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Pharmacologic versus direct-current electrical cardioversion of atrial flutter and fibrillation
Pharmacologic Versus Direct-Current Electrical Cardioversion of Atrial Flutter and Fibrillation Isabelle C. Van Gelder, MD, PhD, Anton E. Tuinenburg, MD, Bas S. Schoonderwoerd, MD, Robert G. Tieleman, MD, and Harry J.G.M. Crijns, MD, PhD Conversion of atrial flutter and atrial fibrillation (AF) can be achieved by either pharmacologic or direct-current (DC) electrical cardioversion. DC electrical cardioversion is more effective and restores sinus rhythm instantaneously; however, general anesthesia is necessary, which can cause severe complications. On the other hand, pharmacologic cardioversion is less effective. First, time to conversion is unpredictable and may be relatively long, especially with oral drug therapy. Also, the rate of conversion is lower and depends on duration of AF. In addition, safety is an important issue. Adverse drug reactions include bradycardia, paradoxical tachycardia due to enhanced atrioventricular conduction, ventricular proarrhythmia, and acute heart failure. In paroxysmal AF, drug therapy is usually aimed at an acute conversion. Class IA and IC drugs are more efficacious than the class III drugs sotalol, amiodarone, and ibutilide. By contrast, class III drugs are more effective for the conversion of atrial flutter. Acute conversion out-of-hospital (“pill in the pocket approach”) should be done only if the drug used appeared effective and safe after a few
in-hospital trials. In persistent AF, DC conversion is preferred because drugs are particularly ineffective if the arrhythmia has lasted >24 – 48 hours. The latter probably relates to electrical and anatomical remodeling of the atria during ongoing atrial fibrillation and flutter. Nevertheless, a wait-and-see approach using, for example, oral amiodarone may be adopted with late DC conversion if the drug fails to convert persistent AF. However, the consequences of remodeling seem to dictate an early conversion. In this respect, echocardiography-guided DC cardioversion may become increasingly important in AF. It will prevent treatment resistance and potentially reduces embolic complications. In a hybrid approach, antiarrhythmic drugs may be used to enhance DC conversion and prevent (sub)acute recurrences of AF. However, it may increase the defibrillation threshold, especially if class IC drugs are used. New treatment options such as automatic defibrillation (implantable atrioverter) are still investigational. 䊚1999 by Excerpta Medica, Inc. Am J Cardiol 1999;84:147R–151R
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electrical and (ultra)structural remodeling of the atria.3,4 It is generally believed that sinus rhythm has several potential benefits compared with atrial fibrillation (AF): relief of symptoms, reduced risk of thromboembolic complications, and an improved exercise tolerance. Because electrical and anatomical remodeling in the atria seem to affect the chance of restoration of sinus rhythm (“atrial fibrillation begets atrial fibrillation”),5 early cardioversion— either pharmacologic or electrical—should be attempted.
fter establishing the indication for conversion, the question arises whether it should be achieved by pharmacologic or direct current (DC) electrical cardioversion. In this respect, the advantages and disadvantages of both strategies should be carefully weighed (Table I). In general, DC cardioversion is more effective than pharmacologic cardioversion. However, it necessitates general anesthesia with potentially severe complications. Not only are drugs less effective, but time to conversion is unpredictable and may be relatively long, especially with oral therapy. Furthermore, antiarrhythmic drugs may induce bradycardia, tachycardia due to enhanced atrioventricular conduction, ventricular proarrhythmia, and acute heart failure. Both pharmacologic and electrical cardioversion, and maintenance of sinus rhythm thereafter, become more difficult the longer the arrhythmia exists.1,2 Recent data revealed that the latter possibly relates to deleterious From the Department of Cardiology, University Hospital Groningen, Groningen, The Netherlands. Dr. Van Gelder was supported by The Netherlands Heart Foundation, grant 94.014. Address for reprints: Harry J.G.M. Crijns, MD, Department of Cardiology, Thoraxcenter, University Hospital, Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. ©1999 by Excerpta Medica, Inc. All rights reserved.
PHARMACOLOGIC CONVERSION OF PAROXYSMAL AF AND ATRIAL FLUTTER Paroxysmal AF has a high tendency to convert spontaneously (Figure 1).6,7 Danias et al7 identified 356 patients (45% male, mean age 68 ⫾ 16 years) with AF ⬍72 hours duration. Spontaneous conversion occurred in up to 70% of patients, predominantly in patients with AF for ⬍24 hours. Converting AF or atrial flutter either electrically or with drugs depends on efficacy and safety, acceptance of either strategy by patient and physician, and the stability of the patient. In an emergency situation, such as in AF with hemodynamic instability or fast ventricular rate in the setting of Wolff–Parkinson–White (WPW) syndrome, 0002-9149/99/$20.00 PII S0002-9149(99)00715-8
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TABLE I Advantages and Disadvantages of Pharmacologic Versus Electrical Cardioversion of Atrial Fibrillation (AF) and Flutter Pharmacologic Cardioversion Advantages
● ● ●
Disadvantages
● ● ● ● ●
Electrical Cardioversion
No need for anesthesia “Pill-in-the-pocket” approach after proving feasibility May be repeated immediately Negative inotropic effect Proarrhythmia Time consuming Only effective if AF is of short duration Thromboembolism risk
● ● ● ● ●
Immediate effect Highly effective, even in long-lasting AF Safe in hemodynamically unstable patients General anesthesia needed Thromboembolism risk
FIGURE 1. Conversion of paroxysmal atrial fibrillation <3 days. Conversion rates in relation to time after start of the infusion found in studies investigating the efficacy of class IC (flecainide and propafenone), class IA and III drugs (procainamide, quinidine, sotalol, ibutilide, dofetilide), and amiodarone are presented. The curve indicating placebo conversion was constructed from placebo conversion rates. Class IC drugs appear most efficacious. Note the late onset of conversion with amiodarone. (Adapted from Eur Heart J.6)
immediate DC cardioversion is appropriate. Conversely, if the attack in the setting of WPW is relatively well tolerated, intravenous flecainide8 (not approved in the United States) or procainamide may be used. In hemodynamically stable patients, antiarrhythmic drugs can be administered to accelerate restoration of sinus rhythm. Figure 1 shows conversion rates with placebo and various antiarrhythmic drugs in recent-onset AF. It demonstrates that, with time, the cumulative conversion rate increases both on placebo and drugs. Although the different data points do not represent direct comparisons, it is clear that drugs facilitate conversion and that class IC drugs are most effective compared with agents from class III.6 Thus, class IC drugs are first-choice therapy for conversion of an acute paroxysm of AF. Conversion rates up to 90% are found 1 hour after intravenous flecainide or propafenone. Success of treatment is strongly related to the previous duration of AF. Unfortunately, intravenous class IC antiarrhythmic drugs are not available in the United States. However, both flecainide and 148R THE AMERICAN JOURNAL OF CARDIOLOGY姞
propafenone can also be administered orally with success rates of ⬎70% at 8 hours.6 Oral drug conversion may be self-administered only if the patient is clinically stable and if the agent is safe and effective in-hospital.6 Conditions in which class IC antiarrhythmic drugs should not be administered for this indication include heart failure, presence of impaired cardiac function, acute ischemia, known sick sinus syndrome, or atrioventricular conduction disturbances. In these patients, proarrhythmic effects or conduction disturbances may occur.9 –11 Although class IC drugs may be considered first-choice therapy for AF, amiodarone is recommended for hemodynamically compromised patients because of its less negative inotropic effect, and even if unsuccessful for conversion, it may control the ventricular rate.12 For acute conversion of AF, intravenous class IA drugs and sotalol are considered ineffective, which only became apparent after these drugs had been used as “active” comparators in trials studying new class III agents.13 The newer class III drug ibutilide, with maximal early conversion rates of
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47%, is also less effective than class IC drugs.14 Digitalis,  blockers, and calcium antagonists are ineffective for acute conversion of AF.6,15,16 In contrast, class III antiarrhythmic drugs, including ibutilide, are more effective than class IC drugs for the conversion of atrial flutter.14,17 A comparison between intravenous ibutilide and sotalol indicated that ibutilide is more effective for conversion of atrial flutter.18 However, proarrhythmic events (torsade de pointes) were more common in ibutilide-treated patients (7.3% vs 3.7%). Clearly, more controlled data are needed in this area, especially on proarrhythmic effects.14,17,18
PHARMACOLOGIC CONVERSION OF PERSISTENT ATRIAL FIBRILLATION Class III and class IA antiarrhythmic drugs seem more effective than class IC drugs for chemical conversion of persistent AF (duration of AF ⬎24 – 48 hours, no spontaneous conversion).18 Oral amiodarone and quinidine are successful in restoring sinus rhythm in approximately 20% to 50%, respectively, of patients with persistent AF. Amiodarone may convert up to 20% of refractory AF and atrial flutter patients,19 obviating electrical cardioversion. Preliminary data suggest that ibutilide and the class III drug dofetilide may convert persistent AF of longer duration, even in patients with impaired cardiac function, but safety may be an issue.14,18,20 An advantage of amiodarone is its ability to lower ventricular rates before conversion, whereas not only quinidine but also class IC drugs may be associated with an uncontrolled ventricular rate. Other problems with chronic oral drugs include torsade de pointes at conversion (class IA and III drugs, except amiodarone, which has a low proarrhythmia risk) and paradoxically, rapid ventricular rates due to enhanced atrioventricular conduction (class IC drugs). Thus, prolonged out-of-hospital loading seems to be safe only with amiodarone.
DC ELECTRICAL CARDIOVERSION OF AF OR ATRIAL FLUTTER DC electrical cardioversion is an effective method for terminating both paroxysmal and persistent AF. Its success rate is 70 –90%. Usually the anterior-lateral paddle position is applied, but a randomized comparison with the alternative anterior-posterior paddle position is lacking. Success of DC shock is related to several clinical parameters: First, and of greatest importance, previous arrhythmia of long duration significantly reduces its success rate.1,21,22 Other parameters lowering its success rate are higher age and larger left atrial size. Based on data from numerous studies, DC electrical cardioversion for persistent AF is unlikely to succeed in patients with AF ⬎3 years or left atrial size ⬎60 mm (long-axis view). Success of cardioversion is a matter of definition and may have consequences for the selection of patients for the serial cardioversion approach and for an implantable atrial defibrillator. In fact, there is no accepted definition. For practical reasons, we consider defibrillation successful if sinus rhythm lasts at least a few hours after the shock, (i.e.,
the minimum time interval our clinical cardioversion protocol allows until discharge of the patient). Lown and coworkers21 counted immediate restoration of sinus rhythm, presumably lasting from a few minutes to 1 hour. It is not known whether patients with very early versus those with later subacute recurrences respond differently to a serial cardioversion strategy or the implantable defibrillator. However, it may be hypothesized that patients with persistent AF maintaining sinus rhythm for a few days may benefit from repeated prompt cardioversions at the time of AF recurrence. Hypothetically, due to a longer period in sinus rhythm and only a short period in AF, electrophysiologic5 and (ultra)structural3,4,23 alterations favoring persistence of AF may be reversed progressively each time sinus rhythm is restored, thereby enhancing long-term maintenance of sinus rhythm.
LATE CONVERSION OF PAROXYSMAL AND PERSISTENT ATRIAL FIBRILLATION A wait-and-see approach may be adopted using oral amiodarone with late DC conversion if amiodarone fails to convert paroxysmal or persistent AF. Although the consequences of remodeling seem to dictate early conversion, for some patients the waitand-see approach may be preferable, as it is more convenient and prevents hospital admission. An example of such a strategy is amiodarone loading for 4 – 6 weeks followed by DC cardioversion if AF does not convert chemically.19,24 In the case of late conversion of paroxysmal AF, class IC antiarrhythmic drugs should not be instituted during AF or atrial flutter, as enhanced atrioventricular conduction, proarrhythmia, and conduction disturbances are more likely to occur during higher heart rates present during the arrhythmia. Sotalol, although not effective for acute conversion, may be an alternative because it effectively reduces heart rate, thereby enhancing restoration of sinus rhythm, possibly by ameliorating left atrial dilatation. Unfortunately, this strategy may lead to torsade de pointes at the time of conversion to sinus rhythm and should therefore be applied after try-out in-hospital to monitor adverse events.
HYBRID THERAPY In a hybrid approach, drugs may be used to enhance DC conversion and prevent acute recurrences after conversion. Advantages of this approach are that at the moment of restoration of sinus rhythm, adequate plasma levels are present, lowering (sub)acute relapses, which in turn improves outcome of the serial cardioversion approach (Figure 2). Furthermore, chemical conversion may occur and, hypothetically, certain drugs may prevent or reverse atrial remodeling. In contrast, loading may increase the defibrillation threshold, especially if class IC drugs are used, and warrants a longer hospitalization due to the risk of proarrhythmic events during loading. Biancioni et al25 recently described the beneficial effects of oral inhospital loading with the class IC antiarrhythmic drug A SYMPOSIUM: CARDIAC ARRHYTHMIAS
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FIGURE 2. Hypothetical curve demonstrating the time course of relapses of atrial fibrillation after restoration of sinus rhythm. Note that most relapses (40 –50%) occur during the first 2 weeks after restoration of sinus rhythm.
propafenone for 48 hours. Compared with those who were randomized to placebo, a comparable number of patients were successfully cardioverted using DC shock (84% vs 83%). However, at discharge after 48 hours, significantly more patients randomized to propafenone were in sinus rhythm (74% vs 53%, p ⬍0.05). Evidence that pretreatment with the calcium antagonist verapamil during AF may improve outcome of the cardioversion strategy is, so far, only observational. In a nonrandomized retrospective study in 61 patients with persistent AF, multivariate analysis revealed that the use of intracellular calcium-lowering drugs during AF (to control the ventricular rate) was the only significant variable related to maintenance of sinus rhythm after cardioversion.26 Additional evidence was demonstrated in a study investigating the efficacy of amiodarone loading on chemical conversion in patients with persistent AF. One of the parameters significantly influencing amiodarone conversion was concomitant treatment with calcium-lowering drugs.24 Preliminary prospective data confirm this observation.27
THROMBOEMBOLIC COMPLICATIONS RELATED TO CARDIOVERSION: STUNNING, HIBERNATION, OR BOTH? Spontaneous, chemical, but especially electrical cardioversion of AF may lead to stunning of the atria as detected on an echocardiogram.28 –30 The echocardiographic definition of stunning is standstill of the atrial wall, atrial dilatation, the emergence of spontaneous echo contrast, and the development of intraatrial thrombi, especially in the left atrial appendage. 150R THE AMERICAN JOURNAL OF CARDIOLOGY姞
The term stunning in the setting of ischemia refers to a postischemic situation in which myocardium is viable but does not function (absence of contraction).31 If blood flow is not restored but remains minimal, this situation may lead to hibernation, especially in the case of repetitive stunning. Hibernation is characterized by specific microscopic findings. Recently, Ausma and Borgers4,32 have shown that the atria harboring chronic AF show hibernation, which is similar to that found in intermittent ischemia. In part, one has to deal with a semantic problem. Characterizing the postconversion situation as stunning does not seem correct; if anything, there is hibernation rather than stunning, especially in patients with long-lasting AF. Using the term stunning to indicate postshock or postchemical cardioversion spontaneous echo contrast suggests that the act of electrical shock or the act of cardioversion itself is responsible for the spontaneous echo contrast and the associated atrial thombogenicity in the atria. Although conversion to sinus rhythm is crucial for the emergence of spontaneous echo contrast, it can only emerge when AF is chronic rather than acute. This means that the duration of AF33,34 and the development of a pathoanatomical picture of hibernation (and possibly associated with endothelial endocardial dysfunction with an increase in von Willebrand factor and soluble thrombomodulin as indicators of endothelial dysfunction and indicators of thrombogenicity)35 form the basis of so called “postconversion stunning.”
CONCLUSIONS The decision whether pharmacologic or electrical cardioversion should be applied depends on several parameters. The first step is to evaluate hemodynamic
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stability. Immediate cardioversion using DC shock rather than intravenous drugs may be indicated. The next step is to assess the duration of AF, because the longer the arrhythmia exists the less successful chemical conversion is. A third step may be to decide whether the conversion should be effected acutely or a wait-and-see procedure should be followed. As a guideline, the following strategy can be applied: For the acute conversion of paroxysmal AF, start a class IC antiarrhythmic drug in hemodynamically stable patients. Intravenous sotalol and other class III antiarrhythmic drugs are not useful for acute conversion of paroxysmal AF. In hemodynamically unstable patients with AF of short duration, DC electrical cardioversion is first-choice therapy. Avoid intravenous antiarrhythmic drugs if AF has been long-standing (arbitrarily: longer than a few days/weeks) because they do not work very well in long-standing AF. On the other hand, in the persistent form of AF, oral amiodarone may be effective in a wait-and-see strategy, with late DC conversion if amiodarone fails. Paroxysmal atrial flutter may be terminated by class III drugs but not by class IC drugs. Stunning (or hibernation) of the atria occurs in AF of longer duration but is dependent on conversion to sinus rhythm. However, it does not depend on the mode of conversion. 1. Van Gelder IC, Crijns HJGM, Tieleman RG, Bru¨gemann J, De Kam PJ,
Gosselink ATM, Verheugt FWA, Lie KI. Value and limitation of electrical cardioversion in patients with chronic atrial fibrillation: importance of arrhythmia risk factors and oral anticoagulation. Arch Intern Med 1996;156:2585–2592. 2. Sopher SM, Camm AJ. Atrial fibrillation: maintenance of sinus rhythm versus rate control. Am J Cardiol 1996;77(suppl):24A–38A. 3. Sanfilippo AJ, Abascal VM, Sheehan M, Oertel LB, Harrigan P, Hughes RA, Weyman AE. Atrial enlargement as a consequence of atrial fibrillation. Circulation 1990;82:792–797. 4. Ausma J, Wijffels M, Thone JF, Wouters L, Allessie M, Borgers M. Structural changes of atrial myocardium due to sustained atrial fibrillation in the goat. Circulation 1997;96:3157–3163. 5. Wijffels MCEF, Kirchof CJHJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation: a study in awake chronically instrumented goats. Circulation 1995;92:1954 –1968. 6. Fresco C, Proclemer A, on behalf of the PAFIT-2 Investigators. Management of recent onset atrial fibrillation. Eur Heart J 1996;17(suppl C):41– 47. 7. Danias PG, Caulfield TA, Weigner MJ, Silverman DI, Manning WJ. Likelihood of spontaneous conversion of atrial fibrillation to sinus rhythm. J Am Coll Cardiol 1998;31:588 –594. 8. Crijns HJ, Den Heijer P, Van Wijk LM, Lie KI. Successful use of flecainide in atrial fibrillation with rapid ventricular rate in the Wolff-Parkinson-White syndrome. Am Heart J 1989;115:1317–1321. 9. Levine JH, Morganroth J, Kadish AH. Mechanism and risk factors for proarrhythmia with type IA compared with IC antiarrhythmic drug therapy. Circulation 1989;80:1063–1069. 10. Murgatroyd FD, Camm AJ. Atrial arrhythmias. Lancet 1993;341:1317–1322. 11. Flaker GC, Blackshear JL, McBride R, Kronmal RA, Halperin JL, Hart RG, on behalf of the Stroke Prevention in Atrial Fibrillation Investigators. Antiarrhythmic drug therapy and cardiac mortality in atrial fibrillation. J Am Coll Cardiol 1992;20:527–532. 12. Hou Z-Y, Chang M-S, Chen C-Y, Tu M-S, Lin S-L, Chiang H-T, Woosley RL. Acute treatment of recent-onset atrial fibrillation and flutter with a tailored dosing regimen of intravenous amiodarone: a randomized, digoxin-controlled study. Eur Heart J 1995;16:521–528. 13. Reisinger J, Gatterer E, Heinze G, Wiesinger K, Zeindlhofer E, Gattermeier M, Poelzl G, Kratzer H, Ebner A, Hohenwallner W, Lenz K, Slany J, Kuhn P.
Prospective comparison of flecainide versus sotalol for immediate cardioversion of atrial fibrillation. Am J Cardiol 1998;81:1450 –1454. 14. Stambler BS, Wood MA, Ellenbogen KA, Perry KT, Wakefield LK, VanderLugt JT, and the Ibutilide Repeat Dose Study investigators. Efficacy and safety of repeated intravenous doses of ibutilide for rapid conversion of atrial flutter or fibrillation. Circulation 1996;94:1613–1621. 15. Falk RH, Knowlton AA, Bernard SA, Gotlieb NE, Battinelli NJ. Digoxin for converting recent-onset atrial fibrillation to sinus rhythm. Ann Intern Med 1987; 106:503–506. 16. Noc M, Stajer D, Horvat M. Intravenous amiodarone versus verapamil for acute conversion of paroxysmal atrial fibrillation to sinus rhythm. Am J Cardiol 1990;65:679 – 680. 17. Crijns HJGM, Van Gelder IC, Kingma JH, Dunselman PHJM, Gosselink ATM, Lie KI. Atrial flutter can be terminated by a class III antiarrhythmic drug but not by a class IC drug. Eur Heart J 1994;15:1403–1408. 18. Vos MA, Golitsyn SR, Stangl K, Ruda MY, Van Wijk L, Harry JD, Perry KT, Touboul P, Steinbeck G, Wellens HJJ, for the Ibutilide/ Sotalol Comparator Study Group. Superiority of ibutilide (a new class III agent) over DL-sotalol in converting atrial flutter and atrial fibrillation. Heart 1998;79:568 –575. 19. Gosselink ATM, Crijns HJ, Van Gelder IC, Hillige H, Wiesfeld ACP, Lie KI. Low-dose amiodarone for maintenance of sinus rhythm after cardioversion of atrial fibrillation or flutter. JAMA 1992;267:3289 –3293. 20. Pedersen OD, The Diamond study group. Dofetilide in the treatment of atrial fibrillation in patients with impaired left ventricular function: atrial fibrillation in the Diamond study. (Abstr.) Circulation 1998;98:I-632. 21. Lown B. Electrical cardioversion of cardiac arrhythmias. Br Heart J 1967; 29:469 – 487. 22. Van Gelder IC, Crijns HJ, Van Gilst WH, Verwer R, Lie KI. Prediction of uneventful cardioversion and maintenance of sinus rhythm from direct-current electrical cardioversion of chronic atrial fibrillation and flutter. Am J Cardiol 1991;68:41– 46. 23. Bailey GWH, Braniff BA, Hancock EW, Cohn KE. Relation of left atrial pathology to AF in mitral valvular disease. Ann Intern Med 1968;69:13–20. 24. Tieleman RG, Gosselink ATM, Crijns HJGM, Van Gelder IC, Van Den Berg MP, De Kam PJ, Van Gilst WH, Lie KI. Efficacy, safety and determinants of conversion of atrial fibrillation and flutter with oral amiodarone. Am J Cardiol 1997;79:53–57. 25. Bianconi L, Mennuni M, Lukic V, Castro A, Chieffi M, Santini M. Effect of oral propafenone administration before electrical cardioversion of chronic atrial fibrillation: placebo controlled study. J Am Coll Cardiol 1996;28:700 –706. 26. Tieleman RG, Van Gelder IC, Crijns HJGM, De Kam PJ, Van Den Berg MP, Haaksma J, Van Der Woude HJ, Allessie MA. Early recurrences of atrial fibrillation after electrical cardioversion: a result of fibrillation-induced electrical remodeling of the atria? J Am Coll Cardiol 1998;31:167–173. 27. Natale A, Tomassoni G, Beheiry S, Kim YH, Pisano E, Leonelli F, Potenza M. Prospective randomized evaluation of combined therapy with amiodarone and a calcium antagonist for treatment of refractory atrial fibrillation. (Abstr.) Circulation 1998;98:I-103. 28. Grimm RA, Stewart WJ, Maloney JD, Cohen GI, Pearce GL, Salcedo EE, Klein AL. Impact of electrical cardioversion for atrial fibrillation on left atrial appendage function and spontaneous echo contrast: characterization by simultaneous transesophageal echocardiography. J Am Coll Cardiol 1993;22:1359 – 1366. 29. Fatkin D, Kelly RP, Feneley MP. Relations between left atrial appendage blood flow velocity, spontaneous echocardiographic contrast and thromboembolic risk in vivo. J Am Coll Cardiol 1994;23:961–969. 30. Grimm RA, Leung DY, Black IW, Stewart WJ, Thomas JD, Klein AL. Left atrial appendage “stunning” after spontaneous conversion of atrial fibrillation demonstrated by transesophageal Doppler echocardiography. Am Heart J 1995; 130:174 –176. 31. Marban E. Myocardial stunning and hibernation: the physiology behind the colloquialisms. Circulation 1991;83:681– 688. 32. Ausma J, Wijffels M, Van Eys G, Koide M, Ramaekers F, Allessie M, Borgers M. Dedifferentiation of atrial cardiomyocytes as a result of chronic atrial fibrillation. Am J Pathol 1997;151:985–997. 33. Manning WJ, Silverman DI, Katz SE, Riley MF, Come PC, Doherty RM, Munson JT, Douglas PS. Impaired left atrial mechanical function after cardioversion: relation to the duration of atrial fibrillation. J Am Coll Cardiol 1994;23: 1535–1540. 34. Verhorst PM, Kamp O, Visser CA, Verheugt FW. Left atrial appendage flow velocity assessment using transesophageal echocardiography in nonrheumatic atrial fibrillation and systemic embolism. Am J Cardiol 1993;71:192–196. 35. Oltrona L, Broccolino M, Merlini PA, Spinola A, Pezzano A, Mannucci PM. Activation of the hemostatic mechanism after pharmacologic cardioversion of acute nonvalvular atrial fibrillation. Circulation 1997;95:2003–2006.
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in-hospital trials. In persistent AF, DC conversion is preferred because drugs are particularly ineffective if the arrhythmia has lasted >24 – 48 hours. The latter probably relates to electrical and anatomical remodeling of the atria during ongoing atrial fibrillation and flutter. Nevertheless, a wait-and-see approach using, for example, oral amiodarone may be adopted with late DC conversion if the drug fails to convert persistent AF. However, the consequences of remodeling seem to dictate an early conversion. In this respect, echocardiography-guided DC cardioversion may become increasingly important in AF. It will prevent treatment resistance and potentially reduces embolic complications. In a hybrid approach, antiarrhythmic drugs may be used to enhance DC conversion and prevent (sub)acute recurrences of AF. However, it may increase the defibrillation threshold, especially if class IC drugs are used. New treatment options such as automatic defibrillation (implantable atrioverter) are still investigational. 䊚1999 by Excerpta Medica, Inc. Am J Cardiol 1999;84:147R–151R
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electrical and (ultra)structural remodeling of the atria.3,4 It is generally believed that sinus rhythm has several potential benefits compared with atrial fibrillation (AF): relief of symptoms, reduced risk of thromboembolic complications, and an improved exercise tolerance. Because electrical and anatomical remodeling in the atria seem to affect the chance of restoration of sinus rhythm (“atrial fibrillation begets atrial fibrillation”),5 early cardioversion— either pharmacologic or electrical—should be attempted.
fter establishing the indication for conversion, the question arises whether it should be achieved by pharmacologic or direct current (DC) electrical cardioversion. In this respect, the advantages and disadvantages of both strategies should be carefully weighed (Table I). In general, DC cardioversion is more effective than pharmacologic cardioversion. However, it necessitates general anesthesia with potentially severe complications. Not only are drugs less effective, but time to conversion is unpredictable and may be relatively long, especially with oral therapy. Furthermore, antiarrhythmic drugs may induce bradycardia, tachycardia due to enhanced atrioventricular conduction, ventricular proarrhythmia, and acute heart failure. Both pharmacologic and electrical cardioversion, and maintenance of sinus rhythm thereafter, become more difficult the longer the arrhythmia exists.1,2 Recent data revealed that the latter possibly relates to deleterious From the Department of Cardiology, University Hospital Groningen, Groningen, The Netherlands. Dr. Van Gelder was supported by The Netherlands Heart Foundation, grant 94.014. Address for reprints: Harry J.G.M. Crijns, MD, Department of Cardiology, Thoraxcenter, University Hospital, Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. ©1999 by Excerpta Medica, Inc. All rights reserved.
PHARMACOLOGIC CONVERSION OF PAROXYSMAL AF AND ATRIAL FLUTTER Paroxysmal AF has a high tendency to convert spontaneously (Figure 1).6,7 Danias et al7 identified 356 patients (45% male, mean age 68 ⫾ 16 years) with AF ⬍72 hours duration. Spontaneous conversion occurred in up to 70% of patients, predominantly in patients with AF for ⬍24 hours. Converting AF or atrial flutter either electrically or with drugs depends on efficacy and safety, acceptance of either strategy by patient and physician, and the stability of the patient. In an emergency situation, such as in AF with hemodynamic instability or fast ventricular rate in the setting of Wolff–Parkinson–White (WPW) syndrome, 0002-9149/99/$20.00 PII S0002-9149(99)00715-8
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TABLE I Advantages and Disadvantages of Pharmacologic Versus Electrical Cardioversion of Atrial Fibrillation (AF) and Flutter Pharmacologic Cardioversion Advantages
● ● ●
Disadvantages
● ● ● ● ●
Electrical Cardioversion
No need for anesthesia “Pill-in-the-pocket” approach after proving feasibility May be repeated immediately Negative inotropic effect Proarrhythmia Time consuming Only effective if AF is of short duration Thromboembolism risk
● ● ● ● ●
Immediate effect Highly effective, even in long-lasting AF Safe in hemodynamically unstable patients General anesthesia needed Thromboembolism risk
FIGURE 1. Conversion of paroxysmal atrial fibrillation <3 days. Conversion rates in relation to time after start of the infusion found in studies investigating the efficacy of class IC (flecainide and propafenone), class IA and III drugs (procainamide, quinidine, sotalol, ibutilide, dofetilide), and amiodarone are presented. The curve indicating placebo conversion was constructed from placebo conversion rates. Class IC drugs appear most efficacious. Note the late onset of conversion with amiodarone. (Adapted from Eur Heart J.6)
immediate DC cardioversion is appropriate. Conversely, if the attack in the setting of WPW is relatively well tolerated, intravenous flecainide8 (not approved in the United States) or procainamide may be used. In hemodynamically stable patients, antiarrhythmic drugs can be administered to accelerate restoration of sinus rhythm. Figure 1 shows conversion rates with placebo and various antiarrhythmic drugs in recent-onset AF. It demonstrates that, with time, the cumulative conversion rate increases both on placebo and drugs. Although the different data points do not represent direct comparisons, it is clear that drugs facilitate conversion and that class IC drugs are most effective compared with agents from class III.6 Thus, class IC drugs are first-choice therapy for conversion of an acute paroxysm of AF. Conversion rates up to 90% are found 1 hour after intravenous flecainide or propafenone. Success of treatment is strongly related to the previous duration of AF. Unfortunately, intravenous class IC antiarrhythmic drugs are not available in the United States. However, both flecainide and 148R THE AMERICAN JOURNAL OF CARDIOLOGY姞
propafenone can also be administered orally with success rates of ⬎70% at 8 hours.6 Oral drug conversion may be self-administered only if the patient is clinically stable and if the agent is safe and effective in-hospital.6 Conditions in which class IC antiarrhythmic drugs should not be administered for this indication include heart failure, presence of impaired cardiac function, acute ischemia, known sick sinus syndrome, or atrioventricular conduction disturbances. In these patients, proarrhythmic effects or conduction disturbances may occur.9 –11 Although class IC drugs may be considered first-choice therapy for AF, amiodarone is recommended for hemodynamically compromised patients because of its less negative inotropic effect, and even if unsuccessful for conversion, it may control the ventricular rate.12 For acute conversion of AF, intravenous class IA drugs and sotalol are considered ineffective, which only became apparent after these drugs had been used as “active” comparators in trials studying new class III agents.13 The newer class III drug ibutilide, with maximal early conversion rates of
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47%, is also less effective than class IC drugs.14 Digitalis,  blockers, and calcium antagonists are ineffective for acute conversion of AF.6,15,16 In contrast, class III antiarrhythmic drugs, including ibutilide, are more effective than class IC drugs for the conversion of atrial flutter.14,17 A comparison between intravenous ibutilide and sotalol indicated that ibutilide is more effective for conversion of atrial flutter.18 However, proarrhythmic events (torsade de pointes) were more common in ibutilide-treated patients (7.3% vs 3.7%). Clearly, more controlled data are needed in this area, especially on proarrhythmic effects.14,17,18
PHARMACOLOGIC CONVERSION OF PERSISTENT ATRIAL FIBRILLATION Class III and class IA antiarrhythmic drugs seem more effective than class IC drugs for chemical conversion of persistent AF (duration of AF ⬎24 – 48 hours, no spontaneous conversion).18 Oral amiodarone and quinidine are successful in restoring sinus rhythm in approximately 20% to 50%, respectively, of patients with persistent AF. Amiodarone may convert up to 20% of refractory AF and atrial flutter patients,19 obviating electrical cardioversion. Preliminary data suggest that ibutilide and the class III drug dofetilide may convert persistent AF of longer duration, even in patients with impaired cardiac function, but safety may be an issue.14,18,20 An advantage of amiodarone is its ability to lower ventricular rates before conversion, whereas not only quinidine but also class IC drugs may be associated with an uncontrolled ventricular rate. Other problems with chronic oral drugs include torsade de pointes at conversion (class IA and III drugs, except amiodarone, which has a low proarrhythmia risk) and paradoxically, rapid ventricular rates due to enhanced atrioventricular conduction (class IC drugs). Thus, prolonged out-of-hospital loading seems to be safe only with amiodarone.
DC ELECTRICAL CARDIOVERSION OF AF OR ATRIAL FLUTTER DC electrical cardioversion is an effective method for terminating both paroxysmal and persistent AF. Its success rate is 70 –90%. Usually the anterior-lateral paddle position is applied, but a randomized comparison with the alternative anterior-posterior paddle position is lacking. Success of DC shock is related to several clinical parameters: First, and of greatest importance, previous arrhythmia of long duration significantly reduces its success rate.1,21,22 Other parameters lowering its success rate are higher age and larger left atrial size. Based on data from numerous studies, DC electrical cardioversion for persistent AF is unlikely to succeed in patients with AF ⬎3 years or left atrial size ⬎60 mm (long-axis view). Success of cardioversion is a matter of definition and may have consequences for the selection of patients for the serial cardioversion approach and for an implantable atrial defibrillator. In fact, there is no accepted definition. For practical reasons, we consider defibrillation successful if sinus rhythm lasts at least a few hours after the shock, (i.e.,
the minimum time interval our clinical cardioversion protocol allows until discharge of the patient). Lown and coworkers21 counted immediate restoration of sinus rhythm, presumably lasting from a few minutes to 1 hour. It is not known whether patients with very early versus those with later subacute recurrences respond differently to a serial cardioversion strategy or the implantable defibrillator. However, it may be hypothesized that patients with persistent AF maintaining sinus rhythm for a few days may benefit from repeated prompt cardioversions at the time of AF recurrence. Hypothetically, due to a longer period in sinus rhythm and only a short period in AF, electrophysiologic5 and (ultra)structural3,4,23 alterations favoring persistence of AF may be reversed progressively each time sinus rhythm is restored, thereby enhancing long-term maintenance of sinus rhythm.
LATE CONVERSION OF PAROXYSMAL AND PERSISTENT ATRIAL FIBRILLATION A wait-and-see approach may be adopted using oral amiodarone with late DC conversion if amiodarone fails to convert paroxysmal or persistent AF. Although the consequences of remodeling seem to dictate early conversion, for some patients the waitand-see approach may be preferable, as it is more convenient and prevents hospital admission. An example of such a strategy is amiodarone loading for 4 – 6 weeks followed by DC cardioversion if AF does not convert chemically.19,24 In the case of late conversion of paroxysmal AF, class IC antiarrhythmic drugs should not be instituted during AF or atrial flutter, as enhanced atrioventricular conduction, proarrhythmia, and conduction disturbances are more likely to occur during higher heart rates present during the arrhythmia. Sotalol, although not effective for acute conversion, may be an alternative because it effectively reduces heart rate, thereby enhancing restoration of sinus rhythm, possibly by ameliorating left atrial dilatation. Unfortunately, this strategy may lead to torsade de pointes at the time of conversion to sinus rhythm and should therefore be applied after try-out in-hospital to monitor adverse events.
HYBRID THERAPY In a hybrid approach, drugs may be used to enhance DC conversion and prevent acute recurrences after conversion. Advantages of this approach are that at the moment of restoration of sinus rhythm, adequate plasma levels are present, lowering (sub)acute relapses, which in turn improves outcome of the serial cardioversion approach (Figure 2). Furthermore, chemical conversion may occur and, hypothetically, certain drugs may prevent or reverse atrial remodeling. In contrast, loading may increase the defibrillation threshold, especially if class IC drugs are used, and warrants a longer hospitalization due to the risk of proarrhythmic events during loading. Biancioni et al25 recently described the beneficial effects of oral inhospital loading with the class IC antiarrhythmic drug A SYMPOSIUM: CARDIAC ARRHYTHMIAS
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FIGURE 2. Hypothetical curve demonstrating the time course of relapses of atrial fibrillation after restoration of sinus rhythm. Note that most relapses (40 –50%) occur during the first 2 weeks after restoration of sinus rhythm.
propafenone for 48 hours. Compared with those who were randomized to placebo, a comparable number of patients were successfully cardioverted using DC shock (84% vs 83%). However, at discharge after 48 hours, significantly more patients randomized to propafenone were in sinus rhythm (74% vs 53%, p ⬍0.05). Evidence that pretreatment with the calcium antagonist verapamil during AF may improve outcome of the cardioversion strategy is, so far, only observational. In a nonrandomized retrospective study in 61 patients with persistent AF, multivariate analysis revealed that the use of intracellular calcium-lowering drugs during AF (to control the ventricular rate) was the only significant variable related to maintenance of sinus rhythm after cardioversion.26 Additional evidence was demonstrated in a study investigating the efficacy of amiodarone loading on chemical conversion in patients with persistent AF. One of the parameters significantly influencing amiodarone conversion was concomitant treatment with calcium-lowering drugs.24 Preliminary prospective data confirm this observation.27
THROMBOEMBOLIC COMPLICATIONS RELATED TO CARDIOVERSION: STUNNING, HIBERNATION, OR BOTH? Spontaneous, chemical, but especially electrical cardioversion of AF may lead to stunning of the atria as detected on an echocardiogram.28 –30 The echocardiographic definition of stunning is standstill of the atrial wall, atrial dilatation, the emergence of spontaneous echo contrast, and the development of intraatrial thrombi, especially in the left atrial appendage. 150R THE AMERICAN JOURNAL OF CARDIOLOGY姞
The term stunning in the setting of ischemia refers to a postischemic situation in which myocardium is viable but does not function (absence of contraction).31 If blood flow is not restored but remains minimal, this situation may lead to hibernation, especially in the case of repetitive stunning. Hibernation is characterized by specific microscopic findings. Recently, Ausma and Borgers4,32 have shown that the atria harboring chronic AF show hibernation, which is similar to that found in intermittent ischemia. In part, one has to deal with a semantic problem. Characterizing the postconversion situation as stunning does not seem correct; if anything, there is hibernation rather than stunning, especially in patients with long-lasting AF. Using the term stunning to indicate postshock or postchemical cardioversion spontaneous echo contrast suggests that the act of electrical shock or the act of cardioversion itself is responsible for the spontaneous echo contrast and the associated atrial thombogenicity in the atria. Although conversion to sinus rhythm is crucial for the emergence of spontaneous echo contrast, it can only emerge when AF is chronic rather than acute. This means that the duration of AF33,34 and the development of a pathoanatomical picture of hibernation (and possibly associated with endothelial endocardial dysfunction with an increase in von Willebrand factor and soluble thrombomodulin as indicators of endothelial dysfunction and indicators of thrombogenicity)35 form the basis of so called “postconversion stunning.”
CONCLUSIONS The decision whether pharmacologic or electrical cardioversion should be applied depends on several parameters. The first step is to evaluate hemodynamic
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stability. Immediate cardioversion using DC shock rather than intravenous drugs may be indicated. The next step is to assess the duration of AF, because the longer the arrhythmia exists the less successful chemical conversion is. A third step may be to decide whether the conversion should be effected acutely or a wait-and-see procedure should be followed. As a guideline, the following strategy can be applied: For the acute conversion of paroxysmal AF, start a class IC antiarrhythmic drug in hemodynamically stable patients. Intravenous sotalol and other class III antiarrhythmic drugs are not useful for acute conversion of paroxysmal AF. In hemodynamically unstable patients with AF of short duration, DC electrical cardioversion is first-choice therapy. Avoid intravenous antiarrhythmic drugs if AF has been long-standing (arbitrarily: longer than a few days/weeks) because they do not work very well in long-standing AF. On the other hand, in the persistent form of AF, oral amiodarone may be effective in a wait-and-see strategy, with late DC conversion if amiodarone fails. Paroxysmal atrial flutter may be terminated by class III drugs but not by class IC drugs. Stunning (or hibernation) of the atria occurs in AF of longer duration but is dependent on conversion to sinus rhythm. However, it does not depend on the mode of conversion. 1. Van Gelder IC, Crijns HJGM, Tieleman RG, Bru¨gemann J, De Kam PJ,
Gosselink ATM, Verheugt FWA, Lie KI. Value and limitation of electrical cardioversion in patients with chronic atrial fibrillation: importance of arrhythmia risk factors and oral anticoagulation. Arch Intern Med 1996;156:2585–2592. 2. Sopher SM, Camm AJ. Atrial fibrillation: maintenance of sinus rhythm versus rate control. Am J Cardiol 1996;77(suppl):24A–38A. 3. Sanfilippo AJ, Abascal VM, Sheehan M, Oertel LB, Harrigan P, Hughes RA, Weyman AE. Atrial enlargement as a consequence of atrial fibrillation. Circulation 1990;82:792–797. 4. Ausma J, Wijffels M, Thone JF, Wouters L, Allessie M, Borgers M. Structural changes of atrial myocardium due to sustained atrial fibrillation in the goat. Circulation 1997;96:3157–3163. 5. Wijffels MCEF, Kirchof CJHJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation: a study in awake chronically instrumented goats. Circulation 1995;92:1954 –1968. 6. Fresco C, Proclemer A, on behalf of the PAFIT-2 Investigators. Management of recent onset atrial fibrillation. Eur Heart J 1996;17(suppl C):41– 47. 7. Danias PG, Caulfield TA, Weigner MJ, Silverman DI, Manning WJ. Likelihood of spontaneous conversion of atrial fibrillation to sinus rhythm. J Am Coll Cardiol 1998;31:588 –594. 8. Crijns HJ, Den Heijer P, Van Wijk LM, Lie KI. Successful use of flecainide in atrial fibrillation with rapid ventricular rate in the Wolff-Parkinson-White syndrome. Am Heart J 1989;115:1317–1321. 9. Levine JH, Morganroth J, Kadish AH. Mechanism and risk factors for proarrhythmia with type IA compared with IC antiarrhythmic drug therapy. Circulation 1989;80:1063–1069. 10. Murgatroyd FD, Camm AJ. Atrial arrhythmias. Lancet 1993;341:1317–1322. 11. Flaker GC, Blackshear JL, McBride R, Kronmal RA, Halperin JL, Hart RG, on behalf of the Stroke Prevention in Atrial Fibrillation Investigators. Antiarrhythmic drug therapy and cardiac mortality in atrial fibrillation. J Am Coll Cardiol 1992;20:527–532. 12. Hou Z-Y, Chang M-S, Chen C-Y, Tu M-S, Lin S-L, Chiang H-T, Woosley RL. Acute treatment of recent-onset atrial fibrillation and flutter with a tailored dosing regimen of intravenous amiodarone: a randomized, digoxin-controlled study. Eur Heart J 1995;16:521–528. 13. Reisinger J, Gatterer E, Heinze G, Wiesinger K, Zeindlhofer E, Gattermeier M, Poelzl G, Kratzer H, Ebner A, Hohenwallner W, Lenz K, Slany J, Kuhn P.
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