The arrhythmogenic consequences of increasing late INa in the cardiomyocyte

Cardiovascular Research

Volumn 99, Issue 4, 2013, Pages 600-611

  Shryock, John C ^a   Song, Yejia ^b   Rajamani, Sridharan ^a   Antzelevitch, Charles ^c   Belardinelli, Luiz ^a  

^a Gilead Sciences   (United States)

^b UNIVERSITY OF FLORIDA COLLEGE OF MEDICINE   (United States)

^c MASONIC MEDICAL RESEARCH LABORATORY   (United States)

Author keywords

Afterpotential; Arrhythmia; Heart; Late INa; Reentry

Indexed keywords

2,3 DIPHOSPHOGLYCERIC ACID; ACONITINE; ANGIOTENSIN II; BATRACHOTOXIN; CALCIUM; CARBON MONOXIDE; HYDROGEN PEROXIDE; LIOTHYRONINE; LYSOPHOSPHATIDYLCHOLINE; NITRIC OXIDE; OUABAIN; PALMITOYLCARNITINE; PROTEIN KINASE FYN; SODIUM ION; VERATRIDINE;

ARRHYTHMOGENESIS; CALCIUM CELL LEVEL; ELECTRIC ACTIVITY; HEART CONTRACTION; HEART DEPOLARIZATION; HEART EXCITATION; HEART FAILURE; HEART MUSCLE CELL; HEART MUSCLE POTENTIAL; HEART REPOLARIZATION; HOMEOSTASIS; HUMAN; HYPERTROPHIC CARDIOMYOPATHY; HYPOXIA; ISCHEMIA; PRIORITY JOURNAL; REENTRY ARRHYTHMIA; REVIEW; SODIUM CELL LEVEL; SODIUM CHANNELOPATHY;

AFTERPOTENTIAL; ARRHYTHMIA; HEART; LATE INA; REENTRY;

ACTION POTENTIALS; ANIMALS; ARRHYTHMIAS, CARDIAC; CALCIUM; HOMEOSTASIS; HUMANS; MYOCYTES, CARDIAC; NAV1.5 VOLTAGE-GATED SODIUM CHANNEL; SODIUM; TETRODOTOXIN;

EID: 84883249961     PISSN: 00086363     EISSN: 17553245     Source Type: Journal    
DOI: 10.1093/cvr/cvt145     Document Type: Review

References (190)

1. Attwell D, Cohen I, Eisner D, Ohba M, Ojeda C. The steady state TTX-sensitive ('window') sodium current in cardiac Purkinje fibres. Pflugers Arch 1979;379:137-142.
2. Coraboeuf E, Deroubaix E, Coulombe A. Effect of tetrodotoxin on action potentials of the conducting system of the dog heart. Am J Physiol 1979;236:H561-H567.
3. Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson JL et al. SCN5A mutations associated with an inherited cardiac arrhythmia, longQTsyndrome. Cell 1995;80:805-811.
4. Bennett PB, Yazawa K, Makita N, George AL Jr. Molecular mechanism for an inherited cardiac arrhythmia. Nature 1995;376:683-685.
5. Noble D, Noble PJ. Late sodium current in the pathophysiology of cardiovascular disease: consequences of sodium-calcium overload. Heart 2006;92(Suppl. iv):1-5.
6. Belardinelli L, Shryock JC, Fraser H. Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor ranolazine. Heart 2006;92(Suppl. iv):6-14.
7. Antzelevitch C, Belardinelli L. The role of sodiumchannel current in modulating transmural dispersion of repolarization and arrhythmogenesis. J Cardiovasc Electrophysiol 2006;17(Suppl. 1):S79-S85.
8. Saint DA. The role of the persistent Na+ current during cardiac ischemia and hypoxia. J Cardiovasc Electrophysiol 2006;17:S96-S103.
9. Shryock JC, Belardinelli L. Inhibition of late sodium current to reduce electrical and mechanical dysfunction of ischaemic myocardium. Br J Pharmacol 2008; 153:1128-1132.
10. Saint DA. The cardiac persistent sodium current: an appealing therapeutic target? Br J Pharmacol 2008;153:1133-1142.
11. Zaza A, Belardinelli L, Shryock JC. Pathophysiology and pharmacology of the cardiac 'late sodium current'. Pharmacol Ther 2008;119:326-339.
12. Undrovinas A, Maltsev VA. Late sodium current is a new therapeutic target to improve contractility and rhythm in failing heart. Cardiovasc Hematol Agents Med Chem 2008; 6:348-359.
13. Hale SL, Shryock JC, Belardinelli L, Sweeney M, Kloner RA. Late sodium current inhibition as a new cardioprotective approach. J Mol Cell Cardiol 2008;44:954-967.
14. Maier LS.Anovel mechanism for the treat of angina, arrhythmias, and diastolic dysfunction: inhibition of late INa using ranolazine. J Cardiovasc Pharmacol 2009;54:279-286.
15. Ruan Y, Liu N, Priori SG. Sodium channel mutations and arrhythmias. Nat Rev Cardiol 2009;6:337-348.
16. Antzelevitch C, Burashnikov A, Sicouri S, Belardinelli L. Electrophysiological basis for the antiarrhythmic actions of ranolazine. Heart Rhythm 2011;8:1281-1290.
17. Moreno JD, Clancy CE. Pathophysiology of the cardiac late Na current and its potential as a drug target. J Mol Cell Cardiol 2012;52:608-619.
18. Trenor B, Cardona K, Gomez JF, Rajamani S, Ferrero JM Jr, Belardinelli L et al. Simulation and mechanistic investigation of the arrhythmogenic role of the late sodium current in human heart failure. PLoS One 2012;7:e32659.
19. Benndorf K. Properties of single cardiac Na channels at 358C. J Gen Physiol 1994; 104:801-820.
20. Patlak JB, Ortiz M. Slow currents through single sodiumchannels of the adult rat heart. J Gen Physiol 1985;86:89-104.
21. Kiyosue T, Arita M. Late sodium current and its contribution to action potential configuration in guinea pig ventricular myocytes. Circ Res 1989;64:389-397.
22. Maltsev VA, Undrovinas AI. A multi-modal composition of the late Na+ current in human ventricular cardiomyocytes. Cardiovasc Res 2006;69:116-127.
23. Undrovinas AI, Maltsev VA, Sabbah HN. Repolarization abnormalities in cardiomyocytes of dogs with chronic heart failure: role of sustained inward current. Cell Mol Life Sci 1999;55:494-505.
24. Undrovinas AI, Maltsev VA, Kyle JW, Silverman N, Sabbah HN. Gating of the late Na+ channel in normal and failing human myocardium. J Mol Cell Cardiol 2002; 34:1477-1489.
25. Valdivia CR,ChuWW,Pu J, Foell JD, HaworthRA,WolffMRet al. Increased late sodium current in myocytes from a canine heart failure model and from failing human heart. J Mol Cell Cardiol 2005;38:475-483.
26. Maltsev VA, Silverman N, Sabbah HN, Undrovinas AI. Chronic heart failure slows late sodium current in human and canine ventricular myocytes: Implication for repolarization variability. Eur J Heart Fail 2007;9:219-227.
27. Wu J, Corr PB. Palmitoylcarnitine increases [Na+]i and initiates transient inward current in adult ventricular myocytes. Am J Physiol 1995;268:H2405-H2417.
28. Ju Y-K, Saint DA, Gage PW. Hypoxia increases persistent sodium current in rat ventricular myocytes. J Physiol 1996;497:337-347.
29. Hammarström AKM, Gage PW. Hypoxia and persistent sodium current. Eur Biophys J 2002;31:323-330.
30. Ward CA, BazzaziH, Clark RB, Nygren A, Giles WR. Actions of emigrated neutrophils on Na+ and K+ currents in rat ventricular myocytes. Prog Biophys Mol Biol 2006; 90:249-269.
31. Ward CA, Giles WR. Ionic mechanism of the effects of hydrogen peroxide in rat ventricular myocytes. J Physiol 1997;500:631-642.
32. Wang YG, Dedkova EN, Fiening JP, Ojamaa K, Blatter LA, Lipsius SL. Acute exposure to thyroid hormone increases Na+ current and intracellular Ca2+ in cat atrial myocytes. J Physiol 2003;546:491-499.
33. George AL Jr. Inherited disorders of voltage-gated sodium channels. J Clin Invest 2005; 115:1990-1999.
34. Abriel H. Cardiac sodium channel NaV1.5 and interacting proteins: physiology and pathophysiology. J Mol Cell Cardiol 2010;48:2-11.
35. Kunze DL, Lacerda AE, Wilson DL, Brown AM. Cardiac Na currents and the inactivating, reopening, and waiting properties of single cardiac Na channels. J Gen Physiol 1985; 86:691-719.
36. Li CZ,Wang XD,WangHW, Bian YT, Liu YM. Four types of late Na channel current in isolated ventricular myocytes with reference to their contribution to the lastingness of action potential plateau. Acta Physiol Sinica 1997;49:241-248.
37. Clancy CE, Tateyama M, Kass RS. Insights into the molecular mechanisms of bradycardia-triggered arrhythmias in long QT-3 syndrome. J Clin Invest 2002; 110:1251-1262.
38. Clancy CE, Tateyama M, Liu H, Wehrens XHT, Kass RS. Non-equilibrium gating in cardiac Na+ channels. An original mechanism of arrhythmia. Circulation 2003; 107:2233-2237.
39. Haigney MCP, Lakatta EG, Stern MD, Silverman HS. Sodium channel blockade reduces hypoxic sodium loading and sodium-dependent calcium loading. Circulation 1994; 90:391-399.
40. Beyder A, Rae JL, Bernard C, Strege PR, Sachs F, Farrugia G. Mechanosensitivity of NaV1.5, a voltage-sensitive sodium channel. J Physiol 2010;588: 4969-4985.
41. Zilberter Y, Starmer CF, Starobin J, Grant AO. Late Na channels in cardiac cells: the physiological role of background Na channels. Biophys J 1994;67:153-160.
42. Bers DM, Barry WH, Despa S. Intracellular Na+ regulation in cardiac myocytes. Cardiovasc Res 2003;57:897-912.
43. Sheu S-S, Lederer WJ. Lidocaine's negative inotropic and antiarrhythmic actions. Dependence on shortening of action potential duration and reduction of intracellular Na+ activity. Circ Res 1985;57:578-590.
44. Makielski JC, Farley AL.Na+current inhuman ventricle: implications for sodium loading and homeostasis. J Cardiovasc Electrophysiol 2006;17:S15-S20.
45. Brill DM,Wasserstrom JA. Intracellular sodiumand the positive inotropic effect of veratridine and cardiac glycoside in sheep Purkinje fibers. Circ Res 1986;58:109-119.
46. Yao L, Fan P, Jiang Z, Viatchenko-Karpinski S, Wu Y, Kornyeyev D et al. NaV1.5-dependent persistent Na+ influx activates CaMKII in rat ventricular myocytes and N1325S mice. Am J Physiol Cell Physiol 2011;301:C577-C586.
47. Sossalla S,Wagner S, Rasenack ECL, RuffH,Weber SL, Schöndube FA et al. Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts: role of late sodium current and intracellular ion accumulation. J Mol Cell Cardiol 2008; 45:32-43.
48. Shattock MJ, Bers DM. Rat vs. rabbit ventricle: Ca flux and intracellular Na assessed by ion-selective microelectrodes. Am J Physiol Cell Physiol 1989;256:C813-C822.
49. Despa S, Islam MA, Pogwizd SM, Bers DM. Intracellular [Na+] and Na+ pump rate in rat and rabbit ventricular myocytes. J Physiol 2002;539:133-143.
50. Zhang XQ, Yamada S, Barry WH. Ranolazine inhibits an oxidative stress-induced increase in myocyte sodium and calcium loading during simulated-demand ischemia. J Cardiovasc Pharmacol 2008;51:443-449.
51. Despa S, Islam MA,Weber CR, Pogwizd SM, Bers DM. Intracellular Na+ concentration is elevated in heart failure but Na/K pump function is unchanged. Circulation 2002; 105:2543-2548.
52. Pieske B, Maier LS, Piacentino V,Weisser J, Hasenfuss G, Houser S. Rate dependence of [Na+]i and contractility in nonfailing and failing human myocardium. Circulation 2002; 106:447-453.
53. Pogwizd SM, Sipido KR, Verdonck F, Bers DM. Intracellular Na in animal models of hypertrophy and heart failure: contractile function and arrhythmogenesis. Cardiovasc Res 2003;57:887-896.
54. Verdonck F, Volders PG, Vos MA, Sipido KR. Increased Na+ concentration and altered Na/K pump activity in hypertrophied canine ventricular cells. Cardiovasc Res 2003; 57:1035-1043.
55. Mills GD, Harris DM, Chen X, Houser SR. Intracellular sodium determines frequencydependent alterations in contractility in hypertrophied feline ventricular myocytes.AmJ Physiol Heart Circ Physiol 2007;292:H1129-H1138.
56. Undrovinas NA, Maltsev VA, Belardinelli L, Sabbah HN, Undrovinas A. Late sodium current contributes to diastolic cell Ca2+ accumulation in chronic heart failure. J Physiol Sci 2010;60:245-257.
57. Cohen CJ, Fozzard HA, Sheu SS. Increase in intracellular sodium ion activity during stimulation in mammalian cardiac muscle. Circ Res 1982;50:651-662.
58. Lee CO, Dagostino M. Effect of strophanthidin on intracellular Na ion activity and twitch tension in constantly driven canine cardiac Purkinje fibers. Biophys J 1982; 40:185-198.
59. Eisner DA, Lederer WJ, Vaughan-Jones RD. The quantitative relationship between twitch tension and intracellular sodium activity in sheep cardiac Purkinje fibres. J Physiol 1984;355:251-266.
60. Leblanc N, Hume JR. Sodium current-induced release of calcium from cardiac sarcoplasmic reticulum. Science 1990;248:372-376.
61. Barry WH. Na+ 'fuzzy space': does it exist, and is it important in ischemic injury? J Cardiovasc Electrophysiol 2006;17(Suppl. 1):S43-S46.
62. Bers DM. Excitation-Contraction Coupling and Cardiac Contractile Force. 2nd ed. Norwell, MA: Kluwer Academic Publishers, 2001.
63. Song Y, Shryock JC, Wagner S, Maier LS, Belardinelli L. Blocking late sodium current reduces hydrogen peroxide-induced arrhythmogenic activity and contractile dysfunction. J Pharmacol Exp Ther 2006;318:214-222.
64. Fraser H, Belardinelli L, Wang L, Light PE, McVeigh JJ, Clanachan AS. Ranolazine decreases diastolic calcium accumulation caused by ATX-II or ischemia in rat hearts. J Mol Cell Cardiol 2006;41:1031-1038.
65. Undrovinas AI, Belardinelli L, UndrovinasNA, Sabbah HN.Ranolazine improves abnormal repolarization and contraction in left ventricular myocytes of dogs with heart failure by inhibiting late sodium current. J Cardiovasc Electrophysiol 2006;17(Suppl. 1): S169-S177.
66. Hoyer K, Song Y,Wang D, Phan D, Balschi J, Ingwall JS et al. Reducing the late sodium current improves cardiac function during sodium pump inhibition by ouabain. J Pharmacol Exp Ther 2011;337:513-523.
67. Levi AJ, Dalton GR, Hancox JC, Mitcheson JS, Issberner J, Bates JA et al. Role of intracellular sodiumoverload in the genesis of cardiac arrhythmias. J Cardiovasc Electrophysiol 1997;8:700-721.
68. WuY, Song Y, Belardinelli L, Shryock JC. The lateNa+current (INa) inhibitor ranolazine attenuates effects of palmitoyl-L-carnitine to increase late INa and cause ventricular diastolic dysfunction. J Pharmacol Exp Ther 2009;330:550-557.
69. Christé G, Chahine M, Chevalier P, Pasek M. Changes in action potentials and intracellular ionic homeostasis in a ventricular cell model related to a persistent sodium current in SCN5A mutations underlying LQT3. Prog Biophys Mol Biol 2008;96:281-293.
70. Le Grand B, Vie B, Talmant JM, Coraboeuf E, John GW. Alleviation of contractile dysfunction in ischemic hearts by slowly inactivating Na+ current blockers. Am J Physiol Heart Circ Physiol 1995;269:H533-H540.
71. Le Grand B, Pignier C, Letienne R, Cuisiat F, Rolland F, Mas A et al. Sodium late current blockers in ischemia reperfusion: Is the bullet magic? J Med Chem 2008;51:3856-3866.
72. Wu L, Ma J, Li H,Wang C, Grandi E, Zhang P et al. Late sodium current contributes to the reverse rate-dependent effect of IKr inhibition on ventricular repolarization. Circulation 2011;123:1713-1720.
73. O'Hara T, Virag L, Varro A, Rudy Y. Simulation of the undiseased human cardiac ventricular action potential: model formulation and experimental validation. PLoS Comput Biol 2011;7:e1002061.
74. Belardinelli L, Liu G, Smith-Maxwell C,WangWQ,El-Bizri N, Hirakawa R et al. Anovel, potent, and selective inhibitor of cardiac late sodium current suppresses experimental arrhythmias. J Pharmacol Exp Ther 2013;344:23-32.
75. Sossalla S, Kallmeyer B,Wagner S, Mazur M, Maurer U, Toischer K et al. Altered Na+ currents in atrial fibrillation. J Am Coll Cardiol 2010;55:2330-2342.
76. Song Y, Shryock JC, Belardinelli L. An increase of late sodium current induces delayed afterdepolarizations and sustained triggered activity in atrial myocytes. Am J Physiol Heart Circ Physiol 2008;294:H2031-H2039.
77. Song Y, Shryock JC, Belardinelli L. A slowly inactivating sodium current contributes to spontaneous diastolic depolarization of atrial myocytes. Am J Physiol Heart Circ Physiol 2009;297:H1254-H1262.
78. Guo D, Young L, Wu Y, Belardinelli L, Kowey PR, Yan GX. Increased late sodium current in left atrial myocytes of rabbits with left ventricular hypertrophy: its role in the genesis of atrial arrhythmias. Am J Physiol Heart Circ Physiol 2010; 298:H1375-H1381.
79. WuL, Shryock JC, Song Y, Li Y, Antzelevitch C, Belardinelli L. Antiarrhythmic effects of ranolazine in a guinea pig in vitro model of long-QT syndrome. J Pharmacol Exp Ther 2004;310:599-605.
80. ShimizuW, Antzelevitch C. Sodium channel block with mexiletine is effective in reducing dispersion of repolarization and preventing torsades de pointes inLQT2andLQT3 models of the long-QT syndrome. Circulation 1997;96:2038-2047.
81. Song Y, Shryock JC, Wu L, Belardinelli L. Antagonism by ranolazine of the pro-arrhythmic effects of increasing late INa in guinea pig ventricular myocytes. J Cardiovasc Pharmacol 2004;44:192-199.
82. Benito B, Brugada R, Perich RM, Lizotte E, Cinca J, Mont L et al.Amutation in the sodium channel is responsible for the association of longQT syndrome and familial atrial fibrillation. Heart Rhythm 2008;5:1434-1440.
83. Darbar D, Kannankeril PJ, Donahue BS, Kucera G, Stubblefield T, Haines JL et al. Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation. Circulation 2008;117:1927-1935.
84. Noble D. The Initiation of the Heartbeat. 2nd ed. Oxford: Clarendon Press, 1979.
85. Trautwein W, Kassebaum DG, Nelson RM, Hecht HH. Electrophysiological study of human heart muscle. Circ Res 1962;10:306-312.
86. Gelband H, Bush HL, Rosen MR, Myerburg RJ, Hoffman BF. Electrophysiologic properties of isolated preparations of human atrial myocardium. Circ Res 1972;30:293-300.
87. Mary-Rabine L, Hordof AJ, Danilo P Jr, Malm JR, Rosen MR. Mechanisms for impulse initiation in isolated human atrial fibers. Circ Res 1980;47:267-277.
88. Hogan PM, Davis LD. Evidence for specialized fibers in the canine right atrium. Circ Res 1968;23:387-396.
89. Wit AL, Cranefield PF. Triggered and automatic activity in the canine coronary sinus. Circ Res 1977;41:434-445.
90. CheungDW. Pulmonary vein as an ectopic focus in digitalis-induced arrhythmia. Nature 1981;294:582-584.
91. Wit AL, Bigger JT Jr. Possible electrophysiological mechanisms for lethal arrhythmias accompanying myocardial ischemia and infarction. Circulation 1975;52(Suppl. 6): III96-III115.
92. Carmeliet E. Slow inactivation of the sodium current in rabbit cardiac Purkinje fibres. Pflügers Arch 1987;408:18-26.
93. Carmeliet E, Saikawa T. Shortening of the action potential and reduction of pacemaker activity by lidocaine, quinidine, and procainamide in sheep cardiac Purkinje fibers. Circ Res 1982;50:257-272.
94. Rota M, Vassalle M. Patch-clamp analysis in canine cardiac Purkinje cells of a novel sodium component in the pacemaker range. J Physiol 2003;548:147-165.
95. Saint DA, Ju Y-K, Gage PW. A persistent sodium current in rat ventricular myocytes. J Physiol 1992;453:219-231.
96. Sakmann BFAS, Spindler AJ, Bryant SM, LinzKW, Noble D. Distribution of a persistent sodium current across the ventricular wall in guinea pigs. Circ Res 2000;87:910-914.
97. Colatsky TJ. Mechanisms of action of lidocaine and quinidine on action potential duration in rabbit cardiac Purkinje fibers. Circ Res 1982;50:17-27.
98. Liu Y-M, DeFelice LJ, Mazzanti M. Nachannels that remain open throughout the cardiac action potential plateau. Biophys J 1992;63:654-662.
99. Maltsev VA, Sabbah HN, Higgins RSD, Silverman N, Lesch M, Undrovinas AI. Novel, ultraslow inactivating sodium current in human ventricular cardiomyocytes. Circulation 1998;98:2545-2552.
100. Roden DM. Taking the 'idio' out of 'idiosyncratic': predicting torsades de pointes. PACE 1998;21:1029-1034.
101. Marban E, RobinsonSW, Wier WG. Mechanisms of arrhythmogenic delayed and early afterdepolarizations in ferret ventricular muscle. J Clin Invest 1986;78:1185-1192.
102. January CT, Riddle JM. Early afterdepolarizations: mechanism of induction and block. A role for L-type Ca2+ current. Circ Res 1989;64:977-990.
103. Zeng J, Rudy Y. Early afterdepolarizations in cardiac myocytes: mechanism and rate dependence. Biophys J 1995;68:949-964.
104. Xie L-H, Chen F, Karagueuzian HS,Weiss JN. Oxidative stress-induced afterdepolarizations and calmodulin kinase II signaling. Circ Res 2009;104:79-86.
105. Weiss JN, Garfinkel A, Karagueuzian HS, Chen P-S,QuZ. Early afterdepolarizations and cardiac arrhythmias. Heart Rhythm 2010;7:1891-1899.
106. JanvierNC,Harrison SM, BoyettMR. The role of inwardNa+-Ca2+exchange current in the ferret ventricular action potential. J Physiol 1997;498:611-625.
107. Armoundas AA, Hobai IA, Tomaselli GF, Winslow RL, O'Rourke B. Role of sodiumcalcium exchanger in modulating the action potential of ventricular myocytes from normal and failing hearts. Circ Res 2003;93:46-53.
108. Spencer CI, Sham JSK. Effects of Na+/Ca2+ exchange induced by SR Ca2+ release on action potentials and afterdepolarizations in guinea pig ventricular myocytes. Am J Physiol Heart Circ Physiol 2003;285:H2552-H2562.
109. Li P, Rudy Y. A model of canine Purkinje cell electrophysiology and Ca2+ cycling. Rate dependence, triggered activity, and comparison to ventricular myocytes. Circ Res 2011; 109:71-79.
110. Ben Caref E, Boutjdir M, Himel HD, El-Sherif N. Role of subendocardial Purkinje network in triggering torsade de pointes arrhythmia in experimental long QT syndrome. Europace 2008;10:1218-1223.
111. Boutjdir M, El-Sherif N. Pharmacological evaluation of early afterdepolarisations induced by sea anemone toxin (ATXII) in dog heart. Cardiovasc Res 1991;25:815-819.
112. Thomas G, Killeen MJ, Grace AA, Huang CL. Pharmacological separation of early afterdepolarizations from arrhythmogenic substrate in deltaKPQ SCN5A murine hearts modelling human long QT 3 syndrome. Acta Physiol 2008;192:505-517.
113. Morita N, Lee JH, Xie Y, Sovari A, Qu Z,Weiss JN et al. Suppression of re-entrant and multifocal ventricular fibrillation by the late sodium current blocker ranolazine. J AmColl Cardiol 2011;57:366-375.
114. Orth PM, Hesketh JC, Mak CK, Yang Y, Lin S, BeatchGNet al. RSD1235 blocks late INa and suppresses early afterdepolarizations and torsades de pointes induced by class III agents. Cardiovasc Res 2006;70:486-496.
115. WuL, Rajamani S, Li H, January CT, Shryock JC, Belardinelli L. Reduction of repolarization reserve unmasks the proarrhythmic role of endogenous late Na+ current in the heart. Am J Physiol Heart Circ Physiol 2009;297:H1048-H1057.
116. Coppini R, Ferrantini C, Yao L, Fan P, Del Lungo M, Stillitano F et al. Late sodium current inhibition reverses electromechanical dysfunction in human hypertrophic cardiomyopathy. Circulation 2013;127:575-584.
117. Jia S, Lian J,GuoD, Xue X, Patel C, Yang L et al. Modulation of the late sodium current by ATX-II and ranolazine affects the reverse use-dependence and proarrhythmic liability of IKr blockade. Br J Pharmacol 2011;164:308-316.
118. Schwartz PJ, Priori SG, Locati EH, Napolitano C, Cantu F, Towbin JA et al. LongQTsyndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ blockade and to increases in heat rate. Implications for gene-specific therapy. Circulation 1995;92:3381-3386.
119. Nagatomo T, January CT, Ye B, Abe H, Nakashima Y, Makielski JC. Rate-dependent QT shortening mechanism for the LQT3 deltaKPQ mutant. Cardiovasc Res 2002; 54:624-629.
120. WuL, Shryock JC, Song Y, Belardinelli L. An increase in late sodium current potentiates the proarrhythmic activities of low-risk QT-prolonging drugs in female rabbit hearts. J Pharmacol Exp Ther 2006;316:718-726.
121. WuL, Guo D, Li H, Hackett J, Yan GX, Jiao Z et al. Role of late sodium current in modulating the proarrhythmic and antiarrhythmic effects of quinidine. Heart Rhythm 2008; 5:1726-1734.
122. WuL, Rajamani S, Shryock JC, Li H, Ruskin J, Antzelevitch C et al. Augmentation of late sodium current unmasks the proarrhythmic effects ofamiodarone. Cardiovasc Res 2008; 77:481-488.
123. RedfernWS,Carlsson L, Davis AS, LynchWG,MacKenzie I, Palethorpe S et al. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc Res 2003;58:32-45.
124. Makita N, Horie M, Nakamura T, Ai T, Sasaki K, Yokoi H et al. Drug-induced long-QT syndrome associated with a subclinical SCN5A mutation. Circulation 2002; 106:1269-1274.
125. Splawski I, Timothy KW, Tateyama M, Clancy CE, Malhotra A, Beggs AH et al. Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia. Science 2002; 297:1333-1336.
126. Pogwizd SM, Schlotthauer K, Li L, YuanW, Bers DM. Arrhythmogenesis and contractile dysfunction in heart failure. Roles of sodium-calcium exchange, inward rectifier potassium current, and residual b-adrenergic responsiveness. Circ Res 2001;88:1159-1167.
127. Fauconnier J, Lacampagne A, Rauzier J-M, Vassort G, Richard S.Ca2+-dependent reduction of IK1 in rat ventricular cells: a novel paradigm for arrhythmia in heart failure? Cardiovasc Res 2005;68:204-212.
128. Lakatta EG, Talo A, Capogrossi MC, Spurgeon HA, Stern MD. Spontaneous sarcoplasmic reticulum Ca2+ release leads to heterogeneity of contractile and electrical properties of the heart. Basic Res Cardiol 1992;87(Suppl. 2):93-104.
129. BersDM,Pogwizd SM, Schlotthauer K. Upregulated Na/Ca exchange is involved in both contractile dysfunction and arrhythmogenesis in heart failure. Basic Res Cardiol 2002; 97(Suppl. 1):36-42.
130. Shannon TR, Pogwizd SM, BersDM.Elevated sarcoplasmic reticulumCa2+leak in intact ventricular myocytes from rabbits in heart failure. Circ Res 2003;93:592-594.
131. Hoeker GS, Katra RP, Wilson LD, Plummer BN, Laurita KR. Spontaneous calcium release in tissue from the failing canine heart. Am J Physiol Heart Circ Physiol 2009; 297:H1235-H1242.
132. Shah M, Akar FG, Tomaselli GF. Molecular basis of arrhythmias. Circulation 2005; 112:2517-2529.
133. Malan D, Friedrichs S, Fleischmann BK, Sasse P.Cardiomyocytes obtained from induced pluripotent stem cells with long-QT syndrome 3 recapitulate typical disease-specific features in vitro. Circ Res 2011;109:841-847.
134. Milberg P, Pott C, Fink M, Frommeyer G, Matsuda T, Baba A et al. Inhibition of the Na+/Ca2+ exchanger suppresses torsades de pointes in an intact heart model of long QT syndrome-2 and long QT syndrome-3. Heart Rhythm 2008;5:1444-1452.
135. Volders PGA, Vos MA, Szabo B, Sipido KR, de Groot SHM, Gorgels APM et al. Progress in the understanding of cardiac early afterdepolarizations and torsades de pointes: time to revise current concepts. Cardiovasc Res 2000;46:376-392.
136. Choi BR, Burton F, Salama G. Cytosolic Ca2+ triggers early afterdepolarizations and torsade de pointes in rabbit hearts with type 2 long QT syndrome. J Physiol 2002; 543:615-631.
137. Flaim SN, Giles WR, McCulloch AD. Arrhythmogenic consequences of Na+ channel mutations in the transmurally heterogeneous mammalian left ventricle: analysis of the I1768 V SCN5A mutation. Heart Rhythm 2007;4:768-778.
138. Maruyama M, Lin S-F, XieY, Chua S-K, Joung B,HanS et al. Genesis of phase 3 early afterdepolarizations and triggered activity in acquired long-QT syndrome. Circ Arrhythm Electrophysiol 2011;4:103-111.
139. Antzelevitch C, ShimizuW, Yan G-X, Sicouri S,Weissenburger J, Nesterenko VV et al. TheMcell: its contribution to the ECG and to normal and abnormal electrical function of the heart. J Cardiovasc Electrophysiol 1999;10:1124-1152.
140. Belardinelli L, Antzelevitch C, VosMA. Assessing predictors of drug-induced torsade de pointes. TIPS 2003;24:619-625.
141. Poelzing S, Rosenbaum DS. Cellular mechanisms of torsade de pointes. Novartis Found Symp 2005;266:204-217.
142. Zygmunt AC, Eddlestone GT, Thomas GP, Nesterenko VV, Antzelevitch CA. Larger late sodium conductance in M cells contributes to electrical heterogeneity in canine ventricle. Am J Physiol Heart Circ Physiol 2001;281:H689-H697.
143. Ferrier GR, Saunders JH, Mendez C. A cellular mechanism for the generation of ventricular arrhythmias by acetylstrophanthidin. Circ Res 1973;32:600-609.
144. Kass RS, Lederer WJ, Tsien RW,Weingart R. Role of calcium ions in transient inward currents and aftercontractions induced by strophanthidin in cardiac Purkinje fibres. J Physiol 1978;281:187-208.
145. Karagueuzian HR, Katzung BG. Voltage-clamp studies of transient inward current and mechanical oscillations induced by ouabain in ferret papillary muscle. J Physiol 1982;327: 255-271.
146. Fedida D, Noble D, Rankin AC, Spindler AJ. The arrhythmogenic transient inward current iTi and related contraction in isolated guinea-pig ventricular myocytes. J Physiol 1987;392:523-542.
147. Capogrossi MC, Houser SR, Bahinski A, Lakatta EG. Synchronous occurrence of spontaneous localized calcium release from the sarcoplasmic reticulum generates action potentials in rat cardiac ventricular myocytes at normal resting membrane potential. Circ Res 1987;61:498-503.
148. Schlotthauer K, Bers DM. Sarcoplasmic reticulum Ca2+ release causes myocyte depolarization. Circ Res 2000;87:774-780.
149. Henning B, Wit AL. The time course of action potential repolarization affects delayed afterdepolarization amplitude in atrial fibers of the canine coronary sinus. Circ Res 1984; 55:110-115.
150. WangcharoenW, Chen YC, Chen YJ, Chen SY, Yeh HI, Lin CI et al. Aging increases pulmonary veins arrhythmogenesis and susceptibility to calcium regulatory agents. Heart Rhythm 2007;4:1338-1349.
151. Chang SL, ChenYC, YehYH, Lin YK,WuTJ, Lin CI et al.Heart failure enhanced pulmonary vein arrhythmogenesis and dysregulated sodium and calcium homeostasis with increased calcium sparks. J Cardiovasc Electrophysiol 2011;22:1378-1386.
152. Sicouri S, Blazek J, Belardinelli L, Antzelevitch C. Electrophysiological characteristics of canine superior vena cava sleeve preparations: effect of ranolazine. Circ Arrhythm Electrophysiol 2012;5:371-379.
153. Joung B, Zhang H, Shinohara T, Maruyama M, Han S, KimDet al. Delayed afterdepolarization in intact canine sinoatrial node as a novel mechanism for atrial arrhythmia. J Cardiovasc Electrophysiol 2011;22:448-454.
154. Katra RP, Laurita KR. Cellular mechanism of calcium-mediated triggered activity in the heart. Circ Res 2005;96:535-542.
155. Kort AA, Capogrossi MC, Lakatta EG. Frequency, amplitude, and propagation velocity of spontaneous Ca++-dependent contractile waves in intact adult rat cardiac muscle and isolated myocytes. Circ Res 1985;57:844-855.
156. Tweedie D, Harding SE, MacLeodKT. Sarcoplasmic reticulumCacontent, sarcolemmal Cainflux and the genesis of arrhythmias in isolated guinea-pig cardiomyocytes. J Mol Cell Cardiol 2000;32:261-272.
157. Fujiwara K, Tanaka H, Mani H, Nakagami T, Takamatsu T. Burst emergence of intracellular Ca2+ waves evokes arrhythmogenic oscillatory depolarization via the Na+-Ca2+ exchanger: simultaneous confocal recording of membrane potential and intracellular Ca2+ in the heart. Circ Res 2008;103:509-518.
158. Faber GM, Rudy Y. Action potential and contractility changes in [Na+]i overloaded cardiac myocytes: a simulation study. Biophys J 2000;78:2392-2404.
159. Honerjager P. Cardioactive substances that prolong the open state of sodiumchannels. Rev Physiol Biochem Pharmacol 1982;92:1-74.
160. Wasserstrom JA, Sharma R, O'Toole MJ, Zheng J, Kelly JE, Shryock J et al. Ranolazine antagonizes the effects of increased late sodium current on intracellular calcium cycling in rat isolated heart. J Pharmacol Exp Ther 2009;331:382-391.
161. Jurevichus JA, Rosenshtraukh LV. Mechanism of delayed afterdepolarization caused by aconitine. Adv Myocardiol 1982;3:159-176.
162. Rosen MR, Danilo P. Effects of tetrodotoxin, lidocaine, verapamil, and AHR-2666 on ouabain-induced delayed afterdepolarizations in canine Purkinje fibers. Circ Res 1980; 46:117-124.
163. Uchida H, Ozawa E,Watanabe Y. Effects of mexiletine on delayed afterdepolarization and triggered activity. Heart Vessels 1990;5:140-145.
164. Vollmer B, Meuter C, Janssen PAJ. R56865 prevents electrical and mechanical signs of ouabain intoxication in guinea-pig papillary muscle. Eur J Pharmacol 1987;142:137-140.
165. Wagner S, Dybkova N, Rasenack EC, Jacobshagen C, Fabritz AL, Kirchhof P et al. Ca2+/calmodulin-dependent protein kinase II regulates cardiac Na+ channels. J Clin Invest 2006;116:3127-3138.
166. Hund TJ, Koval OM, Li J, Wright PJ, Qian L, Snyder JS et al. A beta(iv)-spectrin/CaMKII signaling complex is essential for membrane excitability in mice. J Clin Invest 2010; 120:3508-3519.
167. Aiba T, Hesketh GG, Liu T, Carlisle R, Villa-Abrille MC, O'Rourke B et al. Na+ channel regulation by Ca2+/calmodulin and Ca2+/calmodulin-dependent protein kinase II in guinea-pig ventricular myocytes. Cardiovasc Res 2010;85:454-463.
168. Ashpole NM, Herren AW, Ginsburg KS, Brogan JD, Johnson DE, Cummins TR et al. Ca2+/Calmodulin-dependent protein kinase II (CaMKII) regulates cardiac sodium channel NaV1.5 gating by multiple phosphorylation sites. J Biol Chem 2012; 287:19856-19869.
169. Koval OM, Snyder JS, Wolf RM, Pavlovicz RE, Glynn P, Curran J et al. CaMKII-based regulation of voltage-gated Na+ channel function in cardiac disease. Circulation 2012; 126:2084-2094.
170. Guo T, Zhang T, Ginsburg KS, Mishra S, Brown JH, Bers DM. CaMKIIdC slows [Ca]i decline in cardiac myocytes by promoting Ca sparks. Biophys J 2012;102:2461-2470.
171. Curran J, Brown KH, Santiago DJ, Pogwizd S, Bers DM, Shannon TR. Spontaneous Ca waves in ventricular myocytes from failing hearts depend on Ca2+-calmodulindependent protein kinase II. J Mol Cell Cardiol 2010;49:25-32.
172. Mines GR. On circulating excitations in heart muscles and their possible relation to tachycardia and fibrillation. Trans R Soc Can 1914;8:43-52.
173. Di Diego JM, Antzelevitch C. Pinacidil-induced electrical heterogeneity and extrasystolic activity in canine ventricular tissues. Does activation of ATP-regulated potassium current promote phase 2 reentry? Circulation 1993;88:1177-1189.
174. Antzelevitch C. Heterogeneity and cardiac arrhythmias: an overview. Heart Rhythm 2007;4:964-972.
175. Galinier M, Vialette J-C, Fourcade J, Cabrol P, Dongay B, Massabuau P et al.QT interval dispersion as a predictor of arrhythmic events in congestive heart failure. Importance of aetiology. Eur Heart J 1998;19:1054-1062.
176. Yan G-X,WuY, Liu T,Wang J, Marinchak RA, Kowey PR. Phase 2 early afterdepolarization as a trigger of polymorphic ventricular tachycardia in acquired long-QT syndrome. Direct evidence from intracellular recordings in the intact left ventricular wall. Circulation 2001;103:2851-2856.
177. Sicouri S, Glass A, Ferreiro M, Antzelevitch C. Transseptal dispersion of repolarization and its role in the development of Torsades de Pointes arrhythmias. J Cardiovasc Electrophysiol 2010;21:441-447.
178. Sidorov VY, Uzelac I, Wikswo JP. Regional increase of extracellular potassium leads to electrical instability and reentry occurrence through the spatial heterogeneity of APD restitution. Am J Physiol Heart Circ Physiol 2011;301:H209-H220.
179. Clayton RH, Holden AV. Dispersion of cardiac action potential duration and the initiation of re-entry: a computational study. Biomed Eng Online 2005;4:11.
180. Aslanidi OV, Boyett MR, Dobrzynski H, Li J, Zhang H. Mechanisms of transition from normal to reentrant electrical activity in a model of rabbit atrial tissue: interaction of tissue heterogeneity and anisotropy. Biophys J 2009;96:798-817.
181. Yamauchi M,Watanabe E, Yasui K, Takeuchi H, Terasawa T, Sawada K et al. Prevention of ventricular extrasystole by mexiletine in patients with normal QT intervals is associated with a reduction of transmural dispersion of repolarization. Int J Cardiol 2005; 103:92-97.
182. ShimizuW, Antzelevitch C. Cellular and ionic basis for t-wave alternans under long-QT conditions. Circulation 1999;99:1499-1507.
183. Restivo M, Caref EB, Kozhevnikov DO, El-Sherif N. Spatial dispersion of repolarization is a key factor in the arrhythmogenicity of long QT syndrome. J Cardiovasc Electrophysiol 2004;15:323-331.
184. Milberg P, Reinsch N,Wasmer K, Monnig G, Strypmann J, Osada N et al. Transmural dispersion of repolarization as a key factor of arrhythmogenicity in a novel intact heart model of LQT3. Cardiovasc Res 2005;65:397-404.
185. ShimizuW, Antzelevitch C. Cellular basis for theECGfeatures of the LQT1 form of the long-QT syndrome: effects of beta-adrenergic agonists and antagonists and sodium channel blockerson transmural dispersion of repolarization and torsade de pointes. Circulation 1998;98:2314-2322.
186. NieminenT,NanbuDY, Datti IP, VazGR, TavaresCAM,Pegler JRM et al. Antifibrillatory effect of ranolazine during severe coronary stenosis in the intact porcine model. Heart Rhythm 2011;8:608-614.
187. Garfinkel A, Kim Y-H, Voroshilovshy O, Qu Z, Kil JR, Lee M-H et al. Preventing ventricular fibrillation by flattening cardiac restitution. Proc Natl Acad Sci USA 2000; 97:6061-6066.
188. NuyensD, Stengl M, Dugarmaa S, RossenbackerT, CompernolleV, RudyYet al. Abrupt rate accelerations or premature beats cause life-threatening arrhythmias in mice with long-QT3 syndrome. Nat Med 2001;7:1021-1027.
189. Fabritz L, Kirchhof P, Franz MR, Nuyens D, Rossenbacker T, Ottenhof A et al. Effect of pacing and mexiletine on dispersion of repolarisation and arrhythmias in deltaKPQ SCN5A (long QT3) mice. Cardiovasc Res 2003;57:1085-1093.
190. Fredj S, Lindegger N, Sampson KJ, Carmeliet P, Kass RS. Altered Na+ channels promote pause-induced spontaneous diastolic activity in long QT syndrome type 3 myocytes. Circ Res 2006;99:1225-1232.