Recent Advances in the Development of Selective Anti-Atrial Fibrillation Drugs

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Asia Pacific Cardiology - Volume 1 Issue 1;2007:1(1):52-53


Atrial fibrillation (AF) is the most common cardiac arrhythmia and the occurrence of AF increases with age. The prevalence of AF rises from 0.5% in people in their 50s to 5% in people over the age of 65 years. This rises to nearly 10% in the octogenarian population.1 AF is a major cause of morbidity and mortality, increasing the risk of death, congestive heart failure (CHF) and embolic phenomena, including stroke.1 It is believed that AF is a lifetime risk in the ageing population2 and it is emerging as a major public health concern.3 The management of AF includes surgery, ablation4,5 and pharmacological therapies.6 However, only some cases are amenable to surgical or ablative therapies, and most of them require antiarrhythmic drug treatment.6 Over the years, delayed rectifier K+ currents (IK), especially the rapidly-activating IK (IKr, encoded by hERG, ether-a-go-go gene), have been important targets for antiarrhythmic drugs. Blockade of these ion channels (class III antiarrhythmic drugs) leads to a prolongation of atrial and ventricular action potential duration (APD) and the refractory period, which is the desired antiarrhythmic effect.7,8 However, prolongation of ventricular repolarisation causes a prolongation of the QT interval and an increased propensity for life-threatening ventricular arrhythmias.9 Therefore, there is a clear need to develop new drugs that may act mainly on electrical activity in the atrium of the human heart to prevent or treat AF.

Ion Channel Currents in the Atrium and Ventricle of the Human Heart

It is well-known that human cardiac APD and the refractory period generally depend on the balance of inward and outward currents in atrial and ventricular myocytes (see Figure 1). Inward currents include the Na+ current (INa) and L-type Ca2+ current (ICa.L), and outward currents include the transient outward K+ current (Ito), IKr and slowly-activating delayed rectifier K+ current (IKs) and inward rectifier K+ current (IK1). In general, INa channel activation depolarises cell membrane and initiates action potential (phase 0), then Ito activation forms a fast repolarisation (phase 1). Activation of ICa.L maintains the plateau of the action potential (phase 2); IKr and IKs gradually activate and induce slow repolarisation during phase 2. Finally, activation of IK1 channels induces final repolarisation (phase 3) and maintains resting membrane potential (phase 4). The electrogenic Na+–Ca2+ exchanger mainly carries an inward current and also plays a role in maintaining the plateau of cardiac action potential.


  1. Stewart S, Hart CL, et al., Am J Med, 2002;113:359–64.
  2. Lloyd-Jones DM, Wang TJ, Leip EP, et al., Circulation, 2004;110:1042–6.
  3. Braunwald E, N Engl J Med, 1997;337:1360–69.
  4. Jahangiri M, Weir G, et al., Ann Thorac Surg, 2006;82:357–64.
  5. Riley MJ, Marrouche NF, Curr Probl Cardiol, 2006;31:361–90.
  6. Nattel S, Khairy P, Roy D, et al., Drugs, 2002;62:2377–97.
  7. Sharma PP, Sarma JS, Singh BN, J Cardiovasc Pharmacol Ther, 1999;4:15–21.
  8. Nattel S, Singh BN, Am J Cardiol, 1999;84:11–19R.
  9. Roden DM, Anderson ME, Handb Exp Pharmacol, 2006;73–97.
  10. Wang Z, Fermini B, Nattel S, Cardiovasc Res, 1994;28:1540–46.
  11. Li GR, Feng J, Yue L, et al., Circ Res, 1996;78:689–96.
  12. Bosch RF, et al., Cardiovasc Res, 1999;44:121–31.
  13. Shi H, Wang H, et al., Cell Physiol Biochem, 2004;14:31–40.
  14. Peukert S, Brendel J, Pirard B, et al., J Med Chem, 2003;46:486–98.
  15. Pecini R, Elming H, Pedersen OD, et al., Expert Opin Emerg Drugs, 2005;10:311–22.
  16. Bachmann A, Gutcher I, Kopp K, et al., Naunyn Schmiedebergs Arch Pharmacol, 2001;364:472–8.
  17. Knobloch K, Brendel J, Peukert S, et al., Naunyn Schmiedebergs Arch Pharmacol, 2002;366:482–7.
  18. Pirard B, Brendel J, Peukert S, J Chem Inf Model, 2005;45:477–85.
  19. Gogelein H, Brendel J, Steinmeyer K, et al., Naunyn Schmiedebergs Arch Pharmacol, 2004;370:183–92.
  20. Wirth KJ, Paehler T, Rosenstein B, et al., Cardiovasc Res, 2003;60:298–306.
  21. Blaauw Y, Gogelein H, et al., Circulation, 2004;110:1717–24.
  22. Matsuda T, Masumiya H, et al., Life Sci, 2001;68:2017–24.
  23. Seki A, et al., J Cardiovasc Pharmacol, 2002;9:29–38.
  24. Matsuda T, et al., J Pharmacol Sci, 2006;101:303–10.
  25. Nagasawa H, Fujiki A, et al., Circ J, 2002;66:185–191.
  26. Lagrutta A, Wang J, et al., J Pharmacol Exp Ther, 2006;317:1054–63.
  27. Regan CP, et al., J Pharmacol Exp Ther, 2006;316:727–32.
  28. Stump GL, et al., J Pharmacol Exp Ther, 2005;315:1362–7.
  29. Li GR, CardioRhythm – Hong Kong Proceedings, 2007; abstract 10.
  30. Li GR, Qin GW, et al., Prog Clin Biol Res, 1988;280:29–44.
  32. Liu ZQ, Luo XY, Sun YX, et al., J Pharm Pharmacol, 2004;56:1557–62.
  33. Kneller J, Kalifa J, Zou R, et al., Circ Res, 2005;96:e35–47.
  34. Fedida D, et al., J Cardiovasc Electrophysiol, 2005;16:1227–38.
  35. Roy D, et al., J Am Coll Cardiol, 2004;44:2355–61.
  36. Persson F, Carlsson L, Duker G, et al., J Cardiovasc Electrophysiol, 2005;16:329–41.
  37. Goldstein RN, et al., J Cardiovasc Electrophysiol, 2004;15:1444–50.
  38. Crijns HJ, Van Gelder IC, et al., Heart Rhythm, 2006;3:1321–31.