaling pathway in cardiomyocytes. J. Biol. Chem. 280:4553–67.CrossRefPubMedGoogle Scholar
  57. 57.
    Gardner D. (2003) Natriuretic peptides: markers or modulators of cardiac hypertrophy? Trends Endocrinol. Metabol. 14:411–6.CrossRefGoogle Scholar
  58. 58.
    Woldbaek PR, et al. (2005) Daily administration of interleukin-18 causes myocardial dysfunction in healthy mice. Am. J. Physiol. Heart Circ. Physiol. 289:H708–14.CrossRefPubMedGoogle Scholar
  59. 59.
    Platis A, et al. (2008) The effect of daily administration of IL-18 on cardiac structure and function. Perfusion. 23:237–42.CrossRefPubMedGoogle Scholar
  60. 60.
    Colston JT, et al. (2007) Interleukin-18 knockout mice display maladaptive cardiac hypertrophy in response to pressure overload. Biochem. Biophys. Res. Commun. 354:552–8.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Chang H, et al. (2013) Effect of hydrodynamics-based delivery of IL-18BP fusion gene on rat experimental autoimmune myocarditis. Clin. Exp. Med. 2013 Oct 12. [Epub ahead of print].Google Scholar
  62. 62.
    Woldbaek PR, et al. (2003) Increased cardiac IL-18 mRNA, pro-IL-18 and plasma IL-18 after myocardial infarction in the mouse; a potential role in cardiac dysfunction. Cardiovasc. Res. 59:122–31.CrossRefPubMedGoogle Scholar
  63. 63.
    Venkatachalam K, et al. (2009) Neutralization of interleukin-18 ameliorates ischemia/reperfusion-induced myocardial injury. J. Biol. Chem. 284:7853–65.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Wang M, et al. (2009) IL-18 binding protein-expressing mesenchymal stem cells improve myocardial protection after ischemia or infarction. Proc. Nat. Acad. Sci. U. S. A. 106:17499–504.CrossRefGoogle Scholar
  65. 65.
    Toldo S, et al. (2014) Formation of the inflammasome in acute myocarditis. Int. J. Cardiol. 171:e119–21.CrossRefPubMedGoogle Scholar
  66. 66.
    Hedayat M, Mahmoudi MJ, Rose NR, Rezaei N. (2010) Proinflammatory cytokines in heart failure: double-edged swords. Heart Fail. Rev. 15:543–62.CrossRefPubMedGoogle Scholar
  67. 67.
    Puren AJ, Fantuzzi G, Gu Y, Su MS, Dinarello CA. (1998) Interleukin-18 (IFNgamma-inducing factor) induces IL-8 and IL-1beta via TNFalpha production from non-CD14+ human blood mononuclear cells. J. Clin. Invest. 101:711–21.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Morel JC, Park CC, Kumar P, Koch AE. (2001) Interleukin-18 induces rheumatoid arthritis synovial fibroblast CXC chemokine production through NFkappaB activation. Lab. Invest. 81:1371–83.CrossRefPubMedGoogle Scholar
  69. 69.
    Netea MG, Kullberg BJ, Verschueren I, Van Der Meer JW. (2000) Interleukin-18 induces production of proinflammatory cytokines in mice: no intermediate role for the cytokines of the tumor necrosis factor family and interleukin-1beta. Eur. J. Immunol. 30:3057–60.CrossRefPubMedGoogle Scholar
  70. 70.
    Dinarello CA. (1999) IL-18: A TH1-inducing, pro inflammatory cytokine and new member of the IL-1 family. J. Allergy Clin. Immunol. 103:11–24.CrossRefPubMedGoogle Scholar
  71. 71.
    Pomerantz BJ, Reznikov LL, Harken AH, Dinarello CA. (2001) Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1beta. Proc. Natl. Acad. Sci. 98:2871–6.CrossRefPubMedGoogle Scholar
  72. 72.
    Raeburn CD, et al. (2002) Neutralization of IL-18 attenuates lipopolysaccharide-induced myocardial dysfunction. Am. J. Physiol. Heart Circ. Phys. 283: H650–7.CrossRefGoogle Scholar
  73. 73.
    Leung BP, et al. (2001) A role for IL-18 in neutrophil activation. J. Immunol. 167:2879–86.CrossRefPubMedGoogle Scholar
  74. 74.
    Toldo S, et al. (2014) Interleukin-18 mediates interleukin-1-induced cardiac dysfunction. Am. J. Physiol. Heart Circ. Physiol. 306:H1025–31.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Fowler MB, Laser JA, Hopkins GL, Minobe W, Bristow MR. (1986) Assessment of the beta-adrenergic receptor pathway in the intact failing human heart: progressive receptor down-regulation and subsensitivity to agonist response. Circulation. 74:1290–302.CrossRefPubMedGoogle Scholar
  76. 76.
    Lefkowitz RJ, Rockman HA, Koch WJ. (2000) Catecholamines, cardiac beta-adrenergic receptors, and heart failure. Circulation. 101:1634–7.CrossRefPubMedGoogle Scholar
  77. 77.
    Naga Prasad SV, Nienaber J, Rockman HA. (2001) Beta-adrenergic axis and heart disease. Trends Gen. 17:S44–49.CrossRefGoogle Scholar
  78. 78.
    Murray DR, et al. (2012) Beta2 adrenergic activation induces the expression of IL-18 binding protein, a potent inhibitor of isoproterenol induced cardiomyocyte hypertrophy in vitro and myocardial hypertrophy in vivo. J. Mol. Cell. Cardiol. 52:206–18.CrossRefPubMedGoogle Scholar
  79. 79.
    Chandrasekar B, et al. (2004) Beta-adrenergic stimulation induces interleukin-18 expression via beta2-AR, PI3K, Akt, IKK, and NF-kappaB. Biochem. Biophys. Res. Comm. 319:304–11.CrossRefPubMedGoogle Scholar
  80. 80.
    Chandrasekar B, et al. (2004) Activation of intrinsic and extrinsic proapoptotic signaling pathways in interleukin-18-mediated human cardiac endothelial cell death. J. Biol. Chem. 279:20221–33.CrossRefPubMedGoogle Scholar
  81. 81.
    Dao T, Ohashi K, Kayano T, Kurimoto M, Okamura H. (1996) Interferon-gamma-inducing factor, a novel cytokine, enhances Fas ligand-mediated cytotoxicity of murine T helper 1 cells. Cell. Immunol. 173:230–5.CrossRefPubMedGoogle Scholar
  82. 82.
    Tsutsui H, et al. (1996) IFN-gamma-inducing factor up-regulates Fas ligand-mediated cytotoxic activity of murine natural killer cell clones. J. Immunol. 157:3967–73.PubMedGoogle Scholar
  83. 83.
    Chandrasekar B, Valente AJ, Freeman GL, Mahimainathan L, Mummidi S. (2006) Interleukin-18 induces human cardiac endothelial cell death via a novel signaling pathway involving NF-kappaB-dependent PTEN activation. Biochem. Biophys. Res. Comm. 339:956–63.CrossRefPubMedGoogle Scholar
  84. 84.
    Yu Q, et al. (2009) IL-18 induction of osteopontin mediates cardiac fibrosis and diastolic dysfunction in mice. Am. J. Physiol. Heart Circ. Physiol. 297:H76–85.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Stawowy P, et al. (2002) Increased myocardial expression of osteopontin in patients with advanced heart failure. Eur. J. Heart Fail. 4:139–46.CrossRefPubMedGoogle Scholar
  86. 86.
    Reddy VS, et al. (2008) Interleukin-18 stimulates fibronectin expression in primary human cardiac fibroblasts via PI3K-Akt-dependent NF-kappaB activation. J. Cell. Physiol. 215:697–707.CrossRefPubMedGoogle Scholar
  87. 87.
    Fix C, Bingham K, Carver W. (2011) Effects of interleukin-18 on cardiac fibroblast function and gene expression. Cytokine. 53:19–28.CrossRefPubMedGoogle Scholar
  88. 88.
    First Time in Human Study of Intravenous Interleukin-18 Antibody (A18110040) [Internet]. [Bethesda (MD)]: U.S. National Institutes of Health, U.S. National Library of Medicine.; [updated 2012 Dec 19; cited 2014 May 2]. Available from: https://doi.org/clinicaltrials.gov/ct2/show/NCT01035645. NLM identifier, NCT01035645.
  89. 89.
    Tak PP, Bacchi M, Bertolino M. (2006) Pharmacokinetics of IL-18 binding protein in healthy volunteers and subjects with rheumatoid arthritis or plaque psoriasis. Eur. J. Drug Metab. Pharmacokinet. 31:109–16.CrossRefPubMedGoogle Scholar
  90. 90.
    Marchetti C, et al. (2013) A novel pharmacologic inhibitor of the NLRP3 inflammasome limits myocardial injury following ischemia-reperfusion in the mouse. J. Cardiovasc. Pharmacol. 63:316–22.CrossRefGoogle Scholar
  91. 91.
    Investigate the Efficacy and Safety of GSK1070806 in Obese Subjects With T2DM [Internet]. [Bethesda (MD)]: U.S. National Institutes of Health, U.S. National Library of Medicine; [updated 2014 Apr 14; cited 2014 May 2]. Available from: https://doi.org/www.clinicaltrials.gov/ct2/show/NCT01648153?term=GSK1070806&rank=1. NLM identifier, NCT01648153.
  92. 92.
    Crossman DC, et al. (2008) Investigation of the effect of Interleukin-1 receptor antagonist (IL-1ra) on markers of inflammation in non-ST elevation acute coronary syndromes (The MRC-ILA-HEART Study). Trials. 9:8.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Abbate A, et al. (2010) 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. 105:1371–7 e1.CrossRefPubMedGoogle Scholar
  94. 94.
    Abbate A, et al. (2013) 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. 111:1394–400.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    IL-1 Blockade in Acute Myocardial Infarction (VCU-ART3) [Internet]. [Bethesda (MD)]: U.S. National Institutes of Health, U.S. National Library of Medicine; [updated 2013 Sep 20; cited 2014 May 2]. Available from: https://doi.org/clinicaltrials.gov/ct2/show/NCT01950299?term=nct01950299&rank=1. NLM identifier, NCT01950299.
  96. 96.
    Van Tassell BW, et al. (2014) Effects of inter-leukin-1 blockade with anakinra on aerobic exercise capacity in patients with heart failure and preserved ejection fraction (from the D-HART pilot study). Am. J. Cardiol. 113:321–7.CrossRefPubMedGoogle Scholar
  97. 97.
    Van Tassell BW, Toldo S, Mezzaroma E, Abbate A. (2013) Targeting interleukin-1 in heart disease. Circulation. 128:1910–23.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Borlaug BA, Paulus WJ. (2011) Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur. Heart J. 32:670–9.CrossRefPubMedGoogle Scholar
  99. 99.
    Westermann D, et al. (2011) Cardiac inflammation contributes to changes in the extracellular matrix in patients with heart failure and normal ejection fraction. Circ. Heart Fail. 4:44–52.CrossRefPubMedGoogle Scholar
  100. 100.
    Stuyt RJ, et al. (2002) Role of interleukin-18 in host defense against disseminated Candida albicans infection. Infect. Immun. 70:3284–6.CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Huang X, McClellan SA, Barrett RP, Hazlett LD. (2002) IL-18 contributes to host resistance against infection with Pseudomonas aeruginosa through induction of IFN-gamma production. J. Immunol. 168:5756–63.CrossRefPubMedGoogle Scholar
  102. 102.
    Liu B, et al. (2004) Interleukin-18 improves the early defence system against influenza virus infection by augmenting natural killer cell-mediated cytotoxicity. J. Gen. Virol. 85:423–8.CrossRefPubMedGoogle Scholar

Copyright information

© The Author(s) 2014

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (https://doi.org/creativecommons.org/licenses/by-nc-nd/4.0/)

Authors and Affiliations

  • Laura C. O’Brien
    • 1
  • Eleonora Mezzaroma
    • 2
    • 3
    • 4
  • Benjamin W. Van Tassell
    • 2
    • 3
    • 4
  • Carlo Marchetti
    • 2
    • 3
  • Salvatore Carbone
    • 2
    • 3
  • Antonio Abbate
    • 1
    • 2
    • 3
  • Stefano Toldo
    • 2
    • 3
  1. 1.Department of Physiology and BiophysicsVirginia Commonwealth UniversityRichmondUSA
  2. 2.Victoria Johnson Research LaboratoriesVirginia Commonwealth UniversityRichmondUSA
  3. 3.Virginia Commonwealth University Pauley Heart Center, School of MedicineVirginia Commonwealth UniversityRichmondUSA
  4. 4.Pharmacotherapy and Outcome Sciences, School of PharmacyVirginia Commonwealth UniversityRichmondUSA

Personalised recommendations