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Does the postrepolarization refractoriness play a role in amiodarone's antiarrhythmic efficacy?
EDITORIAL COMMENTARY
Does the postrepolarization refractoriness play a role in amiodarone’s antiarrhythmic efficacy? Vadim V. Fedorov, PhD From the Department of Biomedical Engineering, Washington University, St. Louis, Missouri. Amiodarone is one of the most effective antiarrhythmic drugs for the treatment of atrial fibrillation (AF)1 and lifethreatening ventricular tachyarrhythmias.2 However, the clinical value of amiodarone is limited by a wide range of side effects.3 The drug blocks many cardiac outward and inward ion currents as well as muscarinic and adrenergic receptors.4 It has numerous effects on cardiac electrophysiology, including an increase in action potential duration (APD), increase in effective refractory period (ERP), and conduction slowing both in working myocardium and the pacemaker/conduction system.4 Chronic amiodarone treatment also induces indirect cardiac effects because of the drug’s two iodine atoms, which can induce hypothyroid-like conditions. Despite more than 3 decades of intensive research5 and clinical application,6 the precise electrophysiologic mechanisms of the high antiarrhythmic efficacy of the drug in different models are not well understood and still debatable. Animal studies have shown that amiodarone can induce prolonged refractoriness beyond repolarization, an effect that has been called postrepolarization refractoriness (PRR).7 The drug’s effects can be explained by a block of the inactivated cardiac sodium channels.8 The lack of a full recovery of sodium channels during the interpulse interval can cause a mild subsequent prolongation of the ERP relative to the APD (ERP/APD90 ratio ⬎1 represents PRR). Many studies have shown that PRR can be induced by different antiarrhythmic drugs with sodium channel blocking properties.9 –11 It was proposed that PRR without significant conduction slowing is a desirable feature for drugs designed to prevent ventricular arrhythmias.7 Interestingly, this antiarrhythmic mechanism was naturally developed for extreme winter conditions experienced by hibernating mammals. Recently, our group showed that hibernation-induced PRR may prevent the slowing of conduction during fast pacing and ventricular tachyarrhythmia induction.12 Kirchhof et al11 showed that PRR induced by sodium channel blockers can prevent induction of ventricular fibrilAddress reprint requests and correspondence: Dr. Vadim V. Fedorov, Department of Biomedical Engineering, Washington University, Campus Box 1097, One Brookings Drive, St. Louis, Missouri 63130-4899. E-mail address: [email protected].
lation. However, if this effect is offset by conduction slowing, it can facilitate induction of monomorphic ventricular tachycardias. Later, Kirchhof et al7 proposed that the high antiarrhythmic efficacy of chronic amiodarone can be explained by the development of PRR without significant conduction slowing. They showed in the rabbit model that chronic amiodarone treatment (6 weeks, 50 mg/kg/day) prolonged ventricular ERP more than monophasic APD, resulting in PRR without much conduction slowing, thereby curtailing the initial part of APD restitution. Antzelevitch’s group introduced an exciting new strategy for suppression of AF: selectively blocking of sodium channels in the atria by using differences in sodium channel inactivation and action potential configuration between the atria and ventricles.13 They found that some drugs (ranolazine, lidocaine) can induce development of PRR primarily in the atria, which can be important for treatment of AF. In this issue of Heart Rhythm, Burashnikov et al14 present data that chronic amiodarone (6 weeks, 40 mg/kg/day) also has potent atrial-predominant effects in depressing sodium channel-mediated parameters, in increasing APD, and in the development of PRR primarily in atria and less in ventricle. They used microelectrodes to study the chronic effects of amiodarone on action potential morphologies and refractoriness of “healthy” coronary-perfused canine atrial and ventricular isolated preparations. Burashnikov et al14 proposed that predominant atrial-selective effects on repolarization and refractoriness related with synergetic action of the drug on IKr and INa could contribute to amiodarone’s effectiveness in suppressing AF. From a research standpoint, these findings may offer new clues to the mechanisms underlying the high efficacy of chronic amiodarone against AF and potentially motivate novel research directions for the development of new antiarrhythmic drugs. Burashnikov et al14 used an acetylcholine-mediated AF model in which they clearly demonstrated the high efficacy of chronic amiodarone. However, they could not precisely investigate the antiarrhythmic mechanism of the drug in this model because of the absence of mapping techniques. Moreover, the antiarrhythmic effects of amiodarone in acetylcholine-mediated AF models also could be explained by its inhibition of IKACh current in atria.15,16 Consequently, more studies are needed to investigate precisely the antiarrhyth-
1547-5271/$ -see front matter. Published by Elsevier Inc. on behalf of the Heart Rhythm Society.
doi:10.1016/j.hrthm.2008.09.032
1744 mic effects of chronic amiodarone and to estimate the role of atrial PRR in remodeled atria. Canine studies by Shinagawa et al17 and Ashikaga et al18 demonstrated that amiodarone can reverse or prevent electrical (ERP shortening and conduction slowing), biochemical (downregulation Ltype Ca2⫹ channel), and structural (interstitial fibrosis) arrhythmogenic remodeling induced by atrial tachycardia during 7 days and 4 weeks, respectively. Thus, inhibition of atrial tachycardia remodeling may contribute to amiodarone’s high efficacy in preventing recurrence of persistent AF. It is well known that some phenomena experimentally observed in animals cannot always be observed in the remodeled human heart.19 Clinical electrophysiologic studies of chronic amiodarone treatment did not demonstrate significant atrial-selective drug effects on refractoriness and monophasic APD in the atria versus the ventricle.3,19 –22 Sager et al21 showed that chronic amiodarone does not exert frequency-dependent effects on ventricular repolarization; it prolongs right ventricular ERP by 15% to 20% and exerts frequency-dependent effects on ventricular conduction (up to 40% increase of QRS). Moreover, the drug significantly increased the right ventricular ERP/APD90 ratio compared with baseline, consistent with greater prolongation of refractoriness than repolarization. However, the ERP/APD90 ratio was not ⬎1 at different pacing cycle lengths (from 300 to 600 ms) in this human study compared with PRR results from the rabbit study by Kirchhof et al.7 Although the study by Burashnikov et al14 clearly demonstrated development of PRR in canine atria, PRR was not observed after cardioversion of persistent AF in amiodarone-treated patients.22 Pandozi et al19,22 found that right atrial ERPs were longer (approximately 5%–10%) in amiodarone-treated patients than in washout patients as well as monophasic APD90 after sinus rhythm restoration. The ERP/APD90 ratio was similar and always ⬍1 at all pacing cycle lengths in both washout and amiodarone groups. These divergent effects of chronic amiodarone on cardiac electrophysiologic parameters in different studies can be explained by different ionic currents responsible for the action potential in diseased human hearts and “healthy” or remodeled animal cardiac preparations as well as different experimental conditions and protocols. Amiodarone has a complex and wide spectrum of direct and indirect effects on the cardiac physiology, which makes its study very complicated.4 It also means that we need to exercise caution when translating results from animal models to clinical situations. In order to more precisely evaluate the antiarrhythmic mechanisms of “old” drugs such as amiodarone as well as new developing drugs, we strongly suggest the use of explanted human hearts instead of cardiac animal preparations and high-resolution optical mapping to directly characterize the drugs’ effects on human cardiac electrophysiology.23,24
Heart Rhythm, Vol 5, No 12, December 2008
References 1. Singh BN, Singh SN, Reda DJ, et al. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 2005;352:1861–1872. 2. Mark DB, Anstrom KJ, Sun JL, et al. Quality of life with defibrillator therapy or amiodarone in heart failure. N Engl J Med 2008;359:999 –1008. 3. Zipes DP, Prystowsky EN, Heger JJ. Amiodarone: electrophysiologic actions, pharmacokinetics and clinical effects. J Am Coll Cardiol 1984;3:1059 –1071. 4. Kodama I, Kamiya K, Toyama J. Amiodarone: ionic and cellular mechanisms of action of the most promising class III agent. Am J Cardiol 1999;84:20R–28R. 5. Singh BN, Vaughan Williams EM. The effect of amiodarone, a new anti-anginal drug, on cardiac muscle. Br J Pharmacol 1970;39:657– 667. 6. Rosenbaum MB, Chiale PA, Halpern MS, et al. Clinical efficacy of amiodarone as an antiarrhythmic agent. Am J Cardiol 1976;38:934 –944. 7. Kirchhof P, Degen H, Franz MR, et al. Amiodarone-induced postrepolarization refractoriness suppresses induction of ventricular fibrillation. J Pharmacol Exp Ther 2003;305:257–263. 8. Mason JW, Hondeghem LM, Katzung BG. Amiodarone blocks inactivated cardiac sodium channels. Pflugers Arch 1983;396:79 – 81. 9. Lee RJ, Liem LB, Cohen TJ, et al. Relation between repolarization and refractoriness in the human ventricle: cycle length dependence and effect of procainamide. J Am Coll Cardiol 1992;19:614 – 618. 10. Haberman RJ, Rials SJ, Stohler JL, et al. Evidence for a reexcitability gap in man after treatment with type I antiarrhythmic drugs. Am Heart J 1993;126: 1121–1126. 11. Kirchhof PF, Fabritz CL, Franz MR. Postrepolarization refractoriness versus conduction slowing caused by class I antiarrhythmic drugs: antiarrhythmic and proarrhythmic effects. Circulation 1998;97:2567–2574. 12. Fedorov VV, Glukhov A, Sudharshan S, et al. Electrophysiological mechanisms of antiarrhythmic protection during hypothermia in winter hibernating versus nonhibernating mammals. Heart Rhythm 2008;5:1587–1596. 13. Burashnikov A, Di Diego JM, Zygmunt AC, et al. 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 2007;116:1449 –1457. 14. Burashnikov A, Di Diego JM, Sicouri S, et al. Atrial-selective effects of chronic amiodarone in the management of atrial fibrillation. Heart Rhythm 2008;5: 1735–1742. 15. Watanabe Y, Hara Y, Tamagawa M, et al. Inhibitory effect of amiodarone on the muscarinic acetylcholine receptor-operated potassium current in guinea pig atrial cells. J Pharmacol Exp Ther 1996;279:617– 624. 16. Huang CX, Zhao QY, Liang JJ, et al. Differential densities of muscarinic acetylcholine receptor and I(K,ACh) in canine supraventricular tissues and the effect of amiodarone on cholinergic atrial fibrillation and I(K,ACh). Cardiology 2006;106:36 – 43. 17. Shinagawa K, Shiroshita-Takeshita A, Schram G, et al. Effects of antiarrhythmic drugs on fibrillation in the remodeled atrium: insights into the mechanism of the superior efficacy of amiodarone. Circulation 2003;107:1440 –1446. 18. Ashikaga K, Kobayashi T, Kimura M, et al. Effects of amiodarone on electrical and structural remodeling induced in a canine rapid pacing-induced persistent atrial fibrillation model. Eur J Pharmacol 2006;536:148 –153. 19. Pandozi C, Bianconi L, Villani M, et al. Electrophysiological characteristics of the human atria after cardioversion of persistent atrial fibrillation. Circulation 1998;98:2860 –2865. 20. Wellens HJ, Brugada P, Abdollah H, et al. A comparison of the electrophysiologic effects of intravenous and oral amiodarone in the same patient. Circulation 1984;69:120 –124. 21. Sager PT, Uppal P, Follmer C, et al. Frequency-dependent electrophysiologic effects of amiodarone in humans. Circulation 1993;88:1063–1071. 22. Pandozi C, Gentilucci G, Calo L, et al. Relations between monophasic action potential duration and refractoriness after cardioversion of persistent atrial fibrillation: results in wash-out and amiodarone-treated patients. Ital Heart J 2003;4:257–263. 23. Hucker WJ, Fedorov VV, Foyil KV, et al. Images in cardiovascular medicine. Optical mapping of the human atrioventricular junction. Circulation 2008;117: 1474 –1477. 24. Fedorov VV, Hucker WJ, Ambrosi CM, et al. Arrhythmogenesis due to alternans of anisotropy in isolated coronary–perfused human ventricle with dilated cardiomyopathy. Heart Rhythm 2008;5:112.
Does the postrepolarization refractoriness play a role in amiodarone’s antiarrhythmic efficacy? Vadim V. Fedorov, PhD From the Department of Biomedical Engineering, Washington University, St. Louis, Missouri. Amiodarone is one of the most effective antiarrhythmic drugs for the treatment of atrial fibrillation (AF)1 and lifethreatening ventricular tachyarrhythmias.2 However, the clinical value of amiodarone is limited by a wide range of side effects.3 The drug blocks many cardiac outward and inward ion currents as well as muscarinic and adrenergic receptors.4 It has numerous effects on cardiac electrophysiology, including an increase in action potential duration (APD), increase in effective refractory period (ERP), and conduction slowing both in working myocardium and the pacemaker/conduction system.4 Chronic amiodarone treatment also induces indirect cardiac effects because of the drug’s two iodine atoms, which can induce hypothyroid-like conditions. Despite more than 3 decades of intensive research5 and clinical application,6 the precise electrophysiologic mechanisms of the high antiarrhythmic efficacy of the drug in different models are not well understood and still debatable. Animal studies have shown that amiodarone can induce prolonged refractoriness beyond repolarization, an effect that has been called postrepolarization refractoriness (PRR).7 The drug’s effects can be explained by a block of the inactivated cardiac sodium channels.8 The lack of a full recovery of sodium channels during the interpulse interval can cause a mild subsequent prolongation of the ERP relative to the APD (ERP/APD90 ratio ⬎1 represents PRR). Many studies have shown that PRR can be induced by different antiarrhythmic drugs with sodium channel blocking properties.9 –11 It was proposed that PRR without significant conduction slowing is a desirable feature for drugs designed to prevent ventricular arrhythmias.7 Interestingly, this antiarrhythmic mechanism was naturally developed for extreme winter conditions experienced by hibernating mammals. Recently, our group showed that hibernation-induced PRR may prevent the slowing of conduction during fast pacing and ventricular tachyarrhythmia induction.12 Kirchhof et al11 showed that PRR induced by sodium channel blockers can prevent induction of ventricular fibrilAddress reprint requests and correspondence: Dr. Vadim V. Fedorov, Department of Biomedical Engineering, Washington University, Campus Box 1097, One Brookings Drive, St. Louis, Missouri 63130-4899. E-mail address: [email protected].
lation. However, if this effect is offset by conduction slowing, it can facilitate induction of monomorphic ventricular tachycardias. Later, Kirchhof et al7 proposed that the high antiarrhythmic efficacy of chronic amiodarone can be explained by the development of PRR without significant conduction slowing. They showed in the rabbit model that chronic amiodarone treatment (6 weeks, 50 mg/kg/day) prolonged ventricular ERP more than monophasic APD, resulting in PRR without much conduction slowing, thereby curtailing the initial part of APD restitution. Antzelevitch’s group introduced an exciting new strategy for suppression of AF: selectively blocking of sodium channels in the atria by using differences in sodium channel inactivation and action potential configuration between the atria and ventricles.13 They found that some drugs (ranolazine, lidocaine) can induce development of PRR primarily in the atria, which can be important for treatment of AF. In this issue of Heart Rhythm, Burashnikov et al14 present data that chronic amiodarone (6 weeks, 40 mg/kg/day) also has potent atrial-predominant effects in depressing sodium channel-mediated parameters, in increasing APD, and in the development of PRR primarily in atria and less in ventricle. They used microelectrodes to study the chronic effects of amiodarone on action potential morphologies and refractoriness of “healthy” coronary-perfused canine atrial and ventricular isolated preparations. Burashnikov et al14 proposed that predominant atrial-selective effects on repolarization and refractoriness related with synergetic action of the drug on IKr and INa could contribute to amiodarone’s effectiveness in suppressing AF. From a research standpoint, these findings may offer new clues to the mechanisms underlying the high efficacy of chronic amiodarone against AF and potentially motivate novel research directions for the development of new antiarrhythmic drugs. Burashnikov et al14 used an acetylcholine-mediated AF model in which they clearly demonstrated the high efficacy of chronic amiodarone. However, they could not precisely investigate the antiarrhythmic mechanism of the drug in this model because of the absence of mapping techniques. Moreover, the antiarrhythmic effects of amiodarone in acetylcholine-mediated AF models also could be explained by its inhibition of IKACh current in atria.15,16 Consequently, more studies are needed to investigate precisely the antiarrhyth-
1547-5271/$ -see front matter. Published by Elsevier Inc. on behalf of the Heart Rhythm Society.
doi:10.1016/j.hrthm.2008.09.032
1744 mic effects of chronic amiodarone and to estimate the role of atrial PRR in remodeled atria. Canine studies by Shinagawa et al17 and Ashikaga et al18 demonstrated that amiodarone can reverse or prevent electrical (ERP shortening and conduction slowing), biochemical (downregulation Ltype Ca2⫹ channel), and structural (interstitial fibrosis) arrhythmogenic remodeling induced by atrial tachycardia during 7 days and 4 weeks, respectively. Thus, inhibition of atrial tachycardia remodeling may contribute to amiodarone’s high efficacy in preventing recurrence of persistent AF. It is well known that some phenomena experimentally observed in animals cannot always be observed in the remodeled human heart.19 Clinical electrophysiologic studies of chronic amiodarone treatment did not demonstrate significant atrial-selective drug effects on refractoriness and monophasic APD in the atria versus the ventricle.3,19 –22 Sager et al21 showed that chronic amiodarone does not exert frequency-dependent effects on ventricular repolarization; it prolongs right ventricular ERP by 15% to 20% and exerts frequency-dependent effects on ventricular conduction (up to 40% increase of QRS). Moreover, the drug significantly increased the right ventricular ERP/APD90 ratio compared with baseline, consistent with greater prolongation of refractoriness than repolarization. However, the ERP/APD90 ratio was not ⬎1 at different pacing cycle lengths (from 300 to 600 ms) in this human study compared with PRR results from the rabbit study by Kirchhof et al.7 Although the study by Burashnikov et al14 clearly demonstrated development of PRR in canine atria, PRR was not observed after cardioversion of persistent AF in amiodarone-treated patients.22 Pandozi et al19,22 found that right atrial ERPs were longer (approximately 5%–10%) in amiodarone-treated patients than in washout patients as well as monophasic APD90 after sinus rhythm restoration. The ERP/APD90 ratio was similar and always ⬍1 at all pacing cycle lengths in both washout and amiodarone groups. These divergent effects of chronic amiodarone on cardiac electrophysiologic parameters in different studies can be explained by different ionic currents responsible for the action potential in diseased human hearts and “healthy” or remodeled animal cardiac preparations as well as different experimental conditions and protocols. Amiodarone has a complex and wide spectrum of direct and indirect effects on the cardiac physiology, which makes its study very complicated.4 It also means that we need to exercise caution when translating results from animal models to clinical situations. In order to more precisely evaluate the antiarrhythmic mechanisms of “old” drugs such as amiodarone as well as new developing drugs, we strongly suggest the use of explanted human hearts instead of cardiac animal preparations and high-resolution optical mapping to directly characterize the drugs’ effects on human cardiac electrophysiology.23,24
Heart Rhythm, Vol 5, No 12, December 2008
References 1. Singh BN, Singh SN, Reda DJ, et al. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 2005;352:1861–1872. 2. Mark DB, Anstrom KJ, Sun JL, et al. Quality of life with defibrillator therapy or amiodarone in heart failure. N Engl J Med 2008;359:999 –1008. 3. Zipes DP, Prystowsky EN, Heger JJ. Amiodarone: electrophysiologic actions, pharmacokinetics and clinical effects. J Am Coll Cardiol 1984;3:1059 –1071. 4. Kodama I, Kamiya K, Toyama J. Amiodarone: ionic and cellular mechanisms of action of the most promising class III agent. Am J Cardiol 1999;84:20R–28R. 5. Singh BN, Vaughan Williams EM. The effect of amiodarone, a new anti-anginal drug, on cardiac muscle. Br J Pharmacol 1970;39:657– 667. 6. Rosenbaum MB, Chiale PA, Halpern MS, et al. Clinical efficacy of amiodarone as an antiarrhythmic agent. Am J Cardiol 1976;38:934 –944. 7. Kirchhof P, Degen H, Franz MR, et al. Amiodarone-induced postrepolarization refractoriness suppresses induction of ventricular fibrillation. J Pharmacol Exp Ther 2003;305:257–263. 8. Mason JW, Hondeghem LM, Katzung BG. Amiodarone blocks inactivated cardiac sodium channels. Pflugers Arch 1983;396:79 – 81. 9. Lee RJ, Liem LB, Cohen TJ, et al. Relation between repolarization and refractoriness in the human ventricle: cycle length dependence and effect of procainamide. J Am Coll Cardiol 1992;19:614 – 618. 10. Haberman RJ, Rials SJ, Stohler JL, et al. Evidence for a reexcitability gap in man after treatment with type I antiarrhythmic drugs. Am Heart J 1993;126: 1121–1126. 11. Kirchhof PF, Fabritz CL, Franz MR. Postrepolarization refractoriness versus conduction slowing caused by class I antiarrhythmic drugs: antiarrhythmic and proarrhythmic effects. Circulation 1998;97:2567–2574. 12. Fedorov VV, Glukhov A, Sudharshan S, et al. Electrophysiological mechanisms of antiarrhythmic protection during hypothermia in winter hibernating versus nonhibernating mammals. Heart Rhythm 2008;5:1587–1596. 13. Burashnikov A, Di Diego JM, Zygmunt AC, et al. 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 2007;116:1449 –1457. 14. Burashnikov A, Di Diego JM, Sicouri S, et al. Atrial-selective effects of chronic amiodarone in the management of atrial fibrillation. Heart Rhythm 2008;5: 1735–1742. 15. Watanabe Y, Hara Y, Tamagawa M, et al. Inhibitory effect of amiodarone on the muscarinic acetylcholine receptor-operated potassium current in guinea pig atrial cells. J Pharmacol Exp Ther 1996;279:617– 624. 16. Huang CX, Zhao QY, Liang JJ, et al. Differential densities of muscarinic acetylcholine receptor and I(K,ACh) in canine supraventricular tissues and the effect of amiodarone on cholinergic atrial fibrillation and I(K,ACh). Cardiology 2006;106:36 – 43. 17. Shinagawa K, Shiroshita-Takeshita A, Schram G, et al. Effects of antiarrhythmic drugs on fibrillation in the remodeled atrium: insights into the mechanism of the superior efficacy of amiodarone. Circulation 2003;107:1440 –1446. 18. Ashikaga K, Kobayashi T, Kimura M, et al. Effects of amiodarone on electrical and structural remodeling induced in a canine rapid pacing-induced persistent atrial fibrillation model. Eur J Pharmacol 2006;536:148 –153. 19. Pandozi C, Bianconi L, Villani M, et al. Electrophysiological characteristics of the human atria after cardioversion of persistent atrial fibrillation. Circulation 1998;98:2860 –2865. 20. Wellens HJ, Brugada P, Abdollah H, et al. A comparison of the electrophysiologic effects of intravenous and oral amiodarone in the same patient. Circulation 1984;69:120 –124. 21. Sager PT, Uppal P, Follmer C, et al. Frequency-dependent electrophysiologic effects of amiodarone in humans. Circulation 1993;88:1063–1071. 22. Pandozi C, Gentilucci G, Calo L, et al. Relations between monophasic action potential duration and refractoriness after cardioversion of persistent atrial fibrillation: results in wash-out and amiodarone-treated patients. Ital Heart J 2003;4:257–263. 23. Hucker WJ, Fedorov VV, Foyil KV, et al. Images in cardiovascular medicine. Optical mapping of the human atrioventricular junction. Circulation 2008;117: 1474 –1477. 24. Fedorov VV, Hucker WJ, Ambrosi CM, et al. Arrhythmogenesis due to alternans of anisotropy in isolated coronary–perfused human ventricle with dilated cardiomyopathy. Heart Rhythm 2008;5:112.