New Insights into Pericarditis: Mechanisms of Injury and Therapeutic Targets

Pericardial Disease (AL Klein, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Pericardial Disease

Abstract

Purpose of Review

This review article aims to provide a contemporary insight into the pathophysiological mechanisms of and therapeutic targets for pericarditis, drawing distinction between autoinflammatory and autoimmune pericarditis.

Recent Findings

Recent research has focused on the distinction between autoinflammatory and autoimmune pericarditis. In autoinflammatory pericarditis, viruses can activate the sensor molecule of the inflammasome, which results in downstream release of cytokines, such as interleukin-1, that recruit neutrophils and macrophages to the site of injury. Conversely, in autoimmune pericarditis, a type I interferon signature predominates, and pericardial manifestations coincide with the severity of the underlying systemic autoimmune disease. In addition, autoimmune pericarditis can also develop after cardiac injury syndromes. With either type of pericarditis, imaging can help stage the inflammatory state. Prominent pericardial delayed hyperenhancement on magnetic resonance imaging suggests ongoing inflammation whereas calcium on computed tomography suggests a completed inflammatory cascade. In patients with ongoing pericarditis, treatments that converge on the inflammasome, such as colchicine and anakinra, have proved effective in recurrent autoinflammatory pericarditis, though further clinical trials with anakinra are warranted.

Summary

An improved understanding of the pathophysiological mechanisms of pericarditis helps unravel effective therapeutic targets for this condition.

Keywords

Pericarditis Pericardial inflammation Autoinflammatory pericarditis Autoimmune pericarditis Anakinra 

Notes

Compliance with Ethical Standards

Conflict of Interest

Bo Xu, Serge C. Harb, and Paul C. Cremer declare that they have 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.

References

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

  1. 1.
    Cosyns B, Plein S, Nihoyanopoulos P, Smiseth O, Achenbach S, Andrade MJ, et al. European Association of Cardiovascular Imaging (EACVI) position paper: multimodality imaging in pericardial disease. Eur Heart J Cardiovasc Imaging. 2015;16:12–31. doi: 10.1093/ehjci/jeu128.CrossRefPubMedGoogle Scholar
  2. 2.
    •• Klein AL, Abbara S, Agler DA, Appleton CP, Asher CR, Hoit B, et al. American society of echocardiography clinical recommendations for multimodality cardiovascular imaging of patients with pericardial disease: endorsed by the society for cardiovascular magnetic resonance and society of cardiovascular computed tomography. J Am Soc Echocardiogr. 2013;26:965–1012.e15. doi: 10.1016/j.echo.2013.06.023. An important guideline document on the management of pericardial conditions, with a focus on multimodality cardiovascular imaging assessment CrossRefPubMedGoogle Scholar
  3. 3.
    •• Adler Y, Charron P, Imazio M, Badano L, Baron-Esquivias G, Bogaert J, et al. 2015 ESC guidelines for the diagnosis and management of pericardial diseases. Eur Heart J. 2015;36:2921–64. doi: 10.1093/eurheartj/ehv318. An important guideline document on pericardial diseases published by the European Society of Cardiology CrossRefPubMedGoogle Scholar
  4. 4.
    Imazio M. Idiopathic recurrent pericarditis as an immune-mediated disease: current insights into pathogenesis and emerging treatment options. Expert Rev Clin Immunol. 2014;10:1487–92. doi: 10.1586/1744666X.2014.965150.CrossRefPubMedGoogle Scholar
  5. 5.
    Cusick MF, Libbey JE, Fujinami RS. Molecular mimicry as a mechanism of autoimmune disease. Clin Rev Allergy Immunol. 2012;42:102–11. doi: 10.1007/s12016-011-8294-7.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Imazio M. Pericardial involvement in systemic inflammatory diseases. Heart. 2011;97:1882–92. doi: 10.1136/heartjnl-2011-300054.CrossRefPubMedGoogle Scholar
  7. 7.
    •• 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;68:2311–28. doi: 10.1016/j.jacc.2016.07.785. An important contemporary review of pericarditis with a focus on multimodality imaging assessment and pathophysiology CrossRefPubMedGoogle Scholar
  8. 8.
    Muruve DA, Petrilli V, Zaiss AK, White LR, Clark SA, Ross PJ, et al. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature. 2008;452:103–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440:237–41.CrossRefPubMedGoogle Scholar
  10. 10.
    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;464:1357–61.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    •• 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. JAMA. 2016;316:1906. doi: 10.1001/jama.2016.15826. The first published randomized trial evidence examining the efficacy of anakinra in recurrent pericarditis in a small number patients CrossRefPubMedGoogle Scholar
  12. 12.
    van Kempen TS, Wenink MH, Leijten EFA, Radstake TRDJ, Boes M. Perception of self: distinguishing autoimmunity from autoinflammation. Nat Rev Rheumatol. 2015;11:483–92.CrossRefPubMedGoogle Scholar
  13. 13.
    Prasad M, Hermann J, Gabriel SE, Weyand CM, Mulvagh S, Mankad R, et al. Cardiorheumatology: cardiac involvement in systemic rheumatic disease. Nat Rev Cardiol. 2015;12:168–76. doi: 10.1038/nrcardio.2014.206.Cardiorheumatology.CrossRefPubMedGoogle Scholar
  14. 14.
    Voskuyl AE. The heart and cardiovascular manifestations in rheumatoid arthritis. Rheumatology. 2006;45:4–7. doi: 10.1093/rheumatology/kel313.CrossRefGoogle Scholar
  15. 15.
    Miner JJ, Kim AHJ. Cardiac manifestations of systemic lupus erythematosus. Rheum Dis Clin. 2014;40:51–60. doi: 10.1016/j.rdc.2013.10.003.CrossRefGoogle Scholar
  16. 16.
    Imazio M, Hoit BD. Post-cardiac injury syndromes. An emerging cause of pericardial diseases. Int J Cardiol. 2013;168:648–52. doi: 10.1016/j.ijcard.2012.09.052.CrossRefPubMedGoogle Scholar
  17. 17.
    Cevik C, Wilborn T, Corona R, Schanzmeyer E, Nugent K. Post-cardiac injury syndrome following transvenous pacemaker insertion: a case report and review of the literature. Hear Lung Circ. 2009;18:379–83. doi: 10.1016/j.hlc.2009.04.001.CrossRefGoogle Scholar
  18. 18.
    Alraies MC, Al Jaroudi W, Shabrang C, Yarmohammadi H, Klein AL, Tamarappoo BK. Clinical features associated with adverse events in patients with post-pericardiotomy syndrome following cardiac surgery. Am J Cardiol. 2014;114:1426–30. doi: 10.1016/j.amjcard.2014.07.078.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Imazio M, Spodick DH, Brucato A, Trinchero R, Adler Y. Controversial issues in the management of pericardial diseases. Circulation. 2010;121:916–28. doi: 10.1161/CIRCULATIONAHA.108.844753.CrossRefPubMedGoogle Scholar
  20. 20.
    Khan AH. The postcardiac injury syndromes. Clin Cardiol. 1992;15:67–72. doi: 10.1002/clc.4960150203.CrossRefPubMedGoogle Scholar
  21. 21.
    Hoffman M, Fried M, Jabareen F, Vardinon N, Turner D, Burke M, et al. Anti-heart antibodies in Postpericardiotomy syndrome: cause or epiphenomenon? Autoimmunity. 2002;35:241–5. doi: 10.1080/08916930290028166.CrossRefPubMedGoogle Scholar
  22. 22.
    Douglas PS, Garcia MJ, Haines DE, Lai WW, Ragosta M, Ward RP, et al. ACCF/ASE/AHA/ASNC/HFSA/HRS/SCAI/SCCM/SCCT/SCMR 2011 appropriate use criteria for echocardiography. J Am Soc Echocardiogr. 2011;24:229–67. doi: 10.1016/j.echo.2010.12.008.CrossRefPubMedGoogle Scholar
  23. 23.
    Zurick AO, Bolen MA, Kwon DH, Tan CD, Popovic ZB, Rajeswaran J, et al. Pericardial delayed hyperenhancement with CMR imaging in patients with constrictive pericarditis undergoing surgical pericardiectomy: a case series with histopathological correlation. JACC Cardiovasc Imaging. 2011;4:1180–91. doi: 10.1016/j.jcmg.2011.08.011.CrossRefPubMedGoogle Scholar
  24. 24.
    Alraies MC, AlJaroudi W, Yarmohammadi H, Yingchoncharoen T, Schuster A, Senapati A, et al. Usefulness of cardiac magnetic resonance-guided management in patients with recurrent pericarditis. Am J Cardiol. 2015;115:542–7. doi: 10.1016/j.amjcard.2014.11.041.CrossRefPubMedGoogle Scholar
  25. 25.
    Cremer PC, Tariq MU, Karwa A, Alraies MC, Benatti R, Schuster A, et al. Quantitative assessment of pericardial delayed hyperenhancement predicts clinical improvement in patients with constrictive pericarditis treated with anti-inflammatory therapy. Circ Cardiovasc Imaging. 2015;8:1–8. doi: 10.1161/CIRCIMAGING.114.003125.CrossRefGoogle Scholar
  26. 26.
    Bogaert J, Francone M. Pericardial disease: value of CT and MR imaging. Radiology. 2013;267:340–56. doi: 10.1148/radiol.13121059.CrossRefPubMedGoogle Scholar
  27. 27.
    Haley JH, Tajik AJ, Danielson GK, Schaff HV, Mulvagh SL, Oh JK. Transient constrictive pericarditis: causes and natural history. J Am Coll Cardiol. 2004;43:271–5. doi: 10.1016/j.jacc.2003.08.032.CrossRefPubMedGoogle Scholar
  28. 28.
    Gentry J, Klein AL, Jellis C. Transient constrictive pericarditis: current diagnostic and therapeutic strategies. Curr Cardiol Rep. 2016;18 doi: 10.1007/s11886-016-0720-2.PubMedGoogle Scholar
  29. 29.
    Imazio M, Brucato A, Cemin R, Ferrua S, Maggiolini S, Beqaraj F, et al. A randomized trial of colchicine for acute pericarditis. N Engl J Med. 2013;369:1522–8. doi: 10.1056/NEJMoa1208536.CrossRefPubMedGoogle Scholar
  30. 30.
    Imazio M, Bobbio M, Cecchi E, Demarie D, Pomari F, Moratti M, et al. Colchicine as first-choice therapy for recurrent pericarditis. Arch Intern Med. 2005;165:1987–91.CrossRefPubMedGoogle Scholar
  31. 31.
    Horneffer P, Miller R, Pearson T, Rykiel M, Reitz B, Gardner T. The effective treatment of postpericardiotomy syndrome after cardiac operations. A randomized placebo-controlled trial. J Thorac Cardiovasc Surg. 1990;100:292–6.PubMedGoogle Scholar
  32. 32.
    Imazio M, Gaita F. Diagnosis and treatment of pericarditis. Heart. 2015;101:1159–68. doi: 10.1136/heartjnl-2014-306362.CrossRefPubMedGoogle Scholar
  33. 33.
    Imazio M, Brucato A, Maestroni S, Cumetti D, Dominelli A, Natale G, et al. Prevalence of C-reactive protein elevation and time course of normalization in acute pericarditis: implications for the diagnosis, therapy, and prognosis of pericarditis. Circulation. 2011;123:1092–7. doi: 10.1161/CIRCULATIONAHA.110.986372.CrossRefPubMedGoogle Scholar
  34. 34.
    Imazio M, Brucato A, Cemin R, Ferrua S, Belli R, Maestroni S, et al. Colchicine for Recurrent Pericarditis (CORP) a randomized trial. Ann Intern Med. 2011;155:409–14. doi: 10.1111/trf.13134.CrossRefPubMedGoogle Scholar
  35. 35.
    Imazio M, Bobbio M, Cecchi E, Demarie D, Demichelis B, Pomari F, et al. Colchicine in addition to conventional therapy for acute pericarditis: results of the COlchicine for acute PEricarditis (COPE) trial. Circulation. 2005;112:2012–6. doi: 10.1161/CIRCULATIONAHA.105.542738.CrossRefPubMedGoogle Scholar
  36. 36.
    Leung YY, Yao Hui LL, Kraus VB. Colchicine—update on mechanisms of action and therapeutic uses. Semin Arthritis Rheum. 2015;45:341–50. doi: 10.1016/j.semarthrit.2015.06.013.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Verma S, Eikelboom JW, Nidorf SM, Al-Omran M, Gupta N, Teoh H, et al. Colchicine in cardiac disease: a systematic review and meta-analysis of randomized controlled trials. BMC Cardiovasc Disord. 2015;15:96. doi: 10.1186/s12872-015-0068-3.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Imazio M, Brucato A, Cemin R, Ferrua S, Belli R, Maestroni S, et al. Colchicine for Recurrent Pericarditis (CORP) a randomized trial. Ann Intern Med. 2011:409–14. doi: 10.1378/chest.13-0162.
  39. 39.
    Imazio M, Belli R, Brucato A, Cemin R, Ferrua S, Beqaraj F, et al. Efficacy and safety of colchicine for treatment of multiple recurrences of pericarditis (CORP-2): a multicentre, double-blind, placebo-controlled, randomised trial. Lancet. 2014;383:2232–7. doi: 10.1016/S0140-6736(13)62709-9.CrossRefPubMedGoogle Scholar
  40. 40.
    Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids—new mechanisms for old drugs. N Engl J Med. 2005;353:1711–23. doi: 10.1056/NEJMra050541.CrossRefPubMedGoogle Scholar
  41. 41.
    Imazio M, Adler Y. Treatment with aspirin, NSAID, corticosteroids, and colchicine in acute and recurrent pericarditis. Heart Fail Rev. 2013;18:355–60. doi: 10.1007/s10741-012-9328-9.CrossRefPubMedGoogle Scholar
  42. 42.
    Artom G, Koren-Morag N, Spodick DH, Brucato A, Guindo J, Bayes-De-Luna A, et al. Pretreatment with corticosteroids attenuates the efficacy of colchicine in preventing recurrent pericarditis: a multi-centre all-case analysis. Eur Heart J. 2005;26:723–7. doi: 10.1093/eurheartj/ehi197.CrossRefPubMedGoogle Scholar
  43. 43.
    Imazio M, Brucato A, Cumetti D, Brambilla G, Demichelis B, Ferro S, et al. Corticosteroids for recurrent pericarditis high versus low doses: a nonrandomized observation. Circulation. 2008;118:667–71. doi: 10.1161/CIRCULATIONAHA.107.761064.CrossRefPubMedGoogle Scholar
  44. 44.
    Imazio M, Brucato A, Trinchero R, Shabetai R, Spodick D, Adler Y. Corticosteroid therapy for pericarditis: a double-edged sword. Nat Clin Pr Cardiovasc Med. 2008;5:118–9.CrossRefGoogle Scholar
  45. 45.
    Elion GB. The purine path to chemotherapy. Science. 1989;244:41–7.CrossRefPubMedGoogle Scholar
  46. 46.
    Sandborn W. A review of immune modifier therapy for inflammatory bowel disease: azathioprine, 6-mercaptopurine, cyclosporine, and methotrexate. Am J Gastroenterol. 1996;91:423–33.PubMedGoogle Scholar
  47. 47.
    Vianello F, Cinetto F, Cavraro M, Battisti A, Castelli M, Imbergamo S, et al. Azathioprine in isolated recurrent pericarditis: a single centre experience. Int J Cardiol. 2011;147:477–8. doi: 10.1016/j.ijcard.2011.01.027.CrossRefPubMedGoogle Scholar
  48. 48.
    Eftimov F, Winer JB, Vermeulen M, de Haan R, van Schaik IN. Intravenous immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev. 2013; doi: 10.1002/14651858.CD001797.pub3.PubMedGoogle Scholar
  49. 49.
    Hughes RAC, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2014; doi: 10.1002/14651858.CD002063.pub6.PubMedCentralGoogle Scholar
  50. 50.
    Salib M, Clayden R, Clare R, Wang G, Warkentin TE, Crowther MA, et al. Difficulties in establishing the diagnosis of immune thrombocytopenia: an agreement study. Am J Hematol. 2016;91:E327–9. doi: 10.1002/ajh.24404.CrossRefPubMedGoogle Scholar
  51. 51.
    Kaneko Y, Nimmerjahn F, Ravetch JV. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science. 2006;313:670–3.Google Scholar
  52. 52.
    Samuelsson A, Towers TL, Ravetch JV. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science. 2001;291:484–6.Google Scholar
  53. 53.
    Imazio M, Lazaros G, Picardi E, Vasileiou P, Carraro M, Tousoulis D, et al. Intravenous human immunoglobulins for refractory recurrent pericarditis: a systematic review of all published cases. J Cardiovasc Med. 2016;17:263–9.CrossRefGoogle Scholar
  54. 54.
    Moretti M, Buiatti A, Merlo M, Massa L, Fabris E, Pinamonti B, et al. Usefulness of high-dose intravenous human immunoglobulins treatment for refractory recurrent pericarditis. Am J Cardiol. 2013;112:1493–8. doi: 10.1016/j.amjcard.2013.06.036.CrossRefPubMedGoogle Scholar
  55. 55.
    Dinarello CA, Wolff SM. The role of interleukin-1 in disease. N Engl J Med. 1993;328:106–13. doi: 10.1056/NEJM199301143280207.CrossRefPubMedGoogle Scholar
  56. 56.
    Dinarello CA, Simon A, van der Meer JWM. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov. 2012;11:633–52.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Zeft A, Spalding S. Autoinflammatory syndromes: fever is not always a sign of infection. Cleve Clin J Med. 2012;79:569–81.CrossRefPubMedGoogle Scholar
  58. 58.
    Bresnihan B, Alvaro-Gracia JM, Cobby M, Doherty M, Domljan Z, Emery P, et al. Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum. 1998;41:2196–204. doi: 10.1002/1529-0131(199812)41:12<2196::AID-ART15>3.0.CO;2-2.CrossRefPubMedGoogle Scholar
  59. 59.
    Simon A, Bodar E, van der Hilst JC, van der Meer JW, Fiselier TJ, Cuppen MP, et al. Beneficial response to interleukin 1 receptor antagonist in traps. Am J Med. 2004;117:208–10.CrossRefPubMedGoogle Scholar
  60. 60.
    So A, de Smedt T, Revaz S, Tschopp J. Research article a pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther. 2007;9:1–6. doi: 10.1186/ar2143.CrossRefGoogle Scholar
  61. 61.
    Zeft A, Hollister R, LaFleur B, Sampath P, Soep J, McNally B, et al. Anakinra for systemic juvenile arthritis: the Rocky Mountain experience. JCR J Clin Rheumatol. 2009;15:161–4.CrossRefPubMedGoogle Scholar
  62. 62.
    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;116:1277–9. doi: 10.1016/j.amjcard.2015.07.047.CrossRefPubMedGoogle Scholar
  63. 63.
    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; doi: 10.1136/annrheumdis-2014-205990.PubMedGoogle Scholar
  64. 64.
    Khandaker MH, Schaff HV, Greason KL, Anavekar NS, Espinosa RE, Hayes SN, et al. Pericardiectomy vs medical management in patients with relapsing pericarditis. Mayo Clin Proc. 2017;87:1062–70. doi: 10.1016/j.mayocp.2012.05.024.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Section of Cardiovascular Imaging, Heart and Vascular InstituteCleveland ClinicClevelandUSA

Personalised recommendations