Rational Pharmacotherapy in Cardiology

Advanced search

Atrial Fibrillation: Development Mechanisms, Approaches and Prospects of Therapy

Full Text:


Atrial fibrillation (AF) is the most common arrhythmia. It is diagnosed in more than 33 million people worldwide and is the leading cause of hospitalization for arrhythmias. AF is characterized by fast and irregular atrial activation without discrete P-waves at a surface electrocardiography. AF pathophysiological mechanisms are very complex and include the dynamic interaction between arrhythmia substrate and triggers. Consequently, the clinical search for effective therapeutic targets should include the entire process of the onset and progression of the disease: from the first paroxysms to the development of a stable permanent form of AF.

About the Authors

O. V. Sapelnikov

Russian Federation

Oleg V. Sapelnikov – MD, PhD, Head of Laboratory of Interventional Treatment of Heart Rhythm Disorders, Department of Cardiovascular Surgery


A. A. Kulikov
National Medical Research Center of Cardiology
Russian Federation

Aleksey A. Kulikov – Junior Researcher, Department of Cardiovascular Surgery

Tretya Cherepkovskaya 15а, Moscow, 121552

D. I. Cherkashin
National Medical Research Center of Cardiology
Russian Federation

Dmitry I. Cherkashin – MD, PhD, Cardiovascular Surgeon, Department of Cardiovascular Surgery

Tretya Cherepkovskaya 15а, Moscow, 121552

I. R. Grishin
National Medical Research Center of Cardiology
Russian Federation

Igor R. Grishin – MD, PhD, Cardiovascular Surgeon, Department of Cardiovascular Surgery

Tretya Cherepkovskaya 15а, Moscow, 121552

O. A. Nikolaeva
National Medical Research Center of Cardiology
Russian Federation

Olga A. Nikolaeva – Junior Researcher, Laboratory of Interventional Treatment of Heart Rhythm Disorders, Department of Cardiovascular Surgery

Tretya Cherepkovskaya 15а, Moscow, 121552

R. S. Akchurin
National Medical Research Center of Cardiology
Russian Federation

Renat S. Akchurin – MD, PhD, Professor, Academician of the Russian Academy of Sciences, Head of Department of Cardiovascular Surgery, Deputy Director General for Surgery

Tretya Cherepkovskaya 15а, Moscow, 121552


1. Chugh S.S., Havmoeller R., Narayanan K., et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation. 2014;129(8):837-47. DOI:10.1161/CIRCULATIONAHA.113.005119.

2. Padfield G.J., Steinberg C., Swampillai J. Progression of paroxysmal to persistent atrial fibrillation: 10year follow-up in the Canadian Registry of Atrial Fibrillation. Heart Rhythm. 2017;14(6):801-7. DOI:10.1016/j.hrthm.2017.01.038.

3. Jalife J., Kaur K. Atrial remodeling, fibrosis, and atrial fibrillation. Trends Cardiovasc Med. 2015;25(6):475-84. DOI:10.1016/j.tcm.2014.12.015.

4. de Vos C.B., Pisters R., Nieuwlaat R., et al. Progression from paroxysmal to persistent atrial fibrillation clinical correlates and prognosis.J Am Coll Cardiol. 2010;55(8):725-31. DOI:10.1016/j.jacc.2009.11.040.

5. Voigt N., Trausch A., Knaut M., et al. Left-to-right atrial inward rectifier potassium current gradients in patients with paroxysmal versus chronic atrial fibrillation. Circ Arrhythm Electrophysiol. 2010;3(5):472-80. DOI:10.1161/CIRCEP.110.954636.

6. Heijman J., Voigt N., Nattel S., Dobrev D. Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression. Circ Res. 2014;114(9):1483-99. DOI:10.1161/CIRCRESAHA.114.302226.

7. Martins R.P., Kaur K., Hwang E., et al. Dominant frequency increase rate predicts transition from paroxysmal to long-term persistent atrial fibrillation. Circulation. 2014;129(14):1472-82. DOI:10.1161/CIRCULATIONAHA.113.004742.

8. Deshmukh A., Barnard J., Sun H., et al. Left atrial transcriptional changes associated with atrial fibrillation susceptibility and persistence. Circ Arrhythm Electrophysiol. 2015;8(1):32-41. DOI:10.1161/CIRCEP.114.001632 .

9. Mancarella S., Yue Y., Karnabi E., et al. Impaired Ca2+ homeostasis is associated with atrial fibrillation in the alpha1D L-type Ca2+ channel KO mouse. Am J Physiol Heart Circ Physiol. 2008;295(5):H201724. DOI:10.1152/ajpheart.00537.2008.

10. Sanders P., Berenfeld O., Hocini M., et al. Spectral analysis identifies sites of high-frequency activity maintaining atrial fibrillation in humans. Circulation. 2005;112(6):789-97. DOI:10.1161/CIRCULATIONAHA.104.517011.

11. Matsushima S., Tsutsui H., Sadoshima J. Physiological and pathological functions of NADPH oxidases during myocardial ischemia-reperfusion. Trends Cardiovasc Med. 2014;24(5):202-5. DOI:10.1016/j.tcm.2014.03.003.

12. Lavall D., Selzer C., Schuster P., et al. The mineralocorticoid receptor promotes fibrotic remodeling in atrial fibrillation. J Biol Chem. 2014;289(10):6656-68. DOI:10.1074/jbc.M113.519256.

13. Takemoto Y., Ramirez R.J., Kaur K., et al. Eplerenone reduces atrial fibrillation burden without preventing atrial electrical remodeling. J Am CollCardiol. 2017;70(23):2893-2905. DOI:10.1016/j.jacc.2017.10.014.

14. Pandit S.V., Jalife J. Rotors and the dynamics of cardiac fibrillation. Circ Res. 2013;112(5):849-62. DOI:10.1161/CIRCRESAHA.111.300158.

15. Fraccarollo D., Berger S., Galuppo P., et al. Deletion of cardiomyocyte mineralocorticoid receptor ameliorates adverse remodeling after myocardial infarction. Circulation. 2011 F;123(4):400-8. DOI:10.1161/CIRCULATIONAHA.110.983023.

16. Zannad F., McMurray J.J., Krum H., et al.Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364(1):11-21. DOI:10.1056/NEJMoa1009492.

17. Rienstra M., Hobbelt A.H., Alings M., Tijssen J.G.P., et al. Targeted therapy of underlying conditions improves sinus rhythm maintenance in patients with persistent atrial fibrillation: results of the RACE 3 trial. Eur Heart J. 2018;39(32):2987-2996. DOI:10.1093/eurheartj/ehx739.

18. GISSI-AF Investigators, Disertori M., Latini R., Barlera S., Franzosi M.G., et al. Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med. 2009;360(16):1606-17. DOI:10.1056/NEJMoa0805710.

19. Takemoto Y., Slough D.P., Meinke G., et al. Structural basis for the antiarrhythmic blockade of a potassium channel with a small molecule. FASEB J. 2018;32(4):1778-93. DOI:10.1096/fj.201700349R.

20. Takemoto Y., Ramirez R.J., Yokokawa M., et al. Galectin-3 regulates atrial fibrillation remodeling and predicts catheter ablation outcomes. JACC Basic Transl Sci. 2016;1(3):143-54.

21. Mackinnon A.C., Gibbons M.A., Farnworth S.L., et al. Regulation of transforming growth factor-β1driven lung fibrosis by galectin-3. Am J Respir Crit Care Med. 2012;185(5):537-46. DOI:10.1164/rccm.201106-0965OC.

22. Salvador-Montañés O., Gómez-Gallanti A., Garofalo D., et al. Polyunsaturated fatty acids in atrial fibrillation: looking for the proper candidates. Front Physiol. 2012;3:370. DOI:10.3389/fphys.2012.00370.

23. Kuhn E.W., Liakopoulos O.J., Stange S., et al. Preoperative statin therapy in cardiac surgery: a metaanalysis of 90,000 patients. Eur J Cardiothorac Surg. 2014;45(1):17-26. DOI:10.1093/ejcts/ezt181.

24. Zhang X., Zhang S., Li Y., et al. Association of obesity and atrial fibrillation among middle-aged and elderly Chinese. Int J Obes (Lond). 2009;33(11):1318-25. DOI:10.1038/ijo.2009.157.

25. Abed H.S., Wittert G.A., Leong D.P., et al. Effect of weight reduction and cardiomelabolic risk factor management on symptom burden and severity in patients with atrial fibrillation: a randomized clinical trial. JAMA. 2013;310(19):2050-60. DOI:10.1001/jama.2013.280521.

26. Pathak R.K., Elliott A., Middeldorp M.E., et al. Impact of CARDIO respiratory FITness on Arrhythmia Recurrence in Obese Individuals with Atrial Fibrillation: The CARDIO-FIT Study. J Am Coll Cardiol. 2015;66(9):985-96. DOI:10.1016/j.jacc.2015.06.488.

27. Iacobellis G., Bianco A.C. Epicardial adipose tissue: emerging physiological, pathophysiological and clinical features. Trends Endocrinol Metab. 2011;22(11):450-7. DOI:10.1016/j.tem.2011.07.003.

28. Haemers P., Hamdi H., Guedj K., et al. Atrial fibrillation is associated with the fibrotic remodelling of adipose tissue in the subepicardium of human and sheep atria. Eur Heart J. 2017;38(1):53-61. DOI:10.1093/eurheartj/ehv625.

29. Wong C.X., Abed H.S., Molaee P., et al. Pericardial fat is associated with atrinl fibrillation severity and ablation outcome. J Am Coll Cardiol. 2011;57(17):1745-51. DOI:10.1016/j.jacc.2010.11.045.

30. O'Connell R.P., Musa H., Gomez M.S., et al. Free fatty acid effects on the atrial myocardium: membrane ionic currents are remodeled by the disruption of T-tubular architecture. PLoS One. 2015;10(8):e0133052. DOI:10.1371/journal.pone.0133052.

31. Chilukoti R.K., Giese A., Malenke W., et al. Atrial fibrillation and rapid acute pacing regulate adipocyte/adipositas-related gene expression in the atria. Int J Cardiol. 2015;187:604-13. DOI:10.1016/j.ijcard.2015.03.072.

32. Pouliopoulos J., Chik W.W., Kanthan A., et al. Intramyocardial adiposity after myocardial infarction: new implications of a substrate for ventricular tachycardia. Circulation. 2013;128(21):2296-308. DOI:10.1161/CIRCULATIONAHA.113.002238.

33. Filgueiras-Rama D., Arias M.A., Iniesta A., et al. Atrial arrhythmias in obstructive sleep apnea: underlying mechanisms and implications in the clinical setting. Pulm Med. 2013;2013:426758. DOI:10.1155/2013/426758.

34. Genovesi S., Dossi C., Viganт M.R., et al. Electrolyte concentration during haemodialysis and QT intervalprolongation in uraemic patients. Europace. 2008;10:771-7. DOI:10.1093/europace/eun028.

35. Krijthe B.P., Heeringa J., Kors J.A., et al. Serum potassium levels and the risk of atrial fibrillation:the Rotterdam Study. Int J Cardiol. 2013;168:5411-5. DOI:10.1016/j.ijcard.2013.08.048.

36. Lancaster T.S., Schill M.R., Greenberg J.W., et al. Potassium and magnesium supplementation do not protect against atrial fibrillation after cardiac operation: atime-matched analysis. Ann Thorac Surg. 2016;102:1181-8. DOI:10.1016/j.athoracsur.2016.06.066.

37. Lu Y.Y., Cheng C.C., Chen Y.C., et al. Electrolyte disturbancesdifferentially regulate sinoatrial node and pulmonary vein electricalactivity: a contribution to hypokalemiaor hyponatremia-induced atrial fibrillation. Heart Rhythm. 2016;13:781-8. DOI:10.1016/j.hrthm.2015.12.005.

38. Hyltén-Cavallius L., Iepsen E.W., Christiansen M., et al. Glucose ingestioncauses cardiac repolarization disturbances in type 1 long QT syndrome patients and healthy subjects. Heart Rhythm. 2017;14:1165-70. DOI:10.1016/j.hrthm.2017.04.018.

39. Sinno H., Derakhchan K., Libersan D., et al. Atrial ischemia promotes atrial fibrillation in dogs. Circulation. 2003;107:1930-6. DOI:10.1161/01.CIR.0000058743.15215.03.

40. Álvarez-García J., Vives-Borrás M., Gomis P., et al. Electrophysiological effects of selective atrial coronary artery occlusionin humans. Circulation. 2016;133:2235-42. DOI:10.1161/CIRCULATIONAHA.116.021700.

41. Viskin S., Golovner M., Malov N., et al. Circadian variation of symptomatic paroxysmalatrial fibrillation. Data from almost 10 000 episodes. Eur Heart J. 1999;20:1429-34. DOI:10.1053/euhj.1999.1632.

42. Gillis A.M., Connolly S.J., Dubuc M., et al. Atrial Pacing Peri-ablation for Prevention of Atrial Fibrillation Trial. Circadian variation of paroxysmal atrial fibrillation. Am J Cardiol. 2001;87:794-8, A8. DOI:10.1016/S0002-9149(00)01509-5.

43. Larsen B.S., Kumarathurai P., Nielsen O.W., Sajadieh A. The circadian variationof premature atrial contractions. Europace. 2016;18:1573-80. DOI:10.1093/europace/euv389.

44. Yamashita T., Murakawa Y., Sezaki K., et al. Circadian variation of paroxysmal atrial fibrillation. Circulation. 1997;96:1537-41. DOI:10.1161/01.cir.96.5.1537.

45. Mitchell A.R., Spurrell P.A., Sulke N. Circadian variation of arrhythmiaonset patterns in patients with persistent atrial fibrillation. Am Heart J. 2003;146:902-7. DOI:10.1016/S0002-8703(03)00405-8.

46. Yamashita T., Sekiguchi A., Iwasaki Y.K., et al. Circadian variation of cardiac K+ channelgene expression. Circulation. 2003;107:1917-22. DOI:10.1161/01.CIR.0000058752.79734.F0.

47. Jeyaraj D., Haldar S.M., Wan X., et al. Circadian rhythms govern cardiacrepolarization and arrhythmogenesis. Nature. 2012;483:96-9. DOI:10.1038/nature10852.

48. Maesen B., Nijs J., Maessen J., et al. Post-operativeatrial fibrillation: a maze of mechanisms. Europace. 2012;14:159-74. DOI:10.1093/europace/eur208.

49. Harada M., Van Wagoner D.R., Nattel S. Role of inflammation in atrial fibrillation pathophysiology and management. Circ J. 2015;79:495-502. DOI:10.1253/circj.CJ-15-0138.

50. Nortamo S., Ukkola O., Lepojärvi S., et al. Association of sST2 and hs-CRP levels withnew-onset atrial fibrillation in coronary artery disease. Int J Cardiol. 2017;248:173-8. DOI:10.1016/j.ijcard.2017.07.022.

51. Ishii Y., Schuessler R.B., Gaynor S.L., et al. Postoperativeatrial fibrillation: the role of the inflammatory response. J Thorac Cardiovasc Surg. 2017;153:1357-65. DOI:10.1016/j.jtcvs.2016.12.051.

52. Yao C., Scott L., Veleva T., et al. Enhanced activation of inflammasome promotes atrial fibrillation. J Mol Cell Cardiol. 2017;112:147. DOI:10.1016/j.yjmcc.2017.07.051.

53. Ko D., Rahman F., Schnabel R.B., et al. Atrial fibrillation in women: epidemiology, pathophysiology, presentation, and prognosis. Nat Rev Cardiol. 2016;13:321-32. DOI:10.1038/nrcardio.2016.45.

54. Rosano G.M., Leonardo F., Sarrel P.M., et al. Cyclical variation in paroxysmal supraventricular tachycardia in women. Lancet. 1996;347:786-8. DOI:10.1016/s0140-6736(96)90867-3.

55. Anneken L., Baumann S., Vigneault P., et al. Estradiol regulates human QT-interval: acceleration of cardiac repolarization by enhanced KCNH2 membrane trafficking. Eur Heart J. 2016;37:640-50. DOI:10.1093/eurheartj/ehv371.

56. Watanabe E., Kuno Y., Takasuga H., et al. Seasonal variation in paroxysmal atrial fibrillationdocumented by 24-hour Holter electrocardiogram. Heart Rhythm. 2007;4:27-31. DOI:10.1016/j.hrthm.2006.09.030.

57. Harada M., Melka J., Sobue Y., Nattel S. Metabolic considerations in atrial fibrillation-mechanistic insights and therapeutic opportunities. Circ J. 2017;81:1749-57. DOI:10.1253/circj.CJ-171058.161.

58. Cardin S., Guasch E., Luo X., et al. Role for MicroRNA-21 in atrial profibrillatory fibrotic remodeling associated with experimental postinfarction heart failure. Circ Arrhythm Electrophysiol. 2012;5:1027-35. DOI:10.1161/CIRCEP.112.973214.

59. Luo X., Pan Z., Shan H., et al. MicroRNA-26 governs profibrillatory inward-rectifier potassium current changes in atrial fibrillation. J Clin Invest. 2013;123:1939-51. DOI:10.1172/JCI62

60. Luo X., Yang B., Nattel S. MicroRNAs and atrial fibrillation: mechanisms and translational potential. Nat Rev Cardiol. 2015;12:80-90. DOI:10.1038/nrcardio.2014.178.

61. Van den Berg N.W.E., Kawasaki M., Berger W.R., et al. MicroRNAs in atrial fibrillation: from expression signatures to functional implications. Cardiovasc Drugs Ther. 2017;31:345-65. DOI:10.1007/s10557-017-6736-z.

62. Amit G., Kikuchi K., Greener I.D., et al. Selective molecular potassium channel blockade prevents atrial fibrillation. Circulation. 2010;121:2263-70. DOI:10.1161/CIRCULATIONAHA.109.911156.

63. Bikou O., Thomas D., Trappe K., et al. Connexin 43 gene therapy prevents persistent atrial fibrillation in a porcine model. Cardiovasc Res. 2011;92:218-25. DOI:10.1093/cvr/cvr209.

64. Igarashi T., Finet J.E., Takeuchi A., et al. Connexin gene transfer preserves conduction velocity and prevents atrial fibrillation. Circulation. 2012;125:216-25. DOI:10.1161/CIRCULATIONAHA.111.053272.

65. Trappe K., Thomas D., Bikou O., et al. A. Suppression of persistent atrial fibrillation by genetic knockdown of caspase 3: a pre-clinical pilot study. Eur Heart J. 2013;34:147-57. DOI:10.1093/eurheartj/ehr269.

66. Hammoudi N., Ishikawa K., Hajjar R. J. Adeno-associated virus-mediated gene therapy in cardiovascular disease. Curr OpinCardiol. 2015;30:228-34. DOI:10.1097/HCO.0000000000000159.

67. Greenberg B., Butler J., Felker G.M., et al. Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial. Lancet. 2016;387:1178-86. DOI:10.1016/S0140-6736(16)00082-9.

68. Tadevosyan A., Vaniotis G., Allen B.G., et al. G proteincoupled receptor signalling in the cardiac nuclear membrane: evidence and possible roles in physiological and pathophysiological function. J Physiol. 2012;590:1313-30. DOI:10.1113/jphysiol.2011.222794.

69. Tadevosyan A., Xiao J., Surinkaew S., et al. Intracellular angiotensinII interacts with nuclear angiotensin receptors in cardiac fibroblasts and regulates RNA synthesis, cell proliferation, and collagen secretion. J Am Heart Assoc. 2017;6:e004965. DOI:10.1161/JAHA.116.004965.

70. Audet N., Dabouz R., Allen B..G, Hebert T.E. Nucleoligands-repurposing GPCR ligands to modulate nuclear-localized GPCRs in the cardiovascular system. J Cardiovasc Pharmacol. 2018;71(4):193204. DOI:10.1097/FJC.0000000000000535.

71. Kanorsky S.G. Antiarrhythmic therapy in patients with a paroxysmal and persistent form of atrial fibrillation, determining an achievable goal and evaluating available funds. Kardiologiia. 2014;2:70-4 (In Russ.)


For citations:

Sapelnikov O.V., Kulikov A.A., Cherkashin D.I., Grishin I.R., Nikolaeva O.A., Akchurin R.S. Atrial Fibrillation: Development Mechanisms, Approaches and Prospects of Therapy. Rational Pharmacotherapy in Cardiology. 2020;16(1):118-125. (In Russ.)

Views: 575

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

ISSN 1819-6446 (Print)
ISSN 2225-3653 (Online)