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Critical inflammatory mechanisms underlying arrhythmias

Zugrundeliegende inflammtorische Mechanismen bei Herzrhythmusstörungen

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Abstract

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.

Zusammenfassung

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.

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References

  1. Klein RM et al (2000) Inflammation of the myocardium as an arrhythmia trigger. Z Kardiol 89(Suppl 3):24–35

    PubMed  Google Scholar 

  2. Boos CJ, Anderson RA, Lip GY (2006) Is atrial fibrillation an inflammatory disorder? Eur Heart J 27(2):136–149

    Article  PubMed  Google Scholar 

  3. Gregor MF, Hotamisligil GS (2011) Inflammatory mechanisms in obesity. Annu Rev Immunol 29:415–445

    Article  CAS  PubMed  Google Scholar 

  4. Marzilli M et al (2012) Obstructive coronary atherosclerosis and Ischemic heart disease: an elusive link! J Am Coll Cardiol 60(11):951–956

    Article  PubMed  Google Scholar 

  5. Harrison DG et al (2011) Inflammation, immunity and hypertension. Hypertension 57(2):132–140

    Article  CAS  PubMed  Google Scholar 

  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):207–208

    Article  PubMed  Google Scholar 

  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):257–261

    Article  CAS  PubMed  Google Scholar 

  8. Park DS et al (2016) Fhf2 gene deletion causes temperature-sensitive cardiac conduction failure. Nat Commun 7:12966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Amin AS et al (2008) FEver increases the risk for cardiac arrest in the brugada syndrome. Ann Intern Med 149(3):216–218

    Article  PubMed  Google Scholar 

  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):e166143

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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):2793–2867

    Article  PubMed  Google Scholar 

  12. Coura JR (2007) Chagas disease: what is known and what is needed—a background article. Mem Inst Oswaldo Cruz 102(Suppl 1):113–122

    Article  PubMed  Google Scholar 

  13. Kim JS et al (2009) Cardiac sarcoidosis. Am Heart J 157(1):9–21

    Article  CAS  PubMed  Google Scholar 

  14. Kumar S et al (2015) Ventricular tachycardia in cardiac sarcoidosis. Circ Arrhythm Electrophysiol 8(1):87–93

    Article  PubMed  Google Scholar 

  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):86–108

    Article  CAS  PubMed  Google Scholar 

  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):R127

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Corrales-Medina VF, Madjid M, Musher DM (2010) Role of acute infection in triggering acute coronary syndromes. Lancet Infect Dis 10(2):83–92

    Article  PubMed  Google Scholar 

  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):479–482

    Article  PubMed  Google Scholar 

  19. Hansson GK, Robertson AK, Soderberg-Naucler C (2006) Inflammation and atherosclerosis. Annu Rev Pathol 1:297–329

    Article  CAS  PubMed  Google Scholar 

  20. Geovanini GR, Libby P (2018) Atherosclerosis and inflammation: overview and updates. Clin Sci 132(12):1243–1252

    Article  CAS  Google Scholar 

  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):936–944

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):1655–1673

    Article  PubMed  Google Scholar 

  23. Nishida K et al (2011) Mechanisms of atrial tachyarrhythmias associated with coronary artery occlusion in a chronic canine model. Circulation 123(2):137–146

    Article  CAS  PubMed  Google Scholar 

  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):499–511

    Article  PubMed  Google Scholar 

  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):2595–2599

    Article  CAS  PubMed  Google Scholar 

  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):954–957

    Article  PubMed  CAS  Google Scholar 

  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):217–222

    Article  PubMed  Google Scholar 

  28. Macfarlane SR et al (2001) Proteinase-activated receptors. Pharmacol Rev 53(2):245–282

    CAS  PubMed  Google Scholar 

  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):429–440

    Article  CAS  PubMed  Google Scholar 

  30. Sabri A et al (2000) Signaling properties and functions of two distinct cardiomyocyte protease-activated receptors. Circ Res 86(10):1054–1061

    Article  CAS  PubMed  Google Scholar 

  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):760–763

    Article  CAS  PubMed  Google Scholar 

  32. Pawlinski R et al (2007) Protease-activated receptor-1 contributes to cardiac remodeling and hypertrophy. Circulation 116(20):2298–2306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Spronk HMH et al (2017) Hypercoagulability causes atrial fibrosis and promotes atrial fibrillation. Eur Heart J 38(1):38–50

    Article  CAS  PubMed  Google Scholar 

  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):841–842

    Article  CAS  PubMed  Google Scholar 

  35. Basso C et al (2001) Postmortem diagnosis in sudden cardiac death victims: macroscopic, microscopic and molecular findings. Cardiovasc Res 50(2):290–300

    Article  CAS  PubMed  Google Scholar 

  36. Kohno K et al (2000) Resuscitation from fulminant myocarditis associated with refractory ventricular fibrillation. Jpn Circ J 64(2):139–143

    Article  CAS  PubMed  Google Scholar 

  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):133–144

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1016/S0735-1097(14)60483-6

    Article  Google Scholar 

  39. Bironaite D et al (2015) Molecular mechanisms behind progressing chronic inflammatory dilated cardiomyopathy. BMC Cardiovasc Disord 15:26

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Kawai C (1999) From myocarditis to cardiomyopathy: mechanisms of inflammation and cell death: learning from the past for the future. Circulation 99(8):1091–1100

    Article  CAS  PubMed  Google Scholar 

  41. Saito J et al (2002) Electrical remodeling of the ventricular myocardium in myocarditis: studies of rat experimental autoimmune myocarditis. Circ J 66(1):97–103

    Article  PubMed  Google Scholar 

  42. Weng LC et al (2018) Genetic predisposition, clinical risk factor burden, and lifetime risk of atrial fibrillation. Circulation 137(10):1027–1038

    Article  PubMed  Google Scholar 

  43. Kirchhof P et al (2016) 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Europace 18(11):1609–1678

    Article  PubMed  Google Scholar 

  44. Hu YF et al (2015) Inflammation and the pathogenesis of atrial fibrillation. Nat Rev Cardiol 12(4):230–243

    Article  CAS  PubMed  Google Scholar 

  45. Wijffels MC et al (1995) Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation 92(7):1954–1968

    Article  CAS  PubMed  Google Scholar 

  46. Dobrev D, Carlsson L, Nattel S (2012) Novel molecular targets for atrial fibrillation therapy. Nat Rev Drug Discov 11(4):275–291

    Article  CAS  PubMed  Google Scholar 

  47. Wakili R et al (2011) Recent advances in the molecular pathophysiology of atrial fibrillation. J Clin Invest 121(8):2955–2968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lee SH et al (2007) Tumor necrosis factor-alpha alters calcium handling and increases arrhythmogenesis of pulmonary vein cardiomyocytes. Life Sci 80(19):1806–1815

    Article  CAS  PubMed  Google Scholar 

  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):217–222

    Article  CAS  PubMed  Google Scholar 

  50. Lu A et al (2014) Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes. Cell 156(6):1193–1206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):417–426

    Article  CAS  PubMed  Google Scholar 

  52. Yao C et al (2018) Enhanced cardiomyocyte NLRP3 Inflammasome signaling promotes atrial fibrillation. Circulation 138(20):2227–2242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Frustaci A et al (1997) Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation 96(4):1180–1184

    Article  CAS  PubMed  Google Scholar 

  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):1151–1160

    Article  CAS  PubMed  Google Scholar 

  55. Aviles RJ et al (2003) Inflammation as a risk factor for atrial fibrillation. Circulation 108(24):3006–3010

    Article  PubMed  Google Scholar 

  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):548–554

    Article  PubMed  PubMed Central  Google Scholar 

  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):e4418

    Article  PubMed  PubMed Central  Google Scholar 

  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):83–89

    Article  CAS  PubMed  Google Scholar 

  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):217–225

    Article  CAS  PubMed  Google Scholar 

  60. Reckman YJ, Creemers EE (2018) Circulating circles predict postoperative atrial fibrillation. J Am Heart Assoc 7(2):e8261

    Article  PubMed  PubMed Central  Google Scholar 

  61. Creswell LL et al (1993) Hazards of postoperative atrial arrhythmias. Ann Thorac Surg 56(3):539–549

    Article  CAS  PubMed  Google Scholar 

  62. Almassi GH et al (1997) Atrial fibrillation after cardiac surgery: a major morbid event? Ann Surg 226(4):501–511 (discussion 511–3)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Banach M et al (2006) Risk factors of atrial fibrillation following coronary artery bypass grafting: a preliminary report. Circ J 70(4):438–441

    Article  PubMed  Google Scholar 

  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):1353–1359

    Article  PubMed  Google Scholar 

  65. Auer J et al (2005) Risk factors of postoperative atrial fibrillation after cardiac surgery. J Card Surg 20(5):425–431

    Article  PubMed  Google Scholar 

  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):3542–3548

    Article  CAS  PubMed  Google Scholar 

  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):53–59

    Article  PubMed  Google Scholar 

  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):2881–2888

    Article  CAS  PubMed  Google Scholar 

  69. Ho KM, Tan JA (2009) Benefits and risks of corticosteroid prophylaxis in adult cardiac surgery: a dose-response meta-analysis. Circulation 119(14):1853–1866

    Article  CAS  PubMed  Google Scholar 

  70. Dernellis J, Panaretou M (2004) Relationship between C‑reactive protein concentrations during glucocorticoid therapy and recurrent atrial fibrillation. Eur Heart J 25(13):1100–1107

    Article  CAS  PubMed  Google Scholar 

  71. Ridker PM et al (2017) Antiinflammatory therapy with Canakinumab for atherosclerotic disease. N Engl J Med 377(12):1119–1131

    Article  CAS  PubMed  Google Scholar 

  72. Du Clos TW (2000) Function of C‑reactive protein. Ann Med 32(4):274–278

    Article  PubMed  Google Scholar 

  73. Li J et al (2010) Role of inflammation and oxidative stress in atrial fibrillation. Heart Rhythm 7(4):438–444

    Article  PubMed  Google Scholar 

  74. Bickel M (1993) The role of interleukin-8 in inflammation and mechanisms of regulation. J Periodontol 64(5 Suppl):456–460

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Klinik für Angiologie und Kardiologie, Westdeutsches Herz- und Gefäßzentrum Essen, Universitätsklinikum der Universität Essen, Hufelandstr. 55, 45147, Essen, Germany

    N. Vonderlin, J. Siebermair, E. Kaya, M. Köhler, T. Rassaf &  R. Wakili

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  1. N. Vonderlin
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  2. J. Siebermair
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  3. E. Kaya
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  4. M. Köhler
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Correspondence to R. Wakili.

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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.

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Vonderlin, N., Siebermair, J., Kaya, E. et al. Critical inflammatory mechanisms underlying arrhythmias. Herz 44, 121–129 (2019). https://doi.org/10.1007/s00059-019-4788-5

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