Abstract
Atrial fibrillation (AF) is a growing clinical problem associated with increased morbidity and mortality. Currently available antiarrhythmic drugs (AADs), although highly effective in acute cardioversion of paroxysmal AF, are generally only moderately successful in long-term maintenance of sinus rhythm. The use of AADs is often associated with an increased risk of ventricular proarrhythmia, extracardiac toxicity, and exacerbation of concomitant diseases such as heart failure. AF is commonly associated with intracardiac and extracardiac disease, which can modulate the efficacy and safety of AAD therapy. In light of the multifactorial intracardiac and extracardiac causes of AF generation, current development of anti-AF agents is focused on modulation of ion channel activity as well as on upstream therapies that reduce structural substrates. The available data indicate that multiple ion channel blockers exhibiting potent inhibition of peak INa with relatively rapid unbinding kinetics, as well as inhibition of late INa and IKr, may be preferable for the management of AF when considering both safety and efficacy.
Key Points
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Atrial fibrillation (AF) is a growing clinical problem associated with increased morbidity and mortality
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Currently available antiarrhythmic drugs (AADs) can be highly effective in acute cardioversion of AF, but are only moderately successful in long-term maintenance of sinus rhythm and may induce adverse effects
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AF is commonly associated with atrial electrical and structural abnormalities as well as extracardiac disease, which may induce or promote AF and determine the efficacy and safety of AAD therapy
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Current development of anti-AF agents is focused on alteration of ion channel activity as well as upstream therapies that reduce structural substrates
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Multiple ion channel blockers exhibiting inhibition of fast INa and late INa, IKr, and IKur are likely to be atrial-selective and may be best suited for the management of AF
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Preventing or reversing atrial structural remodeling ('upstream therapy') seems to be beneficial for some AF pathologies, such as postoperative AF or AF associated with severe heart failure
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References
Fuster, V. et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation--executive summary: 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 (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). J. Am. Coll. Cardiol. 48, 854–906 (2006).
Reiffel, J. A. Rate versus rhythm control pharmacotherapy for atrial fibrillation: where are we in 2008? JAFIB 1, 31–47 (2008).
Naccarelli, G. V. & Gonzalez, M. D. Atrial fibrillation and the expanding role of catheter ablation: do antiarrhythmic drugs have a future? J. Cardiovasc. Pharmacol. 52, 203–209 (2008).
Roux, J. F. et al. Antiarrhythmics after ablation of atrial aibrillation (5A Study). Circulation 120, 1036–1040 (2009).
Cain, M. E. & Curtis, A. B. Rhythm control in atrial fibrillation—one setback after another. N. Engl. J. Med. 358, 2725–2727 (2008).
Savelieva, I. & Camm, J. Anti-arrhythmic drug therapy for atrial fibrillation: current anti-arrhythmic drugs, investigational agents, and innovative approaches. Europace 10, 647–665 (2008).
Wyse, D. G. et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N. Engl. J. Med. 347, 1825–1833 (2002).
Roy, D. et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N. Engl. J. Med. 358, 2667–2677 (2008).
Van, G. I. et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N. Engl. J. Med. 347, 1834–1840 (2002).
Hohnloser, S. H., Kuck, K. H. & Lilienthal, J. Rhythm or rate control in atrial fibrillation—Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet 356, 1789–1794 (2000).
Corley, S. D. et al. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study. Circulation 109, 1509–1513 (2004).
Jais, P. et al. Catheter ablation versus antiarrhythmic drugs for atrial fibrillation: the A4 study. Circulation 118, 2498–2505 (2008).
Calkins, H. et al. Treatment of atrial fibrillation with antiarrhythmic drugs or radiofrequency ablation: Two systematic literature reviews and meta analysis. Circ. Arrhythm. Electrophysiol. 2, 349–361 (2009).
Le Bouter, S. et al. Long-term amiodarone administration remodels expression of ion channel transcripts in the mouse heart. Circulation 110, 3028–3035 (2004).
Schumacher, S. M. et al. Antiarrhythmic drug-induced internalization of the atrial-specific K+ channel Kv1.5. Circ. Res. 104, 1390–1398 (2009).
Shinagawa, K., Shiroshita-Takeshita, A., Schram, G. & Nattel, S. Effects of antiarrhythmic drugs on fibrillation in the remodeled atrium: insights into the mechanism of the superior efficacy of amiodarone. Circulation 107, 1440–1446 (2003).
Ashikaga, H. et al. Transmural dispersion of myofiber mechanics: implications for electrical heterogeneity in vivo. J. Am. Coll. Cardiol. 49, 909–916 (2007).
Alboni, P. et al. Outpatient treatment of recent-onset atrial fibrillation with the “pill-in-the-pocket” approach. N. Engl. J. Med. 351, 2384–2391 (2004).
Geller, J. C. et al. Rapid conversion of persistent atrial fibrillation to sinus rhythm by intravenous AZD7009. J. Clin. Pharmacol. 49, 312–322 (2009).
Banchs, J. E. et al. Efficacy and safety of dofetilide in patients with atrial fibrillation and atrial flutter. J. Interv. Card. Electrophysiol. 23, 111–115 (2008).
Roy, D. et al. Amiodarone to prevent recurrence of atrial fibrillation. Canadian Trial of Atrial Fibrillation Investigators. N. Engl. J. Med. 342, 913–920 (2000).
Kober, L. et al. Increased mortality after dronedarone therapy for severe heart failure. N. Engl. J. Med. 358, 2678–2687 (2008).
CAST Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N. Engl. J. Med. 321, 406–412 (1989).
Singh, B. N. Amiodarone as paradigm for developing new drugs for atrial fibrillation. J. Cardiovasc. Pharmacol. 52, 300–305 (2008).
Zimetbaum, P. Amiodarone for atrial fibrillation. N. Engl. J. Med. 356, 935–941 (2007).
Steinberg, J. S. et al. Analysis of cause-specific mortality in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. Circulation 109, 1973–1980 (2004).
Bardy, G. H. et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N. Engl. J. Med. 352, 225–237 (2005).
Solomon, S. D. et al. Influence of nonfatal hospitalization for heart failure on subsequent mortality in patients with chronic heart failure. Circulation 116, 1482–1487 (2007).
Nattel, S. & Carlsson, L. Innovative approaches to anti-arrhythmic drug therapy. Nat. Rev. Drug Discov. 5, 1034–1049 (2006).
Burashnikov, A. & Antzelevitch, C. How do atrial-selective drugs differ from antiarrhythmic drugs currently used in the treatment of atrial fibrillation? JAFIB 1, 98–107 (2008).
Burashnikov, A. & Antzelevitch, C. Atrial-selective sodium channel blockers: do they exist? J. Cardiovasc. Pharmacol. 52, 121–128 (2008).
Burashnikov, A. & Antzelevitch, C. Atrial-selective sodium channel block for the treatment of atrial fibrillation. Expert Opin. Emerg. Drugs 14, 233–249 (2009).
Ehrlich, J. R. & Nattel, S. Atrial-selective pharmacological therapy for atrial fibrillation: hype or hope? Curr. Opin. Cardiol. 24, 50–55 (2009).
Fedida, D. Vernakalant (RSD1235): a novel, atrial-selective antifibrillatory agent. Expert Opin. Investig. Drugs 16, 519–532 (2007).
Carlsson, L., Chartier, D. & Nattel, S. Characterization of the in vivo and in vitro electrophysiological effects of the novel antiarrhythmic agent AZD7009 in atrial and ventricular tissue of the dog. J. Cardiovasc. Pharmacol. 47, 123–132 (2006).
Blaauw, Y. et al. “Early” class III drugs for the treatment of atrial fibrillation: efficacy and atrial selectivity of AVE0118 in remodeled atria of the goat. Circulation 110, 1717–1724 (2004).
Christ, T. et al. Pathology-specific effects of the IKur/Ito/IK, ACh blocker AVE0118 on ion channels in human chronic atrial fibrillation. Br. J. Pharmacol. 154, 1619–1630 (2008).
Burashnikov, A. et al. The atrial-selective potassium channel blocker AVE0118 prolongs effective refractory period in canine atria by inhibiting sodium channels. Heart Rhythm 6, S98 (2009).
Goldstein, R. N., Khrestian, C., Carlsson, L. & Waldo, A. L. AZD7009: a new antiarrhythmic drug with predominant effects on the atria effectively terminates and prevents reinduction of atrial fibrillation and flutter in the sterile pericarditis model. J. Cardiovasc. Electrophysiol. 15, 1444–1450 (2004).
Ford, J. W. & Milnes, J. T. New drugs targeting the cardiac ultra-rapid delayed-rectifier current (IKur): rationale, pharmacology and evidence for potential therapeutic value. J. Cardiovasc. Pharmacol. 52, 105–120 (2008).
Burashnikov, A. & Antzelevitch, C. Can inhibition of IKur promote atrial fibrillation? Heart Rhythm 5, 1304–1309 (2008).
Feng, J., Xu, D., Wang, Z. & Nattel, S. Ultrarapid delayed rectifier current inactivation in human atrial myocytes: properties and consequences. Am. J. Physiol. 275, H1717–H1725 (1998).
Courtemanche, M., Ramirez, R. J. & Nattel, S. Ionic targets for drug therapy and atrial fibrillation-induced electrical remodeling: insights from a mathematical model. Cardiovasc. Res. 42, 477–489 (1999).
Van Wagoner, D. R., Pond, A. L., McCarthy, P. M., Trimmer, J. S. & Nerbonne, J. M. Outward K+ current densities and Kv1.5 expression are reduced in chronic human atrial fibrillation. Circ. Res. 80, 772–781 (1997).
Wettwer, E. et al. Role of IKur in controlling action potential shape and contractility in the human atrium: influence of chronic atrial fibrillation. Circulation 110, 2299–2306 (2004).
Olson, T. M. et al. Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation. Hum. Mol. Genet. 15, 2185–2191 (2006).
Bettoni, M. & Zimmermann, M. Autonomic tone variations before the onset of paroxysmal atrial fibrillation. Circulation 105, 2753–2759 (2002).
Pappone, C. et al. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation. Circulation 109, 327–334 (2004).
Cha, T. J. et al. Kir3-based inward rectifier potassium current: potential role in atrial tachycardia remodeling effects on atrial repolarization and arrhythmias. Circulation 113, 1730–1737 (2006).
Hashimoto, N., Yamashita, T. & Tsuruzoe, N. Tertiapin, a selective, IKACh blocker, terminates atrial fibrillation with selective atrial effective refractory period prolongation. Pharmacol. Res. 54, 136–141 (2006).
Dobrev, D. et al. The G protein-gated potassium current, IKACh is constitutively active in patients with chronic atrial fibrillation. Circulation 112, 3697–3706 (2005).
Voigt, N. et al. Differential phosphorylation-dependent regulation of constitutively active and muscarinic receptor-activated, IKACh channels in patients with chronic atrial fibrillation. Cardiovasc. Res. 74, 426–437 (2007).
Ehrlich, J. R. et al. Characterization of a hyperpolarization-activated time-dependent potassium current in canine cardiomyocytes from pulmonary vein myocardial sleeves and left atrium. J. Physiol. 557, 583–597 (2004).
Ravens, U. Potassium channels in atrial fibrillation: targets for atrial and pathology-specific therapy? Heart Rhythm 5, 758–759 (2008).
Burashnikov, A., Di Diego, J. M., Zygmunt, A. C., Belardinelli, L. & Antzelevitch, C. 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, 1449–1457 (2007).
Spinelli, W., Parsons, R. W. & Colatsky, T. J. Effects of WAY-123,398, a new class-III antiarrhythmic agent, on cardiac refractoriness and ventricular fibrillation threshold in anesthetized dogs—a comparison with UK-68798, E-4031, and dl-sotalol. J. Cardiovasc. Pharmacol. 20, 913–922 (1992).
Wiesfeld, A. C. et al. Rate-dependent effects of the class III antiarrhythmic drug almokalant on refractoriness in the pig. J. Cardiovasc. Pharmacol. 27, 594–600 (1996).
Baskin, E. P. & Lynch, J. J. Jr. Differential atrial versus ventricular activities of class III potassium channel blockers. J. Pharmacol. Exp. Ther. 285, 135–142 (1998).
Stump, G. L., Wallace, A. A., Regan, C. P. & Lynch, J. J. Jr. In vivo antiarrhythmic and cardiac electrophysiologic effects of a novel diphenylphosphine oxide I Kur blocker (2-isopropyl-5-methylcyclohexyl) diphenylphosphine oxide. J. Pharmacol. Exp. Ther. 315, 1362–1367 (2005).
Wang, J., Feng, J. & Nattel, S. Class III antiarrhythmic drug action in experimental atrial fibrillation. Differences in reverse use dependence and effectiveness between d-sotalol and the new antiarrhythmic drug ambasilide. Circulation 90, 2032–2040 (1994).
Echt, D. S. et al. Prolongation of the human monophasic action potential by sotalol. Am. J. Cardiol. 50, 1082–1086 (1982).
Buchanan, L. V. et al. Antiarrhythmic and electrophysiologic effects of intravenous ibutilide and sotalol in the canine sterile pericarditis model. J. Cardiovasc. Electrophysiol. 7, 113–119 (1996).
Burashnikov, A. et al. Atrial-selective effects of chronic amiodarone in the management of atrial fibrillation. Heart Rhythm 5, 1735–1742 (2008).
Burashnikov, A. & Antzelevitch, C. New pharmacological strategies for the treatment of atrial fibrillation. Ann. Noninvasive Electrocardiol. 14, 290–300 (2009).
Burashnikov, A., Di Diego, J. M., Zygmunt, A. C., Belardinelli, L. & Antzelevitch, C. Atrial-selective sodium channel block as a strategy for suppression of atrial fibrillation. Ann. N. Y. Acad. Sci. 1123, 105–112 (2008).
Sicouri, S., Glass, A., Belardinelli, L. & Antzelevitch, C. Antiarrhythmic effects of ranolazine in canine pulmonary vein sleeve preparations. Heart Rhythm 5, 1019–1026 (2008).
Sicouri, S., Belardinelli, L., Carlsson, L. & Antzelevitch, C. Potent antiarrhythmic effects of chronic amiodarone in canine pulmonary vein sleeve preparations. J. Cardiovasc. Electrophysiol. 20, 803–810 (2009).
Scirica, B. M. et al. Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST-segment elevation acute coronary syndrome: results from the Metabolic Efficiency with Ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation 116, 1647–1652 (2007).
Murdock, D. K., Overton, N., Kersten, M., Kaliebe, J. & Devecchi, F. The effect of ranolazine on maintaining sinus rhythm in patients with resistant atrial fibrillation. Indian Pacing Electrophysiol. J. 8, 175–181 (2008).
Crijns, H. J. et al. Safe and effective conversion of persistent atrial fibrillation to sinus rhythm by intravenous AZD7009. Heart Rhythm 3, 1321–1331 (2006).
Duytschaever, M., Blaauw, Y. & Allessie, M. Consequences of atrial electrical remodeling for the anti-arrhythmic action of class IC and class III drugs. Cardiovasc. Res. 67, 69–76 (2005).
Billman, G. E. & Kukielka, M. Novel transient outward and ultra-rapid delayed rectifier current antagonist, AVE0118, protects against ventricular fibrillation induced by myocardial ischemia. J. Cardiovasc. Pharmacol. 51, 352–358 (2008).
Li, G. R., Lau, C. P. & Shrier, A. Heterogeneity of sodium current in atrial vs epicardial ventricular myocytes of adult guinea pig hearts. J. Mol. Cell Cardiol. 34, 1185–1194 (2002).
Carmeliet, E. & Mubagwa, K. Antiarrhythmic drugs and cardiac ion channels: mechanisms of action. Prog. Biophys. Mol. Biol. 70, 1–72 (1998).
Hondeghem, L. M. & Katzung, B. G. Mechanism of Action of Antiarrhythmic Drugs in Physiology and Pathophysiology of the Heart (ed. Sperelakis, N.) 589–603 (Kluwer Academic Publishers, 1995).
Burashnikov, A., Belardinelli, L. & Antzelevitch, C. Ranolazine and propafenone both suppress atrial fibrillation but ranolazine unlike propafenone does it without prominent effects on ventricular myocardium. Heart Rhythm 4, S163 (2007).
Antzelevitch, C. & Burashnikov, A. Atrial selective sodium channel block as a novel strategy for the management of atrial fibrillation. J. Electrocardiol. 42, 543–548 (2009).
Comtois, P. et al. Mechanisms of atrial fibrillation termination by rapidly unbinding Na+ channel blockers. Insights from mathematical models and experimental correlates. Am. J. Physiol. Heart Circ. Physiol. 295, H1489–H1504 (2008).
Antzelevitch, C. et al. The M cell: its contribution to the ECG and to normal and abnormal electrical function of the heart. J. Cardiovasc. Electrophysiol. 10, 1124–1152 (1999).
Burashnikov, A. & Antzelevitch, C. Late-phase 3 EAD. A unique mechanism contributing to initiation of atrial fibrillation. PACE 29, 290–295 (2006).
Blaauw, Y., Schotten, U., van, H. A., Neuberger, H. R. & Allessie, M. A. Cardioversion of persistent atrial fibrillation by a combination of atrial specific and non-specific class III drugs in the goat. Cardiovasc. Res. 75, 89–98 (2007).
Antzelevitch, C. Electrical heterogeneity, cardiac arrhythmias, and the sodium channel. Circ. Res. 87, 964–965 (2000).
Antzelevitch, C. et al. Electrophysiologic properties and antiarrhythmic actions of a novel anti-anginal agent. J. Cardiovasc. Pharmacol. Therapeut. 9 (Suppl. 1) S65–S83 (2004).
Shryock, J. C. & Belardinelli, L. Inhibition of late sodium current to reduce electrical and mechanical dysfunction of ischaemic myocardium. Br. J. Pharmacol. 153, 1128–1132 (2008).
Persson, F., Andersson, B., Duker, G., Jacobson, I. & Carlsson, L. Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre. Eur. J. Pharmacol. 558, 133–143 (2007).
Waldo, A. L. et al. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival with oral d-sotalol. Lancet 348, 7–12 (1996).
Koren, M. J., Crager, M. R. & Sweeney, M. Long-term safety of a novel antianginal agent in patients with severe chronic stable angina: the Ranolazine Open Label Experience (ROLE). J. Am. Coll. Cardiol. 49, 1027–1034 (2007).
Zimetbaum, P. J. Dronedarone for atrial fibrillation--an odyssey. N. Engl. J. Med. 360, 1811–1813 (2009).
Singh, B. N. et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N. Engl. J. Med. 357, 987–999 (2007).
Davy, J. M. et al. Dronedarone for the control of ventricular rate in permanent atrial fibrillation: the Efficacy and safety of dRonedArone for the cOntrol of ventricular rate during atrial fibrillation (ERATO) study. Am. Heart J. 156, 527.e1–527e9 (2008).
Hohnloser, S. H. et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N. Engl. J. Med. 360, 668–678 (2009).
Connolly, S. J. et al. Analysis of stroke in ATHENA: a placebo-controlled, double-blind, parallel-arm trial to assess the efficacy of dronedarone 400 mg BID for the prevention of cardiovascular hospitalization or death from any cause in patients with atrial fibrillation/atrial flutter. Circulation 120, 1174–1180 (2009).
Gautier, P. et al. Electrophysiologic characterization of dronedarone in guinea pig ventricular cells. J. Cardiovasc. Pharmacol. 41, 191–202 (2003).
Carlsson, L., Andersson, B., Linhardt, G. & Lofberg, L. Assessment of the ion channel-blocking profile of the novel combined ion channel blocker AZD1305 and its proarrhythmic potential versus dofetilide in the methoxamine-sensitized rabbit in vivo. J. Cardiovasc. Pharmacol. 54, 82–89 (2009).
Wirth, K. J. et al. In vitro and in vivo effects of the atrial selective antiarrhythmic compound AVE1231. J. Cardiovasc. Pharmacol. 49, 197–206 (2007).
Kleber, A. G. & Rudy, Y. Basic mechanisms of cardiac impulse propagation and associated arrhythmias. Physiol. Rev. 84, 431–488 (2004).
Ehrlich, J. R., Biliczki, P., Hohnloser, S. H. & Nattel, S. Atrial-selective approaches for the treatment of atrial fibrillation. J. Am. Coll. Cardiol. 51, 787–792 (2008).
Guerra, J. M., Everett, T. H., Lee, K. W., Wilson, E. & Olgin, J. E. Effects of the gap junction modifier rotigaptide (ZP123) on atrial conduction and vulnerability to atrial fibrillation. Circulation 114, 110–118 (2006).
Shiroshita-Takeshita, A., Sakabe, M., Haugan, K., Hennan, J. K. & Nattel, S. Model-dependent effects of the gap junction conduction-enhancing antiarrhythmic peptide rotigaptide (ZP123) on experimental atrial fibrillation in dogs. Circulation 115, 310–318 (2007).
Laurent, G. et al. Effects of chronic gap junction conduction–enhancing antiarrhythmic peptide GAP-134 administration on experimental atrial fibrillation in dogs. Circ. Arrhythm. Electrophysiol. 2, 171–178 (2009).
Rossman, E. I. et al. The gap junction modifier, GAP-134 [(2S, 4R)-1-(2-aminoacetyl)-4-benzamido-pyrrolidine-2-carboxylic acid], improves conduction and reduces atrial fibrillation/flutter in the canine sterile pericarditis model. J. Pharmacol. Exp. Ther. 329, 1127–1133 (2009).
Burashnikov, A. & Antzelevitch, C. Reinduction of atrial fibrillation immediately after termination of the arrhythmia is mediated by late phase 3 early afterdepolarization-induced triggered activity. Circulation 107, 2355–2360 (2003).
Hove-Madsen, L. et al. Atrial fibrillation is associated with increased spontaneous calcium release from the sarcoplasmic reticulum in human atrial myocytes. Circulation 110, 1358–1363 (2004).
Vest, J. A. et al. Defective cardiac ryanodine receptor regulation during atrial fibrillation. Circulation 111, 2025–2032 (2005).
Dobrev, D. & Nattel, S. Calcium handling abnormalities in atrial fibrillation as a target for innovative therapeutics. J. Cardiovasc. Pharmacol. 52, 293–299 (2008).
Murdock, D. K., Kersten, M., Kaliebe, J. & Larrian, G. The use of oral ranolazine to convert new or paroxysmal atrial fibrillation: a reveiw of experience with implications for possible “pill in the pocket” approach to atrial fibrillation. Indian Pacing Electrophysiol. J. 9, 260–267 (2009).
Kirchhof, P. et al. Early and comprehensive management of atrial fibrillation: proceedings from the 2nd AFNET/EHRA consensus conference on atrial fibrillation entitled 'research perspectives in atrial fibrillation'. Europace 11, 860–885 (2009).
Ahmed, S. et al. Continuous vs episodic prophylactic treatment with amiodarone for the prevention of atrial fibrillation: a randomized trial. JAMA 300, 1784–1792 (2008).
Li, D., Fareh, S., Leung, T. K. & Nattel, S. Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. Circulation 100, 87–95 (1999).
Goette, A., Bukowska, A. & Lendeckel, U. Non-ion channel blockers as anti-arrhythmic drugs (reversal of structural remodeling). Curr. Opin. Pharmacol. 7, 219–224 (2007).
Savelieva, I. & Camm, J. Statins and polyunsaturated fatty acids for treatment of atrial fibrillation. Nat. Clin. Pract. Cardiovasc. Med. 5, 30–41 (2008).
Nattel, S., Burstein, B. & Dobrev, D. Atrial remodeling and atrial fibrillation: mechanisms and implications. Circ. Arrhythm. Electrophysiol. 1, 62–73 (2008).
Van Wagoner, D. R. Oxidative stress and inflammation in atrial fibrillation: role in pathogenesis and potential as a therapeutic target. J. Cardiovasc. Pharmacol. 52, 306–313 (2008).
Disertori, M. et al. Valsartan for prevention of recurrent atrial fibrillation. N. Engl. J. Med. 360, 1606–1617 (2009).
Pratt, C. M., Reiffel, J. A., Ellenbogen, K. A., Naccarelli, G. V. & Kowey, P. R. Efficacy and safety of prescription omega-3-acid ethyl esters for the prevention of recurrent symptomatic atrial fibrillation: a prospective study. Am. Heart J. 158, 163–169 (2009).
Dawe, D. E., Ariyarajah, V. & Khadem, A. Is there a role for statins in atrial fibrillation? Pacing Clin. Electrophysiol. 32, 1063–1072 (2009).
Barra, S., Silvestri, N., Vitagliano, G., Madrid, A. & Gaeta, G. Angiotensin II receptor blockers in the prevention of atrial fibrillation. Expert Opin. Pharmacother. 10, 1395–1411 (2009).
Ehrlich, J. R. & Nattel, S. Novel approaches for pharmacological management of atrial fibrillation. Drugs 69, 757–774 (2009).
Liakopoulos, O. J. et al. Statins for prevention of atrial fibrillation after cardiac surgery: a systematic literature review. J. Thorac. Cardiovasc. Surg. 138, 678–686 (2009).
Calo, L. et al. N-3 fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a randomized, controlled trial. J. Am. Coll. Cardiol. 45, 1723–1728 (2005).
Heidt, M. C. et al. Beneficial effects of intravenously administered N-3 fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a prospective randomized study. Thorac. Cardiovasc. Surg. 57, 276–280 (2009).
Murray, K. T. et al. Inhibition of angiotensin II signaling and recurrence of atrial fibrillation in AFFIRM. Heart Rhythm 1, 669–675 (2004).
Healey, J. S. et al. Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: a meta-analysis. J. Am. Coll. Cardiol. 45, 1832–1839 (2005).
Maggioni, A. P. et al. Effects of rosuvastatin on atrial fibrillation occurrence: ancillary results of the GISSI-HF trial. Eur. Heart J. 30, 2327–2336 (2009).
Salehian, O. et al. Impact of ramipril on the incidence of atrial fibrillation: results of the Heart Outcomes Prevention Evaluation study. Am. Heart J. 154, 448–453 (2007).
Almroth, H. et al. Atorvastatin and persistent atrial fibrillation following cardioversion: a randomized placebo-controlled multicentre study. Eur. Heart J. 30, 827–833 (2009).
Cleland, J. G. et al. Clinical trials update from the European Society of Cardiology Meeting 2009: AAA, RELY, PROTECT, ACTIVE-I, European CRT survey, German pre-SCD II registry, and MADIT-CRT. Eur. J. Heart Fail. 11, 1214–1219 (2009).
Goette, A. et al. Angiotensin II antagonist in paroxysmal atrial fibrillation (ANTIPAF) trial: rationale and study design. Clin. Drug Investig. 27, 697–705 (2007).
Nakajima, H. et al. Atrial but not ventricular fibrosis in mice expressing a mutant transforming growth factor-b1 transgene in the heart. Circ. Res. 86, 571–579 (2000).
Hanna, N., Cardin, S., Leung, T. K. & Nattel, S. Differences in atrial versus ventricular remodeling in dogs with ventricular tachypacing-induced congestive heart failure. Cardiovasc. Res. 63, 236–244 (2004).
Verheule, S. et al. Increased vulnerability to atrial fibrillation in transgenic mice with selective atrial fibrosis caused by overexpression of TGF-beta1. Circ. Res. 94, 1458–1465 (2004).
Adam, O. et al. Role of Rac1 GTPase activation in atrial fibrillation. J. Am. Coll. Cardiol. 50, 359–367 (2007).
Burstein, B., Libby, E., Calderone, A. & Nattel, S. Differential behaviors of atrial versus ventricular fibroblasts: a potential role for platelet-derived growth factor in atrial-ventricular remodeling differences. Circulation 117, 1630–1641 (2008).
Burashnikov, A. Are there atrial selective/predominant targets for “upstream” atrial fibrillation therapy? Heart Rhythm 5, 1294–1295 (2008).
Lafuente-Lafuente, C., Mouly, S., Longas-Tejero, M. A. & Bergmann, J. F. Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation. Cochrane Database Syst. Rev. 17, CD005049 (2007).
Torp-Pedersen, C. et al. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. N. Engl. J. Med. 341, 857–865 (1999).
Pedersen, O. D. et al. Efficacy of dofetilide in the treatment of atrial fibrillation-flutter in patients with reduced left ventricular function: a Danish investigations of arrhythmia and mortality on dofetilide (DIAMOND) substudy. Circulation 104, 292–296 (2001).
Hohnloser, S. H. Dronedarone in clinical context. The 2009 Atrial Fibrillation Forum; 14 November 2009, Orlando, USA.
Julian, D. G. et al. Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. European Myocardial Infarct Amiodarone Trial Investigators. Lancet 349, 667–674 (1997).
Cairns, J. A., Connolly, S. J., Roberts, R. & Gent, M. Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators. Lancet 349, 675–682 (1997).
Antzelevitch, C. & Burashnikov, A. Atrial-selective sodium channel block as a novel strategy for the management of atrial fibrillation. J. Electrocardiol. 42, 543–548 (2009).
Lalevee, N., Nargeot, J., Barrere-Lemaire, S., Gautier, P. & Richard, S. Effects of amiodarone and dronedarone on voltage-dependent sodium current in human cardiomyocytes. J. Cardiovasc. Electrophysiol. 14, 885–890 (2003).
Sicouri, S., Burashnikov, A., Belardinelli, L. & Antzelevitch, C. Synergistic electrophysiologic and antiarrhythmic effects of the combination of ranolazine and chronic amiodarone in canine atria. Circ. Arrhythm. Electrophysiol. doi:10.1161/CIRCEP.109.886275.
Acknowledgements
Supported by grant HL47678 from NHLBI (C. Antzelevitch) and NYS and Florida Grand Lodges F. & A. M.
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A. Burashnikov declares no competing interests.
C. Antzelevitch declares that he is a consultant and patent holder/applicant for AstraZeneca and Gilead Sciences, Inc. He has also received grant/research support from AstraZeneca, Cardiome, Gilead Sciences, Inc., Lundbeck, and Solvay.
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Burashnikov, A., Antzelevitch, C. New developments in atrial antiarrhythmic drug therapy. Nat Rev Cardiol 7, 139–148 (2010). https://doi.org/10.1038/nrcardio.2009.245
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DOI: https://doi.org/10.1038/nrcardio.2009.245