Ranolazine for congenital and acquired late iNa-linked arrhythmias: In silico pharmacological screening

Circulation Research

Volumn 113, Issue 7, 2013, Pages

  Moreno, Jonathan D ^a   Yang, Pei Chi ^b   Bankston, John R ^c   Grandi, Eleonora ^b   Bers, Donald M ^b   Kass, Robert S ^c   Clancy, Colleen E ^b  

^a WEILL CORNELL MEDICAL COLLEGE   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c University College of Physcians and Sugeons ^*  (United States)

Author keywords

computational model; heart failure; late INa; long QT syndrome type 3; ranolazine

Indexed keywords

CALCIUM CALMODULIN DEPENDENT PROTEIN KINASE II; CYCLIC AMP DEPENDENT PROTEIN KINASE; RANOLAZINE; SODIUM CHANNEL;

ARTICLE; BRADYCARDIA; COMPUTER MODEL; CONCENTRATION RESPONSE; CONTROLLED STUDY; DRUG BINDING; DRUG EFFICACY; DRUG METABOLISM; DRUG SCREENING; GENOTYPE; HEART ARRHYTHMIA; HEART DEPOLARIZATION; HEART FAILURE; HEART MUSCLE CELL; HEART REPOLARIZATION; HUMAN; HUMAN CELL; LONG QT SYNDROME 3; LOW DRUG DOSE; MEMBRANE POTENTIAL; OXIDATIVE PHOSPHORYLATION; PHENOTYPE; PRIORITY JOURNAL; SODIUM CURRENT; STEADY STATE;

COMPUTATIONAL MODEL; HEART FAILURE; LATE INA; LONG-QT SYNDROME TYPE 3; RANOLAZINE;

ACETANILIDES; ACTION POTENTIALS; ANTI-ARRHYTHMIA AGENTS; COMPUTER SIMULATION; ETHER-A-GO-GO POTASSIUM CHANNELS; HUMANS; KINETICS; LONG QT SYNDROME; MUTATION; PIPERAZINES; SODIUM CHANNEL BLOCKERS; SODIUM CHANNELS;

EID: 84884815637     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.113.301971     Document Type: Article

References (75)

1. Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction. The Cardiac Arrhythmia Suppression Trial II Investigators. N Engl J Med. 1992;327:227-233.
2. Waldo AL, Camm AJ, deRuyter H, Friedman PL, MacNeil DJ, Pauls JF, Pitt B, Pratt CM, Schwartz PJ, Veltri EP. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol. Lancet. 1996;348:7-12.
3. Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, Arensberg D, Baker A, Friedman L, Greene HL. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991;324:781-788.
4. Lu HR, Rohrbacher J, Vlaminckx E, Van Ammel K, Yan GX, Gallacher DJ. Predicting drug-induced slowing of conduction and pro-arrhythmia: identifying the ?bad? sodium current blockers. Br J Pharmacol. 2010;160:60-76.
5. Burton L, Chabner B, Knollan B. Goodman and Gilman?s The Pharmacological Basis of Therapeutics. 12 ed. New York, NY: McGraw-Hill Professional; 2010.
6. Slawsky MT, Castle NA. K+ channel blocking actions of flecainide compared with those of propafenone and quinidine in adult rat ventricular myocytes. J Pharmacol Exp Ther. 1994;269:66-74.
7. Wang DW, Kiyosue T, Sato T, Arita M. Comparison of the effects of class I anti-arrhythmic drugs, cibenzoline, mexiletine and flecainide, on the delayed rectifier K+ current of guinea-pig ventricular myocytes. J Mol Cell Cardiol. 1996;28:893-903.
8. Watanabe H, Chopra N, Laver D, Hwang HS, Davies SS, Roach DE, Duff HJ, Roden DM, Wilde AA, Knollmann BC. Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans. Nat Med. 2009;15:380-383.
9. Scamps F, Undrovinas A, Vassort G. Inhibition of ICa in single frog cardiac cells by quinidine, flecainide, ethmozin, and ethacizin. Am J Physiol. 1989;256:C549-C559.
10. 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;110:904-910.
11. Koren MJ, Crager MR, Sweeney M. Long-term safety of a novel antianginal agent in patients with severe chronic stable angina: the Ranolazine Open Label Experience (ROLE). J Am Coll Cardiol. 2007;49:1027-1034.
12. Kaufman ES. Use of ranolazine in long-QT syndrome type. J Cardiovasc Electrophysiol. 2008;19:1294-1295.
13. Wang DW, Yazawa K, Makita N, George AL Jr, Bennett PB. Pharmacological targeting of long QT mutant sodium channels. J Clin Invest. 1997;99:1714-1720.
14. Abriel H, Cabo C, Wehrens XHT, Rivolta I. Novel arrhythmogenic mechanism revealed by a long-QT syndrome mutation in the cardiac Na+ channel. Circ Res. 2001;88:740-745.
15. Liu H, Tateyama M, Clancy C, Abriel H, Kass R. Channel openings are necessary but not sufficient for use-dependent block of cardiac Na+ channels by flecainide evidence from the analysis of disease-linked mutations. J Gen Physiol. 2002;120:39-51.
16. Balser JR. The cardiac sodium channel: gating function and molecular pharmacology. J Mol Cell Cardiol. 2001;33:599-613.
17. Zhu Y, Kyle JW, Lee PJ. Flecainide sensitivity of a Na channel long QT mutation shows an open-channel blocking mechanism for use-dependent block. Am J Physiol Heart Circ Physiol. 2006;291:H29-H37.
18. 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.
19. Abdallah H, Jerling M. Effect of hepatic impairment on the multipledose pharmacokinetics of ranolazine sustained-release tablets. J Clin Pharmacol. 2005;45:802-809.
20. Jerling M, Huan BL, Leung K, Chu N, Abdallah H, Hussein Z. Studies to investigate the pharmacokinetic interactions between ranolazine and ketoconazole, diltiazem, or simvastatin during combined administration in healthy subjects. J Clin Pharmacol. 2005;45:422-433.
21. Moreno JD, Zhu ZI, Yang PC, Bankston JR, Jeng MT, Kang C, Wang L, Bayer JD, Christini DJ, Trayanova NA, Ripplinger CM, Kass RS, Clancy CE. A computational model to predict the effects of class I anti-arrhythmic drugs on ventricular rhythms. Sci Transl Med. 2011;3:98ra83.
22. Hille B. Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction. J Gen Physiol. 1977;69:497-515.
23. Balser JR, Nuss HB, Orias DW, Johns DC, Marban E, Tomaselli GF, Lawrence JH. Local anesthetics as effectors of allosteric gating. Lidocaine effects on inactivation-deficient rat skeletal muscle Na channels. J Clin Invest. 1996;98:2874-2886.
24. Clancy CE, Rudy Y. Linking a genetic defect to its cellular phenotype in a cardiac arrhythmia. Nature. 1999;400:566-569.
25. 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.
26. Chaitman BR. Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions. Circulation. 2006;113:2462-2472.
27. Liu H, Atkins J, Kass RS. Common molecular determinants of flecainide and lidocaine block of heart Na+ channels: evidence from experiments with neutral and quaternary flecainide analogues. J Gen Physiol. 2003;121:199-214.
28. Starmer CF, Lastra AA, Nesterenko VV, Grant AO. Proarrhythmic response to sodium channel blockade. Theoretical model and numerical experiments. Circulation. 1991;84:1364-1377.
29. Chandra R, Starmer CF, Grant AO. Multiple effects of KPQ deletion mutation on gating of human cardiac Na+ channels expressed in mammalian cells. Am J Physiol. 1998;274:H1643-H1654.
30. 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.
31. Dumaine R, Kirsch GE. Mechanism of lidocaine block of late current in long QT mutant Na+ channels. Am J Physiol Heart Circ Physiol. 1998;274:H477-H487.
32. 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.
33. 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-S177.
34. Rajamani S, Shryock JC, Belardinelli L. Rapid kinetic interactions of ranolazine with HERG K+ current. J Cardiovasc Pharmacol. 2008;51:581-589.
35. Gordon M. Medical review of safety (ranolazine). US Food and Drug Administration. Available at: www.fda.gov/ohrms/dockets/ac/03/briefing/4012B2- 02-Division%20Dir%20%20Memo.htm. Accessed April 2011.
36. O?Hara T, Virág L, Varró A, Rudy Y. Simulation of the undiseased human cardiac ventricular action potential: model formulation and experimental validation. PLoS Comput Biol. 2011;7:e1002061.
37. Grandi E, Pasqualini FS, Bers DM. A novel computational model of the human ventricular action potential and Ca transient. J Mol Cell Cardiol. 2010;48:112-121.
38. ten Tusscher KH, Noble D, Noble PJ, Panfilov AV. A model for human ventricular tissue. Am J Physiol Heart Circ Physiol. 2004;286:H1573-H1589.
39. ten Tusscher KH, Panfilov AV. Alternans and spiral breakup in a human ventricular tissue model. Am J Physiol Heart Circ Physiol. 2006;291:H1088-H1100.
40. Nuyens D, Stengl M, Dugarmaa S, et al. Abrupt rate accelerations or premature beats cause life-threatening arrhythmias in mice with long-QT3 syndrome. Nat Med. 2001;7:1021-1027.
41. Viswanathan PC, Rudy Y. Pause induced early afterdepolarizations in the long QT syndrome: a simulation study. Cardiovasc Res. 1999;42:530-542.
42. Jackman WM, Friday KJ, Anderson JL, Aliot EM, Clark M, Lazzara R. The long QT syndromes: a critical review, new clinical observations and a unifying hypothesis. Prog Cardiovasc Dis. 1988;31:115-172.
43. Leclercq JF, Maisonblanche P, Cauchemez B, Coumel P. Respective role of sympathetic tone and of cardiac pauses in the genesis of 62 cases of ventricular fibrillation recorded during Holter monitoring. Eur Heart J. 1988;9:1276-1283.
44. Kay GN, Plumb VJ, Arciniegas JG, Henthorn RW, Waldo AL. Torsade de pointes: the long-short initiating sequence and other clinical features: observations in 32 patients. J Am Coll Cardiol. 1983;2:806-817.
45. Viskin S, Fish R, Zeltser D, Belhassen B, Heller K, Brosh D, Laniado S, Barron HV. Arrhythmias in the congenital long QT syndrome: how often is torsade de pointes pause dependent? Heart. 2000;83:661-666.
46. Maltsev VA, Sabbah HN, Undrovinas AI. Late sodium current is a novel target for amiodarone: studies in failing human myocardium. J Mol Cell Cardiol. 2001;33:923-932.
47. 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;9:219-227.
48. 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? is required for late I(Na) augmentation leading to cellular Na and Ca overload. Circ Res. 2011;108:555-565.
49. Glukhov AV, Fedorov VV, Lou Q, Ravikumar VK, Kalish PW, Schuessler RB, Moazami N, Efimov IR. Transmural dispersion of repolarization in failing and nonfailing human ventricle. Circ Res. 2010;106:981-991.
50. 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.
51. Soltis AR, Saucerman JJ. Synergy between CaMKII substrates and ?-adrenergic signaling in regulation of cardiac myocyte Ca(2+) handling. Biophys J. 2010;99:2038-2047.
52. 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;84:713-721.
53. Drouin E, Lande G, Charpentier F. Amiodarone reduces transmural heterogeneity of repolarization in the human heart. J Am Coll Cardiol. 1998;32:1063-1067.
54. Maltsev VA, Undrovinas AI. A multi-modal composition of the late Na+ current in human ventricular cardiomyocytes. Cardiovasc Res. 2006;69: 116-127.
55. Wingo TL, Shah VN, Anderson ME, Lybrand TP, Chazin WJ, Balser JR. An EF-hand in the sodium channel couples intracellular calcium to cardiac excitability. Nat Struct Mol Biol. 2004;11:219-225.
56. Mori M, Konno T, Ozawa T, Murata M, Imoto K, Nagayama K. Novel interaction of the voltage-dependent sodium channel (VDSC) with calmodulin: does VDSC acquire calmodulin-mediated Ca2+-sensitivity? Biochemistry. 2000;39:1316-1323.
57. 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;116:3127-3138.
58. 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.
59. Ward CA, Giles WR. Ionic mechanism of the effects of hydrogen peroxide in rat ventricular myocytes. J Physiol. 1997;500(Pt 3):631-642.
60. Eigel BN, Hadley RW. Contribution of the Na(+) channel and Na(+)/H(+) exchanger to the anoxic rise of [Na(+)] in ventricular myocytes. Am J Physiol. 1999;277:H1817-H1822.
61. 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;30:829-835.
62. Xiao XH, Allen DG. Role of Na(+)/H(+) exchanger during ischemia and preconditioning in the isolated rat heart. Circ Res. 1999;85: 723-730.
63. Bielen FV, Bosteels S, Verdonck F. Consequences of CO2 acidosis for transmembrane Na+ transport and membrane current in rabbit cardiac Purkinje fibres. J Physiol. 1990;427:325-345.
64. Coppini R, Ferrantini C, Yao L, et al. Late sodium current inhibition reverses electromechanical dysfunction in human hypertrophic cardiomyopathy. Circulation. 2013;127:575-584.
65. Wu L, 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.
66. Wu L, 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.
67. 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.
68. Wasserstrom JA, Sharma R, O?Toole MJ, Zheng J, Kelly JE, Shryock J, Belardinelli L, Aistrup GL. Ranolazine antagonizes the effects of increased late sodium current on intracellular calcium cycling in rat isolated intact heart. J Pharmacol Exp Ther. 2009;331:382-391.
69. Moss AJ, Zareba W, Schwarz KQ, Rosero S, McNitt S, Robinson JL. Ranolazine shortens repolarization in patients with sustained inward sodium current due to type-3 long-QT syndrome. J Cardiovasc Electrophysiol. 2008;19:1289-1293.
70. Schwartz PJ, Priori SG, Locati EH, Napolitano C, Cantù F, Towbin JA, Keating MT, Hammoude H, Brown AM, Chen LS. 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;92:3381-3386.
71. Velebit V, Podrid P, Lown B, Cohen BH, Graboys TB. Aggravation and provocation of ventricular arrhythmias by antiarrhythmic drugs. Circulation. 1982;65:886-894.
72. Campbell RW. Arrhythmogenesis-a European perspective. Am J Cardiol. 1987;59:49E-51E.
73. Podrid PJ, Lampert S, Graboys TB, Blatt CM, Lown B. Aggravation of arrhythmia by antiarrhythmic drugs-incidence and predictors. Am J Cardiol. 1987;59:38E-44E.
74. Liu J, Laurita KR. The mechanism of pause-induced torsade de pointes in long QT syndrome. J Cardiovasc Electrophysiol. 2005;16:981-987.
75. Ramanathan C, Jia P, Ghanem R, Ryu K, Rudy Y. Activation and repolarization of the normal human heart under complete physiological conditions. Proc Natl Acad Sci USA. 2006;103:6309-6314.