Electrophysiological effects of flecainide and sotalol in the human atrium during persistent atrial fibrillation
- 121 Downloads
Atrial fibrillation (AF) shortens the atrial action potential and the atrial refractory period. These changes promote persistence of AF. Pharmacological prolongation of atrial action potential duration (APD) may therefore help to prevent recurrent AF. In addition to prolonging APD, sodium channel blockers may prevent AF by inducing post–repolarization refractoriness (PRR). We studied whether two antiarrhythmic drugs (sotalol, flecainide) prolong APD or induce PRR in the fibrillating human atrium.
In 12 patients with persistent AF (11 male, 58 ± 5 yrs, 27 ± 7 months duration of AF), we recorded monophasic action potentials from the right atrial appendage and inferior right atrium at baseline and 15 minutes after intravenous administration of sotalol (1.5 mg/kg) or flecainide (2 mg/kg). APD and effective refractory periods (ERP) were determined.
Both drugs prolonged APD90 during AF (flecainide from 109 ± 7 ms to 137 ± 10 ms, sotalol from 108 ± 6 ms to 131 ± 8 ms, both p < 0.05 vs. baseline). Sotalol prolonged ERP in parallel to APD (from 119 ± 8 ms to 139 ± 8 ms, p < 0.05). Flecainide induced PRR by prolonging ERP more than APD90 (from 134 ± 9 ms to 197 ± 28 ms, p < 0.05 vs. baseline and vs. sotalol).
Flecainide and sotalol prolong the atrial action potential during atrial fibrillation in humans. In addition, flecainide induces atrial PRR. These electrophysiological effects may reduce AF recurrences and prevent their persistence.
Key wordsAtrial fibrillation antiarrhythmic agents action potential refractoriness human pharmacology electrophysiology
Action Potential Duration
Effective Refractory Period
Monophasic Action Potential
Unable to display preview. Download preview PDF.
- 1.AFFIRM Investigators (2002) A comparison of rate control and rhythm control in patients with atrial .brillation. N Engl J Med 347:1825–1833Google Scholar
- 2.Bode F, Kilborn M, Karasik P, Franz MR (2001) The repolarization-excitability relationship in the human right atrium is unaffected by cycle length, recording site and prior arrhythmias. J Am Coll Cardiol 37:920–925Google Scholar
- 3.Bosch RF, Scherer CR, Rüb N, Wöhrl S, Steinmeyer K, Haase H, Busch AE, Seipel L, Kuhlkamp V (2003) Molecular mechanisms of early electrical remodeling: transcriptional downregulation of ion channel subunits reduces I(Ca,L) and I(to) in rapid atrial pacing in rabbits. J Am Coll Cardiol 41:858–869Google Scholar
- 5.Fabritz L, Kirchhof P, Franz MR, Eckardt L, Mönnig G, Milberg P, Breithardt G, Haverkamp W (2003) Prolonged action potential durations, increased dispersion of repolarization, and polymorphic ventricular tachycardia in a mouse model of proarrhythmia. Basic Res Cardiol 98:25–32Google Scholar
- 7.Fuster V, Ryden LE, Asinger RW, Cannom DS, Crijns HJ, Frye RL, Halperin JL, Kay GN, Klein WW, Levy S, McNamara RL, Prystowsky EN, Wann LS, Wyse DG (2001) ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to develop guidelines for the management of patients with atrial fibrillation) developed in collaboration with the North American Society of Pacing and Electrophysiology. Eur Heart J 22:1852–1923CrossRefPubMedGoogle Scholar
- 8.Hobbs WJ, Fynn S, Todd DM, Wolfson P, Galloway M, Garratt CJ (2000) Reversal of atrial electrical remodeling after cardioversion of persistent atrial fibrillation in humans. Circulation 101:1145–1151Google Scholar
- 9.Kirchhof P, Degen H, Franz M, Eckardt L, Fabritz L, Milberg P, Laer S, Neumann J, Breithardt G, Haverkamp W (2003) Amiodarone-induced post-repolarization refractoriness suppresses induction of ventricular fibrillation. J Pharmacol Exp Ther 305:257–263Google Scholar
- 10.Kirchhof P, Eckardt L, Franz MR, Mönnig G, Loh P, Wedekind H, Schulze-Bahr E, Breithardt G, Haverkamp W (2003) Prolonged atrial action potential durations and polymorphic atrial tachyarrhythmias in patients with long QT syndrome. J Cardiovasc Electrophysiol 14:1027–1033Google Scholar
- 11.Kirchhof P, Eckardt L, Loh P, Weber K, Fischer RJ, Seidl KH, Böcker D, Breithardt G, Haverkamp W, Borggrefe M (2002) Anterior-posterior versus anterior-lateral electrode positions for external cardioversion of atrial fibrillation: a randomised trial. Lancet 360:1275–1279Google Scholar
- 12.Kirchhof P, Fabritz L, Franz MR (1998) Post-repolarization refractoriness versus conduction slowing caused by class I antiarrhythmic drugs – antiarrhythmic and proarrhythmic effects. Circulation 97:2567–2574Google Scholar
- 13.Koller BS, Karasik PE, Solomon AJ, Franz MR (1995) Relation between repolarization and refractoriness during programmed electrical stimulation in the human right ventricle. Implications for ventricular tachycardia induction. Circulation 91:2378–2384Google Scholar
- 14.Madrid AH, Moro C, Marin Huerta E, Mestre JL, Novo L, Costa A (1993) Comparison of flecainide and procainamide in cardioversion of atrial fibrillation. Eur Heart J 14:1127–1131Google Scholar
- 15.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 33:923–932Google Scholar
- 16.Mandapati R, Skanes A, Chen J, Berenfeld O, Jalife J (2000) Stable microreentrant sources as a mechanism of atrial fibrillation in the isolated sheep heart. Circulation 101:194–199Google Scholar
- 18.Martin CL, Palomo MA, McMahon EG (1996) Comparison of bidisomide, flecainide and dofetilide on action potential duration in isolated canine atria: effect of isoproterenol. J Pharmacol Exp Ther 278:154–162Google Scholar
- 19.Maruyama T, Richardson LC, Sun W, McCarthy JJ, Gettes LS (1995) Acute effects of amiodarone on membrane properties, refractoriness, and conduction in guinea pig papillary muscles. Heart Vessels 10:78–86Google Scholar
- 20.Mittal S, Ayati S, Stein KM, Schwartzman D, Cavlovich D, Tchou PJ, Markowitz SM, Slotwiner DJ, Scheiner MA, Lerman BB (2000) Transthoracic cardioversion of atrial fibrillation: comparison of rectilinear biphasic versus damped sine wave monophasic shocks. Circulation 101:1282–1287Google Scholar
- 21.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 57:101–107Google Scholar
- 22.Nattel S (2002) New ideas about atrial fibrillation 50 years on. Nature 415:219–226Google Scholar
- 23.Osaka T, Yamazaki M, Yokoyama E, Ito A, Kodama I (2004) Sotalol reverses remodeled action potential in patients with chronic atrial fibrillation but does not prevent arrhythmia recurrence. J Cardiovasc Electrophysiol 15:877–884Google Scholar
- 24.Pandozi C, Bianconi L, Villani M, Castro A, Altamura G, Toscano S, Jesi AP, Gentilucci G, Ammirati F, Lo Bianco F, Santini M (1997) Local capture by atrial pacing in spontaneous chronic atrial fibrillation. Circulation 95:2416–2422Google Scholar
- 25.Reisinger J, Gatterer E, Lang W, Vanicek T, Eisserer G, Bachleitner T, Niemeth C, Aicher F, Grander W, Heinze G, Kuhn P, Siostrzonek P (2004) Flecainide versus ibutilide for immediate cardioversion of atrial fibrillation of recent onset atrial fibrillation. Eur Heart J 25:1318–1324Google Scholar
- 26.Schotten U, Greiser M, Benke D, Buerkel K, Ehrenteidt B, Stellbrink C, Vazquez-Jimenez JF, Schoendube F, Hanrath P, Allessie M (2002) Atrial fibrillationinduced atrial contractile dysfunction: a tachycardiomyopathy of a different sort. Cardiovasc Res 53:192–201Google Scholar
- 27.Schumacher B, Jung W, Lewalter T, Vahlhaus C, Wolpert C, Luderitz B (1999) Radiofrequency ablation of atrial flutter due to administration of class IC antiarrhythmic drugs for atrial fibrillation. Am J Cardiol 83:710–713Google Scholar
- 28.Stabile G, De Simone A, Turco P, La Rocca V, Nocerino P, Astarita C, Maresca F, De Matteis C, Di Napoli T, Stabile E, Vitale DF (2001) Response to flecainide infusion predicts long-term success of hybrid pharmacologic and ablation therapy in patients with atrial fibrillation. J Am Coll Cardiol 37:1639–1644Google Scholar
- 29.Stambler BS, Wood MA, Ellenbogen KA (1997) Antiarrhythmic actions of intravenous ibutilide compared with procainamide during human atrial flutter and fibrillation: electrophysiological determinants of enhanced conversion efficacy. Circulation 96:4298–4306Google Scholar
- 32.Wijffels MC, Dorland R, Mast F, Allessie MA (2000) Widening of the excitable gap during pharmacological cardioversion of atrial fibrillation in the goat: effects of cibenzoline, hydroquinidine, flecainide, and d-sotalol. Circulation 102:260–267Google Scholar
- 33.Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA (1995) Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation 92:1954–1968Google Scholar
- 34.Wijffels MC, Kirchhof CJ, Dorland R, Power J, Allessie MA (1997) Electrical remodeling due to atrial fibrillation in chronically instrumented conscious goats: roles of neurohumoral changes, ischemia, atrial stretch, and high rate of electrical activation. Circulation 96:3710–3720Google Scholar