Heart failure constitutes a major public health problem worldwide. The electrophysiological remodeling of failing hearts sets the stage for malignant arrhythmias, in which the role of the late Na+ current (INaL) is relevant and is currently under investigation. In this study we examined the role of INaL in the electrophysiological phenotype of ventricular myocytes, and its proarrhythmic effects in the failing heart. A model for cellular heart failure was proposed using a modified version of Grandi et al. model for human ventricular action potential that incorporates the formulation of INaL. A sensitivity analysis of the model was performed and simulations of the pathological electrical activity of the cell were conducted. The proposed model for the human INaL and the electrophysiological remodeling of myocytes from failing hearts accurately reproduce experimental observations. The sensitivity analysis of the modulation of electrophysiological parameters of myocytes from failing hearts due to ion channels remodeling, revealed a role for INaL in the prolongation of action potential duration (APD), triangulation of the shape of the AP, and changes in Ca2+ transient. A mechanistic investigation of intracellular Na+ accumulation and APD shortening with increasing frequency of stimulation of failing myocytes revealed a role for the Na+/K+ pump, the Na+/Ca2+ exchanger and INaL. The results of the simulations also showed that in failing myocytes, the enhancement of INaL increased the reverse rate-dependent APD prolongation and the probability of initiating early afterdepolarizations. The electrophysiological remodeling of failing hearts and especially the enhancement of the INaL prolong APD and alter Ca2+ transient facilitating the development of early afterdepolarizations. An enhanced INaL appears to be an important contributor to the electrophysiological phenotype and to the dysregulation of [Ca2+]i homeostasis of failing myocytes.
References
[1]
Rosamond W, Flegal K, Friday G, Furie K, Go A, et al. (2007) Heart disease and stroke statistics–2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 115: e69–171.
[2]
Janse MJ (2004) Electrophysiological changes in heart failure and their relationship to arrhythmogenesis. Cardiovasc Res 61: 208–217.
[3]
Tomaselli GF, Marban E (1999) Electrophysiological remodeling in hypertrophy and heart failure. Cardiovasc Res 42: 270–283.
[4]
Tomaselli GF, Zipes DP (2004) What causes sudden death in heart failure? Circ Res 95: 754–763.
[5]
Priebe L, Beuckelmann DJ (1998) Simulation study of cellular electric properties in heart failure. Circ Res 82: 1206–1223.
[6]
Li GR, Lau CP, Ducharme A, Tardif JC, Nattel S (2002) Transmural action potential and ionic current remodeling in ventricles of failing canine hearts. Am J Physiol Heart Circ Physiol 283: H1031–H1041.
[7]
Li GR, Lau CP, Leung TK, Nattel S (2004) Ionic current abnormalities associated with prolonged action potentials in cardiomyocytes from diseased human right ventricles. Heart Rhythm 1: 460–468.
[8]
Li GR, Feng J, Yue L, Carrier M (1998) Transmural heterogeneity of action potentials and Ito1 in myocytes isolated from the human right ventricle. Am J Physiol 275: H369–H377.
[9]
Bers DM, Despa S, Bossuyt J (2006) Regulation of Ca2+ and Na+ in normal and failing cardiac myocytes. Ann N Y Acad Sci 1080: 165–177.
[10]
Beuckelmann DJ, Nabauer M, Erdmann E (1993) Alterations of K+ currents in isolated human ventricular myocytes from patients with terminal heart failure. Circ Res 73: 379–385.
[11]
Piacentino V , Weber CR, Chen X, Weisser-Thomas J, Margulies KB, et al. (2003) Cellular basis of abnormal calcium transients of failing human ventricular myocytes. Circ Res 92: 651–658.
[12]
Winslow RL, Rice J, Jafri S, Marban E, O'Rourke B (1999) Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart failure, II: model studies. Circ Res 84: 571–586.
[13]
Antoons G, Oros A, Bito V, Sipido KR, Vos MA (2007) Cellular basis for triggered ventricular arrhythmias that occur in the setting of compensated hypertrophy and heart failure: considerations for diagnosis and treatment. J Electrocardiol 40: S8–14.
[14]
Bundgaard H, Kjeldsen K (1996) Human myocardial Na,K-ATPase concentration in heart failure. Mol Cell Biochem 163–164: 277–283.
[15]
Maltsev VA, Silverman N, Sabbah HN, Undrovinas AI (2007) Chronic heart failure slows late sodium current in human and canine ventricular myocytes: implications for repolarization variability. Eur J Heart Fail 9: 219–227.
[16]
Valdivia CR, Chu WW, Pu J, Foell JD, Haworth RA, et al. (2005) Increased late sodium current in myocytes from a canine heart failure model and from failing human heart. J Mol Cell Cardiol 38: 475–483.
[17]
Zaza A, Belardinelli L, Shryock JC (2008) Pathophysiology and pharmacology of the cardiac “late sodium current.”. Pharmacol Ther 119: 326–339.
[18]
Undrovinas AI, Belardinelli L, Undrovinas NA, Sabbah HN (2006) Ranolazine improves abnormal repolarization and contraction in left ventricular myocytes of dogs with heart failure by inhibiting late sodium current. J Cardiovasc Electrophysiol 17: Suppl 1S169–S177.
[19]
Undrovinas NA, Maltsev VA, Belardinelli L, Sabbah HN, Undrovinas A (2010) Late sodium current contributes to diastolic cell Ca2+ accumulation in chronic heart failure. J Physiol Sci 60: 245–257.
[20]
Milberg P, Pott C, Fink M, Frommeyer G, Matsuda T, et al. (2008) 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 5: 1444–1452.
[21]
Wu L, Guo D, Li H, Hackett J, Yan GX, et al. (2008) Role of late sodium current in modulating the proarrhythmic and antiarrhythmic effects of quinidine. Heart Rhythm 5: 1726–1734.
[22]
Wu L, Rajamani S, Li H, January CT, Shryock JC, et al. (2009) Reduction of repolarization reserve unmasks the proarrhythmic role of endogenous late Na(+) current in the heart. Am J Physiol Heart Circ Physiol 297: H1048–H1057.
[23]
Wu L, Ma J, Li H, Wang C, Grandi E, et al. (2011) Late Sodium Current Contributes to the Reverse Rate-Dependent Effect of IKr Inhibition on Ventricular Repolarization. Circulation 123: 1713–1720.
[24]
Wu L, Shryock JC, Song Y, Li Y, Antzelevitch C, et al. (2004) Antiarrhythmic effects of ranolazine in a guinea pig in vitro model of long-QT syndrome. J Pharmacol Exp Ther 310: 599–605.
[25]
Grandi E, Pasqualini FS, Bers DM (2010) A novel computational model of the human ventricular action potential and Ca transient. J Mol Cell Cardiol 48: 112–121.
[26]
Maltsev VA, Sabbah HN, Higgins RS, Silverman N, Lesch M, et al. (1998) Novel, ultraslow inactivating sodium current in human ventricular cardiomyocytes. Circulation 98: 2545–2552.
[27]
Drouin E, Charpentier F, Gauthier C, Laurent K, Le Marec H (1995) Electrophysiologic characteristics of cells spanning the left ventricular wall of human heart: evidence for presence of M cells. J Am Coll Cardiol 26: 185–192.
[28]
Glukhov AV, Fedorov VV, Lou Q, Ravikumar VK, Kalish PW, et al. (2010) Transmural dispersion of repolarization in failing and nonfailing human ventricle. Circ Res 106: 981–991.
[29]
So PP, Backx PH, Dorian P (2008) Slow delayed rectifier K+ current block by HMR 1556 increases dispersion of repolarization and promotes Torsades de Pointes in rabbit ventricles. Br J Pharmacol 155: 1185–1194.
[30]
Grandi E, Puglisi JL, Wagner S, Maier LS, Severi S, et al. (2007) Simulation of Ca-calmodulin-dependent protein kinase II on rabbit ventricular myocyte ion currents and action potentials. Biophys J 93: 3835–3847.
[31]
Weber CR, Piacentino V , Houser SR, Bers DM (2003) Dynamic regulation of sodium/calcium exchange function in human heart failure. Circulation 108: 2224–2229.
[32]
Romero L, Pueyo E, Fink M, Rodriguez B (2009) Impact of ionic current variability on human ventricular cellular electrophysiology. Am J Physiol Heart Circ Physiol.
[33]
Pieske B, Maier LS, Piacentino V 3rd, Weisser J, Hasenfuss G, et al. (2002) Rate dependence of [Na+]i and contractility in nonfailing and failing human myocardium. Circulation 106: 447–453.
[34]
Carro J, Rodriguez JF, Laguna P, Pueyo E (2011) A human ventricular cell model for investigation of cardiac arrhythmias under hyperkalaemic conditions. Philos Transact A Math Phys Eng Sci 369: 4205–4232.
[35]
Baartscheer A, Schumacher CA, Belterman CN, Coronel R, Fiolet JW (2003) [Na+]i and the driving force of the Na+/Ca2+-exchanger in heart failure. Cardiovasc Res 57: 986–995.
[36]
Despa S, Islam MA, Weber CR, Pogwizd SM, Bers DM (2002) Intracellular Na(+) concentration is elevated in heart failure but Na/K pump function is unchanged. Circulation 105: 2543–2548.
[37]
Levi AJ, Dalton GR, Hancox JC, Mitcheson JS, Issberner J, et al. (1997) Role of intracellular sodium overload in the genesis of cardiac arrhythmias. J Cardiovasc Electrophysiol 8: 700–721.
[38]
Dorian P, Newman D (2000) Rate dependence of the effect of antiarrhythmic drugs delaying cardiac repolarization: an overview. Europace 2: 277–285.
[39]
Zygmunt AC, Eddlestone GT, Thomas GP, Nesterenko VV, Antzelevitch C (2001) Larger late sodium conductance in M cells contributes to electrical heterogeneity in canine ventricle. Am J Physiol Heart Circ Physiol 281: H689–H697.
[40]
Nagatomo T, January CT, Makielski JC (2000) Preferential block of late sodium current in the LQT3 DeltaKPQ mutant by the class I(C) antiarrhythmic flecainide. Mol Pharmacol 57: 101–107.
[41]
Rajamani S, El-Bizri , Shryock JC, Makielski JC, Belardinelli L (2009) Use-dependent block of cardiac late Na current by ranolazine. Heart Rhythm.
[42]
January CT, Riddle JM, Salata JJ (1988) A model for early afterdepolarizations: induction with the Ca2+ channel agonist Bay K 8644. Circ Res 62: 563–571.
[43]
O'Hara T, Virag L, Varro A, Rudy Y (2011) Simulation of the undiseased human cardiac ventricular action potential: model formulation and experimental validation. PLoS Comput Biol 7: e1002061.
[44]
Zhang Y, Shou G, Xia L (2005) Simulation study of transmural cellular electrical properties in failed human heart. Conf Proc IEEE Eng Med Biol Soc 1: 337–340.
[45]
Ten Tusscher KH, Noble D, Noble PJ, Panfilov AV (2004) A model for human ventricular tissue. Am J Physiol Heart Circ Physiol 286: H1573–H1589.
[46]
Hund TJ, Rudy Y (2004) Rate dependence and regulation of action potential and calcium transient in a canine cardiac ventricular cell model. Circulation 110: 3168–3174.
[47]
Shannon TR, Wang F, Bers DM (2005) Regulation of cardiac sarcoplasmic reticulum Ca release by luminal [Ca] and altered gating assessed with a mathematical model. Biophys J 89: 4096–4110.
[48]
Ten Tusscher KH, Panfilov AV (2006) Alternans and spiral breakup in a human ventricular tissue model. Am J Physiol Heart Circ Physiol 291: H1088–H1100.
[49]
von Lewinski D, Bisping E, Elgner A, Kockskamper J, Pieske B (2007) Mechanistic insight into the functional and toxic effects of Strophanthidin in the failing human myocardium. Eur J Heart Fail 9: 1086–1094.
[50]
Pogwizd SM, Sipido KR, Verdonck F, Bers DM (2003) Intracellular Na in animal models of hypertrophy and heart failure: contractile function and arrhythmogenesis. Cardiovasc Res 57: 887–896.
[51]
Wagner S, Ruff HM, Weber SL, Bellmann S, Sowa T, et al. (2011) Reactive oxygen species-activated Ca/Calmodulin Kinase IIdelta is required for late I(Na) augmentation leading to cellular Na and Ca overload. Circ Res 108: 555–565.
[52]
Shannon TR, Wang F, Puglisi J, Weber C, Bers DM (2004) A mathematical treatment of integrated Ca dynamics within the ventricular myocyte. Biophys J 87: 3351–3371.
[53]
Carmeliet E (2004) Intracellular Ca(2+) concentration and rate adaptation of the cardiac action potential. Cell Calcium 35: 557–573.
[54]
Eisner DA, Dibb KM, Trafford AW (2009) The mechanism and significance of the slow changes of ventricular action potential duration following a change of heart rate. Exp Physiol 94: 520–528.
[55]
Pueyo E, Husti Z, Hornyik T, Baczko I, Laguna P, et al. (2010) Mechanisms of ventricular rate adaptation as a predictor of arrhythmic risk. Am J Physiol Heart Circ Physiol 298: H1577–H1587.
[56]
Faber GM, Rudy Y (2000) Action potential and contractility changes in [Na(+)](i) overloaded cardiac myocytes: a simulation study. Biophys J 78: 2392–2404.
[57]
Biliczki P, Virag L, Iost N, Papp JG, Varro A (2002) Interaction of different potassium channels in cardiac repolarization in dog ventricular preparations: role of repolarization reserve. Br J Pharmacol 137: 361–368.
[58]
Maltsev VA, Undrovinas AI (2006) A multi-modal composition of the late Na+ current in human ventricular cardiomyocytes. Cardiovasc Res 69: 116–127.
[59]
Noble D, Varghese A, Kohl P, Noble P (1998) Improved guinea-pig ventricular cell model incorporating a diadic space, IKr and IKs, and length- and tension-dependent processes. Can J Cardiol 14: 123–134.
[60]
Cardona K, Trenor B, Rajamani S, Romero L, Ferrero JM, et al. (2010) Effects of Late Sodium Current Enhancement During LQT-relatedArrhythmias. A Simulation Study. IEEE-EMBS 3237–3240.
[61]
Undrovinas AI, Maltsev VA, Kyle JW, Silverman N, Sabbah HN (2002) Gating of the late Na+ channel in normal and failing human myocardium. J Mol Cell Cardiol 34: 1477–1489.
[62]
Antoons G, Oros A, Beekman JD, Engelen MA, Houtman MJ, et al. (2010) Late na(+) current inhibition by ranolazine reduces torsades de pointes in the chronic atrioventricular block dog model. J Am Coll Cardiol 55: 801–809.
[63]
Hund TJ, Koval OM, Li J, Wright PJ, Qian L, et al. (2010) A beta(IV)-spectrin/CaMKII signaling complex is essential for membrane excitability in mice. J Clin Invest 120: 3508–3519.
[64]
Maltsev VA, Sabbah HN, Undrovinas AI (2001) Late sodium current is a novel target for amiodarone: studies in failing human myocardium. J Mol Cell Cardiol 33: 923–932.
[65]
Nagatomo T, Fan Z, Ye B, Tonkovich GS, January CT, et al. (1998) Temperature dependence of early and late currents in human cardiac wild-type and long Q-T DeltaKPQ Na+ channels. Am J Physiol 275: H2016–H2024.
[66]
Beuckelmann DJ, Nabauer M, Erdmann E (1992) Intracellular calcium handling in isolated ventricular myocytes from patients with terminal heart failure. Circulation 85: 1046–1055.
[67]
Undrovinas AI, Maltsev VA, Sabbah HN (1999) Repolarization abnormalities in cardiomyocytes of dogs with chronic heart failure: role of sustained inward current. Cell Mol Life Sci 55: 494–505.
[68]
Reinecke H, Studer R, Vetter R, Holtz J, Drexler H (1996) Cardiac Na+/Ca2+ exchange activity in patients with end-stage heart failure. Cardiovasc Res 31: 48–54.
[69]
Curran J, Brown KH, Santiago DJ, Pogwizd S, Bers DM, et al. (2010) Spontaneous Ca waves in ventricular myocytes from failing hearts depend on Ca(2+)-calmodulin-dependent protein kinase II. J Mol Cell Cardiol 49: 25–32.
[70]
Wettwer E, Amos GJ, Posival H, Ravens U (1994) Transient outward current in human ventricular myocytes of subepicardial and subendocardial origin. Circ Res 75: 473–482.
[71]
Nabauer M, Beuckelmann DJ, Uberfuhr P, Steinbeck G (1996) Regional differences in current density and rate-dependent properties of the transient outward current in subepicardial and subendocardial myocytes of human left ventricle. Circulation 93: 168–177.
[72]
Hasenfuss G, Reinecke H, Studer R, Meyer M, Pieske B, et al. (1994) Relation between myocardial function and expression of sarcoplasmic reticulum Ca(2+)-ATPase in failing and nonfailing human myocardium. Circ Res 75: 434–442.
[73]
Schwinger RH, Bohm M, Schmidt U, Karczewski P, Bavendiek U, et al. (1995) Unchanged protein levels of SERCA II and phospholamban but reduced Ca2+ uptake and Ca(2+)-ATPase activity of cardiac sarcoplasmic reticulum from dilated cardiomyopathy patients compared with patients with nonfailing hearts. Circulation 92: 3220–3228.
