pp 1–8 | Cite as

Critical inflammatory mechanisms underlying arrhythmias

  • N. Vonderlin
  • J. Siebermair
  • E. Kaya
  • M. Köhler
  • T. Rassaf
  • R. WakiliEmail author
Main topic


During the past few decades, cardiovascular research has increasingly focused on systemic inflammatory mechanisms, particularly in the field of atherosclerosis but also in association with cardiac arrhythmogenesis. Objective inflammatory markers including C‑reactive protein and cytokines, also called “biomarkers,” seem to serve as predictors of onset and prognosis of cardiac arrhythmias. This review gives an overview of potential mechanisms underlying inflammatory processes and arrhythmias, especially atrial fibrillation, which is the most common sustained arrhythmia in daily clinical routine. The association between inflammatory pathways and cardiac arrhythmia is highly complex and includes direct as well as indirect pathways. While past research into arrhythmia focused on fibrosis, altered action potential properties, and ischemia, novel concepts include coagulation and inflammation in cardiac tissue. The underlying mechanisms are altered electrophysiological properties, including ion channel disturbance, early and late afterdepolarizations, as well as enhanced fibrosis and structural remodeling in cardiomyopathies. These pathophysiological factors favor the occurrence of ectopic pacemakers as well as re-entry tachycardia. Further studies are essential to better understand the main inflammatory signal cascades and the exact proarrhythmic effect of interacting key mediators. This will facilitate the evaluation of future anti-inflammatory therapeutic approaches for arrhythmias, analogous to recent developments in atherosclerosis.


Atrial fibrillation Cardiac arrhythmogenesis Atherosclerosis C-reactive protein Cytokines 

Zugrundeliegende inflammtorische Mechanismen bei Herzrhythmusstörungen


In den letzten Jahren rückte die Rolle von inflammatorischen Prozessen bei Herzkreislauferkrankungen immer mehr in den Vordergrund. Der wissenschaftliche Fokus lag hier primär auf Atherosklerose, aber auch die Assoziation mit kardialen Arrhythmien wurde intensiv untersucht. Neben der Rolle von Biomarkern, z. B. C-reaktives Protein (CRP) oder Zytokine, wurden auch gemeinsame pathophysiologische Mechanismen von Entzündungen und Arrhythmien evaluiert. Dieser Artikel gibt einen Überblick über die komplexen Zusammenhänge zwischen inflammatorischen Prozessen und verschiedenen kardialen Arrhythmien, insbesondere bei Vorhofflimmern. Ältere wissenschaftliche Arbeiten fokussierten sich primär auf das Auftreten von Fibrose und veränderten Eigenschaften des Aktionspotenzials. Neue Konzepte beschäftigen sich mit der kausalen Interaktion von Koagulationsmechanismen und Arrhythmien sowie intrazellulären Entzündungsprozessen in Kardiomyozyten. Es gibt verschiedene Faktoren, die aus einer akuten oder chronischen Entzündungsreaktion resultieren, welche die Entstehung von Herzrhythmusstörungen begünstigen können: eine gestörte Ionenkanal-Homöostase, frühe und späte Nachdepolarisationen, Fibrosierung und strukturelles Remodeling des Myokards. Als Folge wird das Auftreten von getriggerter ektoper Aktivität, kreisenden Erregungen (Re-entry) und damit die Entstehung und Aufrechterhaltung von kardialen Arrhythmien begünstigt. In der Zukunft werden weitere grundlagenwissenschaftliche sowie klinische Studien benötigt, um die zugrundeliegenden inflammatorischen Signalkaskaden und den exakten proarrhythmischen Effekt von interagierenden Biomarkern zu entschlüsseln. Auf dieser Grundlage könnten, analog zur Atherosklerose, neue Therapieansätze für inflammationsassoziierte Rhythmusstörungen etabliert werden.


Vorhofflimmern Kardiale Arrhythmogenese Atherosklerose C-reaktives Protein Zytokine 


Compliance with ethical guidelines

Conflict of interest

N. Vonderlin, J. Siebermair, E. Kaya, M. Köhler, T. Rassaf, and R. Wakili declare that they have no competing interests.

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. 1.
    Klein RM et al (2000) Inflammation of the myocardium as an arrhythmia trigger. Z Kardiol 89(Suppl 3):24–35PubMedGoogle Scholar
  2. 2.
    Boos CJ, Anderson RA, Lip GY (2006) Is atrial fibrillation an inflammatory disorder? Eur Heart J 27(2):136–149PubMedGoogle Scholar
  3. 3.
    Gregor MF, Hotamisligil GS (2011) Inflammatory mechanisms in obesity. Annu Rev Immunol 29:415–445PubMedGoogle Scholar
  4. 4.
    Marzilli M et al (2012) Obstructive coronary atherosclerosis and Ischemic heart disease: an elusive link! J Am Coll Cardiol 60(11):951–956PubMedGoogle Scholar
  5. 5.
    Harrison DG et al (2011) Inflammation, immunity and hypertension. Hypertension 57(2):132–140PubMedGoogle Scholar
  6. 6.
    D’Aloia A et al (2005) Recurrent ventricular fibrillation during a febrile illness and hyperthermia in a patient with dilated cardiomyopathy and automatic implantable cardioverter defibrillator. An example of reversible electrical storm. Int J Cardiol 103(2):207–208PubMedGoogle Scholar
  7. 7.
    Dinckal MH et al (2003) Incessant monomorphic ventricular tachycardia during febrile illness in a patient with Brugada syndrome: fatal electrical storm. Europace 5(3):257–261PubMedGoogle Scholar
  8. 8.
    Park DS et al (2016) Fhf2 gene deletion causes temperature-sensitive cardiac conduction failure. Nat Commun 7:12966PubMedPubMedCentralGoogle Scholar
  9. 9.
    Amin AS et al (2008) FEver increases the risk for cardiac arrest in the brugada syndrome. Ann Intern Med 149(3):216–218PubMedGoogle Scholar
  10. 10.
    El-Battrawy I et al (2016) Hyperthermia influences the effects of sodium channel blocking drugs in human-induced pluripotent stem cell-derived cardiomyocytes. PLoS ONE 11(11):e166143PubMedPubMedCentralGoogle Scholar
  11. 11.
    Priori SG et al (2015) 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: the Task Force for the Management of Patients with ventricular arrhythmias and the prevention of sudden cardiac death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J 36(41):2793–2867PubMedGoogle Scholar
  12. 12.
    Coura JR (2007) Chagas disease: what is known and what is needed—a background article. Mem Inst Oswaldo Cruz 102(Suppl 1):113–122PubMedGoogle Scholar
  13. 13.
    Kim JS et al (2009) Cardiac sarcoidosis. Am Heart J 157(1):9–21PubMedGoogle Scholar
  14. 14.
    Kumar S et al (2015) Ventricular tachycardia in cardiac sarcoidosis. Circ Arrhythm Electrophysiol 8(1):87–93PubMedGoogle Scholar
  15. 15.
    Roberts WC, McAllister HA Jr., Ferrans VJ (1977) Sarcoidosis of the heart. A clinicopathologic study of 35 necropsy patients (group 1) and review of 78 previously described necropsy patients (group 11). Am J Med 63(1):86–108PubMedGoogle Scholar
  16. 16.
    Ljung L et al (2014) The risk of acute coronary syndrome in rheumatoid arthritis in relation to tumour necrosis factor inhibitors and the risk in the general population: a national cohort study. Arthritis Res Ther 16(3):R127PubMedPubMedCentralGoogle Scholar
  17. 17.
    Corrales-Medina VF, Madjid M, Musher DM (2010) Role of acute infection in triggering acute coronary syndromes. Lancet Infect Dis 10(2):83–92PubMedGoogle Scholar
  18. 18.
    Dong M, Liu T, Li G (2011) Association between acute infections and risk of acute coronary syndrome: a meta-analysis. Int J Cardiol 147(3):479–482PubMedGoogle Scholar
  19. 19.
    Hansson GK, Robertson AK, Soderberg-Naucler C (2006) Inflammation and atherosclerosis. Annu Rev Pathol 1:297–329PubMedGoogle Scholar
  20. 20.
    Geovanini GR, Libby P (2018) Atherosclerosis and inflammation: overview and updates. Clin Sci 132(12):1243–1252PubMedGoogle Scholar
  21. 21.
    Said M et al (2011) Calcium-calmodulin dependent protein kinase II (CaMKII): a main signal responsible for early reperfusion arrhythmias. J Mol Cell Cardiol 51(6):936–944PubMedPubMedCentralGoogle Scholar
  22. 22.
    Gorenek B et al (2014) Cardiac arrhythmias in acute coronary syndromes: position paper from the joint EHRA, ACCA, and EAPCI task force. Europace 16(11):1655–1673PubMedGoogle Scholar
  23. 23.
    Nishida K et al (2011) Mechanisms of atrial tachyarrhythmias associated with coronary artery occlusion in a chronic canine model. Circulation 123(2):137–146PubMedGoogle Scholar
  24. 24.
    Pearson TA et al (2003) Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 107(3):499–511Google Scholar
  25. 25.
    Albert CM et al (2002) Prospective study of C‑reactive protein, homocysteine, and plasma lipid levels as predictors of sudden cardiac death. Circulation 105(22):2595–2599PubMedGoogle Scholar
  26. 26.
    van den Oever IA, Sattar N, Nurmohamed MT (2014) Thromboembolic and cardiovascular risk in rheumatoid arthritis: role of the haemostatic system. Ann Rheum Dis 73(6):954–957PubMedGoogle Scholar
  27. 27.
    Alonso A et al (2012) Hemostatic markers are associated with the risk and prognosis of atrial fibrillation: the ARIC study. Int J Cardiol 155(2):217–222PubMedGoogle Scholar
  28. 28.
    Macfarlane SR et al (2001) Proteinase-activated receptors. Pharmacol Rev 53(2):245–282PubMedGoogle Scholar
  29. 29.
    Borensztajn K, Peppelenbosch MP, Spek CA (2008) Factor Xa: at the crossroads between coagulation and signaling in physiology and disease. Trends Mol Med 14(10):429–440PubMedGoogle Scholar
  30. 30.
    Sabri A et al (2000) Signaling properties and functions of two distinct cardiomyocyte protease-activated receptors. Circ Res 86(10):1054–1061PubMedGoogle Scholar
  31. 31.
    Ide J et al (2007) Proteinase-activated receptor agonists stimulate the increase in intracellular Ca2+ in cardiomyocytes and proliferation of cardiac fibroblasts from chick embryos. Bull Exp Biol Med 144(6):760–763PubMedGoogle Scholar
  32. 32.
    Pawlinski R et al (2007) Protease-activated receptor-1 contributes to cardiac remodeling and hypertrophy. Circulation 116(20):2298–2306PubMedPubMedCentralGoogle Scholar
  33. 33.
    Spronk HMH et al (2017) Hypercoagulability causes atrial fibrosis and promotes atrial fibrillation. Eur Heart J 38(1):38–50PubMedGoogle Scholar
  34. 34.
    Richardson P et al (1996) Report of the 1995 world health organization/international society and federation of cardiology task force on the definition and classification of cardiomyopathies. Circulation 93(5):841–842PubMedGoogle Scholar
  35. 35.
    Basso C et al (2001) Postmortem diagnosis in sudden cardiac death victims: macroscopic, microscopic and molecular findings. Cardiovasc Res 50(2):290–300PubMedGoogle Scholar
  36. 36.
    Kohno K et al (2000) Resuscitation from fulminant myocarditis associated with refractory ventricular fibrillation. Jpn Circ J 64(2):139–143PubMedGoogle Scholar
  37. 37.
    Aoyama N et al (2002) National survey of fulminant myocarditis in Japan: therapeutic guidelines and long-term prognosis of using percutaneous cardiopulmonary support for fulminant myocarditis (special report from a scientific committee). Circ J 66(2):133–144PubMedGoogle Scholar
  38. 38.
    Liberman L et al (2014) Incidence AND characteristics OF arrhythmias IN pediatric patients WITH myocarditis: a multicenter study. J Am Coll Cardiol 63(12 Suppl):A483. Google Scholar
  39. 39.
    Bironaite D et al (2015) Molecular mechanisms behind progressing chronic inflammatory dilated cardiomyopathy. BMC Cardiovasc Disord 15:26PubMedPubMedCentralGoogle Scholar
  40. 40.
    Kawai C (1999) From myocarditis to cardiomyopathy: mechanisms of inflammation and cell death: learning from the past for the future. Circulation 99(8):1091–1100PubMedGoogle Scholar
  41. 41.
    Saito J et al (2002) Electrical remodeling of the ventricular myocardium in myocarditis: studies of rat experimental autoimmune myocarditis. Circ J 66(1):97–103PubMedGoogle Scholar
  42. 42.
    Weng LC et al (2018) Genetic predisposition, clinical risk factor burden, and lifetime risk of atrial fibrillation. Circulation 137(10):1027–1038PubMedGoogle Scholar
  43. 43.
    Kirchhof P et al (2016) 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Europace 18(11):1609–1678PubMedGoogle Scholar
  44. 44.
    Hu YF et al (2015) Inflammation and the pathogenesis of atrial fibrillation. Nat Rev Cardiol 12(4):230–243PubMedGoogle Scholar
  45. 45.
    Wijffels MC et al (1995) Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation 92(7):1954–1968PubMedGoogle Scholar
  46. 46.
    Dobrev D, Carlsson L, Nattel S (2012) Novel molecular targets for atrial fibrillation therapy. Nat Rev Drug Discov 11(4):275–291PubMedGoogle Scholar
  47. 47.
    Wakili R et al (2011) Recent advances in the molecular pathophysiology of atrial fibrillation. J Clin Invest 121(8):2955–2968PubMedPubMedCentralGoogle Scholar
  48. 48.
    Lee SH et al (2007) Tumor necrosis factor-alpha alters calcium handling and increases arrhythmogenesis of pulmonary vein cardiomyocytes. Life Sci 80(19):1806–1815PubMedGoogle Scholar
  49. 49.
    Kao YH et al (2010) Tumor necrosis factor-alpha decreases sarcoplasmic reticulum Ca2+-ATPase expressions via the promoter methylation in cardiomyocytes. Crit Care Med 38(1):217–222PubMedGoogle Scholar
  50. 50.
    Lu A et al (2014) Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes. Cell 156(6):1193–1206PubMedPubMedCentralGoogle Scholar
  51. 51.
    Martinon F, Burns K, Tschopp J (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 10(2):417–426Google Scholar
  52. 52.
    Yao C et al (2018) Enhanced cardiomyocyte NLRP3 Inflammasome signaling promotes atrial fibrillation. Circulation 138(20):2227–2242PubMedGoogle Scholar
  53. 53.
    Frustaci A et al (1997) Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation 96(4):1180–1184PubMedGoogle Scholar
  54. 54.
    Aulin J et al (2015) Interleukin-6 and C‑reactive protein and risk for death and cardiovascular events in patients with atrial fibrillation. Am Heart J 170(6):1151–1160PubMedGoogle Scholar
  55. 55.
    Aviles RJ et al (2003) Inflammation as a risk factor for atrial fibrillation. Circulation 108(24):3006–3010PubMedGoogle Scholar
  56. 56.
    Jiang Z et al (2013) Association between C‑reactive protein and atrial fibrillation recurrence after catheter ablation: a meta-analysis. Clin Cardiol 36(9):548–554PubMedGoogle Scholar
  57. 57.
    Yo CH et al (2014) Value of high-sensitivity C‑reactive protein assays in predicting atrial fibrillation recurrence: a systematic review and meta-analysis. BMJ Open 4(2):e4418PubMedPubMedCentralGoogle Scholar
  58. 58.
    Lim HS et al (2014) Time course of inflammation, myocardial injury, and prothrombotic response after radiofrequency catheter ablation for atrial fibrillation. Circ Arrhythm Electrophysiol 7(1):83–89PubMedGoogle Scholar
  59. 59.
    Richter B et al (2012) Markers of oxidative stress after ablation of atrial fibrillation are associated with inflammation, delivered radiofrequency energy and early recurrence of atrial fibrillation. Clin Res Cardiol 101(3):217–225PubMedGoogle Scholar
  60. 60.
    Reckman YJ, Creemers EE (2018) Circulating circles predict postoperative atrial fibrillation. J Am Heart Assoc 7(2):e8261PubMedPubMedCentralGoogle Scholar
  61. 61.
    Creswell LL et al (1993) Hazards of postoperative atrial arrhythmias. Ann Thorac Surg 56(3):539–549PubMedGoogle Scholar
  62. 62.
    Almassi GH et al (1997) Atrial fibrillation after cardiac surgery: a major morbid event? Ann Surg 226(4):501–511 (discussion 511–3)PubMedPubMedCentralGoogle Scholar
  63. 63.
    Banach M et al (2006) Risk factors of atrial fibrillation following coronary artery bypass grafting: a preliminary report. Circ J 70(4):438–441PubMedGoogle Scholar
  64. 64.
    Ahlsson A et al (2010) Postoperative atrial fibrillation in patients undergoing aortocoronary bypass surgery carries an eightfold risk of future atrial fibrillation and a doubled cardiovascular mortality. Eur J Cardiothorac Surg 37(6):1353–1359PubMedGoogle Scholar
  65. 65.
    Auer J et al (2005) Risk factors of postoperative atrial fibrillation after cardiac surgery. J Card Surg 20(5):425–431PubMedGoogle Scholar
  66. 66.
    Bruins P et al (1997) Activation of the complement system during and after cardiopulmonary bypass surgery: postsurgery activation involves C‑reactive protein and is associated with postoperative arrhythmia. Circulation 96(10):3542–3548PubMedGoogle Scholar
  67. 67.
    Zhang B et al (2014) Polyunsaturated fatty acids for the prevention of atrial fibrillation after cardiac surgery: an updated meta-analysis of randomized controlled trials. J Cardiol 63(1):53–59PubMedGoogle Scholar
  68. 68.
    Ishii Y et al (2005) Inflammation of atrium after cardiac surgery is associated with inhomogeneity of atrial conduction and atrial fibrillation. Circulation 111(22):2881–2888PubMedGoogle Scholar
  69. 69.
    Ho KM, Tan JA (2009) Benefits and risks of corticosteroid prophylaxis in adult cardiac surgery: a dose-response meta-analysis. Circulation 119(14):1853–1866PubMedGoogle Scholar
  70. 70.
    Dernellis J, Panaretou M (2004) Relationship between C‑reactive protein concentrations during glucocorticoid therapy and recurrent atrial fibrillation. Eur Heart J 25(13):1100–1107PubMedGoogle Scholar
  71. 71.
    Ridker PM et al (2017) Antiinflammatory therapy with Canakinumab for atherosclerotic disease. N Engl J Med 377(12):1119–1131PubMedPubMedCentralGoogle Scholar
  72. 72.
    Du Clos TW (2000) Function of C‑reactive protein. Ann Med 32(4):274–278PubMedGoogle Scholar
  73. 73.
    Li J et al (2010) Role of inflammation and oxidative stress in atrial fibrillation. Heart Rhythm 7(4):438–444PubMedGoogle Scholar
  74. 74.
    Bickel M (1993) The role of interleukin-8 in inflammation and mechanisms of regulation. J Periodontol 64(5 Suppl):456–460PubMedGoogle Scholar

Copyright information

© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2019

Authors and Affiliations

  • N. Vonderlin
    • 1
  • J. Siebermair
    • 1
  • E. Kaya
    • 1
  • M. Köhler
    • 1
  • T. Rassaf
    • 1
  • R. Wakili
    • 1
    Email author
  1. 1.Klinik für Angiologie und Kardiologie, Westdeutsches Herz- und Gefäßzentrum EssenUniversitätsklinikum der Universität EssenEssenGermany

Personalised recommendations