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Pathological Roles of the Cardiac Sodium Channel Late Current (Late INa)

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Electrical Diseases of the Heart

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Abstract

The causes, consequences, and potential therapeutic benefit of inhibiting cardiac late sodium current are reviewed. Myocardial sodium channels enable electrical excitability and impulse conduction in the heart. Depolarization induces sodium channel openings and a large inward Na+ current that forms the upstroke of the cardiac action potential (AP). The cardiac AP is characterized by a long plateau phase during which Na+ channels are inactivated. Disruption of the process of Na+ channel inactivation, even when it affects only a small fraction of Na+ channels, results in a late or persistent inward Na+ current (late INa) that flows throughout the AP plateau. The magnitude of late INa is normally small but an increase can have pathological consequences. Both inherited (congenital) and acquired diseases may cause late INa to be enhanced. Mutations in genes encoding Na+ channel alpha and beta subunits and channel-associated proteins are causes of an enhanced late INa and LQT3 syndrome. Ischemia, heart failure, oxidative stress, and increased activities of certain protein kinases are associated with an increase of late INa. The consequences of an increased late INa include prolongation of the duration of the AP and facilitation of early after-depolarizations, and increased loading of myocytes with Na+. Myocyte Na+ loading leads to Ca2+ loading via Na+/Ca2+ exchange, delayed after-depolarizations, and activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII). CaMKII activation is associated with phosphorylation of the Na+ channel that further increases late INa, creating a potential positive feedback loop. Inhibition of late INa ameliorates electrical and mechanical dysfunction caused by LQT3 syndrome, ischemia, heart failure, and Na+/Ca2+ overload. In these settings, the advantages of reducing an enhanced late INa may include: increased repolarization reserve associated with decreased AP duration and variability; decreased occurrences of early and delayed after-depolarizations and triggered arrhythmias; improvements of myocardial Ca2+ handling, ventricular diastolic relaxation, and contractile efficiency.

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Abbreviations

AP:

Action potential

CaMKII:

Ca2+/calmodulin-dependent protein kinase II

DAD:

Delayed afterdepolarization

EAD:

Early afterdepolarization

RR:

Repolarization reserve

RyR2:

Ryanodine receptors subtype 2

References

  1. Valdivia CR, Chu WW, Pu J, Foell JD, Haworth RA, Wolff MR, Kamp TJ, Makielski JC. Increased late sodium current in myocytes from a canine heart failure model and from failing human heart. J Mol Cell Cardiol. 2005;38:475–83.

    Article  PubMed  CAS  Google Scholar 

  2. 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.

    Article  PubMed  CAS  Google Scholar 

  3. Wilde AA, Brugada R. Phenotypical manifestations of mutations in the genes encoding subunits of the cardiac sodium channel. Circ Res. 2011;108:884–97.

    Article  PubMed  CAS  Google Scholar 

  4. Zimmer T, Surber R. SCN5A channelopathies – an update on mutations and mechanisms. Prog Biophys Mol Biol. 2008;98:120–36.

    Article  PubMed  CAS  Google Scholar 

  5. Amin AS, Asghari-Roodsari A, Tan HL. Cardiac sodium channelopathies. Pflugers Arch. 2010;460:223–37.

    Article  PubMed  CAS  Google Scholar 

  6. Antzelevitch C, Belardinelli L. The role of sodium channel current in modulating transmural dispersion of repolarization and arrhythmogenesis. J Cardiovasc Electrophysiol. 2006;17 Suppl 1:S79–85.

    Article  PubMed  Google Scholar 

  7. George Jr AL. Inherited disorders of voltage-gated sodium channels. J Clin Invest. 2005;115:1990–9.

    Article  PubMed  CAS  Google Scholar 

  8. Hammarstrom AK, Gage PW. Hypoxia and persistent sodium current. Eur Biophys J. 2002;31:323–30.

    Article  PubMed  CAS  Google Scholar 

  9. Maier LS, Hasenfuss G. Role of [Na+]i and the emerging involvement of the late sodium current in the pathophysiology of cardiovascular disease. Eur Heart J Suppl. 2006;8:A6–9.

    Article  CAS  Google Scholar 

  10. Remme CA, Bezzina CR. Sodium channel (dys)function and cardiac arrhythmias. Cardiovasc Ther. 2010;28:287–94.

    Article  PubMed  CAS  Google Scholar 

  11. Saint DA. The role of the persistent Na(+) current during cardiac ischemia and hypoxia. J Cardiovasc Electrophysiol. 2006;17 Suppl 1:S96–103.

    Article  PubMed  Google Scholar 

  12. Saint DA. Persistent (current) in the face of adversity … a new class of cardiac anti-ischaemic ­compounds on the horizon? Br J Pharmacol. 2009;156:211–3.

    Article  PubMed  CAS  Google Scholar 

  13. Shryock JC, Belardinelli L. Inhibition of late sodium current to reduce electrical and mechanical dysfunction of ischaemic myocardium. Br J Pharmacol. 2008;153:1128–32.

    Article  PubMed  CAS  Google Scholar 

  14. Tan HL. Sodium channel variants in heart disease: expanding horizons. J Cardiovasc Electro­physiol. 2006;17 Suppl 1:S151–7.

    Article  PubMed  Google Scholar 

  15. Zaza A, Belardinelli L, Shryock JC. Pathophysiology and pharmacology of the cardiac “late sodium current”. Pharmacol Ther. 2008;119:326–39.

    Article  PubMed  CAS  Google Scholar 

  16. Shryock JC. Role of late sodium channel current in arrhythmogenesis. Card Electrophysiol Clin. 2011;3:125–40.

    Article  Google Scholar 

  17. Saint DA. The cardiac persistent sodium current: an appealing therapeutic target? Br J Pharmacol. 2008;153:1133–42.

    Article  PubMed  CAS  Google Scholar 

  18. 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;6:348–59.

    Article  PubMed  CAS  Google Scholar 

  19. Ruan Y, Liu N, Priori SG. Sodium channel mutations and arrhythmias. Nature reviews. Cardiology. 2009;6:337–48.

    PubMed  CAS  Google Scholar 

  20. Liu YM, DeFelice LJ, Mazzanti M. Na channels that remain open throughout the cardiac action potential plateau. Biophys J. 1992;63:654–62.

    Article  PubMed  CAS  Google Scholar 

  21. 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;379:137–42.

    Article  PubMed  CAS  Google Scholar 

  22. Kiyosue T, Arita M. Late sodium current and its contribution to action potential configuration in guinea pig ventricular myocytes. Circ Res. 1989;64:389–97.

    Article  PubMed  CAS  Google Scholar 

  23. Patlak JB, Ortiz M. Slow currents through single sodium channels of the adult rat heart. J Gen Physiol. 1985;86:89–104.

    Article  PubMed  CAS  Google Scholar 

  24. Saint DA, Ju YK, Gage PW. A persistent sodium current in rat ventricular myocytes. J Physiol. 1992;453:219–31.

    PubMed  CAS  Google Scholar 

  25. Zilberter Yu I, Starmer CF, Starobin J, Grant AO. Late Na channels in cardiac cells: the physiological role of background Na channels. Biophys J. 1994;67:153–60.

    Article  PubMed  Google Scholar 

  26. 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.

    Article  PubMed  CAS  Google Scholar 

  27. Makielski JC, Farley AL. Na(+) current in human ventricle: implications for sodium loading and homeostasis. J Cardiovasc Electrophysiol. 2006;17 Suppl 1:S15–20.

    Article  PubMed  Google Scholar 

  28. Ward CA, Giles WR. Ionic mechanism of the effects of hydrogen peroxide in rat ventricular myocytes. J Physiol. 1997;500(Pt 3):631–42.

    PubMed  CAS  Google Scholar 

  29. Sakmann BF, Spindler AJ, Bryant SM, Linz KW, Noble D. Distribution of a persistent sodium current across the ventricular wall in guinea pigs. Circ Res. 2000;87:910–4.

    Article  PubMed  CAS  Google Scholar 

  30. Fozzard HA, Hanck DA, Makielski JC, Scanley BE, Sheets MF. Sodium channels in cardiac Purkinje cells. Experientia. 1987;43:1162–8.

    Article  PubMed  CAS  Google Scholar 

  31. Zygmunt AC, Eddlestone GT, Thomas GP, Nesterenko VV, Antzelevitch C. Larger late sodium conductance in M-cells contributes to electrical heterogeneity in canine ventricle. Am J Physiol Heart Circ Physiol. 2001;281:H689–97.

    PubMed  CAS  Google Scholar 

  32. Antzelevitch C, Shimizu W, Yan GX, Sicouri S, Weissenburger J, Nesterenko VV, Burashnikov A, Di Diego J, Saffitz J, Thomas GP. The M cell: its contribution to the ECG and to normal and abnormal electrical function of the heart. J Cardiovasc Electrophysiol. 1999;10:1124–52.

    Article  PubMed  CAS  Google Scholar 

  33. Antzelevitch C, Sicouri S. Clinical relevance of cardiac arrhythmias generated by afterdepolarizations. Role of M cells in the generation of U waves, triggered activity and torsade de pointes. J Am Coll Cardiol. 1994;23:259–77.

    Article  PubMed  CAS  Google Scholar 

  34. Gintant GA, Datyner NB, Cohen IS. Slow inactivation of a tetrodotoxin-sensitive current in canine cardiac purkinje fibers. Biophys J. 1984;45:509–12.

    Article  PubMed  CAS  Google Scholar 

  35. Vassalle M, Bocchi L, Du F. A slowly inactivating sodium current (INa2) in the plateau range in canine cardiac Purkinje single cells. Exp Physiol. 2007;92:161–73.

    Article  PubMed  CAS  Google Scholar 

  36. Colatsky TJ. Mechanisms of action of lidocaine and quinidine on action potential duration in rabbit cardiac purkinje fibers. An effect on steady state sodium currents? Circ Res. 1982;50:17–27.

    Article  PubMed  CAS  Google Scholar 

  37. Wang DW, Yazawa K, George Jr AL, Bennett PB. Characterization of human cardiac Na+ channel mutations in the congenital long QT syndrome. Proc Natl Acad Sci U S A. 1996;93:13200–5.

    Article  PubMed  CAS  Google Scholar 

  38. Kiss T. Persistent Na-channels: origin and ­function. A review. Acta Biol Hung. 2008;59(Suppl):1–12.

    Article  PubMed  Google Scholar 

  39. Huang H, Priori SG, Napolitano C, O’Leary ME, Chahine M. Y1767C, a novel SCN5A mutation, induces a persistent Na+ current and potentiates ranolazine inhibition of NaV1.5 channels. Am J Physiol Heart Circ Physiol. 2011;300:H288–99.

    Article  PubMed  CAS  Google Scholar 

  40. Baruscotti M, DiFrancesco D, Robinson RB. Na(+) current contribution to the diastolic depolarization in newborn rabbit SA node cells. Am J Physiol Heart Circ Physiol. 2000;279:H2303–9.

    PubMed  CAS  Google Scholar 

  41. Bohle T, Brandt MC, Lindner M, Beuckelmann DJ. Identification of gating modes in single native Na+ channels from human atrium and ventricle. Circ Res. 2002;91:421–6.

    Article  PubMed  Google Scholar 

  42. Conforti L, Tohse N, Sperelakis N. Tetrodotoxin-sensitive sodium current in rat fetal ventricular myocytes-contribution to the plateau phase of action potential. J Mol Cell Cardiol. 1993;25:159–73.

    Article  PubMed  CAS  Google Scholar 

  43. Persson F, Andersson B, Duker G, Jacobson I, Carlsson L. Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre. Eur J Pharmacol. 2007;558:133–43.

    Article  PubMed  CAS  Google Scholar 

  44. Wasserstrom JA, Salata JJ. Basis for tetrodotoxin and lidocaine effects on action potentials in dog ventricular myocytes. Am J Physiol. 1988;254:H1157–66.

    PubMed  CAS  Google Scholar 

  45. Maltsev VA, Undrovinas AI. A multi-modal composition of the late Na+ current in human ventricular cardiomyocytes. Cardiovasc Res. 2006;69:116–27.

    Article  PubMed  CAS  Google Scholar 

  46. 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;34:1477–89.

    Article  PubMed  CAS  Google Scholar 

  47. Maltsev VA, Kyle JW, Mishra S, Undrovinas A. Molecular identity of the late sodium current in adult dog cardiomyocytes identified by NaV1.5 antisense inhibition. Am J Physiol Heart Circ Physiol. 2008;295:H667–76.

    Article  PubMed  CAS  Google Scholar 

  48. Dhar Malhotra J, Chen C, Rivolta I, Abriel H, Malhotra R, Mattei LN, Brosius FC, Kass RS, Isom LL. Characterization of sodium channel alpha- and beta-subunits in rat and mouse cardiac myocytes. Circulation. 2001;103:1303–10.

    Article  PubMed  CAS  Google Scholar 

  49. Haufe V, Cordeiro JM, Zimmer T, Wu YS, Schiccitano S, Benndorf K, Dumaine R. Contribution of neuronal sodium channels to the cardiac fast sodium current INa is greater in dog heart Purkinje fibers than in ventricles. Cardiovasc Res. 2005;65:117–27.

    Article  PubMed  CAS  Google Scholar 

  50. Maier SK, Westenbroek RE, McCormick KA, Curtis R, Scheuer T, Catterall WA. Distinct subcellular localization of different sodium channel alpha and beta subunits in single ventricular myocytes from mouse heart. Circulation. 2004;109:1421–7.

    Article  PubMed  CAS  Google Scholar 

  51. Maltsev VA, Silverman N, Sabbah HN, Undrovinas AI. Chronic heart failure slows late sodium current in human and canine ventricular myocytes: Implications for repolarization variability. Eur J Heart Fail. 2007;9:219–27.

    Article  PubMed  CAS  Google Scholar 

  52. Maier SK, Westenbroek RE, Schenkman KA, Feigl EO, Scheuer T, Catterall WA. An unexpected role for brain-type sodium channels in coupling of cell surface depolarization to contraction in the heart. Proc Natl Acad Sci U S A. 2002;99:4073–8.

    Article  PubMed  CAS  Google Scholar 

  53. Maier SK, Westenbroek RE, Yamanushi TT, Dobrzynski H, Boyett MR, Catterall WA, Scheuer T. An unexpected requirement for brain-type sodium channels for control of heart rate in the mouse sinoatrial node. Proc Natl Acad Sci U S A. 2003;100:3507–12.

    Article  PubMed  CAS  Google Scholar 

  54. Bennett PB, Yazawa K, Makita N, George Jr AL. Molecular mechanism for an inherited cardiac arrhythmia. Nature. 1995;376:683–5.

    Article  PubMed  CAS  Google Scholar 

  55. Ma JH, Luo AT, Zhang PH. Effect of hydrogen peroxide on persistent sodium current in guinea pig ventricular myocytes. Acta Pharmacol Sin. 2005;26:828–34.

    Article  PubMed  CAS  Google Scholar 

  56. Motoike HK, Liu H, Glaaser IW, Yang AS, Tateyama M, Kass RS. The Na+ channel inactivation gate is a molecular complex: a novel role of the COOH-terminal domain. J Gen Physiol. 2004;123:155–65.

    Article  PubMed  CAS  Google Scholar 

  57. Wedekind H, Smits JP, Schulze-Bahr E, Arnold R, Veldkamp MW, Bajanowski T, Borggrefe M, Brinkmann B, Warnecke I, Funke H, Bhuiyan ZA, Wilde AA, Breithardt G, Haverkamp W. De novo mutation in the SCN5A gene associated with early onset of sudden infant death. Circulation. 2001;104:1158–64.

    Article  PubMed  CAS  Google Scholar 

  58. Ruan Y, Liu N, Bloise R, Napolitano C, Priori SG. Gating properties of SCN5A mutations and the response to mexiletine in long-QT syndrome type 3 patients. Circulation. 2007;116:1137–44.

    Article  PubMed  CAS  Google Scholar 

  59. Ahern CA, Zhang JF, Wookalis MJ, Horn R. Modulation of the cardiac sodium channel NaV1.5 by Fyn, a Src family tyrosine kinase. Circ Res. 2005;96:991–8.

    Article  PubMed  CAS  Google Scholar 

  60. Tateyama M, Rivolta I, Clancy CE, Kass RS. Modulation of cardiac sodium channel gating by protein kinase a can be altered by disease-linked mutation 221. J Biol Chem. 2003;278:46718–26.

    Article  PubMed  CAS  Google Scholar 

  61. Isom LL, De Jongh KS, Patton DE, Reber BF, Offord J, Charbonneau H, Walsh K, Goldin AL, Catterall WA. Primary structure and functional expression of the beta 1 subunit of the rat brain sodium channel. Science. 1992;256:839–42.

    Article  PubMed  CAS  Google Scholar 

  62. Johnson D, Bennett ES. Isoform-specific effects of the beta2 subunit on voltage-gated sodium channel gating. J Biol Chem. 2006;281:25875–81.

    Article  PubMed  CAS  Google Scholar 

  63. McClatchey AI, Cannon SC, Slaugenhaupt SA, Gusella JF. The cloning and expression of a sodium channel beta 1-subunit cDNA from human brain. Hum Mol Genet. 1993;2:745–9.

    Article  PubMed  CAS  Google Scholar 

  64. Meadows LS, Isom LL. Sodium channels as macromolecular complexes: implications for inherited arrhythmia syndromes. Cardiovasc Res. 2005;67:448–58.

    Article  PubMed  CAS  Google Scholar 

  65. Morgan K, Stevens EB, Shah B, Cox PJ, Dixon AK, Lee K, Pinnock RD, Hughes J, Richardson PJ, Mizuguchi K, Jackson AP. Beta 3: an additional auxiliary subunit of the voltage-sensitive sodium channel that modulates channel gating with distinct kinetics. Proc Natl Acad Sci U S A. 2000;97:2308–13.

    Article  PubMed  CAS  Google Scholar 

  66. Yu FH, Westenbroek RE, Silos-Santiago I, McCormick KA, Lawson D, Ge P, Ferriera H, Lilly J, DiStefano PS, Catterall WA, Scheuer T, Curtis R. Sodium channel beta4, a new disulfide-linked auxiliary subunit with similarity to beta2. J Neurosci. 2003;23:7577–85.

    PubMed  CAS  Google Scholar 

  67. Maltsev VA, Kyle JW, Undrovinas A. Late Na+ ­current produced by human cardiac Na+ channel isoform NaV1.5 is modulated by its beta1 subunit. J Physiol Sci. 2009;59:217–25.

    Article  PubMed  CAS  Google Scholar 

  68. Medeiros-Domingo A, Kaku T, Tester DJ, ­Iturralde-Torres P, Itty A, Ye B, Valdivia C, Ueda K, Canizales-Quinteros S, Tusie-Luna MT, Makielski JC, Ackerman MJ. SCN4B-encoded sodium channel beta4 subunit in congenital long-QT syndrome. Circulation. 2007;116:134–42.

    Article  PubMed  Google Scholar 

  69. Tan BH, Pundi KN, Van Norstrand DW, Valdivia CR, Tester DJ, Medeiros-Domingo A, Makielski JC, Ackerman MJ. Sudden infant death syndrome-associated mutations in the sodium channel beta subunits. Heart Rhythm. 2010;7:771–8.

    Article  PubMed  Google Scholar 

  70. Wallace RH, Scheffer IE, Parasivam G, Barnett S, Wallace GB, Sutherland GR, Berkovic SF, Mulley JC. Generalized epilepsy with febrile seizures plus: mutation of the sodium channel subunit scn1b. Neurology. 2002;58:1426–9.

    Article  PubMed  CAS  Google Scholar 

  71. Cohen AW, Hnasko R, Schubert W, Lisanti MP. Role of caveolae and caveolins in health and disease. Physiol Rev. 2004;84:1341–79.

    Article  PubMed  CAS  Google Scholar 

  72. Balijepalli RC, Kamp TJ. Caveolae, ion channels and cardiac arrhythmias. Prog Biophys Mol Biol. 2008;98:149–60.

    Article  PubMed  CAS  Google Scholar 

  73. Yarbrough TL, Lu T, Lee HC, Shibata EF. Localization of cardiac sodium channels in caveolin-rich membrane domains: regulation of sodium current amplitude. Circ Res. 2002;90:443–9.

    Article  PubMed  CAS  Google Scholar 

  74. Vatta M, Ackerman MJ, Ye B, Makielski JC, Ughanze EE, Taylor EW, Tester DJ, Balijepalli RC, Foell JD, Li Z, Kamp TJ, Towbin JA. Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation. 2006;114:2104–12.

    Article  PubMed  CAS  Google Scholar 

  75. Cronk LB, Ye B, Kaku T, Tester DJ, Vatta M, Makielski JC, Ackerman MJ. Novel mechanism for sudden infant death syndrome: persistent late sodium current secondary to mutations in caveolin-3. Heart Rhythm. 2007;4:161–6.

    Article  PubMed  Google Scholar 

  76. Gavillet B, Rougier JS, Domenighetti AA, Behar R, Boixel C, Ruchat P, Lehr HA, Pedrazzini T, Abriel H. Cardiac sodium channel NaV1.5 is regulated by a multiprotein complex composed of syntrophins and dystrophin. Circ Res. 2006;99:407–14.

    Article  PubMed  CAS  Google Scholar 

  77. Williams JC, Armesilla AL, Mohamed TM, Hagarty CL, McIntyre FH, Schomburg S, Zaki AO, Oceandy D, Cartwright EJ, Buch MH, Emerson M, Neyses L. The sarcolemmal calcium pump, alpha-1 syntrophin, and neuronal nitric-oxide synthase are parts of a macromolecular protein complex. J Biol Chem. 2006;281:23341–8.

    Article  PubMed  CAS  Google Scholar 

  78. Ahern GP, Hsu SF, Klyachko VA, Jackson MB. Induction of persistent sodium current by exogenous and endogenous nitric oxide. J Biol Chem. 2000;275:28810–5.

    Article  PubMed  CAS  Google Scholar 

  79. Cheng J, Van Norstrand DW, Medeiros-Domingo A, Valdivia C, Tan BH, Ye B, Kroboth S, Vatta M, Tester DJ, January CT, Makielski JC, Ackerman MJ. Alpha1-syntrophin mutations identified in sudden infant death syndrome cause an increase in late cardiac sodium current. Circ Arrhythm Electrophysiol. 2009;2:667–76.

    Article  PubMed  Google Scholar 

  80. Ueda K, Valdivia C, Medeiros-Domingo A, Tester DJ, Vatta M, Farrugia G, Ackerman MJ, Makielski JC. Syntrophin mutation associated with long QT syndrome through activation of the nNOS-SCN5A macromolecular complex. Proc Natl Acad Sci U S A. 2008;105:9355–60.

    Article  PubMed  CAS  Google Scholar 

  81. Wu G, Ai T, Kim JJ, Mohapatra B, Xi Y, Li Z, Abbasi S, Purevjav E, Samani K, Ackerman MJ, Qi M, Moss AJ, Shimizu W, Towbin JA, Cheng J, Vatta M. Alpha-­1-syntrophin mutation and the ­long-QT syndrome: a disease of sodium channel disruption. Circ Arrhythm Electrophysiol. 2008;1:193–201.

    Article  PubMed  CAS  Google Scholar 

  82. Mohler PJ, Rivolta I, Napolitano C, LeMaillet G, Lambert S, Priori SG, Bennett V. NaV1.5 e1053k mutation causing Brugada syndrome blocks binding to Ankyrin-G and expression of nav1.5 on the surface of cardiomyocytes. Proc Natl Acad Sci U S A. 2004;101:17533–8.

    Article  PubMed  CAS  Google Scholar 

  83. Hund TJ, Koval OM, Li J, Wright PJ, Qian L, Snyder JS, Gudmundsson H, Kline CF, Davidson NP, Cardona N, Rasband MN, Anderson ME, Mohler PJ. A beta(IV)-spectrin/CaMKII signaling complex is essential for membrane excitability in mice. J Clin Invest. 2010;120:3508–19.

    Article  PubMed  CAS  Google Scholar 

  84. Aiba T, Hesketh GG, Liu T, Carlisle R, Villa-Abrille MC, O’Rourke B, Akar FG, Tomaselli GF. Na+ channel regulation by Ca2+/calmodulin and Ca2+/calmodulin-dependent protein kinase II in guinea-pig ventricular myocytes. Cardiovasc Res. 2010;85:454–63.

    Article  PubMed  CAS  Google Scholar 

  85. Wagner S, Dybkova N, Rasenack EC, Jacobshagen C, Fabritz L, Kirchhof P, Maier SK, Zhang T, Hasenfuss G, Brown JH, Bers DM, Maier LS. Ca2+/calmodulin-dependent protein kinase ii regulates cardiac Na+ channels. J Clin Invest. 2006;116:3127–38.

    Article  PubMed  CAS  Google Scholar 

  86. Wagner S, Ruff HM, Weber SL, Bellmann S, Sowa T, Schulte T, Anderson ME, Grandi E, Bers DM, Backs J, Belardinelli L, Maier LS. Reactive oxygen species-activated Ca/calmodulin kinase II delta is required for late I(Na) augmentation leading to cellular Na and Ca overload. Circ Res. 2011;108:555–65.

    Article  PubMed  CAS  Google Scholar 

  87. Abriel H. Cardiac sodium channel Na(V)1.5 and interacting proteins: physiology and pathophysiology. J Mol Cell Cardiol. 2010;48:2–11.

    Article  PubMed  CAS  Google Scholar 

  88. Pieske B, Houser SR. [Na+]i handling in the failing human heart. Cardiovasc Res. 2003;57:874–86.

    Article  PubMed  CAS  Google Scholar 

  89. Silverman HS, Stern MD. Ionic basis of ischaemic cardiac injury: insights from cellular studies. Cardiovasc Res. 1994;28:581–97.

    Article  PubMed  CAS  Google Scholar 

  90. Ju YK, Saint DA, Gage PW. Hypoxia increases persistent sodium current in rat ventricular myocytes. J Physiol. 1996;497(Pt 2):337–47.

    PubMed  CAS  Google Scholar 

  91. Eng S, Maddaford TG, Kardami E, Pierce GN. Protection against myocardial ischemic/reperfusion injury by inhibitors of two separate pathways of Na+ entry. J Mol Cell Cardiol. 1998;30:829–35.

    Article  PubMed  CAS  Google Scholar 

  92. Huang B, El Sherif T, Gidh-Jain M, Qin D, El Sherif N. Alterations of sodium channel kinetics and gene expression in the postinfarction remodeled myocardium. J Cardiovasc Electrophysiol. 2001;12:218–25.

    Article  PubMed  CAS  Google Scholar 

  93. 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. 1995;269:H533–40.

    PubMed  Google Scholar 

  94. Undrovinas AI, Fleidervish IA, Makielski JC. Inward sodium current at resting potentials in single cardiac myocytes induced by the ischemic metabolite lysophosphatidylcholine 147. Circ Res. 1992;71:1231–41.

    Article  PubMed  CAS  Google Scholar 

  95. Wu J, Corr PB. Palmitoylcarnitine increases [Na+]i and initiates transient inward current in adult ventricular myocytes. Am J Physiol. 1995;268:H2405–17.

    PubMed  CAS  Google Scholar 

  96. Fearon IM, Brown ST. Acute and chronic hypoxic regulation of recombinant hNa(v)1.5 alpha subunits. Biochem Biophys Res Commun. 2004;324:1289–95.

    Article  PubMed  CAS  Google Scholar 

  97. Gautier M, Zhang H, Fearon IM. Peroxynitrite formation mediates LPC-induced augmentation of cardiac late sodium currents. J Mol Cell Cardiol. 2008;44:241–51.

    Article  PubMed  CAS  Google Scholar 

  98. 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;318:214–22.

    Article  PubMed  CAS  Google Scholar 

  99. Wu Y, Song Y, Belardinelli L, Shryock JC. The late Na+ current (INa) inhibitor ranolazine attenuates effects of palmitoyl-l-carnitine to increase late INa and cause ventricular diastolic dysfunction. J Pharmacol Exp Ther. 2009;330:550–7.

    Article  PubMed  CAS  Google Scholar 

  100. Kohlhardt M, Fichtner H, Frobe U. Metabolites of the glycolytic pathway modulate the activity of single cardiac Na+ channels. FASEB J. 1989;3:1963–7.

    PubMed  CAS  Google Scholar 

  101. Haigney MC, Lakatta EG, Stern MD, Silverman HS. Sodium channel blockade reduces hypoxic sodium loading and sodium-dependent calcium loading. Circulation. 1994;90:391–9.

    Article  PubMed  CAS  Google Scholar 

  102. Van Emous JG, Nederhoff MG, Ruigrok TJ, Van Echteld CJ. The role of the Na+ channel in the accumulation of intracellular Na+ during myocardial ischemia: consequences for post-ischemic recovery 38. J Mol Cell Cardiol. 1997;29:85–96.

    Article  PubMed  Google Scholar 

  103. Vie B, Sablayrolles S, Letienne R, Vacher B, Darmellah A, Bernard M, Feuvray D, Le Grand B. 3-(R)-[3-(2-methoxyphenylthio-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5- benzoxathiepine bromhydrate (F 15845) prevents ischemia-induced heart remodeling by reduction of the intracellular Na+ overload. J Pharmacol Exp Ther. 2009;330:696–703.

    Article  PubMed  CAS  Google Scholar 

  104. 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;51:443–9.

    Article  PubMed  CAS  Google Scholar 

  105. Letienne R, Bel L, Bessac AM, Vacher B, Le Grand B. Myocardial protection by F 15845, a persistent sodium current blocker, in an ischemia-reperfusion model in the pig. Eur J Pharmacol. 2009;624:16–22.

    Article  PubMed  CAS  Google Scholar 

  106. Vacher B, Pignier C, Letienne R, Verscheure Y, Le Grand B. F 15845 inhibits persistent sodium current in the heart and prevents angina in animal models. Br J Pharmacol. 2009;156:214–25.

    Article  PubMed  CAS  Google Scholar 

  107. 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 4:iv6–14.

    Article  PubMed  CAS  Google Scholar 

  108. Ver DL, Borgers M, Verdonck F. Inhibition of sodium and calcium overload pathology in the myocardium: a new cytoprotective principle 252. Cardiovasc Res. 1993;27:349–57.

    Article  Google Scholar 

  109. Tamareille S, Le Grand B, John GW, Feuvray D, Coulombe A. Anti-ischemic compound KC 12291 prevents diastolic contracture in isolated atria by blockade of voltage-gated sodium channels. J Cardiovasc Pharmacol. 2002;40:346–55.

    Article  PubMed  CAS  Google Scholar 

  110. Le Grand B, Pignier C, Letienne R, Cuisiat F, Rolland F, Mas A, Vacher B. Sodium late current blockers in ischemia reperfusion: is the bullet magic? J Med Chem. 2008;51:3856–66.

    Article  PubMed  CAS  Google Scholar 

  111. Hartmann M, Decking UK, Schrader J. Cardioprotective actions of KC 12291. II. Delaying Na+ overload in ischemia improves cardiac function and energy status in reperfusion. Naunyn Schmiedebergs Arch Pharmacol. 1998;358:554–60.

    Article  PubMed  CAS  Google Scholar 

  112. Undrovinas AI, Belardinelli L, Undovinas NA, Sabbah H. 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:S169–77.

    Article  PubMed  Google Scholar 

  113. 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;60:245–57.

    Article  PubMed  CAS  Google Scholar 

  114. Sossalla S, Wagner S, Rasenack EC, Ruff H, Weber SL, Schondube FA, Tirilomis T, Tenderich G, Hasenfuss G, Belardinelli L, Maier LS. 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.

    Article  PubMed  CAS  Google Scholar 

  115. Pieske B, Maier LS, Piacentino 3rd V, Weisser J, Hasenfuss G, Houser S. Rate dependence of [Na+]i and contractility in nonfailing and failing human myocardium. Circulation. 2002;106:447–53.

    Article  PubMed  CAS  Google Scholar 

  116. Maltsev VA, Sabbah HN, Higgins RS, Silverman N, Lesch M, Undrovinas AI. Novel, ultraslow inactivating sodium current in human ventricular cardiomyocytes. Circulation. 1998;98:2545–52.

    Article  PubMed  CAS  Google Scholar 

  117. 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:H1375–81.

    Article  PubMed  CAS  Google Scholar 

  118. 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:H2031–9.

    Article  PubMed  CAS  Google Scholar 

  119. 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:H1254–62.

    Article  PubMed  CAS  Google Scholar 

  120. Garlick PB, Davies MJ, Hearse DJ, Slater TF. Direct detection of free radicals in the reperfused rat heart using electron spin resonance spectroscopy. Circ Res. 1987;61:757–60.

    Article  PubMed  CAS  Google Scholar 

  121. Zweier JL, Flaherty JT, Weisfeldt ML. Direct measurement of free radical generation following reperfusion of ischemic myocardium. Proc Natl Acad Sci U S A. 1987;84:1404–7.

    Article  PubMed  CAS  Google Scholar 

  122. Matsumura H, Hara A, Hashizume H, Maruyama K, Abiko Y. Protective effects of ranolazine, a novel anti-ischemic drug, on the hydrogen peroxide-induced derangements in isolated, perfused rat heart: comparison with dichloroacetate. Jpn J Pharmacol. 1998;77:31–9.

    Article  PubMed  CAS  Google Scholar 

  123. Morita N, Lee JH, Xie Y, Sovari A, Qu Z, Weiss JN, Karagueuzian HS. Suppression of re-entrant and multifocal ventricular fibrillation by the late sodium current blocker ranolazine. J Am Coll Cardiol. 2011;57:366–75.

    Article  PubMed  CAS  Google Scholar 

  124. Maack C, Cortassa S, Aon MA, Ganesan AN, Liu T, O’Rourke B. Elevated cytosolic Na+ decreases mitochondrial Ca2+ uptake during excitation-contraction coupling and impairs energetic adaptation in cardiac myocytes. Circ Res. 2006;99:172–82.

    Article  PubMed  CAS  Google Scholar 

  125. Kohlhaas M, Liu T, Knopp A, Zeller T, Ong MF, Bohm M, O’Rourke B, Maack C. Elevated cytosolic Na+ increases mitochondrial formation of reactive oxygen species in failing cardiac myocytes. Circulation. 2010;121:1606–13.

    Article  PubMed  CAS  Google Scholar 

  126. Braun AP, Schulman H. A non-selective cation current activated via the multifunctional Ca(2+)-calmodulin-dependent protein kinase in human epithelial cells. J Physiol. 1995;488(Pt 1):37–55.

    PubMed  CAS  Google Scholar 

  127. Erickson JR, Joiner ML, Guan X, Kutschke W, Yang J, Oddis CV, Bartlett RK, Lowe JS, O’Donnell SE, Aykin-Burns N, Zimmerman MC, Zimmerman K, Ham AJ, Weiss RM, Spitz DR, Shea MA, Colbran RJ, Mohler PJ, Anderson ME. A dynamic pathway for calcium-independent activation of camkii by methionine oxidation. Cell. 2008;133:462–74.

    Article  PubMed  CAS  Google Scholar 

  128. Howe CJ, Lahair MM, McCubrey JA, Franklin RA. Redox regulation of the calcium/calmodulin-dependent protein kinases. J Biol Chem. 2004;279:44573–81.

    Article  PubMed  CAS  Google Scholar 

  129. Xie LH, Chen F, Karagueuzian HS, Weiss JN. Oxidative-stress-induced afterdepolarizations and calmodulin kinase II signaling. Circ Res. 2009;104:79–86.

    Article  PubMed  CAS  Google Scholar 

  130. Wagner S, Maier LS. Modulation of cardiac Na(+) and Ca(2+) currents by cam and camkii. J Cardiovasc Electrophysiol. 2006;17 Suppl 1:S26–33.

    Article  PubMed  Google Scholar 

  131. Maltsev VA, Reznikov V, Undrovinas NA, Sabbah HN, Undrovinas A. Modulation of late sodium current by Ca2+, calmodulin, and camkii in normal and failing dog cardiomyocytes: similarities and differences. Am J Physiol Heart Circ Physiol. 2008;294:H1597–608.

    Article  PubMed  CAS  Google Scholar 

  132. Yao L, Fan P, Jiang Z, Viatchenko-Karpinski S, Wu Y, Kornyeyev D, Hirakawa R, Budas GR, Rajamani S, Shryock JC, Belardinelli L. NaV1.5-dependent persistent Na+ influx activates CaMKII in rat ventricular myocytes and N1325S mice. Am J Physiol Cell Physiol. 2011;301:C577–86.

    Article  PubMed  CAS  Google Scholar 

  133. Ai X, Curran JW, Shannon TR, Bers DM, Pogwizd SM. Ca2+/calmodulin-dependent protein kinase modulates cardiac ryanodine receptor phosphorylation and sarcoplasmic reticulum Ca2+ leak in heart failure. Circ Res. 2005;97:1314–22.

    Article  PubMed  CAS  Google Scholar 

  134. Hoch B, Meyer R, Hetzer R, Krause EG, Karczewski P. Identification and expression of delta-isoforms of the multifunctional Ca2+/calmodulin-dependent protein kinase in failing and nonfailing human myocardium. Circ Res. 1999;84:713–21.

    Article  PubMed  CAS  Google Scholar 

  135. Hund TJ, Decker KF, Kanter E, Mohler PJ, Boyden PA, Schuessler RB, Yamada KA, Rudy Y. Role of activated CaMKII in abnormal calcium homeostasis and I(Na) remodeling after myocardial infarction: Insights from mathematical modeling. J Mol Cell Cardiol. 2008;45:420–8.

    Article  PubMed  CAS  Google Scholar 

  136. Light PE, Wallace CH, Dyck JR. Constitutively active adenosine monophosphate-activated protein kinase regulates voltage-gated sodium channels in ventricular myocytes. Circulation. 2003;107:1962–5.

    Article  PubMed  CAS  Google Scholar 

  137. Murray KT, Hu NN, Daw JR, Shin HG, Watson MT, Mashburn AB, George Jr AL. Functional effects of protein kinase C activation on the human cardiac Na+ channel. Circ Res. 1997;80:370–6.

    Article  PubMed  CAS  Google Scholar 

  138. Tateyama M, Kurokawa J, Terrenoire C, Rivolta I, Kass RS. Stimulation of protein kinase C inhibits bursting in disease-linked mutant human cardiac sodium channels. Circulation. 2003;107:3216–22.

    Article  PubMed  CAS  Google Scholar 

  139. Antzelevitch C. Ionic, molecular, and cellular bases of QT-interval prolongation and torsade de pointes. Europace. 2007;9 Suppl 4:iv4–15.

    Article  PubMed  Google Scholar 

  140. Belardinelli L, Antzelevitch C, Vos MA. Assessing predictors of drug-induced torsade de pointes. Trends Pharmacol Sci. 2003;24:619–25.

    Article  PubMed  CAS  Google Scholar 

  141. Antzelevitch C. Arrhythmogenic mechanisms of QT prolonging drugs: is QT prolongation really the problem? J Electrocardiol. 2004;37(Suppl):15–24.

    Article  PubMed  Google Scholar 

  142. Viswanathan PC, Rudy Y. Pause induced early afterdepolarizations in the long QT syndrome: a simulation study. Cardiovasc Res. 1999;42:530–42.

    Article  PubMed  CAS  Google Scholar 

  143. Wu L, Ma J, Li H, Wang C, Grandi E, Zhang P, Luo A, Bers DM, Shryock JC, Belardinelli L. Late sodium current contributes to the reverse rate-dependent effect of IKr inhibition on ventricular repolarization. Circulation. 2011;123:1713–20.

    Article  PubMed  CAS  Google Scholar 

  144. Lederer WJ, Tsien RW. Transient inward current underlying arrhythmogenic effects of cardiotonic steroids in purkinje fibres. J Physiol. 1976;263:73–100.

    PubMed  CAS  Google Scholar 

  145. Spencer CI, Sham JS. 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:H2552–62.

    PubMed  CAS  Google Scholar 

  146. Schlotthauer K, Bers DM. Sarcoplasmic reticulum Ca(2+) release causes myocyte depolarization. Underlying mechanism and threshold for triggered action potentials. Circ Res. 2000;87:774–80.

    Article  PubMed  CAS  Google Scholar 

  147. Volders PG, Vos MA, Szabo B, Sipido KR, de Groot SH, Gorgels AP, Wellens HJ, Lazzara R. Progress in the understanding of cardiac early afterdepolarizations and torsades de pointes: time to revise current concepts 187. Cardiovasc Res. 2000;46:376–92.

    Article  PubMed  CAS  Google Scholar 

  148. Bers DM, Barry WH, Despa S. Intracellular Na+ regulation in cardiac myocytes. Cardiovasc Res. 2003;57:897–912.

    Article  PubMed  CAS  Google Scholar 

  149. Milberg P, Pott C, Fink M, Frommeyer G, Matsuda T, Baba A, Osada N, Breithardt G, Noble D, Eckardt L. 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;5:1444–52.

    Article  PubMed  Google Scholar 

  150. Shimizu W, Antzelevitch C. Cellular and ionic basis for T-wave alternans under long-QT conditions. Circulation. 1999;99:1499–507.

    Article  PubMed  CAS  Google Scholar 

  151. Wasserstrom JA, Sharma R, Kapur S, Kelly JE, Kadish AH, Balke CW, Aistrup GL. Multiple defects in intracellular calcium cycling in whole failing rat heart. Circ Heart Fail. 2009;2:223–32.

    Article  PubMed  CAS  Google Scholar 

  152. Hagihara H, Yoshikawa Y, Ohga Y, Takenaka C, Murata KY, Taniguchi S, Takaki M. Na+/Ca2+ exchange inhibition protects the rat heart from ischemia-reperfusion injury by blocking energy-wasting processes. Am J Physiol Heart Circ Physiol. 2005;288:H1699–707.

    Article  PubMed  CAS  Google Scholar 

  153. Schafer C, Ladilov Y, Inserte J, Schafer M, Haffner S, Garcia-Dorado D, Piper HM. Role of the reverse mode of the Na+/Ca2+ exchanger in reoxygenation-induced cardiomyocyte injury. Cardiovasc Res. 2001;51:241–50.

    Article  PubMed  CAS  Google Scholar 

  154. Eigel BN, Gursahani H, Hadley RW. Ros are required for rapid reactivation of Na+/Ca2+ exchanger in hypoxic reoxygenated guinea pig ventricular myocytes. Am J Physiol Heart Circ Physiol. 2004;286:H955–63.

    Article  PubMed  CAS  Google Scholar 

  155. Imahashi K, Pott C, Goldhaber JI, Steenbergen C, Philipson KD, Murphy E. Cardiac-specific ablation of the Na+-Ca2+ exchanger confers protection against ischemia/reperfusion injury. Circ Res. 2005;97:916–21.

    Article  PubMed  CAS  Google Scholar 

  156. Schillinger W, Fiolet JW, Schlotthauer K, Hasenfuss G. Relevance of Na+-Ca2+ exchange in heart failure. Cardiovasc Res. 2003;57:921–33.

    Article  PubMed  CAS  Google Scholar 

  157. Koval OM, Guan X, Wu Y, Joiner ML, Gao Z, Chen B, Grumbach IM, Luczak ED, Colbran RJ, Song LS, Hund TJ, Mohler PJ, Anderson ME. CaV12 beta-subunit coordinates camkii-triggered cardiomyocyte death and afterdepolarizations. Proc Natl Acad Sci U S A. 2010;107:4996–5000.

    Article  PubMed  CAS  Google Scholar 

  158. Tamargo J, Caballero R, Delpon E. Ranolazine: an antianginal drug with antiarrhythmic properties. Expert Rev Cardiovasc Ther. 2011;9:815–27.

    Article  PubMed  CAS  Google Scholar 

  159. Vadnais DS, Wenger NK. Emerging clinical role of ranolazine in the management of angina. Ther Clin Risk Manag. 2010;6:517–30.

    PubMed  CAS  Google Scholar 

  160. Antzelevitch C, Burashnikov A, Sicouri S, Belardinelli L. Electrophysiologic basis for the antiarrhythmic actions of ranolazine. Heart Rhythm. 2011;8:1281–90.

    Article  PubMed  Google Scholar 

  161. Hale SL, Shryock JC, Belardinelli L, Sweeney M, Kloner RA. Late sodium current inhibition as a new cardioprotective approach. J Mol Cell Cardiol. 2008;44:954–67.

    Article  PubMed  CAS  Google Scholar 

  162. Antzelevitch C, Belardinelli L, Zygmunt AC, Burashnikov A, Di Diego JM, Fish JM, Cordeiro JM, Thomas G. Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties. Circulation. 2004;110:904–10.

    Article  PubMed  CAS  Google Scholar 

  163. Fredj S, Sampson KJ, Liu H, Kass RS. Molecular basis of ranolazine block of LQT-3 mutant sodium channels: evidence for site of action. Br J Pharmacol. 2006;148:16–24.

    Article  PubMed  CAS  Google Scholar 

  164. Rajamani S, El-Bizri N, Shryock JC, Makielski JC, Belardinelli L. Use-dependent block of cardiac late Na(+) current by ranolazine. Heart Rhythm. 2009;6:1625–31.

    Article  PubMed  Google Scholar 

  165. Kumar K, Nearing BD, Bartoli CR, Kwaku KF, Belardinelli L, Verrier RL. Effect of ranolazine on ventricular vulnerability and defibrillation threshold in the intact porcine heart. J Cardiovasc Electrophysiol. 2008;19:1073–9.

    Article  PubMed  Google Scholar 

  166. Scirica BM, Morrow DA, Hod H, Murphy SA, Belardinelli L, Hedgepeth CM, Molhoek P, Verheugt FW, Gersh BJ, McCabe CH, Braunwald E. Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST-segment elevation acute coronary syndrome: results from the metabolic efficiency with ranolazine for less ischemia in non ST-elevation acute coronary syndrome thrombolysis in myocardial infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation. 2007;116:1647–52.

    Article  PubMed  CAS  Google Scholar 

  167. Rajamani S, Shryock JC, Belardinelli L. Rapid kinetic interactions of ranolazine with HERG K plus current. J Cardiovasc Pharmacol. 2008;51:581–9.

    Article  PubMed  CAS  Google Scholar 

  168. Wang WQ, Robertson C, Dhalla AK, Belardinelli L. Antitorsadogenic effects of ({+/-})-N-(2,6-dimethyl-phenyl)-(4[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1 -piperazine (ranolazine) in anesthetized rabbits. J Pharmacol Exp Ther. 2008;325:875–81.

    Article  PubMed  CAS  Google Scholar 

  169. Wu L, 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:H1048–57.

    Article  PubMed  CAS  Google Scholar 

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  1. Biology Department, Gilead Sciences, 7601 Dumbarton Circle, Fremont, CA, USA

    Sridharan Rajamani PhD & John C. Shryock PhD

  2. Cardiovascular Therapeutics, Gilead Sciences, Foster City, CA, USA

    Luiz Belardinelli MD

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  1. Sridharan Rajamani PhD
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  3. Luiz Belardinelli MD
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  1. , Department of Internal Medicine, UMDNJ-RWJ Medical School, Robert Wood Johnson Pl. 1, New Brunswick, 08903-0019, New Jersey, USA

    Ihor Gussak

  2. , Gordon K. Moe Scholar, Masonic Medical Research Laboratory, Bleecker Street, Utica, 13501-1787, New York, USA

    Charles Antzelevitch

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Rajamani, S., Shryock, J.C., Belardinelli, L. (2013). Pathological Roles of the Cardiac Sodium Channel Late Current (Late INa). In: Gussak, I., Antzelevitch, C. (eds) Electrical Diseases of the Heart. Springer, London. https://doi.org/10.1007/978-1-4471-4881-4_10

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