Role of Late Sodium Current During Repolarization and Its Pathophysiology

  • Mohamed ChahineEmail author


Voltage-gated Na channels produce the rapid upstroke of the action potential and are critical elements for maintaining electrical excitability and assuring the coordination of excitation-contraction coupling in the heart. During their activity, these channels cycle between three processes: closing, activation, and inactivation. There is much evidence for the existence of additional channel conformations, modal gating, for instance. The existence of these modes has been observed in cardiac sodium channels. It, therefore, is an intrinsic property of these channels that is in some way related to their proper function. The model gating is thought to underlie the persistent activity of these channels known as late sodium current. Therefore, sodium channels are also involved in determining the duration of action potentials. Excessive residency of sodium channels in a slow mode of gating increases the late sodium current and causes an increase in intracellular sodium and may result in calcium overload and early afterdepolarizations which are substrates for myocyte abnormal electrical activity. This abnormal sodium activity has been found in different pathologies such as type 3 long QT syndrome or heart failure. Ranolazine, an antianginal and a well-tolerated drug, exhibited some beneficial effects in reducing late sodium channel currents and exhibited beneficial effect in animal models of heart failure and proven to be beneficial in several clinical trials.


Heart Voltage-gated sodium channels Nav1.5 Late sodium current Persistent sodium current Ranolazine Antiarrhythmic drugs Heart failure Long QT syndrome Cardiac repolarization 



Supported by the Canadian Institutes of Health Research (MOP-111072 and MOP-130373 to MC). Association Française contre les Myopathies (AFM) – Téléthon (Research Grant AFM19962 to MC).


  1. 1.
    Kirsch GE, Brown AM. Kinetic properties of single sodium channels in rat heart and rat brain. J Gen Physiol. 1989;93(1):85–99.PubMedCrossRefGoogle Scholar
  2. 2.
    Kiyosue T, Arita M. Late sodium current and its contribution to action potential configuration in guinea pig ventricular myocytes. Circ Res. 1989;64(2):389–97.PubMedCrossRefGoogle Scholar
  3. 3.
    Nilius B. Modal gating behavior of cardiac sodium channels in cell-free membrane patches. Biophys J. 1988;53(6):857–62.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Patlak JB, Ortiz M. Slow currents through single sodium channels of the adult rat heart. J Gen Physiol. 1985;86:89–104.PubMedCrossRefGoogle Scholar
  5. 5.
    Patlak JB, Ortiz M. Two modes of gating during late Na+ channel currents in frog sartorius muscle. J Gen Physiol. 1986;87(2):305–26.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Grant AO. Electrophysiological basis and genetics of Brugada syndrome. J Cardiovasc Electrophysiol. 2005;16(Suppl 1):S3–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Gellens ME, George AL Jr, Chen LQ, Chahine M, Horn R, Barchi RL, et al. Primary structure and functional expression of the human cardiac tetrodotoxin-insensitive voltage-dependent sodium channel. Proc Natl Acad Sci U S A. 1992;89(2):554–8.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Wang Q, Li Z, Shen J, Keating MT. Genomic organization of the human SCN5A gene encoding the cardiac sodium channel. Genomics. 1996;34(1):9–16.PubMedCrossRefGoogle Scholar
  9. 9.
    Hilber K, Sandtner W, Kudlacek O, Schreiner B, Glaaser I, Schutz W, et al. Interaction between fast and ultra-slow inactivation in the voltage-gated sodium channel. Does the inactivation gate stabilize the channel structure? J Biol Chem. 2002;277(40):37105–15.PubMedCrossRefGoogle Scholar
  10. 10.
    Townsend C, Horn R. Interaction between the pore and a fast gate of the cardiac sodium channel. J Gen Physiol. 1999;113(2):321–32.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Balser JR, Nuss HB, Chiamvimonvat N, Pérez-garcía MT, Marban E, Tomaselli GF. External pore residue mediates slow inactivation in m1 rat skeletal muscle sodium channels. J Physiol. 1996;494(Pt 2):431–42.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Attwell D, Cohen I, Eisner D, Ohba M, Ojeda C. The steady state TTX-sensitive (“window”) sodium current in cardiac Purkinje fibres. Pflügers Arch. 1979;379(2):137–42.PubMedCrossRefGoogle Scholar
  13. 13.
    Coraboeuf E, Deroubaix E, Coulombe A. Effect of tetrodotoxin on action potentials of the conducting system in the dog heart. Am J Phys. 1979;236(4):H561–H7.Google Scholar
  14. 14.
    Coraboeuf E, Deroubaix E. Shortening effect of tetrodotoxin on action potentials of the conducting system in the dog heart. J Physiol. 1978;280:24P.PubMedGoogle Scholar
  15. 15.
    Wagner S, Ruff HM, Weber SL, Bellmann S, Sowa T, Schulte T, et al. Reactive oxygen species-activated Ca/calmodulin kinase IIdelta is required for late I(Na) augmentation leading to cellular Na and Ca overload. Circ Res. 2011;108(5):555–65.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Ward CA, Giles WR. Ionic mechanism of the effects of hydrogen peroxide in rat ventricular myocytes. J Physiol. 1997;500.(Pt 3:631–42.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Medeiros-Domingo A, Kaku T, Tester DJ, Iturralde-Torres P, Itty A, Ye B, et al. SCN4B-encoded sodium channel beta4 subunit in congenital long-QT syndrome. Circulation. 2007;116(2):134–42.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Vatta M, Ackerman MJ, Ye B, Makielski JC, Ughanze EE, Taylor EW, et al. Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation. 2006;114(20):2104–12.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Cronk LB, Ye B, Kaku T, Tester DJ, Vatta M, Makielski JC, et al. Novel mechanism for sudden infant death syndrome: persistent late sodium current secondary to mutations in caveolin-3. Heart Rhythm. 2007;4(2):161–6.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    George AL Jr, Varkony TA, Drabkin HA, Han J, Knops JF, Finley WH, et al. Assignment of the human heart tetrodotoxin-resistant voltage-gated Na+ channel a-subunit gene (SCN5A) to band 3p21. Cytogenet Cell Genet. 1995;68(1–2):67–70.PubMedCrossRefGoogle Scholar
  21. 21.
    Bennett PB, Yazawa K, Makita N, George AL Jr. Molecular mechanism for an inherited cardiac arrhythmia. Nature. 1995;376(6542):683–5.PubMedCrossRefGoogle Scholar
  22. 22.
    Tan HL, Bezzina CR, Smits JPP, Verkerk AO, Wilde AAM. Genetic control of sodium channel function. Cardiovasc Res. 2003;57(4):961–73.PubMedCrossRefGoogle Scholar
  23. 23.
    Wattanasirichaigoon D, Vesely MR, Duggal P, Levine JC, Blume ED, Wolff GS, et al. Sodium channel abnormalities are infrequent in patients with long QT syndrome: identification of two novel SCN5A mutations. Am J Med Genet. 1999;86(5):470–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Dumaine R, Wang Q, Keating MT, Hartmann HA, Schwartz PJ, Brown AM, et al. Multiple mechanisms of Na+ channel-linked long-QT syndrome. Circ Res. 1996;78(5):916–24.PubMedCrossRefGoogle Scholar
  25. 25.
    Estes NA 3rd. Predicting and preventing sudden cardiac death. Circulation. 2011;124(5):651–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Savarese G, Lund LH. Global public health burden of heart failure. Card Fail Rev. 2017;3(1):7–11.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Valdivia CR, Chu WW, Pu J, Foell JD, Haworth RA, Wolff MR, et al. Increased late sodium current in myocytes from a canine heart failure model and from failing human heart. J Mol Cell Cardiol. 2005;38(3):475–83.PubMedCrossRefGoogle Scholar
  28. 28.
    Maltsev VA, Sabbah HN, Higgins RS, Silverman N, Lesch M, Undrovinas AI. Novel, ultraslow inactivating sodium current in human ventricular cardiomyocytes. Circulation. 1998;98(23):2545–52.PubMedCrossRefGoogle Scholar
  29. 29.
    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(2):218–25.PubMedCrossRefGoogle Scholar
  30. 30.
    Noble D, Noble PJ. Late sodium current in the pathophysiology of cardiovascular disease: consequences of sodium-calcium overload. Heart. 2006;92(Suppl 4):iv1–5.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Christe 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(1–3):281–93.PubMedCrossRefGoogle Scholar
  32. 32.
    Schwartz PJ, Priori SG, Locati EH, Napolitano C, Cantù F, Towbin JA, et al. Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate. Implications for gene-specific therapy. Circulation. 1995;92(12):3381–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Benhorin J, Taub R, Goldmit M, Kerem B, Kass RS, Windman I, et al. Effects of flecainide in patients with new SCN5A mutation: mutation-specific therapy for long-QT syndrome? Circulation. 2000;101(14):1698–706.PubMedCrossRefGoogle Scholar
  34. 34.
    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(1):H288–H99.PubMedCrossRefGoogle Scholar
  35. 35.
    O’Leary ME, Chahine M. Mechanisms of drug binding to voltage-gated sodium channels. Handb Exp Pharmacol. 2018;246:209–31.PubMedCrossRefGoogle Scholar
  36. 36.
    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(1):16–24.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Undrovinas AI, Belardinelli L, Undrovinas NA, 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–s77.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Pepine CJ, Wolff AA. A controlled trial with a novel anti-ischemic agent, ranolazine, in chronic stable angina pectoris that is responsive to conventional antianginal agents. Ranolazine Study Group. Am J Cardiol. 1999;84(1):46–50.PubMedCrossRefGoogle Scholar
  39. 39.
    Ju YK, Saint DA, Gage PW. Hypoxia increases persistent sodium current in rat ventricular myocytes. J Physiol. 1996;497(Pt 2):337–47.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Murphy E, Perlman M, London RE, Steenbergen C. Amiloride delays the ischemia-induced rise in cytosolic free calcium. Circ Res. 1991;68(5):1250–8.PubMedCrossRefGoogle Scholar
  41. 41.
    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(2):192–9.PubMedCrossRefGoogle Scholar
  42. 42.
    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–iv14.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Chaitman BR, Skettino SL, Parker JO, Hanley P, Meluzin J, Kuch J, et al. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol. 2004;43(8):1375–82.PubMedCrossRefGoogle Scholar
  44. 44.
    Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J, et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA. 2004;291(3):309–16.PubMedCrossRefGoogle Scholar
  45. 45.
    Alexopoulos D, Kochiadakis G, Afthonidis D, Barbetseas J, Kelembekoglou P, Limberi S, et al. Ranolazine reduces angina frequency and severity and improves quality of life: observational study in patients with chronic angina under ranolazine treatment in Greece (OSCAR-GR). Int J Cardiol. 2016;205:111–6.PubMedCrossRefGoogle Scholar
  46. 46.
    Kosiborod M, Arnold SV, Spertus JA, McGuire DK, Li Y, Yue P, et al. Evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina: results from the TERISA randomized clinical trial (type 2 diabetes evaluation of ranolazine in subjects with chronic stable angina). J Am Coll Cardiol. 2013;61(20):2038–45.PubMedCrossRefGoogle Scholar
  47. 47.
    Stone PH, Gratsiansky NA, Blokhin A, Huang IZ, Meng L. Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (efficacy of ranolazine in chronic angina) trial. J Am Coll Cardiol. 2006;48(3):566–75.PubMedCrossRefGoogle Scholar
  48. 48.
    Rastogi S, Sharov VG, Mishra S, Gupta RC, Blackburn B, Belardinelli L, et al. Ranolazine combined with enalapril or metoprolol prevents progressive LV dysfunction and remodeling in dogs with moderate heart failure. Am J Physiol Heart Circ Physiol. 2008;295(5):H2149–55.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Maier LS, Layug B, Karwatowska-Prokopczuk E, Belardinelli L, Lee S, Sander J, et al. RAnoLazIne for the treatment of diastolic heart failure in patients with preserved ejection fraction: the RALI-DHF proof-of-concept study. JACC Heart Fail. 2013;1(2):115–22.PubMedCrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.CERVO Research Center, Institut Universitaire en Santé Mentale de QuébecQuebec CityCanada
  2. 2.Department of MedicineUniversité LavalQuebec CityCanada

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