Экспериментальные поиски препаратов для лечения фибрилляции предсердий (литературный обзор)

Фибрилляция предсердий или мерцательная аритмия является самым распространённым нарушением ритма сердца с частыми осложнениями. Несмотря на столетие исследования и предположения, механизмы, лежащие в основе фибрилляции предсердий, так и не были до конца установлены, а терапия, особенно постоянной формы, остаётся неоптимальной. Назначение современных антиаритмических препаратов связано со значительным уровнем побочных эффектов, особенно проаритмическими. Многие пациенты с выраженной симптоматикой фибрилляции предсердий не получают терапии для контроля ритма. В этом обзоре основное внимание уделено фармакологическим разработкам в лечении фибрилляции предсердий. Проанализирован нынешний статус некоторых антиаритмических препаратов и их дальнейшая возможность в терапии ФП, рассмотрены молекулярные механизмы и клиническое использование некоторых селективных для предсердий антифибрилляторных препаратов. Подробно описаны ключевые фармакодинамические и фармакокинетические свойства этих препаратов с целью предупреждения проаритмических эффектов, а также препаратов, влияющих на ремоделирование предсердий, воспаление и фиброз, которые проходят тестирования в качестве потенциальных методов лечения фибрилляции предсердий.

1. Nattel S. Atrial Electrophysiology and Mechanisms of Atrial Fibrillation. J. Cardiovasc. Pharmacol. Ther. 2003;8:5–11. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 10.1161/01.CIR.96.4.1180.

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

20. Tahhan A.S. Association between oxidative stress and atrial fibrillation. Heart Rhythm. 2017;14:1849–1855. doi: 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. doi: 10.1093/cvr/cvt074.

22. Tan A.Y., Zimetbaum P. Atrial fibrillation and atrial fibrosis. Cardiovasc. Pharmacol. 2011;57:625–629. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 10.3390/jcm10235679.

33. Iwasaki Y.K., Nishida K., Kato T., Nattel S. Atrial Fibrillation Pathophysiology Implications for Management. Circulation. 2011;124:2264–2274. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 10.1093/eurheartj/ehv375.

40. Stephane N. Hatem and Prashanthan Sanders Epicardial adipose tissue and atrial fibrillation. Cardiovasc. Res. 2014;102:205–213. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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., Hildick-Smith D., et al. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N.Engl. J. Med. 2017;377:1033–1042. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. Long-term outcomes of secondary atrial fibrillation in the community: The Framingham Heart Study. Circulation. 2015;131:1648–1655. doi: 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. doi: 10.1016/j.jacc.2003.11.023.