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European Heart Journal 2001 22(23):2148-2163; doi:10.1053/euhj.2001.3036
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Review Article

New approaches to antiarrhythmic therapy; emerging therapeutic applications of the cell biology of cardiac arrhythmias

Members of the Sicilian Gambitf1

Received June 29, 2001; accepted September 19, 2001

Abstract

Cardiac arrhythmias complicate many diseases affecting the heart and the circulation, and incorporate a multiplicity of underlying mechanisms. The evolution of scientific knowledge has made the complex changes produced by cardiovascular disease sufficiently understood at the organ, cellular, and molecular levels such that there is a diversity of therapeutic targets for pharmacological therapy and/or prevention. Moreover, the approach of rational drug design, in mechanism- and disease-specific fashion, facilitates targeting of therapy via molecular, structural and translational biology. Additional approaches, employing similar drug-design strategies but based on gene therapy and transcriptional and translational modification are on the horizon. Hence, there is reason to be optimistic regarding the design, testing and clinical availability of novel antiarrhythmic therapies.

Key Words: Molecular biology, gene therapy, genes, electrophysiology, pharmacology

f1 Correspondence: Michael R. Rosen, MD, Gustavus A. Pfeiffer Professor of Pharmacology, Professor of Pediatrics, Director, Center for Molecular Therapeutics, College of Physicians & Surgeons of Columbia University, Department of Pharmacology, 630 West 168 Street, PH7W-321, New York, NY 10032, U.S.A.

References

  1. Echt DS, Liebson PR, Mitchell LB. Mortality and morbidity in patients receiving encainide, flecainide or placebo. The Cardiac Arrhythmia Suppression Trial (CAST). N Engl J Med. 1991;324:781–788[Abstract]
  2. Waldo AL, Camm AJ, Deruyter H. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. Lancet. 1996;348:7–12[CrossRef][ISI][Medline]
  3. Julian DG, Camm AJ, Frangin G. The European Myocardial Infarct Amiodarone Trial Investigators. Lancet. 1997;349:667–674[CrossRef][ISI][Medline]
  4. Cairns JA, Connolly SJ, Roberts R. The Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators (CAMIAT). Lancet. 1997;349:675–682[CrossRef][ISI][Medline]
  5. Torp-Pederson C, Moller M, Bloch-Thomsen PE. The Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. N Engl J Med. 1999;341:879–911[Free Full Text]
  6. Hodgkin A, Huxley A. A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol (Lond). 1952;117:500–544[Free Full Text]
  7. Beeler GW, Reuter H. Reconstruction of the action potential of ventricular myocardial fibres. J Physiol (Lond). 1977;268:177–210[Abstract/Free Full Text]
  8. Luo CH, Rudy Y. A model of the ventricular cardiac action potential—depolarization, repolarization, and their interaction. Circ Res. 1991;68:1501–1526[Abstract/Free Full Text]
  9. Luo CH, Rudy Y. A dynamic model of the cardiac ventricular action potential. 1. Simulations of ionic currents and concentration changes. Circ Res. 1994;74:1071–1096[Abstract/Free Full Text]
  10. Viswanathan PC, Shaw RM, Rudy Y. Effects of IKrand IKsheterogeneity on action potential duration and its rate dependence: a simulation study. Circulation. 1999;99:2466–2474[Abstract/Free Full Text]
  11. Winslow RL, Rice J, Jafri S. Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart failure, II: model studies. Circ Res. 1999;84:571–586[Abstract/Free Full Text]
  12. Lindblad DS, Murphey CR, Clark JW. A model of the action potential and underlying membrane currents in a rabbit atrial cell. Am J Physiol. 1996;271:H1666–96[ISI][Medline]
  13. Nygren A, Fiset C, Firek L. Mathematical model of an adult human atrial cell: the role of K+currents in repolarization. Circ Res. 1998;82:63–81[Abstract/Free Full Text]
  14. Courtemanche M, Ramirez RJ, Nattel S. Ionic mechanisms underlying human atrial action potential properties: insights from a mathematical model. Am J Physiol. 1998;275:H301–21[ISI][Medline]
  15. Yanagihara K, Noma A, Irisawa H. Reconstruction of sinoatrial node pacemaker potential based on the voltage clamp experiments. Jpn J Physiol. 1980;30:841–857[ISI][Medline]
  16. Wilders R, Jongsma HJ, van Ginneken AC. Pacemaker activity of the rabbit sinoatrial node. A comparison of mathematical models. Biophys J. 1991;60:1202–1216[Medline]
  17. Di Francesco D, Noble D. A model of cardiac electrical activity incorporating ionic pumps and concentration changes. Philos Trans R Soc Lond B Biol Sci. 1985;307:353–398[ISI][Medline]
  18. McAllister RE, Noble D, Tsien RW. Reconstruction of the electrical activity of cardiac Purkinje fibres. J Physiol (Lond). 1975;251:1–59[Abstract/Free Full Text]
  19. Tomaselli GF, Chiamvimonvat N, Nuss HB. A mutation in the pore of the sodium channel alters gating. Biophys J. 1995;68:1814–1827[Medline]
  20. Clancy CE, Rudy Y. Linking a genetic defect to its cellular phenotype in a cardiac arrhythmia. Nature. 1999;400:566–569[CrossRef][Medline]
  21. Clancy CE, Rudy Y. Cellular consequences of HERG mutations in the Long QT Syndrome: precursors to sudden cardiac death. Cardiovasc Res. 2001;50:301–313[Abstract/Free Full Text]
  22. Wit AL, Rosen MR. Afterdepolarizations and triggered activity. Fozzard H, Haber E, Jennings R. The Heart and Cardiovascular System. New York: Raven Press; 1986. p. 1449–1491
  23. Janse MJ, Wit AL. Electrophysiological mechanisms of ventricular arrhythmias resulting from ischemia and infarction. Physiol Rev. 1989;69:1049–1169[Free Full Text]
  24. Rohr S, Kucera JP, Kléber AG. Slow conduction in cardiac tissue: I. Effects of a reduction of excitability vs. a reduction in cell-to-cell coupling on microconduction. Circ Res. 1998;83:781–794[ISI][Medline]
  25. Fast VG, Kléber AG. Microscopic conduction in cultured strands of neonatal rat heart cells measured with voltage-sensitive dyes. Circ Res. 1993;73:914–925[Abstract/Free Full Text]
  26. Rudy Y, Quan W. A model study of the effects of the discrete cellular structure on electrical propagation in cardiac tissue. Circ Res. 1987;61:815–823[Abstract/Free Full Text]
  27. Efimov IR, Krinsky VI, Jalife J. Dynamics of rotating vortices in the Beeler-Reuter model of cardiac tissue. Chaos Solitons Fractals. 1995;5:513–526[CrossRef][ISI]
  28. Joyner RW. Effects of the discrete pattern of electrical coupling on propagation through an electrical syncitium. Circ Res. 1982;50:192–200[Abstract/Free Full Text]
  29. Berenfeld O, Pertsov AM. Dynamics of intramural scroll waves in three-dimensional continuous myocardium with rotational anisotropy. J Theoret Biol. 1999;199:383–394[CrossRef][ISI][Medline]
  30. el-Sherif N, Caref EB, Yin H. The electrophysiological mechanism of ventricular arrhythmias in the long QT syndrome. Tridimensional mapping of activation and recovery patterns. Circ Res. 1996;79:474–492[Abstract/Free Full Text]
  31. De Bakker JMT, Van Capelle FJL, Janse MJ. Slow conduction in the infarcted human heart—zigzag course of activation. Circulation. 1993;88:915–926[Abstract/Free Full Text]
  32. Zipes DP. Atrial fibrillation. A tachycardia-induced atrial cardiomyopathy [editorial; comment]. Circulation. 1997;95:562–564[Free Full Text]
  33. Fast VG, Kléber AG. Role of wavefront curvature in propagation of cardiac impulse. Cardiovasc Res. 1997;33:258–271[Abstract/Free Full Text]
  34. Knisley SB, Hill BC. Effects of bipolar point and line stimulation in anisotropic rabbit epicardium: assessment of the critical radius of curvature for longitudinal block. IEEE Trans Biomed Eng. 1995;42:957–966[CrossRef][ISI][Medline]
  35. Beaumont J, Davidenko N, Davidenko JM. Spiral waves in two-dimensional models of ventricular muscle; formation of a stationary core. Biophys J. 1998;75:1–14[Medline]
  36. Davidenko JM, Pertsov AV, Salomonsz R. Stationary and drifting spiral waves of excitation in isolated cardiac muscle. Nature. 1992;355:349–351[CrossRef][Medline]
  37. Cabo C, Pertsov AM, Davidenko JM. Vortex shedding as a result of turbulent electrical activity in cardiac muscle. Biophys J. 1996;70:1105–1111[ISI][Medline]
  38. Krinsky VI, Efimov IR, Jalife J. Vortices with linear cores in excitable media. Proc Roy Soc London Ser A. 1992;437:645–655
  39. Hund TJ, Otani NF, Rudy Y. Dynamics of action potential head-tail interaction during reentry in cardiac tissue: ionic mechanisms. Am J Physiol. 2000;279:H1869–H1879[ISI]
  40. Starmer CF, Biktashev VN, Romashko DN. Vulnerability in an excitable medium: analytical and numerical studies of initiating unidirectional propagation. Biophys J. 1993;65:1775–1787[Medline]
  41. Vinet A, Roberge FA. The dynamics of sustained reentry in a ring model of cardiac tissue. Ann Biomed Eng. 1994;22:568–591[CrossRef][ISI][Medline]
  42. Van Capelle FJL, Durrer D. Computer simulation of arrhythmias in a network of coupled excitable elements. Circ Res. 1980;47:453–466
  43. Winfree AT. Scroll-shaped waves of chemical activity in three dimensions. Science. 1973;181:937–939[Abstract/Free Full Text]
  44. Karma A. Electrical alternans and spiral wave breakup in cardiac tissue. Chaos. 1994;4:461–472[CrossRef][ISI][Medline]
  45. Antzelevitch, C, Yan, GX, Shimizu, W, Electrical heterogeneity, the ECG, and cardiac arrhythmias, Zipes, DJalife, J, Cardiac Electrophysiology: From Cell to Bedside, Philadelphia, W.B. Saunders Co. 2000, 222, 38
  46. Zygmunt AC, Goodrow RJ, Antzelevitch C. I(Na,Ca) contributes to electrical heterogeneity within the canine ventricle. Am J Physiol. 2000;278:H1671–8[ISI]
  47. Shaw RM, Rudy Y. Ionic mechanisms of propagation in cardiac tissue. Roles of the sodium and L-type calcium currents during reduced excitability and decreased gap junction coupling. Circ Res. 1997;81:727–741[Abstract/Free Full Text]
  48. Schalij, MJ, Anisotropic conduction and ventricular tachycardia, Rijksuniversiteit Limburg, Maastricht, The Netherlands, 1988
  49. Kucera JP, Kléber AG, Rohr R. Slow conduction in cardiac tissue: II. Effects of branching tissue geometry. Circ Res. 1998;83:795–805[ISI][Medline]
  50. Wijffels MC, Dorland R, Mast F. Widening of the excitable gap during pharmacological cardioversion of atrial fibrillation in the goat: effects of cibenzoline, hydroquinidine, flecainide, and d-sotalol. Circulation. 2000;102:260–267[Abstract/Free Full Text]
  51. Haissaguerre M, Jais P, Shah DC. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998;339:659–666[Abstract/Free Full Text]
  52. Janse MJ, Schwartz PJ, Wilms-Schopman F. Effects of unilateral stellate ganglion stimulation and ablation on electrophysiologic changes induced by acute myocardial ischemia in dogs. Circulation. 1985;72:585–595[Abstract/Free Full Text]
  53. Ito M, Zipes DP. Efferent sympathetic and vagal innervation of the canine right ventricle. Circulation. 1994;90:1459–1468[Abstract/Free Full Text]
  54. Dae MW, Lee RJ, Ursell PC. Heterogeneous sympathetic innervation in German shepherd dogs with inherited ventricular arrhythmia and sudden cardiac death. Circulation. 1997;96:1337–1342[Abstract/Free Full Text]
  55. Sosunov EA, Anyukhovsky EP, Shvilkin A. Abnormal cardiac repolarization and impulse initiation in German shepherd dogs with inherited ventricular arrhythmias and sudden death. Cardiovasc Res. 1999;42:65–79[Abstract/Free Full Text]
  56. Burnes JE, Taccardi B, Rudy Y. A noninvasive imaging modality for cardiac arrhythmias. Circulation. 2000;102:2152–2158[Abstract/Free Full Text]
  57. Rudy Y. Electrocardiogram and cardiac excitation. Sperelakis N, Kurachi Y, Terzic A. Heart Physiology and Pathophysiology. San Diego: Academic Press; 2001. p. 133–148
  58. Boyett MR, Honjo H, Kodama I. The sinoatrial node, a heterogeneous pacemaker structure. Cardiovasc Res. 2000;47:658–687[Abstract/Free Full Text]
  59. Spach MS, Miller WTI, Gezelowitz DB. The discontinuous nature of propagation in normal canine cardiac muscle. Evidence for recurrent discontinuities of intracellular resistance that affect the membrane currents. Circ Res. 1981;48:39–54[Free Full Text]
  60. Pollard AE, Barr RC. The construction of an anatomically based model of the human ventricular conduction system. IEEE Trans Biomed Eng. 1990;37:1173–1185[CrossRef][ISI][Medline]
  61. Wiedmann R, Tan RC, Joyner RW. Discontinuous conduction at Purkinje-ventricular muscle junction. Am J Physiol. 1996;271:H1507–16[ISI][Medline]
  62. Colli Franzone P, Guerri L, Rovida S. Wavefront propagation in an activation model of the anisotropic cardiac tissue: asymptotic analysis and numerical simulations. J Math Biol. 1990;28:121–176[CrossRef][ISI][Medline]
  63. Simon AM, Goodenough DA, Paul DL. Mice lacking connexin40 have cardiac conduction abnormalities characteristic of atrioventricular block and bundle branch block. Curr Biol. 1998;8:295–298[CrossRef][ISI][Medline]
  64. Guerrero PA, Schuessler RB, Davis LM. Slow ventricular conduction in mice heterozygous for a connexin-43 null mutation. J Clin Invest. 1997;99:1991–1998[ISI][Medline]
  65. Temple J, Frias PA, Kupershmidt S. Spontaneous and induced atrial fibrillation in minK knockout mice (Abstr). Circulation. 2000;102:153
  66. Xu H, Barry DM, Li H. Attenuation of the slow component of delayed rectification, action potential prolongation, and triggered activity in mice expressing a dominant-negative Kv2 {alpha} subunit. Circ Res. 1999;85:623–633[Abstract/Free Full Text]
  67. Barry DM, Xu H, Schuessler RB. Functional knockout of the transient outward current, long-QT syndrome, and cardiac remodeling in mice expressing a dominant-negative Kv4 alpha subunit. Circ Res. 1998;83:560–567[Abstract/Free Full Text]
  68. London B, Jeron A, Zhou J. Long QT and ventricular arrhythmias in transgenic mice expressing the N terminus and first transmembrane segment of a voltage-gated potassium channel. Proc Natl Acad Sci. 1998;95:2926–2931[Abstract/Free Full Text]
  69. Keating MT, Sanguinetti MC. Molecular genetic insights into cardiovascular disease. Science. 1996;272:681–685[Abstract]
  70. Roden DM, Spooner PM. Inherited long QT syndromes: A paradigm for understanding arrhythmogenesis. J Cardiovasc Electrophysiol. 1999;10:1664–1683[ISI][Medline]
  71. Priori SG, Barhanin J, Hauer RN. Genetic and molecular basis of cardiac arrhythmias; impact on clinical management. Study group on molecular basis of arrhythmias of the Working Group on Arrhythmias of the European Society of Cardiology. Eur Heart J. 1999;20:174–195[Free Full Text]
  72. Chien KR. Genomic circuits and the integrative biology of cardiac diseases. Nature. 2000;407:227–232[CrossRef][Medline]
  73. Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation. 1999;99:529–533[Abstract/Free Full Text]
  74. Benson DW, Silberbach GM, Kavanaugh-McHugh A. Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways. J Clin Invest. 1999;104:1567–1573[ISI][Medline]
  75. Wang Q, Curran ME, Splawski I. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Gen. 1996;12:17–23[CrossRef][ISI][Medline]
  76. Riordan JR, Rommens JM, Kerem B. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989;245:1066–1073[Abstract/Free Full Text]
  77. Pericak-Vance MA, Bass MP, Yamaoka LH. Complete genomic screen in late-onset familial Alzheimer disease. Evidence for a new locus on chromosome 12. JAMA. 1997;278:1237–1241[Abstract]
  78. Roses AD. Pharmacogenetics and the practice of medicine. Nature. 2000;405:857–865[CrossRef][Medline]
  79. Liggett SB, Wagoner LE, Craft LL. The Ile164 ß2-adrenergic receptor polymorphism adversely affects the outcome of congestive heart failure. J Clin Invest. 1998;102:1534–1539[ISI][Medline]
  80. Turki J, Lorenz JN, Green SA. Myocardial signaling defects and impaired cardiac function of a human ß2-adrenergic receptor polymorphism expressed in transgenic mice. Proc Natl Acad Sci. 1996;93:10483–10488[Abstract/Free Full Text]
  81. Drysdale CM, McGraw DW, Stack CB. Complex promoter and coding region ß2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci USA. 2000;97:10483–10488[Abstract/Free Full Text]
  82. Schwartz PJ. Another role for the sympathetic nervous system in the long QT syndrome? J Cardiovasc Electrophysiol. 2001;12:500–502[CrossRef][ISI][Medline]
  83. Morillo CA, Klein GJ, Jones DL. Chronic rapid atrial pacing: structural, functional and electrophysiologic characteristics of a new model of sustained atrial fibrillation. Circulation. 1995;91:1588–1595[Abstract/Free Full Text]
  84. Wijffels MCEF, Kirchof CJHJ, Dorland R. Atrial fibrillation begets atrial fibrillation: a study in awake chronically instrumented goats. Circulation. 1995;92:1954–1968[Abstract/Free Full Text]
  85. Gaspo R, Bosch RF, Talajic M. Functional mechanisms underlying tachycardia-induced sustained atrial fibrillation in a chronic dog model. Circulation. 1997;96:4027–4035[Abstract/Free Full Text]
  86. Shvilkin A, Danilo P Jr, Wang J. Evolution and resolution of long-term cardiac memory. Circulation. 1998;97:1810–1817[Abstract/Free Full Text]
  87. Allessie MA, Boyden PA, Camm AJ. Pathophysiology and prevention of atrial fibrillation. Circulation. 2001;103:769–777[Free Full Text]
  88. Herweg B, Chang F, Chandra P. Cardiac memory in canine atrium. Identification and Implications. Circulation. 2001;103:455–461[Abstract/Free Full Text]
  89. Eur Heart J. 1998;19:1178–1196[Free Full Text]
  90. Kandzari DE, Goldschmidt-Clermont PJ. Coronary events with lipid-lowering therapy: the AFCAPS/TexCAPS trial. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1999;281:415–419[ISI][Medline]
  91. Pitt B, Zannad F, Remme WJ. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 2000;341:709–717[CrossRef][ISI]
  92. Kober L, Torp-Pedersen C, Carlsen JE. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med. 1995;333:1670–1676[Abstract/Free Full Text]
  93. Moye LA, Pfeffer MA, Wun CC. Uniformity of captopril benefit in the SAVE Study: subgroup analysis. Survival and Ventricular Enlargement Study. Eur Heart J. 1994;15:2–30[Free Full Text]
  94. Dodge SM, Beardslee MA, Darrow BJ. Effects of angiotensin II on expression of the gap junction channel protein connexin43 in neonatal rat ventricular myocytes. J Am Coll Cardiol. 1998;32:800–807[Abstract/Free Full Text]
  95. Kass RS, Blair ML. Effects of angiotensin II on membrane current in cardiac Purkinje fibers. J Mol Cell Cardiol. 1981;13:797–809[CrossRef][ISI][Medline]
  96. Yu H, Gao J, Wang H. Effects of the renin-angiotensin system on the current Itoin epicardial and endocardial ventricular myocytes from the canine heart. Circ Res. 2000;86:1062–1068[Abstract/Free Full Text]
  97. Shimoni Y. Hormonal control of cardiac ion channels and transporters. Prog Biophys Mol Biol. 1999;72:67–108[CrossRef][ISI][Medline]
  98. Cranefield PF, Wit AL, Hoffman BF. Conduction of the cardiac impulse. Characteristics of very slow conduction. J Gen Physiol. 1972;59:227–246[Abstract/Free Full Text]
  99. Wit AL, Hoffman BF, Cranefield PF. Slow conduction and reentry in the ventricular conducting system. I. Return extrasystole in canine Purkinje fibers. Circ Res. 1972;30:1–10[Abstract/Free Full Text]
  100. Kamkin A, Kiseleva I, Wagner KD. Mechanically induced potentials in fibroblasts from human right atrium. Exp Physiol. 1999;84:347–356[Abstract]
  101. Prinzen FW, Augustijn CH, Arts T. Redistribution of myocardial fiber strain and blood flow by asynchronous activation. Am J Physiol. 1990;259:H300–H308[ISI][Medline]
  102. Prinzen FW, van Oosterhout MFM, Arts T. Local functional and structural changes in the myocardium during ventricular pacing. J Interven Cardiol. 1996;9:319–326[CrossRef][ISI]
  103. Sadoshima J-I, Izumo S. Mechanical stretch activates multiple signal transduction pathways in cardiac myocytes: potential involvement of an autocrine/paracrine mechanism. EMBO J. 1993;12:1681–1692[ISI][Medline]
  104. Sadoshima J-I, Izumo S. Molecular characterization of angiotensin II-induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Circ Res. 1993;73:413–423[Abstract/Free Full Text]
  105. Sadoshima J-I, Izumo S. Signal transduction pathways of angiotensin II-induced c-fos gene expression of cardiac myocytes in vitro. Circ Res. 1993;73:424–438[Abstract/Free Full Text]
  106. Sadoshima J-I, Jahn L, Takahashi T. Molecular characterization of the stretch-induced adaptation of cultured cardiac cells. J Biol Chem. 2001;267:10551–10560
  107. Ricard P, Danilo P, Cohen IS. A role for the renin-angiotensin system in the evolution of cardiac memory. J Cardiovasc Electrophysiol. 1999;10:545–551[ISI][Medline]
  108. Schnee JM, Hseuh WA. Review: angiotensin II, Adhesion and Cardiac Fibrosis. Cardiovasc Res. 2000;46:264–268[Abstract/Free Full Text]
  109. Pederson OD, Bagger H, Kober L. Trandolapril reducs the incidence of atrial fibrilaltion after myocardial infarction in patients with left ventricular dysfunction. Circulation. 1999;100:376–380[Abstract/Free Full Text]
  110. Crijns HJ, van den Berg MP, van Gelder IC. Management of atrial fibrillation in the setting of heart failure. Eur Heart J. 1997;18:C45–C49[ISI][Medline]
  111. Young M, Funder JW. Aldosterone and the Heart. Trends Endocrinol Metab (TEM). 2000;11:224–226
  112. Herskowitz A, Choi S, Ansari A. Cytokine mRNA expression in postischemic reperfused myocardium. Am J Pathol. 1995;146:419–428[Abstract]
  113. Krown KA, Yasui K, Brooker MJ. TNF{alpha} receptor expression in rat cardiac myocytes: TNF{alpha} inhibition of L-type Ca2+current and Ca2+transients. FEBS Lett. 1995;376:24–30[CrossRef][ISI][Medline]
  114. Kunugawa S, Tsutsui H, Hayashidani S. Treatment with dimethylthiourea prevents left ventricular remodeling and failure after experimental myocardial infarction in mice: role of oxidative stress. Circ Res. 2000;87:392–398[Abstract/Free Full Text]
  115. Fearon IM, Palmer AC, Balmforth AJ. Hypoxia inhibits the recombinant {alpha}1C-subunit of the human cardiac L-type Ca2+channel. J Physiol. 1997;500:551–556[Abstract/Free Full Text]
  116. Fearon IM, Palmer AC, Balmforth AJ. Modulation of recombinant human cardiac L-type Ca2+channel {alpha}1Csubunits by redox agents and hypoxia. J Physiol. 1999;514:629–637[Abstract/Free Full Text]
  117. Tomaselli GF, Marban E. Electrophysiological remodeling in hypertrophy and heart failure. Cardiovasc Res. 1999;42:270–283[Free Full Text]
  118. Pinto JMB, Boyden PA. Electrical remodeling in ischemia and infarction. Cardiovasc Res. 1999;42:284–297[Abstract/Free Full Text]
  119. Nattel S, Li D. Ionic remodeling of the heart. Pathophysiological significance and new therapeutic opportunities for atrial fibrillation. Circ Res. 2000;87:440–447[Abstract/Free Full Text]
  120. Yu H, McKinnon D, Dixon JE. Transient outward current, Ito1, is altered in cardiac memory. Circulation. 1999;99:1898–1905[Abstract/Free Full Text]
  121. Jeck CD, Boyden PA. Age-related appearance of outward currents may contribute to developmental differences in ventricular repolarization. Circ Res. 1992;71:1390–1403[Abstract/Free Full Text]
  122. Marks AR. Cardiac intracellular calcium release channels: role in heart failure. Circ Res. 2000;87:8–11[Free Full Text]
  123. Ter Keurs HED, Boyden PA. Ca2+and arrhythmias. Spooner PM, Rosen MR. Foundations of Cardiac Arrhythmias. New York: Marcel Dekker Inc; 2000. p. 287–317
  124. Priori SG, Napolitano C, Tiso N. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation. 2001;103:196–200[Abstract/Free Full Text]
  125. Beardslee MA, Laing JG, Beyer EC. Rapid turnover of connexin43 in the adult rat heart. Circ Res. 1998;83:629–635[Abstract/Free Full Text]
  126. Darrow BJ, Fast VG, Kléber AG. Functional and structural assessment of intercellular communication. Increased conduction velocity and enhanced connexin expression in dibutyryl cAMP-treated cultured cardiac myocytes. Circ Res. 1996;79:174–183[Abstract/Free Full Text]
  127. Mukherjee DP, McTiernan CF, Sen S. Myotrophin induces early response genes and enhances cardiac gene expression. Hypertension. 1993;21:142–148[Abstract/Free Full Text]
  128. Fernandez-Cobo M, Gingalewski C, Drujan D. A downregulation of connexin 43 gene expression in rat heart during inflammation. The role of tumour necrosis factor. Cytokine. 1999;11:216–224[CrossRef][ISI][Medline]
  129. Buxton AE, Lee KL, Fisher JD. A randomized study of the prevention of sudden death in patients with coronary artery disease. MUSTT Investigators. N Engl J Med. 1999;341:1882–1890[Abstract/Free Full Text]
  130. N Engl J Med. 1997;337:1576–1583[Abstract/Free Full Text]
  131. Moss AJ, Hall J, Cannom DS. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmias. N Engl J Med. 1996;335:1933–1940[Abstract/Free Full Text]
  132. Ragsdale DS, McPhee JC, Scheuer T. Molecular determinants of state-dependent block of Na channels by local anesthetics. Science (Wash, DC). 1994;265:1724–1728[Abstract/Free Full Text]
  133. Hockerman GH, Peterson BZ, Johnson BD. Molecular determinants of drug binding and action on L-type calcium channels. Annu Rev Pharmacol Toxicol. 1997;37:361–396[CrossRef][ISI][Medline]
  134. Sunami A, Dudley SC, Fozzard HA. Sodium channel selectivity filter regulates antiarrhythmic drug binding. Proc Natl Acad Sci. USA. 1997;94:14126–14131[Abstract/Free Full Text]
  135. Mitcheson JS, Chen J, Lin M. A structural basis for drug-induced long QT syndrome. Proc Natl Acad Sci USA. 2000;97:12329–12333[Abstract/Free Full Text]
  136. Yarov-Yarovoy V, Brown J, Sharp EM. Molecular determinants of voltage-dependent gating and binding of pore-blocking drugs in transmembrane segment IIIS6 of the Na channel {alpha} subunit. J Biol Chem. 2001;276:20–27[Abstract/Free Full Text]
  137. Antzelevitch C. Electrical heterogeneity, cardiac arrhythmias, and the sodium channel. Circ Res. 2000;87:964–965[Free Full Text]
  138. Antzelevitch C. The Brugada syndrome: Ionic basis and arrhythmia mechanisms. J Cardiovasc Electrophysiol. 2001;12:268–272[CrossRef][ISI][Medline]
  139. Hille B. Ionic Currents of Excitable Membranes. Sunderland: Sinauer Associates; 1992.
  140. Roden DM. Antiarrhythmic drugs. Hardman JL, Limbird LE, Gilman AG. The Pharmacological Basis of Therapeutics. New York: McGraw-Hill; 2001. p. 933–970
  141. Hancox JC, Patel KC, Jones JU. Antiarrhythmics—from cell to clinic: past, present, and future. Heart. 2000;84:14–24[Free Full Text]
  142. Kass RS. Voltage-dependent modulation of cardiac calcium channel current by optical isomers of BayK 8644: Implications for channel gating. Circ Res. 1987;61:I1–5[Medline]
  143. Lee KS. Ibutilide, a new compound with potent class III antiarrhythmic activity, activates a slow inward Na+current in guinea pig ventricular cells. JPET. 1992;262:99–108[Abstract/Free Full Text]
  144. Shivkumar K, Weiss JN. Adenosine triphosphate-sensitive potassium channels. Zipes DP, Jalife J. Cardiac Electrophysiology: From Cell to Bedside. Philadelphia: W.B. Saunders Co; 2000. p. 86–93
  145. Vandenberg JI, Rees SA, Wright AR. Cell swelling and ion transport pathways in cardiac myocytes. Cardiovasc Res. 1996;32:85–97[CrossRef][ISI][Medline]
  146. Wu Y, Macmillan LB, McNeill RB. CaM kinase augments cardiac L-type Ca2+current: a cellular mechanism for long Q-T arrhythmias. Am J Physiol. 1999;276:H2168–78[ISI][Medline]
  147. Wu Y, Roden DM, Anderson ME. Calmodulin kinase inhibition prevents development of the arrhythmogenic transient inward current. Circ Res. 1999;84:906–912[Abstract/Free Full Text]
  148. Dzhura Y, Wu RJ, Colbran JR. Calmodulin kinase determines calcium dependent facilitation of L-type calcium channels. Nat Cell Biol. 2000;2:173–177[CrossRef][ISI][Medline]
  149. Undrovinas AI, Shander GS, Makielski JC. Cytoskeleton modulates gating of voltage-dependent sodium current in heart. Am J Physiol. 1995;269:H203–14[ISI][Medline]
  150. Van Wagoner DR. Mechanosensitive gating of atrial ATP-sensitive potassium channels. Circ Res. 1993;72:973–983[Abstract/Free Full Text]
  151. Furukawa T, Yamane T, Katayama Y. Functional linkage of the cardiac ATP-sensitive K channel to the actin cytoskeleton. Pflugers Arch. 1996;431:504–512[ISI][Medline]
  152. Greer J. Rational drug discovery. Conn PM, Means AR. Principles of Molecular Regulation. Totowa: Humana Press; 2000. p. 439–459
  153. Haverkamp W, Breithardt G, Camm AJ. The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: Clinical and regulatory implications. Report on a Policy Conference of the European Society of Cardiology. Eur Heart J. 2000;21:1216–1231[Free Full Text]
  154. Young K, Lin S, Sun L. Identification of a calcium channel modulator using a high throughput yeast two-hybrid screen. Nat Biotechnol. 1998;16:946–950[CrossRef][ISI][Medline]
  155. Shuker SB, Hajduk PJ, Meadows RP. Discovering high-affinity ligands for proteins: SAR by NMR. Science (Wash DC). 1996;274:1531–1534[Abstract/Free Full Text]
  156. Gordon EM, Kerwin JF. Combinatorial Chemistry and Molecular Diversity in Drug Discovery. New York: John Wiley & Sons; 1998.
  157. Doyle DA, Cabral JM, Pfuetzner RA. The structure of the potassium channel: molecular basis of K+conduction and selectivity. Science (Wash DC). 1998;280:69–77[Abstract/Free Full Text]
  158. Lipkind GM, Fozzard HA. KcsA crystal structure as framework for a molecular model of the Na+channel pore. Biochemistry. 2000;39:8161–8170[CrossRef][Medline]
  159. Rohl CA, Boeckman FA, Baker C. Solution structure of the sodium channel inactivation gate. Biochemistry. 1999;38:855–861[CrossRef][Medline]
  160. Kreusch A, Pfaffinger PJ, Stevens CF. Crystal structure of the tetramerization domain of the Shaker potassium channel. Nature. 1998;392:945–948[CrossRef][Medline]
  161. Zhou Z, Gong Q, January CT. Correction of defective protein trafficking of a mutant HERG potassium channel in human long QT syndrome. Pharmacological and temperature effects. J Biol Chem. 1999;274:31123–31126[Abstract/Free Full Text]
  162. January CT, Gong Q, Zhou Z. Long QT syndrome: cellular basis and arrhythmia mechanism in LQT2. J Cardiovasc Electrophysiol. 2000;11:1413–1418[CrossRef][ISI][Medline]
  163. Brahmajothi MV, Morales MJ, Liu S. In situ hybridization reveals extensive diversity of K channel mRNA in isolated ferret cardiac myocytes. Circ Res. 1996;78:1083–1089[Abstract/Free Full Text]
  164. Zhuang J, Yamada KA, Saffitz JE. Pulsatile stretch remodels cell-to-cell communication in cultured myocytes. Circ Res. 2000;87:316–322[Abstract/Free Full Text]
  165. Zhang H, Maldonado MN, Barchi RL. Dual tandem promoter elements containing CCAC-like motifs from the tetrodotoxin-resistant voltage-sensitive Na+channel (rSKM2) gene can independently drive muscle-specific transcription in L6 cells. Gene Expr. 1999;8:85–103[ISI][Medline]
  166. Shimoni Y, Fiset C, Clark RB. Thyroid hormone regulates postnatal expression of transient K+channel isoforms in rat ventricle. J Physiol (Lond). 1997;500:65–73[Abstract/Free Full Text]
  167. Nuss HB, Marban E, Johns DC. Overexpression of a human potassium channel suppresses cardiac hyperexcitability in rabbit ventricular myocytes. J Clin Invest. 1999;103:889–896[ISI][Medline]
  168. Hoppe UC, Marban E, Johns DC. Molecular dissection of cardiac repolarization by in vivo Kv4.3 gene transfer. J Clin Invest. 2000;105:1077–1084[ISI][Medline]
  169. Donahue JK, Heldman AW, Fraser H. Focal modification of electrical conduction in the heart by viral gene transfer. Nat Med. 2001;6:1395–1398[CrossRef][ISI]

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