МОЛЕКУЛЯРНЫЕ МЕХАНИЗМЫ СИНДРОМА БРУГАДА ПОДТИПА 1

Синдром Бругада – тяжелое наследственное аритмогенное заболевание. Несмотря на большое число данных, накопившихся с момента его открытия в 1992 году, до сих пор отсутствует понимание связи генотип-фенотип в проявлении и развитии данной патологии при миссенс-мутациях в гене SCN5A, кодирующем альфа-субъединицу потенциал-зависимых натриевых каналов Nav 1.5. Целью данного обзора является систематизация полученных за последние 25 лет данных по электрофизиологии, биофизическим и молекулярным механизмам возникновения дефектов функции канала Nav 1.5 при синдроме Бругада 1 типа. Рассмотрены клиническая картина, гипотезы развития данной аритмии на клеточном уровне и вклад изменений электрофизиологических параметров каналов Nav 1.5 в патологическое состояние. Описано влияние на активность мутантных форм канала фармакологических агентов и различных компонентов сигнальных путей в кардиомиоцитах. 

1. Antzelevitch C, Brugada P, Brugada J et. al. Brugada Syndrome: From Cell to Bedside. Curr Probl Cardiol. 2005;6:2166–2171.

2. Brugada P, Brugada J Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome A multicenter report. J Am. Coll. Cardiol. 1992; 20:1391– 1396.

3. Antzelevitch C, Brugada P, Borggrefe M et. al. Brugada Syndrome: Report of the Second Consensus Conference: Endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circ J.. 2005; 111:659–670.

4. Priori SG, Wilde AA, Horie M et. al. Executive Summary: HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes. Heart Rhythm. 2013; 10:e85–e108.

5. Miyazaki T, Mitamura H, Miyoshi S et. al. Autonomic and antiarrhythmic drug modulation of ST segment elevation in patients with Brugada syndrome. J Am. Coll. Cardiol. 27 1996;27:1061–1070.

6. Manohar S, Dahal BR, Gitler B, Fever-Induced Brugada Syndrome. J Investig. Med. high impact case reports. 2015; 3:1-4.

7. Peters CH, Abdelsayed M, Ruben PC, Triggers for arrhythmogenesis in the Brugada and long QT 3 syndromes. Prog. Biophys. Mol. Biol. 2016; 120:77–88.

8. Keller DI., Rougier JS, Kucera JP et. al. Brugada syndrome and fever: Genetic and molecular characterization of patients carrying SCN5A mutations. CardiovasC Res. 2005; 67:510–519.

9. Gehi AK, Duong TD, Metz LD et. al. Risk Stratification of Individuals with the Brugada Electrocardiogram: A Meta-Analysis. J Cardiovasc. Electrophysiol. 2006; 17:577–583.

10. Nademanee K, Veerakul G, Nimmannit S et. al. Arrhythmogenic marker for the sudden unexplained death syndrome in Thai men, Circ J. 1997; 96:2595–600.

11. Junttila MJ, Gonzalez M, Lizotte E et. al. Induced Brugada-Type Electrocardiogram, a Sign for Imminent Malignant Arrhythmias. Circ J. 2008; 117:1890–1893. 12. Donohue D, Tehrani F, Jamehdor R et. al. The prevalence of Brugada ECG in adult patients in a large university hospital in the western United States. Am. Heart Hosp. J. 2008; 6:48–50.

12. Sinner MF, Pfeufer A, Perz S et.al. Spontaneous Brugada electrocardiogram patterns are rare in the German general population: results from the KORA study, Europace. 2009; 11:1338–1344.

13. Matsuo K, Akahoshi M, Nakashima E et.al. The prevalence, incidence and prognostic value of the Brugadatype electrocardiogram: a population-based study of four decades. J. Am. Coll. Cardiol. 2001; 38:765–770.

14. Matsuo K, Kurita T, Inagaki M et.al. The circadian pattern of the development of ventricular fibrillation in patients with Brugada syndrome. Eur. Heart J. 1999; 20:465–470.

15. Mizumaki K, Fujiki A, Tsuneda T et.al. Vagal Activity Modulates Spontaneous Augmentation of ST Elevation in the Daily Life of Patients with Brugada Syndrome. J. Cardiovasc. Electrophysiol. 2004; 15:667– 673.

16. Martini B, Nava A, Thiene G et.al.Ventricular fibrillation without apparent heart disease: description of six cases. Am. Heart J. 1989; 118:1203–1209.

17. Leoni AL, Gavillet B, Rougier JS et.al. Variable Na(v)15 protein expression from the wild-type allele correlates with the penetrance of cardiac conduction disease in the Scn5a(+/-) mouse model. PLoS One. 2010; 5:e9298.

18. Boukens BJ, Sylva M, de Gier-de Vries C et.al. Reduced sodium channel function unmasks residual embryonic slow conduction in the adult right ventricular outflow tract. Circ. Res. 2013; 113:137–141.

19. Schweizer PA, Fink T, Yampolsky P et.al. Generation and characterization of SCN5A loss-of-function mutant mice modeling human brugada syndrome. Eur. Heart J. 2014; 34:4556–4556.

20. Royer A, van Veen T, Le Bouter S et.al. Mouse model of SCN5A-linked hereditary Lenègre’s disease: agerelated conduction slowing and myocardial fibrosis. Circ J. 2005; 111:1738–1746.

21. Cohen SA Immunocytochemical localization of rH1 sodium channel in adult rat heart atria and ventricle Presence in terminal intercalated disks. Circ J. 1996; 94:3083–3086.

22. Rhett JM, Gourdie RG The perinexus: a new feature of Cx43 gap junction organization. Heart Rhythm. 2012; 9:619–623.

23. Rhett JM, Veeraraghavan R, Poelzing S et.al. The perinexus: sign-post on the path to a new model of cardiac conduction? Trends Cardiovasc. Med. 2013; 23:222–228.

24. Agullo-Pascual E, Cerrone M, Delmar M Arrhythmogenic cardiomyopathy and Brugada syndrome: diseases of the connexome. FEBS Lett. 2014; 558:1322– 1330.

25. Veeraraghavan R, Poelzing S, Gourdie RG, Old cogs, new tricks: a scaffolding role for connexin43 and a junctional role for sodium channels? FEBS Lett. 2014; 558:1244–1248.

26. Veeraraghavan R, Gourdie RG, Poelzing S Mechanisms of cardiac conduction: a history of revisions. Am. J. Physiol. Heart Circ. Physiol. 2014; 306:H619-627.

27. Veeraraghavan R, Lin J,Hoeker GS et.al. Sodium channels in the Cx43 gap junction perinexus may constitute a cardiac ephapse: an experimental and modeling study. Pflugers Arch. 2015; 467:2093–2105.

28. George SA, Sciuto KJ, Lin J et.al. Extracellular sodium and potassium levels modulate cardiac conduction in mice heterozygous null for the Connexin43 gene. Pflugers Arch. 2015; 467:2287–2297.

29. Campuzano O, Fernández-FalguerasA, Iglesias A et.al. Brugada Syndrome and PKP2: Evidences and uncertainties. Int. J. Cardiol. 2016; 214:403–405.

30. Nademanee K, Raju H, de Noronha S V et.al. Fibrosis, Connexin-43, and Conduction Abnormalities in the Brugada Syndrome. J. Am. Coll. Cardiol. 2015; 66:1976–1986.

31. Nagase S, Kusano KF, Morita H et.al. Epicardial electrogram of the right ventricular outflow tract in patients with the Brugada syndrome: using the epicardial lead. J. Am. Coll. Cardiol. 2002; 39:1992–1995.

32. Tukkie R, Sogaard P, Vleugels J et.al. Delay in right ventricular activation contributes to Brugada syndrome. Circ J. 2004; 109:1272–1277.

33. Coronel R, Casini S, Koopmann TT et.al. Right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada syndrome: a combined electrophysiological, genetic, histopathologic, and computational study. Circ J. 2005; 112:2769–2777.

34. Postema PG, van Dessel PFHM, de Bakker JMT et.al. Slow and discontinuous conduction conspire in Brugada syndrome: a right ventricular mapping and stimulation study. Circ. Arrhythm. Electrophysiol. 2008; 1:379–386.

35. Postema PG, van Dessel PFHM, Kors JA et.al. Local depolarization abnormalities are the dominant pathophysiologic mechanism for type 1 electrocardiogram in brugada syndrome a study of electrocardiograms, vectorcardiograms, and body surface potential maps during ajmaline provocation. J. Am. Coll. Cardiol. 2010; 55:789–797.

36. Lambiase PD, Ahmed AK, Ciaccio EJ et.al. Highdensity substrate mapping in Brugada syndrome: combined role of conduction and repolarization heterogeneities in arrhythmogenesis. Circ J. 2009; 120:106–117.

37. Nademanee K, Veerakul G, Chandanamattha P et.al. Prevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium. Circ J. 2011; 123:1270–1279.

38. Ten Sande JN, Coronel R, Conrath CE et.al. ST-Segment Elevation and Fractionated Electrograms in Brugada Syndrome Patients Arise From the Same Structurally Abnormal Subepicardial RVOT Area but Have a Different Mechanism. Circ. Arrhythm. Electrophysiol. 2015; 8:1382–1392.

39. Zhang J, Sacher F, Hoffmayer K et.al. Cardiac electrophysiological substrate underlying the ECG phenotype and electrogram abnormalities in Brugada syndrome patients, Circ J. 2015; 131:1950–1959.

40. Brugada J, Pappone C, Berruezo A et.al. Brugada Syndrome Phenotype Elimination by Epicardial Substrate Ablation. Circ. Arrhythmia Electrophysiol. 2015; 8:1373-1381.

41. Di Diego JM, Antzelevitch C Cellular basis for ST-segment changes observed during ischemia. J. Electrocardiol. 2003; 36:1–5.

42. Antzelevitch C, Oliva A Amplification of spatial dispersion of repolarization underlies sudden cardiac death associated with catecholaminergic polymorphic VT, long QT, short QT and Brugada syndromes. J. Intern. Med. 2006; 259:48–58.

43. Antzelevitch C. Brugada syndrome. Pacing Clin. Electrophysiol. 2006; 29:1130–1159.

44. Tsuboi M, Antzelevitch C Cellular basis for electrocardiographic and arrhythmic manifestations of Andersen-Tawil syndrome (LQT7). Heart Rhythm 2006; 3:328–335.

45. Sicouri S, Blazek J, Belardinelli L et.al. Electrophysiological characteristics of canine superior vena cava sleeve preparations: effect of ranolazine. Circ. Arrhythm. Electrophysiol. 2012; 5:371–379.

46. Yan GX., Antzelevitch C Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation. Circ J. 1999; 100:1660–1666.

47. Antzelevitch C Transmural dispersion of repolarization and the T wave. Cardiovasc. Res. 2001; 50:426–431.

48. Fish JM, Antzelevitch C Role of sodium and calcium channel block in unmasking the Brugada syndrome. Heart Rhythm. 2004; 1:210–217.

49. Fish JM, Antzelevitch C Cellular mechanism and arrhythmogenic potential of T-wave alternans in the Brugada syndrome. J. Cardiovasc. Electrophysiol. 2008; 19:301–308.

50. Veldkamp MW, Viswanathan PC, Bezzina C et.al. Two distinct congenital arrhythmias evoked by a multidysfunctional Na(+) channel. Circ. Res. 2000; 86:E91-97.

51. Tse G, Liu T, Li KHC et.al. Electrophysiological mechanisms of Brugada syndrome: Insights from preclinical and clinical studies. Front. Physiol. 2016; 7:467.

52. Antzelevitch C, Pollevick GD, Cordeiro JM et.al. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circ J. 2007; 115:442–449.

53. Hoogendijk MG, Potse M, Linnenbank AC et.al. Mechanism of right precordial ST-segment elevation in structural heart disease: Excitation failure by current-to-load mismatch. Heart Rhythm. 2010; 7:238–248.

54. Hoogendijk MG, Potse M, Vinet A et.al. ST segment elevation by current-to-load mismatch: an experimental and computational study. Heart Rhythm. 2011; 8:111–118.

55. Frustaci A, Priori SG, Pieroni M et.al. Cardiac Histological Substrate in Patients With Clinical Phenotype of Brugada Syndrome. Circ J. 2005; 112:3680-3687.

56. Catalano O, Antonaci S, Moro G et.al. Magnetic resonance investigations in Brugada syndrome reveal unexpectedly high rate of structural abnormalities. Eur. Heart J. 2009; 30:2241–2248.

57. Schulze-Bahr E, Eckardt L, Breithardt G et.al. Sodium channel gene (SCN5A) mutations in 44 index patients with Brugada syndrome: Different incidences in familial and sporadic disease. Hum. Mutat. 2003; 21:651– 652.

58. Nielsen MW, Holst AG, Olesen SP et.al. The genetic component of Brugada syndrome. Front. Physiol. 2013; 4:179.

59. Catterall WA, Goldin AL,Waxman SG International Union of Pharmacology XLVII Nomenclature and StructureFunction Relationships of Voltage-Gated Sodium Channels. Pharmacol. Rev. 2005; 57:397–409.

60. Wang Q., Li Z., Shen J et.al. Genomic organization of the human SCN5A gene encoding the cardiac sodium channel. Genomics. 1996; 34:9–16.

61. Balser JR The Cardiac Sodium Channel: Gating Function and Molecular Pharmacology. J. Mol. Cell. Cardiol. 2001; 33:599–613.

62. Rivolta I., Abriel H, Tateyama M et.al. Inherited Brugada and Long QT-3 Syndrome Mutations of a Single Residue of the Cardiac Sodium Channel Confer Distinct Channel and Clinical Phenotypes. J. Biol. Chem. 2001; 276:30623–30630.

63. Olson TM, Michels V V, Ballew JD et.al. Sodium Channel Mutations and Susceptibility to Heart Failure and Atrial Fibrillation. JAMA. 2005; 293:447.

64. Ruan Y, Liu N, Bloise R et.al. Gating properties of SCN5A mutations and the response to mexiletine in longQT syndrome type 3 patients. Circ J. 2007; 116:1137–1144.

65. Samani K, Wu G, Ai T et.al. A novel SCN5A mutation V1340I in Brugada syndrome augmenting arrhythmias during febrile illness. Heart Rhythm 2009; 6:1318–1326.

66. Huang W, Liu M, Yan SF et.al. Structure-based assessment of disease-related mutations in human voltagegated sodium channels. Protein Cell, 8 (2017) 401–438.

67. Abriel H Cardiac sodium channel Nav15 and interacting proteins: Physiology and pathophysiology. J. Mol. Cell. Cardiol. 2010; 48:2–11.

68. Shy D, Gillet L, Abriel H Cardiac sodium channel NaV15 distribution in myocytes via interacting proteins: The multiple pool model. Biochim. Biophys. Acta – Mol. Cell Res. 2013; 1833:886–894.

69. Brackenbury WJ, Isom LL Na Channel β Subunits: Overachievers of the Ion Channel Family. Front. Pharmacol. 2011; 2:53.

70. London B, Michalec M,Mehdi H et.al. Mutation in Glycerol-3-Phosphate Dehydrogenase 1-Like Gene (GPD1-L) Decreases Cardiac Na+ Current and Causes Inherited Arrhythmias. Circ J. 2007; 116:2260–2268.

71. Lowe JS, Palygin O, Bhasin N et.al. Voltage-gated Na v channel targeting in the heart requires an ankyrin-G– dependent cellular pathway. J. Cell Biol. 2008; 180:173– 186.

72. Zimmer T, Surber R SCN5A channelopathies – An update on mutations and mechanisms. Prog. Biophys. Mol. Biol. 2008; 98:120–136.

73. Baroudi G, Pouliot V, Denjoy I. et.al. Novel Mechanism for Brugada Syndrome Surface Defective Mutant Scna (R1432G). Circ. Res. 2001; 88:E78–E83

74. Cordeiro JM, Barajas-Martinez H, Hong K et.al. Compound heterozygous mutations P336L and I1660V in the human cardiac sodium channel associated with the Brugada syndrome. Circ J. 2006; 114:2026–2033.

75. Valdivia CR, Tester DJ,. Rok BA et.al. A trafficking defective, Brugada syndrome-causing SCN5A mutation rescued by drugs. Cardiovasc. Res. 2004; 62:53–62.

76. Pfahnl AE, Viswanathan PC,Weiss R et.al. A Sodium Channel Pore Mutation Causing Brugada Syndrome. Heart Rhythm. 2007; 27:590–609.

77. Kanters JK, Yuan L, Hedley PL et.al. Flecainide Provocation Reveals Concealed Brugada Syndrome in a Long QT Syndrome Family With a Novel L1786Q Mutation in SCN5A. Circ. J. 2014; 78:1136–1143.

78. Hille B. Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction. J. Gen. Physiol. 1977; 69:497–515.

79. Hondeghem LM, Katzung BG. Antiarrhythmic Agents: The Modulated Receptor Mechanism of Action of Sodium and Calcium Channel-Blocking Drugs. Annu. Rev. Pharmacol. Toxicol. 1984; 24:387–423.

80. Roden DM. Pharmacology and Toxicology of Nav1.5-Class 1 anti-arrhythmic drugs. Card Electrophysiol Clin. 2014; 6:695–704.

81. Tikhonov DB, Zhorov BS Mechanism of sodium channel block by local anesthetics, antiarrhythmics, and anticonvulsants. J. Gen. Physiol. 2017; 149:465-481.

82. Balser JR, Nuss HB, Orias DW et.al. Local anesthetics as effectors of allosteric gating Lidocaine effects on inactivation-deficient rat skeletal muscle Na channels. J. Clin. Invest. 1996; 98:2874–2886.

83. Valdivia CR, Ackerman MJ, Tester DJ et.al. A novel SCN5A arrhythmia mutation, M1766L, with expression defect rescued by mexiletine. Cardiovasc. Res. 2002; 55:279–289.

84. Makita N, Horie M, Nakamura T et.al. Druginduced long-QT syndrome associated with a subclinical SCN5A mutation. Circ J. 2002; 106:1269–1274.

85. Liu K, Yang T, Viswanathan PC et.al. New mechanism contributing to drug-induced arrhythmia: rescue of a misprocessed LQT3 mutant. Circ J. 2005; 112:3239–3246.

86. Bezzina CR, Tan HL Pharmacological rescue of mutant ion channels. Cardiovasc. Res. 2002; 55:229–232.

87. Liu H, Clancy C, Cormier J et.al. Mutations in cardiac sodium channels: clinical implications. Am. J. Pharmacogenomics. 2003; 3:173–179.

88. Itoh H, Shimizu M, Takata S et.al. A novel missense mutation in the SCN5A gene associated with Brugada syndrome bidirectionally affecting blocking actions of antiarrhythmic drugs. J. Cardiovasc. Electrophysiol. 2005; 16:486–493.

89. Itoh H, Tsuji K, Sakaguchi T et.al. A paradoxical effect of lidocaine for the N406S mutation of SCN5A associated with Brugada syndrome. Int. J. Cardiol. 2007; 121:239–248.

90. Ruan Y, Denegri M, Liu N et.al. Trafficking defects and gating abnormalities of a novel SCN5A mutation question gene-specific therapy in long QT syndrome type 3. Circ. Res. 2010; 106:1374–1383.

91. Gourraud J-B, Barc J, Thollet A et.al. The Brugada Syndrome: A Rare Arrhythmia Disorder with Complex Inheritance. Front Cardiovasc Med. 2016; 3:9.

92. Zimmer T, Haufe V, Blechschmidt S Voltage-gated sodium channels in the mammalian heart. Glob. Cardiol. Sci. Pract. 2014; 58:449–463.

93. Amin AS, Asghari-Roodsari A, Tan HL Cardiac sodium channelopathies. Pflugers Arch. Eur. J. Physiol. 2009; 460:223–237.