Experimental search for drugs for the treatment of atrial fibrillation (literature review)

Atrial fibrillation is the most common cardiac arrhythmia with frequent complications. Despite a century of research and speculation, the mechanisms underlying AF have not been fully elucidated, and therapy, especially for the permanent form, remains suboptimal. The use of modern antiarrhythmic drugs is associated with a significant level of side effects, especially proarrhythmic ones. Many patients with severe atrial fibrillation symptoms do not receive any therapy for rhythm control. In this review, the main focus will be on pharmacological developments in the treatment of atrial fibrillation. We will discuss the current status of some antiarrhythmic drugs and their future potential in the treatment of atrial fibrillation, reviewing the molecular mechanisms and clinical use of some atrial-selective antifibrillatory drugs. We will review in detail the key pharmacodynamic and pharmacokinetic properties of these drugs in order to prevent proarrhythmic effects. As well as drugs that affect atrial remodeling, inflammation and fibrosis, which are being tested as potential treatments for atrial fibrillation.

1. Nattel S. Atrial Electrophysiology and Mechanisms of Atrial Fibrillation. J. Cardiovasc. Pharmacol. Ther. 2003;8:5–11. https://doi.org/10.1177/107424840300800102

2. Ehrlich J.R., Cha T.J., Zhang L., Chartier D., Melnyk P., Hohnloser S.H., Nattel S. Cellular electrophysiology of canine pulmonary vein cardiomyocytes: Action potential and ionic current properties. J. Physiol. 2003;551:801–813. https://doi.org/10.1113/jphysiol.2003.046417

3. Weber K.T., Brilla C.G., Campbell S.E., Guarda E., Zhou G., Sriram K. Myocardial fibrosis: Role of angiotensin II and aldosterone. Angiotensin Heart. 1993;88:107–124. https://doi.org/10.1007/978-3-642-72497-8_8

4. Harada M., Van Wagoner D.R., Nattel S. Role of Inflammation in Atrial Fibrillation Pathophysiology and Management. Circ. J. 2015;79:495–502. https://doi.org/10.1253/circj.CJ-15-0138

5. Voigt N., Dobrev D. The biology of human pulmonary veins: Does it help us to better understand AF pathophysiology in patients? Heart Rhythm. 2013;10:392–393. https://doi.org/10.1016/j.hrthm.2012.12.010

6. Santangeli P., Marchlinski F.E. Techniques for the provocation, localization, and ablation of non-pulmonary vein triggers for atrial fibrillation. Heart Rhythm. 2017;14:1087–1096. https://doi.org/10.1016/j.hrthm.2017.02.030

7. Nagarakanti R., Ung K., Strahan H. Critical Role of the Posterior Left Atrium in the Perpetuation of Persistent Atrial Fibrillation and the Hybrid Ablation Approach for Persistent Atrial Fibrillation Management: A Single-center Outcomes Study. J. Innov. Card. Rhythm Manag. 2018;9:3372. https://doi.org/10.19102/icrm.2018.091003

8. Kistler P. M., Chieng D., Sugumar H., Ling L. H., Segan L., Azzopardi S., Al-Kaisey A., Parameswaran R., Anderson R. D., Hawson J., et al. Effect of Catheter Ablation Using Pulmonary Vein Isolation With vs Without Posterior Left Atrial Wall Isolation on Atrial Arrhythmia Recurrence in Patients With Persistent Atrial Fibrillation The CAPLA Randomized Clinical Trial. JAMA. 2023;329:127–135. https://doi.org/10.1001/jama.2022.23722

9. Sauer W. H., Alonso C., Zado E., Cooper J. M., Lin D., Dixit S., Russo A., Verdino R., Ji S., Gerstenfeld E. P., et al. Atrioventricular nodal reentrant tachycardia in patients referred for atrial fibrillation ablation: Response to ablation that incorporates slow-pathway modification. Circulation. 2006;114:191–195. https://doi.org/10.1161/CIRCULATIONAHA.106.621896

10. Moe G.K., Abildskov J.A. Atrial fibrillation as a self-sustaining arrhythmia independent of focal discharge. Am. Heart J. 1959;58:59. https://doi.org/10.1016/0002-8703(59)90274-1

11. Allessie M.A., de Groot N.M., Houben R.P., Schotten U., Boersma E., Smeets J.L., Crijns H.J. Electropathological substrate of long-standing persistent atrial fibrillation in patients with structural heart disease: Longitudinal dissociation. Circ. Arrhythmia Electrophysiol. 2010;3:606–615. https://doi.org/10.1161/CIRCEP.109.910125

12. Jalife J., Berenfeld O., Mansour M. Mother rotors and fibrillatory conduction: A mechanism of atrial fibrillation. Cardiovasc. Res. 2002;54:204–216. https://doi.org/10.1016/S0008-6363(02)00223-7

13. Aronis K.N., Berger R.D., Ashikaga H. Rotors How Do We Know When They Are Real? Circ. Arrhythmia Electrophysiol. 2017;10:e005634. https://doi.org/10.1161/CIRCEP.117.005634

14. Narayan S.M., Krummen D.E., Shivkumar K., Clopton P., Rappel W.J., Miller J.M. Treatment of Atrial Fibrillation by the Ablation of Localized Sources CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation). J. Am. Coll. Cardiol. 2012;60:628–636. https://doi.org/10.1016/j.jacc.2012.05.022

15. Parameswaran R., Voskoboinik A., Gorelik A., Lee G., Kistler P.M., Sanders P., Kalman J.M. Clinical impact of rotor ablation in atrial fibrillation: A systematic review. Europace. 2018;20:1099–1106. https://doi.org/10.1093/europace/eux370

16. Cuculich P. S., Wang Y., Lindsay B. D., Faddis M. N., Schuessler R. B., Damiano R. J., Jr., Li L., Rudy Y. Noninvasive characterization of epicardial activation in humans with diverse atrial fibrillation patterns. Circulation. 2010;122:1364–1372. https://doi.org/10.1161/CIRCULATIONAHA.110.945709

17. Ausma J., Wijffels M., Thoné F., Wouters L., Allessie M., Borgers M. Structural changes of atrial myocardium due to sustained atrial fibrillation in the goat. Circulation. 1997;96:3157–3163. https://doi.org/10.1161/01.CIR.96.9.3157

18. Frustaci A., Chimenti C., Bellocci F., Morgante E., Russo M.A., Maseri A. Histological substrate of atrial biopsies in patients with single atrial fibrillation. Circulation. 1997;96:1180–1184. https://doi.org/10.1161/01.CIR.96.4.1180

19. Wijesurendra R. S., Casadei B. Mechanisms of atrial fibrillation. Heart. 2019;105:1860–1867. https://doi.org/10.1136/heartjnl-2018-314267.

20. Tahhan A.S. Association between oxidative stress and atrial fibrillation. Heart Rhythm. 2017;14:1849–1855. https://doi.org/10.1016/j.hrthm.2017.07.028

21. Rahmutula D., Marcus G.M., Wilson E.E., Ding C.H., Xiao Y., Paquet A.C. Molecular basis of selective atrial fibrosis due to overexpression of transforming growth factor-beta1. Cardiovasc. Res. 2013;99:769–779. https://doi.org/10.1093/cvr/cvt074

22. Tan A.Y., Zimetbaum P. Atrial fibrillation and atrial fibrosis. Cardiovasc. Pharmacol. 2011;57:625–629. https://doi.org/10.1097/FJC.0b013e3182073c78

23. Harada M., Luo X., Qi X.Y., Tadevosyan A., Maguy A., Ordog B., Ledoux J., Kato T., Naud P., Voigt N., et al. Transient Receptor Potential Canonical-3 Channel–Dependent Fibroblast Regulation in Atrial Fibrillation. Circulation. 2012;126:2051–2064. https://doi.org/10.1161/CIRCULATIONAHA.112.121830

24. Yoo S., Aistrup G., Shiferaw Y., Ng J., Mohler P.J., Hund T.J., Waugh T., Browne S., Gussak G., Gilani M., et al. Oxidative stress creates a unique CaMKII-mediated substrate for atrial fibrillation in heart failure. JCI Insight. 2018;3:e120728. https://doi.org/10.1172/jci.insight.120728

25. Ho E., Galougahi K.K., Liu C.C., Bhindi R., Figtree G.A. Biological markers of oxidative stress: Applications to cardiovascular research practice. Redox Biol. 2013;1:483–491. https://doi.org/10.1016/j.redox.2013.07.006

26. Sagris M., Vardas E.P., Theofilis P., Antonopoulos A.S., Oikonomou E., Tousoulis D. Antonopoulos, Evangelos Oikonomou and Dimitris Tousoulis Atrial Fibrillation: Pathogenesis, Predisposing Factors, and Genetics. Int. J. Mol. Sci. 2022;23:6. https://doi.org/10.3390/ijms23010006

27. Zaidi Y., Aguilar E.G., Troncoso M., Ilatovskaya D.V., DeLeon-Pennell K.Y. Immune regulation of cardiac fibrosis post myocardial infarction. Cell Signal. 2021;77:109837. https://doi.org/10.1016/j.cellsig.2020.109837

28. Dumitriu I.E., Dimou P., Kaur S., Dinkla S., Kaski J.C., Camm A.J. Increase in inflammatory T cell subsets in atrial fibrillation: The missing link underlying inflammation in AF. Eur. Heart J. 2020;41((Suppl. 2)):ehaa946.3692. https://doi.org/10.1093/ehjci/ehaa946.3692

29. Legere S.A., Haidl I.D., Légaré J.F., Marshall J.S. Mast Cells in Cardiac Fibrosis: New Insights Suggest Opportunities for Intervention. Front. Immunol. 2019;10:580. https://doi.org/10.3389/fimmu.2019.00580

30. Murray D.B., McLarty-Williams J., Nagalla K.T., Janicki J.S. Tryptase activates isolated adult cardiac fibroblasts via protease activated receptor-2 (PAR-2). J. Cell Commun. Signal. 2012;6:45–51. doi:10.1007/s12079-011-0146-y

31. Shiota N., Jin D., Takai S., Kawamura T., Koyama M., Nakamura N. Miyazaki Chymase is activated in the hamster heart following ventricular fibrosis during the chronic stage of hypertension. FEBS Lett. 1997;406:301–304. https://doi.org/10.1016/S0014-5793(97)00295-0

32. Deb B., Ganesan P., Feng R., Narayan S.M. Identifying Atrial Fibrillation Mechanisms for Personalized Medicine. J. Clin. Med. 2021;10:5679. https://doi.org/10.3390/jcm10235679

33. Iwasaki Y.K., Nishida K., Kato T., Nattel S. Atrial Fibrillation Pathophysiology Implications for Management. Circulation. 2011;124:2264–2274. https://doi.org/10.1161/CIRCULATIONAHA.111.019893

34. Heijman J., Voigt N., Nattel S., Dobrev D. Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression. Circ. Res. 2014;114:1483–1499. https://doi.org/10.1161/CIRCRESAHA.114.302226

35. Chaldoupi S.M., Loh P., Hauer R.N., De Bakker J.M., van Rijen H.V. The role of connexin40 in atrial fibrillation. Cardiovasc. Res. 2009;84:15–23. https://doi.org/10.1093/cvr/cvp203

36. Marrouche N. F., Wilber D., Hindricks G., Jais P., Akoum N., Marchlinski F., Kholmovski E., Burgon N., Hu N., Mont L., et al. Association of Atrial Tissue Fibrosis Identified by Delayed Enhancement MRI and Atrial Fibrillation Catheter Ablation The DECAAF Study. JAMA. 2014;311:498–506. https://doi.org/10.1001/jama.2014.3

37. Marrouche N.F., Greene T., Dean J.M., Kholmovski E.G., Boer L.M. D., Mansour M., Calkins H., Marchlinski F., Wilber D., Hindricks G., et al. Efficacy of LGE-MRI-guided fibrosis ablation versus conventional catheter ablation of atrial fibrillation: The DECAAF II trial: Study design. J. Cardiovasc. Electrophysiol. 2021;32:916–924. https://doi.org/10.1111/jce.14957

38. Chen P. S., Chen L. S., Fishbein M. C., Lin S. F., Nattel S. Role of the Autonomic Nervous System in Atrial Fibrillation Pathophysiology and Therapy. Circ. Res. 2014;114:1500–1515. https://doi.org/10.1161/CIRCRESAHA.114.303772

39. Lau D.H., Schotten U., Mahajan R., Antic N.A., Hatem S.N., Pathak R.K., Hendriks J.M.L., Kalman J.M., Sanders P. Novel mechanisms in the pathogenesis of atrial fibrillation: Practical applications. Eur. Heart J. 2016;37:1573–1581. https://doi.org/10.1093/eurheartj/ehv375

40. Stephane N. Hatem and Prashanthan Sanders Epicardial adipose tissue and atrial fibrillation. Cardiovasc. Res. 2014;102:205–213. https://doi.org/10.1093/cvr/cvu045

41. Thanassoulis G., Massaro J.M., O'Donnell C.J., Hoffmann U., Levy D., Ellinor P.T., Wang T.J., Schnabel R.B., Vasan R.S., Fox C.S., et al. Pericardial fat is associated with prevalent atrial fibrillation: The Framingham Heart Study. Circ. Arrhythmia Electrophysiol. 2010;3:345–350. https://doi.org/10.1161/CIRCEP.109.912055

42. Mahajan R., Nelson A., Pathak R.K., Middeldorp M.E., Wong C.X., Twomey D.J., Carbone A., Teo K., Agbaedeng T., Linz D., et al. Electroanatomical Remodeling of the Atria in Obesity: Impact of Adjacent Epicardial Fat. JACC Clin. Electrophysiol. 2018;4:1529–1540. https://doi.org/10.1016/j.jacep.2018.08.014

43. Pathak R.K., Middeldorp M.E., Meredith M., Mehta A.B., Mahajan R., Wong C.X. Long-Term Effect of Goal-Directed Weight Management in an Atrial Fibrillation CohortA Long-Term Follow-Up Study (LEGACY). J. Am. Coll. Cardiol. 2015;65:2159–2169. https://doi.org/10.1016/j.jacc.2015.03.002

44. Yeghiazarians Y., Jneid H., Tietjens J.R., Redline S., Brown D.L., El-Sherif N., Mehra R., Bozkurt B., Ndumele C.E., Somers V.K. Obstructive Sleep Apnea and Cardiovascular Disease: A Scientific Statement From the American Heart Association. Circulation. 2021;144:e56–e67. https://doi.org/10.1161/CIR.0000000000000988.

45. Voskoboinik A., Prabhu S., Ling L.H., Kalman J.M., Kistler P.M. Alcohol and Atrial Fibrillation. J. Am. Coll. Cardiol. 2016;68:2567–2576. https://doi.org/10.1016/j.jacc.2016.08.074

46. Lubitz S.A., Yin X., Fontes J.D., Magnani J.W., Rienstra M., Pai M. Association Between Familial Atrial Fibrillation and Risk of New-Onset Atrial Fibrillation. JAMA. 2010;304:2263–2269. https://doi.org/10.1001/jama.2010.1690

47. Christophersen I.E., Ellinor P.T. Genetics of atrial fibrillation: From families to genomes. J. Hum. Genet. 2016;61:61–70. https://doi.org/10.1038/jhg.2015.44

48. Nielsen J.B., Graff C., Pietersen A., Lind B., Struijk J.J., Olesen M.S., Haunsø S., Gerds T.A., Svendsen J.H., Køber L., et al. J-shaped association between QTc interval duration and the risk of atrial fibrillation: Results from the Copenhagen ECG Study. J. Am. Coll. Cardiol. 2013;61:2557–2564. https://doi.org/10.1016/j.jacc.2013.03.032

49. Tucker N.R., Ellinor P.T. Ellinor Emerging Directions in the Genetics of Atrial Fibrillation. Circ. Res. 2014;114:1469–1482. https://doi.org/10.1161/CIRCRESAHA.114.302225

50. Li Q., Huang H., Liu G., Lam K., Rutberg J., Green M.S. Gain-of-function mutation of Nav1.5 in atrial fibrillation enhances cellular excitability and lowers the threshold for action potential firing. Biochem. Biophys. Res. Commun. 2009;380:132–137. https://doi.org/10.1016/j.bbrc.2009.01.052

51. Yang Y., Wang M., Zhang X., Tan H.W., Shi H.F., Jiang W.F., Wang X.H., Gang W.Y. GATA4 loss-of-function mutations in familial atrial fibrillation. Clin. Chim. Acta. 2011;412:1825–1830. https://doi.org/10.1016/j.cca.2011.06.017

52. Yang Y.Q., Wang J., Wang X.H., Wang Q., Tan H.W., Zhang M., Shen F.F., Jiang J.Q., Fang W.Y., Liu X. Mutational spectrum of the GATA5 gene associated with familial atrial fibrillation. Int. J. Cardiol. 2012;157:305–307. https://doi.org/10.1016/j.ijcard.2012.03.132

53. Yang Y., Wang X., Tan H.W., Jiang W.F., Fang W.Y., Liu X. Prevalence and spectrum of GATA6 mutations associated with familial atrial fibrillation. Int. J. Cardiol. 2012;155:494–496. https://doi.org/10.1016/j.ijcard.2011.12.091

54. Xie W.H., Chang C., Xu Y.J., Li R.G., Qu X.K., Fang W.Y., Liu X., Yang Y.Q. Prevalence and spectrum of Nkx2.5 mutations associated with idiopathic atrial fibrillation. Clinics. 2013;68:777–784. https://doi.org/10.6061/clinics/2013(06)09

55. Wang J., Zhang D.F., Sun Y.M., Li R.G., Qui X.B., Qu X.K., Liu X., Gang W.Y., Yang Y.Q. NKX2-6 mutation predisposes to familial atrial fibrillation. Int. J. Mol. Med. 2014;34:1581–1590. https://doi.org/10.3892/ijmm.2014.1971

56. Feghaly J., Zakka P., London B., MacRae C.A., Refaat M.M. Genetics of Atrial. J. Am. Heart Assoc. 2018;7:e009884. https://doi.org/10.1161/JAHA.118.009884

57. Chinchilla A., Daimi H., Lozano-Velasco E., Dominguez J.N., Caballero R., Delpón E. PITX2 Insufficiency Leads to Atrial Electrical and Structural Remodeling Linked to Arrhythmogenesis. Circ. Cardiovasc. Genet. 2011;4:269–279. https://doi.org/10.1161/CIRCGENETICS.110.958116

58. Bhatia G.S., Lip G.Y. Atrial Fibrillation Post-Myocardial Infarction: Frequency, Consequences and Management. Curr. Heart Fail. Rep. 2004;1:149–155. https://doi.org/10.1007/s11897-004-0002-y

59. Soliman E. Z., Safford M. M., Muntner P., Khodneva Y., Dawood F. Z., Zakai N. A., Thacker E. L., Judd S., Howard V. J., Howard G., et al. Atrial fibrillation and the risk of myocardial infraction. JAMA Intern. Med. 2014;174:107–114. https://doi.org/10.1001/jamainternmed.2013.11912

60. Schmitt J., Duray G., Gersh B.J., Hohnloser S.H. Atrial fibrillation in acute myocardial infarction: A systematic review of the incidence, clinical features and prognostic implications. Eur. Heart J. 2009;30:1038–1045. https://doi.org/10.1093/eurheartj/ehn579

61. Goldberg R.J., Yarzebski J., Lessard D., Wu J., Gore J.M. Recent trends in the incidence rates of and mortality rates from atrial fibrillation complicating initial acute myocardial infarction: A community-wide perspective. Am. Heart J. 2002;143:519–527. https://doi.org/10.1067/mhj.2002.120410

62. Carnicelli A.P., Owen R., Pocock S.J., Brieger D.B., Yasuda S., Nicolau J.C. Atrial fibrillation and clinical outcomes 1 to 3 years after myocardial infarction. Open Heart. 2021;8:e001726. https://doi.org/10.1136/openhrt-2021-001726

63. Jabre P., Jouven X., Adnet F., Thabut G., Bielinski S.J., Weston S.A., Roger V.L. Atrial Fibrillation and Death After Myocardial. Circulation. 2011;123:2094–2100. https://doi.org/10.1161/CIRCULATIONAHA.110.990192

64. Parashar S., Kella D., Reid K.J., Spertus J.A., Tang F., Langberg J., Vaccarino V., Kontos M.C., Lopes R.D., Lloyd M.S. New-Onset Atrial Fibrillation After Acute Myocardial Infarction and Its Relation to Admission Biomarkers (from the TRIUMPH Registry) Susmita. Am. J. Cardiol. 2013;112:1390–1395. https://doi.org/10.1016/j.amjcard.2013.07.006

65. Xu Y., Sharma D., Du F., Liu Y. The role of Toll-like receptor 2 and hypoxia-induced transcription factor-1α in the atrial structural remodeling of non-valvular atrial fibrillation. Int. J. Cardiol. 2013;168:2940–2941. https://doi.org/10.1016/j.ijcard.2013.03.174

66. Liang F., Wang Y. Coronary heart disease and atrial fibrillation: A vicious cycle. Am. J. Physiol. Heart Circ. Physiol. 2021;320:H1–H12. https://doi.org/10.1152/ajpheart.00702.2020

67. Zukela T., Zhou Q., Wang H., Zhou X., Li Y., Zhang Y. Relationship between new-onset atrial fibrillation and sympathetic neural remodeling in a canine acute myocardial infarction model. Zhonghua Xin Xue Guan Bing Za Zhi. 2015;43:975–981.

68. Landstrom A.P., Dobrev D., Wehrens X.H. Calcium Signaling and Cardiac Arrhythmias. Circ. Res. 2017;120:1969–1993. https://doi.org/10.1161/CIRCRESAHA.117.310083

69. Mas J. L., Derumeaux G., Guillon B., Massardier E., Hosseini H., Mechtouff L., Arquizan C., Béjot Y., Vuillier F., Detante O., et al. Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. N. Engl. J. Med. 2017;377:1011–1021. https://doi.org/10.1056/NEJMoa1705915

70. Søndergaard L., Kasner S. E., Rhodes J. F., Andersen G., Iversen H. K., Nielsen-Kudsk J. E., Settergren M., Sjöstrand C., Roine R. O., HildickSmith D., et al. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N.Engl. J. Med. 2017;377:1033–1042. https://doi.org/10.1056/NEJMoa1707404

71. Mojadidi M.K., Zaman M.O., Elgendy I.Y., Mahmoud A.N., Patel N.K., Agarwal N., Tobis J.M., Meier B. Cryptogenic Stroke and Patent Foramen Ovale. J. Am. Coll. Cardiol. 2018;71:1035–1043. https://doi.org/10.1016/j.jacc.2017.12.059

72. Guedeney P., Laredo M., Zeitouni M., Hauguel-Moreau M., Wallet T., Elegamandji B., Alamowitch S., Crozier S., Sabben C., Deltour S., et al. Supraventricular Arrhythmia Following Patent Foramen Ovale Percutaneous Closure. Cardiovasc. Interv. 2022;15:2315–2322. https://doi.org/10.1016/j.jcin.2022.07.044

73. Frendl G., Sodickson A.C., Chung M.K., Waldo A.L., Gersh B.J., Tisdale J.E., Calkins H., Aranki S., Kaneko T., Cassivi S., et al. AATS guidelines for the prevention and management of perioperative atrial fibrillation and flutter for thoracic surgical procedures. J. Thorac. Cardiovasc. Surg. 2014;148:e153–e193. https://doi.org/10.1016/j.jtcvs.2014.06.036

74. Philip I., Berroeta C., Leblanc I. Perioperative challenges of atrial fibrillation. Curr. Opin. Anesthesiol. 2014;27:344–352. https://doi.org/10.1097/ACO.0000000000000070

75. Lubitz S. A., Yin X., Rienstra M., Schnabel R. B., Walkey A. J., Magnani J. W., Rahman F., McManus D. D., Tadros T. M., Levy D., et al. Longterm outcomes of secondary atrial fibrillation in the community: The Framingham Heart Study. Circulation. 2015;131:1648–1655. https://doi.org/10.1161/CIRCULATIONAHA.114.014058

76. Villareal R.P., Hariharan R., Liu B.C., Kar B., Lee V.V., Elayda M., Lopez J.A., Rasekh A., Wilson J.M., Massumi A. Postoperative atrial fibrillation and mortality after coronary artery bypass surgery. J. Am. Coll. Cardiol. 2004;43:742–748. https://doi.org/10.1016/j.jacc.2003.11.023