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Use of Interleukin-1 Blockers in Pericardial and Cardiovascular Diseases

  • Giacomo Emmi
  • Maria Letizia Urban
  • Massimo Imazio
  • Marco Gattorno
  • Silvia Maestroni
  • Giuseppe Lopalco
  • Luca Cantarini
  • Domenico Prisco
  • Antonio Brucato
Pericardial Disease (AL Klein, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Pericardial Disease

Abstract

Purpose of Review

This review aims to summarize the role of the interleukin-1 (IL-1) blocking agents in cardiovascular diseases, briefly describing the pathogenetic rationale and the most relevant clinical studies.

Recent Findings

IL-1 is a pivotal cytokine of the innate immune system. Anti-IL-1 agents are currently used for the treatment of several autoimmune and autoinflammatory conditions. Recently, the role of IL-1 has also emerged in cardiovascular diseases. Indeed, two recent randomized controlled trials have shown that the IL-1 receptor antagonist anakinra is effective for the treatment of idiopathic recurrent pericarditis and the IL-1β blocking agent canakinumab is effective in reducing myocardial infarction in people at risk. Interestingly, interfering with IL-1 has proved to be also effective in other cardiovascular manifestations, such as myocarditis, arrhythmias, and heart failure.

Summary

Blocking the IL-1 pathway is a possible new therapeutic strategy, potentially leading to innovative therapies in many acute and chronic cardiovascular diseases.

Keywords

Interleukin-1 Anakinra Canakinumab Pericarditis Atherosclerosis Cardiovascular disease 

Abbreviations

IL-1

Interleukin-1

NOD

Nucleotide-binding domain

NLR

Nucleotide-binding domain-like receptor

CARD

Caspase activation recruitment domain

AIM

Absent in melanoma

NLRP

Nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing

NLRC

NLR-CARD (caspase activating and recruitment domain) containing

PAMPs

Pathogen-associated molecular patterns

DAMPs

Damage-associated molecular patterns

TIR

Toll/interleukin-1 receptor

MyD88

Myeloid differentiation primary response protein 88

NF-kb

Nuclear factor-kb

MAPK

Mitogen-activated protein kinase

RA

Rheumatoid arthritis

CAPS

Cryopyrin-associated periodic syndromes

IRP

Idiopathic recurrent pericarditis

TRAPS

Tumor necrosis factor receptor-1-associated periodic syndrome

AIRTRIP

Anakinra treatment of recurrent idiopathic pericarditis

NSAIDs

Non-steroidal anti-inflammatory drugs

AIR-HF

Anakinra (recombinant human interleukin-1 receptor antagonist) in heart failure

CRP

C-reactive protein

ADHF

Acute decompensated heart failure

HF

Heart failure

LVEF

Left ventricle ejection fraction

D-HART

Decompensated Heart failure Anakinra Response Trial

HFpEF

HF and preserved ejection fraction

NYHA

New York Heart Association

REDHART

Recently Decompensated Heart failure Anakinra Response Trial

MI

Myocardial infarction

CAD

Coronary artery disease

VCU-ART

Virginia Commonwealth University - Anakinra Remodeling Trial

STEMI

ST segment elevation

MR

Magnetic resonance

QTc

Corrected QT

AF

Atrial fibrillation

FMF

familial Mediterranean fever

CANTOS

Canakinumab Anti-inflammatory Thrombosis Outcome Study

IL-6

Interleukin-6

Notes

Compliance with Ethical Standards

Conflict of Interest

Giacomo Emmi has received personal fees for consultancy from GSK and for advisory board from Novartis.

Maria Letizia Urban and Silvia Maestroni declare that they have no conflict of interest.

Massimo Imazio has received an Institutional Grant for Clinical Research from SOBI.

Marco Gattorno has received fees and unrestricted grants from SOBI and Novartis.

Giuseppe Lopalco has received speaker fees from Novartis and SOBI.

Luca Cantarini has received personal fees from Novartis and SOBI.

Domenico Prisco has received grants for advisory boards from Bayer, Daichi Sankyo, Boehringer Ingelheim, BMS Pfizer, and Baxter.

Antonio Brucato has received unrestricted grants from ACARPIA and SOBI and for advisory board from SOBI.

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.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance•• Of major Importance

  1. 1.
    • Szekely Y, Arbel Y. A review of interleukin-1 in heart disease: where do we stand today? Cardiol Ther. 2018;  https://doi.org/10.1007/s40119-018-0104-3. Relevant review focused on the role of IL-1 in heart diseases and potential therapeutic effects of anti-IL-1 treatments.
  2. 2.
    Garlanda C, Dinarello CA, Mantovani A. The interleukin-1 family: back to the future. Immunity. 2013;39(6):1003–18.  https://doi.org/10.1016/j.immuni.2013.11.010.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    • Cavalli G, Dinarello CA. Treating rheumatological diseases and co-morbidities with interleukin-1 blocking therapies. Rheumatol Oxf Engl. 2015;54(12):2134–44.  https://doi.org/10.1093/rheumatology/kev269. Clinical review highlighting the role of interfering with IL-1 in cardiovascular diseases and type 2 diabetes, conditions that are frequently encountered as co-morbidities in patients with rheumatic diseases. CrossRefGoogle Scholar
  4. 4.
    •• Brucato A, Imazio M, Gattorno M, Lazaros G, Maestroni S, Carraro M, et al. Effect of anakinra on recurrent pericarditis among patients with colchicine resistance and corticosteroid dependence: the AIRTRIP randomized clinical trial. JAMA. 2016;316(18):1906–12.  https://doi.org/10.1001/jama.2016.15826. First controlled, randomized trial to determine the efficacy of anakinra for colchicine-resistant and corticosteroid-dependent recurrent pericarditis. CrossRefPubMedGoogle Scholar
  5. 5.
    •• 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(12):1119–31.  https://doi.org/10.1056/NEJMoa1707914. First controlled randomized double-blind trial to evaluate the efficacy of canakinumab for patients with previous myocardial infarction and a high-sensitivity C-reactive protein. CrossRefPubMedGoogle Scholar
  6. 6.
    Cavalli G, Pappalardo F, Mangieri A, Dinarello CA, Dagna L, Tresoldi M. Treating life-threatening myocarditis by blocking interleukin-1. Crit Care Med. 2016;44(8):e751–4.  https://doi.org/10.1097/CCM.0000000000001654.CrossRefPubMedGoogle Scholar
  7. 7.
    De Jesus NM, Wang L, Lai J, Rigor RR, Francis Stuart SD, Bers DM, et al. Antiarrhythmic effects of interleukin 1 inhibition after myocardial infarction. Heart Rhythm. 2017;14(5):727–36.  https://doi.org/10.1016/j.hrthm.2017.01.027.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Van Tassell BW, Raleigh JMV, Abbate A. Targeting interleukin-1 in heart failure and inflammatory heart disease. Curr Heart Fail Rep. 2015;12(1):33–41.  https://doi.org/10.1007/s11897-014-0231-7.CrossRefPubMedGoogle Scholar
  9. 9.
    Rathinam VAK, Chan FK-M. Inflammasome, inflammation, and tissue homeostasis. Trends Mol Med. 2018;24:304–18.  https://doi.org/10.1016/j.molmed.2018.01.004.CrossRefPubMedGoogle Scholar
  10. 10.
    Rubartelli A. Redox control of NLRP3 inflammasome activation in health and disease. J Leukoc Biol. 2012;92(5):951–8.  https://doi.org/10.1189/jlb.0512265.CrossRefPubMedGoogle Scholar
  11. 11.
    Fernandes-Alnemri T, Yu J-W, Datta P, Wu J, Alnemri ES. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature. 2009;458(7237):509–13.  https://doi.org/10.1038/nature07710.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Haneklaus M, O’Neill LAJ, Coll RC. Modulatory mechanisms controlling the NLRP3 inflammasome in inflammation: recent developments. Curr Opin Immunol. 2013;25(1):40–5.  https://doi.org/10.1016/j.coi.2012.12.004.CrossRefPubMedGoogle Scholar
  13. 13.
    Tschopp J, Schroder K. NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nat Rev Immunol. 2010;10(3):210–5.  https://doi.org/10.1038/nri2725.CrossRefPubMedGoogle Scholar
  14. 14.
    Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464(7293):1357–61.  https://doi.org/10.1038/nature08938.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Kawaguchi M, Takahashi M, Hata T, Kashima Y, Usui F, Morimoto H, et al. Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. Circulation. 2011 Feb 15;123(6):594–604.  https://doi.org/10.1161/CIRCULATIONAHA.110.982777.CrossRefPubMedGoogle Scholar
  16. 16.
    • Cremer PC, Kumar A, Kontzias A, Tan CD, Rodriguez ER, Imazio M, et al. Complicated pericarditis: understanding risk factors and pathophysiology to inform imaging and treatment. J Am Coll Cardiol. 2016;68(21):2311–28.  https://doi.org/10.1016/j.jacc.2016.07.785. Relevant review focused on complicated pericarditis, in particular risk factors, pathogenetic mechanisms, management, and imaging. CrossRefPubMedGoogle Scholar
  17. 17.
    Sims JE, Smith DE. The IL-1 family: regulators of immunity. Nat Rev Immunol. 2010;10(2):89–102.  https://doi.org/10.1038/nri2691.CrossRefPubMedGoogle Scholar
  18. 18.
    Dinarello CA, van der Meer JWM. Treating inflammation by blocking interleukin-1 in humans. Semin Immunol. 2013;25(6):469–84.  https://doi.org/10.1016/j.smim.2013.10.008.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Martínez GJ, Celermajer DS, Patel S. The NLRP3 inflammasome and the emerging role of colchicine to inhibit atherosclerosis-associated inflammation. Atherosclerosis. 2018 Feb;269:262–71.  https://doi.org/10.1016/j.atherosclerosis.2017.12.027.CrossRefPubMedGoogle Scholar
  20. 20.
    Galea J, Armstrong J, Gadsdon P, Holden H, Francis SE, Holt CM. Interleukin-1 beta in coronary arteries of patients with ischemic heart disease. Arterioscler Thromb Vasc Biol. 1996;16(8):1000–6.  https://doi.org/10.1161/01.ATV.16.8.1000.CrossRefPubMedGoogle Scholar
  21. 21.
    Bujak M, Dobaczewski M, Chatila K, Mendoza LH, Li N, Reddy A, et al. Interleukin-1 receptor type I signaling critically regulates infarct healing and cardiac remodeling. Am J Pathol. 2008;173(1):57–67.  https://doi.org/10.2353/ajpath.2008.070974.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Portincasa P. Colchicine, Biologic agents and more for the treatment of familial Mediterranean fever. The old, the new, and the rare. Curr Med Chem. 2016;23(1):60–86.  https://doi.org/10.2174/0929867323666151117121706.CrossRefPubMedGoogle Scholar
  23. 23.
    Emmi G, Talarico R, Lopalco G, Cimaz R, Cantini F, Viapiana O, et al. Efficacy and safety profile of anti-interleukin-1 treatment in Behçet’s disease: a multicenter retrospective study. Clin Rheumatol. 2016;35(5):1281–6.  https://doi.org/10.1007/s10067-015-3004-0.CrossRefPubMedGoogle Scholar
  24. 24.
    Vitale A, Insalaco A, Sfriso P, Lopalco G, Emmi G, Cattalini M, et al. A snapshot on the on-label and off-label use of the interleukin-1 inhibitors in Italy among rheumatologists and pediatric rheumatologists: a nationwide multi-center retrospective observational study. Front Pharmacol. 2016;7:380.  https://doi.org/10.3389/fphar.2016.00380.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Colafrancesco S, Priori R, Valesini G, Argolini L, Baldissera E, Bartoloni E, et al. Response to interleukin-1 inhibitors in 140 Italian patients with adult-onset Still’s disease: a multicentre retrospective observational study. Front Pharmacol. 2017;8:369.  https://doi.org/10.3389/fphar.2017.00369.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Fabiani C, Vitale A, Emmi G, Lopalco G, Vannozzi L, Guerriero S, et al. Interleukin (IL)-1 inhibition with anakinra and canakinumab in Behçet’s disease-related uveitis: a multicenter retrospective observational study. Clin Rheumatol. 2017;36(1):191–7.  https://doi.org/10.1007/s10067-016-3506-4.CrossRefPubMedGoogle Scholar
  27. 27.
    • Lazaros G, Antonatou K, Vassilopoulos D. The therapeutic role of interleukin-1 inhibition in idiopathic recurrent pericarditis: current evidence and future challenges. Front Med. 2017;4:78.  https://doi.org/10.3389/fmed.2017.00078. Clinical review by opinion leaders in the field of treatment of recurrent pericarditis. CrossRefGoogle Scholar
  28. 28.
    Adler Y, Charron P, Imazio M, Badano L, Barón-Esquivias G, Bogaert J, et al. 2015 ESC guidelines for the diagnosis and management of pericardial diseases: The Task Force for the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology (ESC) Endorsed by: The European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2015;36(42):2921–64.  https://doi.org/10.1093/eurheartj/ehv318.CrossRefPubMedGoogle Scholar
  29. 29.
    Picco P, Brisca G, Traverso F, Loy A, Gattorno M, Martini A. Successful treatment of idiopathic recurrent pericarditis in children with interleukin-1beta receptor antagonist (anakinra): an unrecognized autoinflammatory disease? Arthritis Rheum. 2009;60(1):264–8.  https://doi.org/10.1002/art.24174.CrossRefPubMedGoogle Scholar
  30. 30.
    Massardier C, Dauphin C, Eschalier R, Lusson JR, Soubrier M. Resistant or recurrent acute pericarditis: a new therapeutic opportunity? Int J Cardiol. 2014;177(2):e75–7.  https://doi.org/10.1016/j.ijcard.2014.09.192.CrossRefPubMedGoogle Scholar
  31. 31.
    Cantarini L, Lucherini OM, Cimaz R, Galeazzi M. Recurrent pericarditis caused by a rare mutation in the TNFRSF1A gene and with excellent response to anakinra treatment. Clin Exp Rheumatol. 2010;28(5):802.PubMedGoogle Scholar
  32. 32.
    Emmi G, Barnini T, Silvestri E, Milco D’Elios M, Emmi L, Prisco D. A new case of idiopathic recurrent acute pericarditis due to R104Q mutation in TNFRSF1A successfully treated with anakinra: expanding the questions. Clin Exp Rheumatol. 2014;32(2):297.PubMedGoogle Scholar
  33. 33.
    Camprubí D, Mitjavila F, Arostegui JI, Corbella X. Efficacy of anakinra in an adult patient with recurrent pericarditis and cardiac tamponade as initial manifestations of tumor necrosis factor receptor-associated periodic syndrome due to the R92Q TNFRSF1A variant. Int J Rheum Dis. 2017;20(4):510–4.  https://doi.org/10.1111/1756-185X.13029.CrossRefPubMedGoogle Scholar
  34. 34.
    D’Elia E, Brucato A, Pedrotti P, Valenti A, De Amici M, Fiocca L, et al. Successful treatment of subacute constrictive pericarditis with interleukin-1β receptor antagonist (anakinra). Clin Exp Rheumatol. 2015;33(2):294–5.PubMedGoogle Scholar
  35. 35.
    Lazaros G, Vasileiou P, Danias P, Koutsianas C, Vlachopoulos C, Tousoulis D, et al. Effusive-constrictive pericarditis successfully treated with anakinra. Clin Exp Rheumatol. 2015 Dec;33(6):945.PubMedGoogle Scholar
  36. 36.
    Schatz A, Trankle C, Yassen A, Chipko C, Rajab M, Abouzaki N, et al. Resolution of pericardial constriction with Anakinra in a patient with effusive-constrictive pericarditis secondary to rheumatoid arthritis. Int J Cardiol. 2016;223:215–6.  https://doi.org/10.1016/j.ijcard.2016.08.131.CrossRefPubMedGoogle Scholar
  37. 37.
    Finetti M, Insalaco A, Cantarini L, Meini A, Breda L, Alessio M, et al. Long-term efficacy of interleukin-1 receptor antagonist (anakinra) in corticosteroid-dependent and colchicine-resistant recurrent pericarditis. J Pediatr. 2014;164(6):1425–1431.e1.  https://doi.org/10.1016/j.jpeds.2014.01.065.CrossRefPubMedGoogle Scholar
  38. 38.
    Jain S, Thongprayoon C, Espinosa RE, Hayes SN, Klarich KW, Cooper LT, et al. Effectiveness and safety of anakinra for management of refractory pericarditis. Am J Cardiol. 2015;116(8):1277–9.  https://doi.org/10.1016/j.amjcard.2015.07.047.CrossRefPubMedGoogle Scholar
  39. 39.
    Imazio M, Brucato A, Pluymaekers N, Breda L, Calabri G, Cantarini L, et al. Recurrent pericarditis in children and adolescents: a multicentre cohort study. J Cardiovasc Med (Hagerstown). 2016;17(9):707–12.  https://doi.org/10.2459/JCM.0000000000000300.CrossRefGoogle Scholar
  40. 40.
    Lazaros G, Vasileiou P, Koutsianas C, Antonatou K, Stefanadis C, Pectasides D, et al. Anakinra for the management of resistant idiopathic recurrent pericarditis. Initial experience in 10 adult cases. Ann Rheum Dis. 2014;73(12):2215–7.  https://doi.org/10.1136/annrheumdis-2014-205990. CrossRefPubMedGoogle Scholar
  41. 41.
    Lopalco G, Rigante D, Giannini M, Galeazzi M, Lapadula G, Iannone F, et al. Safety profile of anakinra in the management of rheumatologic, metabolic and autoinflammatory disorders. Clin Exp Rheumatol. 2016;34(3):531–8.PubMedGoogle Scholar
  42. 42.
    Emmi G, Silvestri E, Squatrito D, Vitale A, Bacherini D, Vannozzi L, et al. Long-term efficacy and safety of anakinra in a patient with Behçet’s disease and concomitant tuberculosis infection. Int J Dermatol. 2017;56(2):218–20.CrossRefPubMedGoogle Scholar
  43. 43.
    Emmi G, Silvestri E, Cantarini L, Lopalco G, Cecchi L, Chiarini F, et al. Rapid desensitization to anakinra-related delayed reaction: need for a standardized protocol. J Dermatol. 2017;44(8):981–2.  https://doi.org/10.1111/ijd.13337. CrossRefPubMedGoogle Scholar
  44. 44.
    Ikonomidis I, Lekakis JP, Nikolaou M, Paraskevaidis I, Andreadou I, Kaplanoglou T, et al. Inhibition of interleukin-1 by anakinra improves vascular and left ventricular function in patients with rheumatoid arthritis. Circulation. 2008;117(20):2662–9.  https://doi.org/10.1161/CIRCULATIONAHA.107.731877.CrossRefPubMedGoogle Scholar
  45. 45.
    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.  https://doi.org/10.1371/journal.pone.0033438.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    • Van Tassell BW, Abouzaki NA, Oddi Erdle C, Carbone S, Trankle CR, Melchior RD, et al. Interleukin-1 blockade in acute decompensated heart failure: a randomized, double-blinded, placebo-controlled pilot study. J Cardiovasc Pharmacol. 2016;67(6):544–51.  https://doi.org/10.1097/FJC.0000000000000378. Interesting randomized, double-blinded, placebo-controlled pilot study to evaluate the role of anakinra in blocking acute inflammatory response during acute decompensated heart failure. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Van Tassell BW, Arena R, Biondi-Zoccai G, Canada JM, Oddi C, Abouzaki NA, et al. Effects of interleukin-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. 2014;113(2):321–7.  https://doi.org/10.1016/j.amjcard.2013.08.047.CrossRefPubMedGoogle Scholar
  48. 48.
    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.  https://doi.org/10.1002/clc.22719.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    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 REDHART (Recently Decompensated Heart Failure Anakinra Response Trial). Circ Heart Fail. 2017;10(11):e004373.  https://doi.org/10.1161/CIRCHEARTFAILURE.117.004373. CrossRefPubMedGoogle Scholar
  50. 50.
    Saxena A, Russo I, Frangogiannis NG. Inflammation as a therapeutic target in myocardial infarction: learning from past failures to meet future challenges. Transl Res. 2016;167(1):152–66.  https://doi.org/10.1016/j.trsl.2015.07.002.CrossRefPubMedGoogle Scholar
  51. 51.
    Ikonomidis I, Tzortzis S, Andreadou I, Paraskevaidis I, Katseli C, Katsimbri P, et al. Increased benefit of interleukin-1 inhibition on vascular function, myocardial deformation, and twisting in patients with coronary artery disease and coexisting rheumatoid arthritis. Circ Cardiovasc Imaging. 2014;7(4):619–28.  https://doi.org/10.1161/CIRCIMAGING.113.001193.CrossRefPubMedGoogle Scholar
  52. 52.
    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):1371–1377.el.  https://doi.org/10.1016/j.amjcard.2009.12.059.CrossRefPubMedGoogle Scholar
  53. 53.
    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.  https://doi.org/10.1016/j.amjcard.2013.01.287.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    • 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.  https://doi.org/10.1016/j.amjcard.2014.11.003. Valuable patient-level pooled analysis on 40 patients from two previous pilot studies, showing that anakinra may prevent new-onset heart failure after STEMI at a long-term follow-up. CrossRefPubMedGoogle Scholar
  55. 55.
    • 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(6):377–84.  https://doi.org/10.1093/eurheartj/ehu272. Interesting phase II, double-blinded, randomized, placebo-controlled trial showing the importance of anakinra in reducing inflammatory markers in acute coronary syndromes. CrossRefPubMedGoogle Scholar
  56. 56.
    Francis Stuart SD, De Jesus NM, Lindsey ML, Ripplinger CM. The crossroads of inflammation, fibrosis, and arrhythmia following myocardial infarction. J Mol Cell Cardiol. 2016;91:114–22.  https://doi.org/10.1016/j.yjmcc.2015.12.024.CrossRefPubMedGoogle Scholar
  57. 57.
    Adlan AM, Panoulas VF, Smith JP, Fisher JP, Kitas GD. Association between corrected QT interval and inflammatory cytokines in rheumatoid arthritis. J Rheumatol. 2015;42(3):421–8.  https://doi.org/10.3899/jrheum.140861.CrossRefPubMedGoogle Scholar
  58. 58.
    Pisoni CN, Reina S, Arakaki D, Eimon A, Carrizo C, Borda E. Elevated IL-1β levels in anti-Ro/SSA connective tissue diseases patients with prolonged corrected QTc interval. Clin Exp Rheumatol. 2015;33(5):715–20.PubMedGoogle Scholar
  59. 59.
    Cheng T, Wang X-F, Hou Y-T, Zhang L. Correlation between atrial fibrillation, serum amyloid protein A and other inflammatory cytokines. Mol Med Rep. 2012;6(3):581–4.  https://doi.org/10.3892/mmr.2012.934.CrossRefPubMedGoogle Scholar
  60. 60.
    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.  https://doi.org/10.1161/CIRCULATIONAHA.112.122556.CrossRefPubMedGoogle Scholar
  61. 61.
    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 Lond Engl. 2018;391(10118):319–28.  https://doi.org/10.1056/NEJMoa1707914.CrossRefGoogle Scholar
  62. 62.
    •• Ridker PM, MacFadyen JG, Thuren T, Everett BM, Libby P, Glynn RJ, et al. 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 Lond Engl. 2017;390(10105):1833–42.  https://doi.org/10.1016/S0140-6736(17)32247-X. Intriguing exploratory analysis on the reduction of mortality by lung cancer after blockade of interleukin-1β pathway. CrossRefGoogle Scholar
  63. 63.
    Neri Serneri GG, Prisco D, Martini F, Gori AM, Brunelli T, Poggesi L, et al. Acute T-cell activation is detectable in unstable angina. Circulation. 1997;95(7):1806–12.CrossRefPubMedGoogle Scholar
  64. 64.
    Neri Serneri GG, Boddi M, Modesti PA, Cecioni I, Coppo M, Papa ML, et al. Immunomediated and ischemia-independent inflammation of coronary microvessels in unstable angina. Circ Res. 2003;92(12):1359–66.  https://doi.org/10.1161/01.RES.0000079025.38826.E1.CrossRefPubMedGoogle Scholar
  65. 65.
    Becatti M, Marcucci R, Bruschi G, Taddei N, Bani D, Gori AM, et al. Oxidative modification of fibrinogen is associated with altered function and structure in the subacute phase of myocardial infarction. Arterioscler Thromb Vasc Biol. 2014;34(7):1355–61.  https://doi.org/10.1161/ATVBAHA.114.303785.CrossRefPubMedGoogle Scholar
  66. 66.
    •• Becatti M, Emmi G, Silvestri E, Bruschi G, Ciucciarelli L, Squatrito D, et al. Neutrophil activation promotes fibrinogen oxidation and thrombus formation in Behçet disease. Circulation. 2016;133(3):302–11.  https://doi.org/10.1161/CIRCULATIONAHA.115.017738. Important evidence that altered fibrinogen structure and impaired fibrinogen function are associated with neutrophil activation and enhanced reactive oxygen species production, suggesting a link between inflammation and thrombosis in systemic vasculitis. PubMedCrossRefGoogle Scholar
  67. 67.
    Van Tassell BW, Varma A, Salloum FN, Das A, Seropian IM, Toldo S, et al. Interleukin-1 trap attenuates cardiac remodeling after experimental acute myocardial infarction in mice. J Cardiovasc Pharmacol. 2010;55(2):117–22.  https://doi.org/10.1097/FJC.0b013e3181c87e53.CrossRefPubMedGoogle Scholar
  68. 68.
    Ridker PM, Lüscher TF. Anti-inflammatory therapies for cardiovascular disease. Eur Heart J. 2014;35(27):1782–91.  https://doi.org/10.1093/eurheartj/ehu203.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Giacomo Emmi
    • 1
  • Maria Letizia Urban
    • 2
  • Massimo Imazio
    • 3
  • Marco Gattorno
    • 4
  • Silvia Maestroni
    • 5
  • Giuseppe Lopalco
    • 6
  • Luca Cantarini
    • 7
  • Domenico Prisco
    • 1
  • Antonio Brucato
    • 5
  1. 1.Department of Experimental and Clinical MedicineUniversity of FirenzeFlorenceItaly
  2. 2.Nephrology UnitUniversity Hospital of ParmaParmaItaly
  3. 3.University Cardiology, Cardiovascular and Thoracic DepartmentAOU Città della Salute e della Scienza of TorinoTurinItaly
  4. 4.Clinic of Pediatrics and Rheumatology, Unit of Autoinflammatory Diseases and Immunodeficiencies“G. Gaslini” InstituteGenoaItaly
  5. 5.Internal MedicineOspedale Papa Giovanni XXIIIBergamoItaly
  6. 6.Department of Emergency and Organ Transplantation, Rheumatology UnitBariItaly
  7. 7.Research Center of Systemic Autoinflammatory Diseases, Behçet’s Disease Clinic and Rheumatology-Ophthalmology Collaborative Uveitis CenterUniversity of SienaSienaItaly

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