Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 381, Issue 3, pp 187–193 | Cite as

Novel pharmacological approaches for antiarrhythmic therapy

EDITORIAL

Abstract

Arrhythmias are caused by the perturbation of physiological impulse formation, impaired conduction, or disturbed electrical recovery. Currently available antiarrhythmic drugs—perhaps with exception of amiodarone—are not sufficiently effective and are burdened by cardiac and extracardiac side effects that may offset their therapeutic benefits. Detailed knowledge about electrical and structural remodelling may provide a better understanding of the mechanisms leading to generation and maintenance of arrhythmias especially in the setting of underlying heart disease and accompanying autonomic dysfunction. Thus, targets for new pharmacological interventions could include atrial-selective ion channels (e.g. atrial INa, IKur and IK,ACh), pathology-selective ion channels (constitutively active IK,ACh, TRP channels), ischemia-uncoupled gap junctions, proteins related to malfunctioning intracellular Ca2+ homeostasis (e.g. “leaky” ryanodine receptors, overactive Na+,Ca2+ exchanger) or risk factors for arrhythmias (“upstream” therapies). In ventricular arrhythmias implantable cardioverter-defibrillator devices rather than antiarrhythmic drugs are the safest treatment option. The domain for new approaches to drug treatment is atrial fibrillation.

Keywords

Atrial and ventricular arrhythmia Electrical and structural remodelling Non-conventional cardiac ion channels 

Reference

  1. Antzelevitch C, Burashnikov A (2009) Atrial-selective sodium channel block as a novel strategy for the management of atrial fibrillation. J Electrocardiol 42:543–548CrossRefPubMedGoogle Scholar
  2. Ausma J, Wijffels M, Thone F, Wouters L, Allessie M, Borgers M (1997) Structural changes of atrial myocardium due to sustained atrial fibrillation in the goat. Circulation 96:3157–3163PubMedGoogle Scholar
  3. Bentzen BH, Andersen RW, Olesen SP, Grunnet M, Nardi A (2009) Synthesis and characterisation of NS13558: a new important tool for addressing KCa1.1 channel function ex vivo. Naunyn Schmiedebergs Arch Pharmacol. doi:10.1007/s00210-009-0456-2 PubMedGoogle Scholar
  4. Bers DM (2002) Cardiac excitation-contraction coupling. Nature 415:198–205CrossRefPubMedGoogle Scholar
  5. Bers DM, Despa S (2006) Cardiac myocytes Ca2+ and Na+ regulation in normal and failing hearts. J Pharmacol Sci 100:315–322CrossRefPubMedGoogle Scholar
  6. Bettoni M, Zimmermann M (2002) Autonomic tone variations before the onset of paroxysmal atrial fibrillation. Circulation 105:2753–2759CrossRefPubMedGoogle Scholar
  7. Bode F, Sachs F, Franz MR (2001) Tarantula peptide inhibits atrial fibrillation. Nature 409:35–36CrossRefPubMedGoogle Scholar
  8. Burashnikov A, Di Diego JM, Zygmunt AC, Belardinelli L, Antzelevitch C (2007) Atrium-selective sodium channel block as a strategy for suppression of atrial fibrillation: differences in sodium channel inactivation between atria and ventricles and the role of ranolazine. Circulation 116:1449–1457CrossRefPubMedGoogle Scholar
  9. Cha TJ, Ehrlich JR, Chartier D, Qi XY, Xiao L, Nattel S (2006) Kir3-based inward rectifier potassium current: potential role in atrial tachycardia remodeling effects on atrial repolarization and arrhythmias. Circulation 113:1730–1737CrossRefPubMedGoogle Scholar
  10. Christ T, Ravens U (2005) Do we need new antiarrhythmic compounds in the era of implantable cardiac devices and percutaneous ablation? Cardiovasc Res 68:341–343CrossRefPubMedGoogle Scholar
  11. Christ T, Wettwer E, Voigt N, Hala O, Radicke S, Matschke K, Varro A, Dobrev D, Ravens U (2008) Pathology-specific effects of the I(Kur)/I(to)/I(K, ACh) blocker AVE0118 on ion channels in human chronic atrial fibrillation. Br J Pharmacol 154:1619–1630CrossRefPubMedGoogle Scholar
  12. Clarke TC, Thomas D, Petersen JS, Evans WH, Martin PE (2006) The antiarrhythmic peptide rotigaptide (ZP123) increases gap junction intercellular communication in cardiac myocytes and HeLa cells expressing connexin 43. Br J Pharmacol 147:486–495CrossRefPubMedGoogle Scholar
  13. Dhein S, Hagen A, Jozwiak J, Dietze A, Garbade J, Barten M, Kostelka M, Mohr FW (2009) Improving cardiac gap junction communication as a new antiarrhythmic mechanism: the action of antiarrhythmic peptides. Naunyn Schmiedebergs Arch Pharmacol. doi:10.1007/s00210-009-0473-1 Google Scholar
  14. Dobrev D (2009) Atrial Ca(2+) signaling in atrial fibrillation as an antiarrhythmic drug target. Naunyn Schmiedebergs Arch Pharmacol. doi:10.1007/s00210-009-0457-1 Google Scholar
  15. Dobrev D, Friedrich A, Voigt N, Jost N, Wettwer E, Christ T, Knaut M, Ravens U (2005) The G protein-gated potassium current I(K, ACh) is constitutively active in patients with chronic atrial fibrillation. Circulation 112:3697–3706CrossRefPubMedGoogle Scholar
  16. Dobrev D, Nattel S (2008) Calcium handling abnormalities in atrial fibrillation as a target for innovative therapeutics. J Cardiovasc Pharmacol 52:293–299CrossRefPubMedGoogle Scholar
  17. Dobrev D, Ravens U (2003) Remodeling of cardiomyocyte ion channels in human atrial fibrillation. Basic Res Cardiol 98:137–148PubMedGoogle Scholar
  18. Dyachenko V, Husse B, Rueckschloss U, Isenberg G (2009) Mechanical deformation of ventricular myocytes modulates both TRPC6 and Kir2.3 channels. Cell Calcium 45:38–54CrossRefPubMedGoogle Scholar
  19. Easton JA, Petersen JS, Martin PE (2009) The anti-arrhythmic peptide AAP10 remodels Cx43 and Cx40 expression and function. Naunyn Schmiedebergs Arch Pharmacol 380:11–24CrossRefPubMedGoogle Scholar
  20. Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, Arensberg D, Baker A, Friedman L, Greene HL (1991) Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 324:781–788PubMedGoogle Scholar
  21. Ford JW, Milnes JT (2008) New drugs targeting the cardiac ultra-rapid delayed-rectifier current (I Kur): rationale, pharmacology and evidence for potential therapeutic value. J Cardiovasc Pharmacol 52:105–120CrossRefPubMedGoogle Scholar
  22. Gierten J, Ficker E, Bloehs R, Schlomer K, Kathofer S, Scholz E, Zitron E, Kiesecker C, Bauer A, Becker R, Katus HA, Karle CA, Thomas D (2008) Regulation of two-pore-domain (K2P) potassium leak channels by the tyrosine kinase inhibitor genistein. Br J Pharmacol 154:1680–1690CrossRefPubMedGoogle Scholar
  23. Gierten J, Ficker E, Bloehs R, Schweizer PA, Zitron E, Scholz E, Karle C, Katus HA, Thomas D (2009) The human cardiac K(2P)3.1 (TASK-1) potassium leak channel is a molecular target for the class III antiarrhythmic drug amiodarone. Naunyn Schmiedebergs Arch Pharmacol (in press)Google Scholar
  24. Goette A, Lendeckel U (2004) Nonchannel drug targets in atrial fibrillation. Pharmacol Ther 102:17–36CrossRefPubMedGoogle Scholar
  25. Goldstein SA, Bockenhauer D, O'Kelly I, Zilberberg N (2001) Potassium leak channels and the KCNK family of two-P-domain subunits. Nat Rev Neurosci 2:175–184CrossRefPubMedGoogle Scholar
  26. Guillemare E, Marion A, Nisato D, Gautier P (2000) Inhibitory effects of dronedarone on muscarinic K+ current in guinea pig atrial cells. J Cardiovasc Pharmacol 36:802–805CrossRefPubMedGoogle Scholar
  27. Guinamard R, Chatelier A, Demion M, Potreau D, Patri S, Rahmati M, Bois P (2004) Functional characterization of a Ca(2+)-activated non-selective cation channel in human atrial cardiomyocytes. J Physiol 558:75–83CrossRefPubMedGoogle Scholar
  28. Guinamard R, Demion M, Chatelier A, Bois P (2006) Calcium-activated nonselective cation channels in mammalian cardiomyocytes. Trends Cardiovasc Med 16:245–250CrossRefPubMedGoogle Scholar
  29. Jalife J (2000) Ventricular fibrillation: mechanisms of initiation and maintenance. Annu Rev Physiol 62:25–50CrossRefPubMedGoogle Scholar
  30. Janse MJ (2004) Electrophysiological changes in heart failure and their relationship to arrhythmogenesis. Cardiovasc Res 61:208–217CrossRefPubMedGoogle Scholar
  31. Jordaens L, Tavernier R, Gorgov N, Kindt H, Dimmer C, Clement DL (1998) Signal-averaged P wave: predictor of atrial fibrillation. J Cardiovasc Electrophysiol 9:S30–S34PubMedGoogle Scholar
  32. Jozwiak J, Dhein S (2008) Local effects and mechanisms of antiarrhythmic peptide AAP10 in acute regional myocardial ischemia: electrophysiological and molecular findings. Naunyn Schmiedebergs Arch Pharmacol 378:459–470CrossRefPubMedGoogle Scholar
  33. Kaab S, Dixon J, Duc J, Ashen D, Nabauer M, Beuckelmann DJ, Steinbeck G, McKinnon D, Tomaselli GF (1998) Molecular basis of transient outward potassium current downregulation in human heart failure: a decrease in Kv4.3 mRNA correlates with a reduction in current density. Circulation 98:1383–1393PubMedGoogle Scholar
  34. Kaufmann R, Theophile U (1967) Autonomously promoted extension effect in Purkinje fibers, papillary muscles and trabeculae carneae of rhesus monkeys. Pflugers Arch Gesamte Physiol Menschen Tiere 297:174–189CrossRefPubMedGoogle Scholar
  35. Koster OF, Szigeti GP, Beuckelmann DJ (1999) Characterization of a [Ca2+]i-dependent current in human atrial and ventricular cardiomyocytes in the absence of Na+ and K+. Cardiovasc Res 41:175–187CrossRefPubMedGoogle Scholar
  36. Kozlowski D, Budrejko S, Lip GY, Mikhailidis DP, Rysz J, Raczak G, Banach M (2009) Vernakalant hydrochloride for the treatment of atrial fibrillation. Expert Opin Investig Drugs 18:1929–1937CrossRefPubMedGoogle Scholar
  37. Ledoux J, Werner ME, Brayden JE, Nelson MT (2006) Calcium-activated potassium channels and the regulation of vascular tone. Physiology (Bethesda) 21:69–78Google Scholar
  38. Li D, Fareh S, Leung TK, Nattel S (1999) Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. Circulation 100:87–95PubMedGoogle Scholar
  39. Li N, Timofeyev V, Tuteja D, Xu D, Lu L, Zhang Q, Zhang Z, Singapuri A, Albert TR, Rajagopal AV, Bond CT, Periasamy M, Adelman J, Chiamvimonvat N (2009) Ablation of a Ca2+ -activated K+ channel (SK2 channel) results in action potential prolongation in atrial myocytes and atrial fibrillation. J Physiol 587:1087–1100CrossRefPubMedGoogle Scholar
  40. Liu L, Nattel S (1997) Differing sympathetic and vagal effects on atrial fibrillation in dogs: role of refractoriness heterogeneity. Am J Physiol 273:H805–H816PubMedGoogle Scholar
  41. 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 33:923–932CrossRefPubMedGoogle Scholar
  42. Miake J, Marban E, Nuss HB (2002) Biological pacemaker created by gene transfer. Nature 419:132–133CrossRefPubMedGoogle Scholar
  43. Miake J, Marban E, Nuss HB (2003) Functional role of inward rectifier current in heart probed by Kir2.1 overexpression and dominant-negative suppression. J Clin Invest 111:1529–1536PubMedGoogle Scholar
  44. Nattel S (2002) New ideas about atrial fibrillation 50 years on. Nature 415:219–226CrossRefPubMedGoogle Scholar
  45. Nattel S (2009) Calcium-activated potassium current: a novel ion channel candidate in atrial fibrillation. J Physiol 587:1385–1386CrossRefPubMedGoogle Scholar
  46. Nattel S, Burstein B, Dobrev D (2008) Atrial remodeling and atrial fibrillation: mechanisms and implications. Circ Arrhythm Electrophysiol 1:62–73CrossRefPubMedGoogle Scholar
  47. Nishida M, Kurose H (2008) Roles of TRP channels in the development of cardiac hypertrophy. Naunyn Schmiedebergs Arch Pharmacol 378:395–406CrossRefPubMedGoogle Scholar
  48. Olson TM, Alekseev AE, Liu XK, Park S, Zingman LV, Bienengraeber M, Sattiraju S, Ballew JD, Jahangir A, Terzic A (2006) Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation. Hum Mol Genet 15:2185–2191CrossRefPubMedGoogle Scholar
  49. Ozgen N, Dun W, Sosunov EA, Anyukhovsky EP, Hirose M, Duffy HS, Boyden PA, Rosen MR (2007) Early electrical remodeling in rabbit pulmonary vein results from trafficking of intracellular SK2 channels to membrane sites. Cardiovasc Res 75:758–769CrossRefPubMedGoogle Scholar
  50. Pandit SV, Berenfeld O, Anumonwo JM, Zaritski RM, Kneller J, Nattel S, Jalife J (2005) Ionic determinants of functional reentry in a 2-D model of human atrial cells during simulated chronic atrial fibrillation. Biophys J 88:3806–3821CrossRefPubMedGoogle Scholar
  51. Patel C, Yan GX, Kowey PR (2009) Dronedarone. Circulation 120:636–644CrossRefPubMedGoogle Scholar
  52. Putzke C, Wemhoner K, Sachse FB, Rinne S, Schlichthorl G, Li XT, Jae L, Eckhardt I, Wischmeyer E, Wulf H, Preisig-Muller R, Daut J, Decher N (2007) The acid-sensitive potassium channel TASK-1 in rat cardiac muscle. Cardiovasc Res 75:59–68CrossRefPubMedGoogle Scholar
  53. Ravens U, Cerbai E (2008) Role of potassium currents in cardiac arrhythmias. Europace 10:1133–1137CrossRefPubMedGoogle Scholar
  54. Sanguinetti MC, Tristani-Firouzi M (2006) hERG potassium channels and cardiac arrhythmia. Nature 440:463–469CrossRefPubMedGoogle Scholar
  55. Savelieva I, Camm J (2007) Is there any hope for angiotensin-converting enzyme inhibitors in atrial fibrillation? Am Heart J 154:403–406CrossRefPubMedGoogle Scholar
  56. Savelieva I, Camm J (2008) Anti-arrhythmic drug therapy for atrial fibrillation: current anti-arrhythmic drugs, investigational agents, and innovative approaches. Europace 10:647–665CrossRefPubMedGoogle Scholar
  57. Savelieva I, Kourliouros A, Camm J (2009) Primary and secondary prevention of atrial fibrillation with statins and polyunsaturated fatty acids: review of evidence and clinical relevance. Naunyn Schmiedebergs Arch Pharmacol (in press)Google Scholar
  58. Seebohm G (2005) Activators of cation channels: potential in treatment of channelopathies. Mol Pharmacol 67:585–588CrossRefPubMedGoogle Scholar
  59. Shiroshita-Takeshita A, Sakabe M, Haugan K, Hennan JK, Nattel S (2007) Model-dependent effects of the gap junction conduction-enhancing antiarrhythmic peptide rotigaptide (ZP123) on experimental atrial fibrillation in dogs. Circulation 115:310–318CrossRefPubMedGoogle Scholar
  60. Tomaselli GF, Beuckelmann DJ, Calkins HG, Berger RD, Kessler PD, Lawrence JH, Kass D, Feldman AM, Marban E (1994) Sudden cardiac death in heart failure. The role of abnormal repolarization. Circulation 90:2534–2539PubMedGoogle Scholar
  61. Tsang TS, Miyasaka Y, Barnes ME, Gersh BJ (2005) Epidemiological profile of atrial fibrillation: a contemporary perspective. Prog Cardiovasc Dis 48:1–8CrossRefPubMedGoogle Scholar
  62. 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 1):S169–S177CrossRefPubMedGoogle Scholar
  63. Valdivia CR, Chu WW, Pu J, Foell JD, Haworth RA, Wolff MR, Kamp TJ, Makielski JC (2005) Increased late sodium current in myocytes from a canine heart failure model and from failing human heart. J Mol Cell Cardiol 38:475–483Google Scholar
  64. Van Wagoner DR, Voigt N, Bunnell B, Barnard J, Schotten U, Nattel S, Ravens U, Dobrev D (2009) Transient receptor potential canonical (TRPC) channel subunit remodeling in clinical and experimental AF. Heart Rhythm AbstractPO06-77Google Scholar
  65. Vaquero M, Calvo D, Jalife J (2008) Cardiac fibrillation: from ion channels to rotors in the human heart. Heart Rhythm 5:872–879CrossRefPubMedGoogle Scholar
  66. Vassort G, Alvarez J (2009) Transient receptor potential: a large family of new channels of which several are involved in cardiac arrhythmia. Can J Physiol Pharmacol 87:100–107CrossRefPubMedGoogle Scholar
  67. Vest JA, Wehrens XH, Reiken SR, Lehnart SE, Dobrev D, Chandra P, Danilo P, Ravens U, Rosen MR, Marks AR (2005) Defective cardiac ryanodine receptor regulation during atrial fibrillation. Circulation 111:2025–2032CrossRefPubMedGoogle Scholar
  68. Voigt N, Friedrich A, Bock M, Wettwer E, Christ T, Knaut M, Strasser RH, Ravens U, Dobrev D (2007) Differential phosphorylation-dependent regulation of constitutively active and muscarinic receptor-activated IK, ACh channels in patients with chronic atrial fibrillation. Cardiovasc Res 74:426–437CrossRefPubMedGoogle Scholar
  69. Voigt N, Rozmaritsa N, Trausch A, Zimniak T, Christ T, Wettwer E, Matschke K, Dobrev D, Ravens U (2009) Inhibition of I(K, ACh) current may contribute to clinical efficacy of class I and class III antiarrhythmic drugs in patients with atrial fibrillation. Naunyn Schmiedebergs Arch Pharmacol. doi:10.1007/s00210-009-0452-6 PubMedGoogle Scholar
  70. Watanabe H, Murakami M, Ohba T, Ono K, Ito H (2009) The pathological role of transient receptor potential channels in heart disease. Circ J 73:419–427CrossRefPubMedGoogle Scholar
  71. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA (1995) Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation 92:1954–1968PubMedGoogle Scholar
  72. Workman AJ (2009) Cardiac adrenergic control and atrial fibrillation. Naunyn Schmiedebergs Arch Pharmacol. doi:10.1007/s00210-009-0474-0 PubMedGoogle Scholar
  73. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, Kellen JC, Greene HL, Mickel MC, Dalquist JE, Corley SD (2002) A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 347:1825–1833PubMedCrossRefGoogle Scholar
  74. Xu W, Liu Y, Wang S, McDonald T, Van Eyk JE, Sidor A, O'Rourke B (2002) Cytoprotective role of Ca2+-activated K+ channels in the cardiac inner mitochondrial membrane. Science 298:1029–1033CrossRefPubMedGoogle Scholar
  75. Xu Y, Tuteja D, Zhang Z, Xu D, Zhang Y, Rodriguez J, Nie L, Tuxson HR, Young JN, Glatter KA, Vazquez AE, Yamoah EN, Chiamvimonvat N (2003) Molecular identification and functional roles of a Ca(2+)-activated K+ channel in human and mouse hearts. J Biol Chem 278:49085–49094CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Department of Pharmacology and ToxicologyMedical Faculty Carl Gustav Carus, Dresden University of TechnologyDresdenGermany

Personalised recommendations