Electrophysiology of the electrocardiographic changes of atrial fibrillation

Journal of Electrocardiology 39 (2006) S174 – S179 www.elsevier.com/locate/jelectrocard

Electrophysiology of the electrocardiographic changes of atrial fibrillation Rory Childers Section of Cardiology, Department of Medicine, University of Chicago, Chicago Illinois 60637, USA Received 23 May 2006; accepted 31 May 2006

Abstract

Keywords:

The history of atrial fibrillation is described in terms of its electrocardiographic delineation, characteristics and clinical associations. The variant configurations are described and their relationship to rhythm duration and cardioversion success. The inter-relationship of fibrillation with flutter and their diagnostic differences are reviewed. The electrophysiologic basis of atrial remodeling is exemplified, together with its relationship to failure of rate adaptation of the atrial refractory period. Electric countershock causes an acute abbreviation of the atrial refractory period as does the induction of hyperthyroidism in the experimental animal. Current theories of the mechanism of fibrillation and the issue of originating pulmonary venous foci are reviewed. The lack of protection from ventricular fibrillation that exists with preexcitation via an accessory pathway is discussed in terms of the teleological role of orthograde downstream refractory periods. D 2006 Elsevier Inc. All rights reserved. Atrial fibrillation; f Waves; AV block

Already known for Stokes-Adams syncope, the first mention of atrial fibrillation was given by Robert Adams1 in the Dublin in 1827; he related it to mitral stenosis. Hering2 in 1903 called it arrhythmia perpetuus; Rothenburger and Winterburg3 used the term Vorhoflimmern, which translates as fibrillation. But the most complete description of its electrocardiographic features was rendered by Sir Thomas Lewis4 in 1913, he summarized the findings as the absence of a P wave to the left of each QRS complex; the presence of oscillatory waves—lower case or small f waves—which are irregular as to configuration, amplitude, rate, and reproducibility in sequential cycles. The large capitalized F wave is reserved for atrial flutter. The small f waves, like P waves, are best seen in leads II and V1 (next best, III and V2); the atrial rate is 320 to 520 bpm. Visibility of f waves varies inversely with ventricular rate, which, untreated, varies from the 80s to the 180s. Rapid rates are associated with exercise, hypoxemia, cardiac failure, the WolffParkinson-White (WPW) syndrome, and clinical states in which sinus tachycardia would be expected (eg, the first few postoperative hours). The R-R interval is irregularly irregular, but diagnosis should not hang on this feature. The configuration of f waves varies from small humps to taller spikes (dfineT versus dcoarseT); humps are generally faster than spikes and more likely to be present in chronic fibrillation. The faster the rate, the less variable is the R-R interval. Fibrillation can be presumed by irregularity alone if E-mail address: [email protected]. 0022-0736/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.jelectrocard.2006.05.012

no f waves or P waves are visible. It is often missed in the presence of continuous ventricular pacing.5 Rate slowing is achieved by the promotion of impaired conduction and an expanded refractory period within the AV node. This is achieved by drugs, by tonic vagal effect, and often by acute inferior myocardial infarction. Prolonged fast ventricular rates (weeks to months) can induce a tachycardiomyopathy but not if the average rate is less than 120 bpm.6 Electrocardiographically, the dend pointT of rate control is signified when the longest R-R intervals become equal: the development of competing junctional escape pacemakers. At first these are single, then sequential, or if AV nodal block attains the third degree, continuous and regular. Fibrillation precludes the diagnosis of first-degree AV block, the dropped beats of types 1 and 2 second-degree AV block, atrial conduction defects, and atrial enlargement. Junctional premature beats are difficult to recognize, not so escapes. Occasionally R-R patterns in fibrillation superficially suggest an organized rhythm. There is a statistical tendency for rapid and slow cadences respectively to stick together. R-R interval variation serves to demonstrate cycle length– dependent T-wave change. The ST-segment depression of digitalis effect becomes more accentuated as the ventricular response speeds up. The amplitude of f waves has no relationship to underlying pathology or chamber size but is perhaps greater with short paroxysms.7 Fibrillation is eventually inevitable in untreated tight mitral stenosis. Its incidence is 30% after coronary bypass surgery (most commonly on day 3 when atrial conduction is maximally

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Fig. 1. Lead V1. A, The f waves are of spike and rounded bottom. They invert in the manner of ventricular torsade de pointes. The QRS complexes are digitally excised in the magnified strip shown in panel (B).

prolonged8) and postpericardiectomy. It is less common and ominous in aortic insufficiency and hypertrophic cardiomyopathy. It is found in 5% of subjects older than 72.9 The f waves of coarse atrial fibrillation form clusters showing rounded nadirs and spiky tops or vice versa. Such clusters may invert in a single strip, going from seemingly negative to positive, often with a low voltage interlude in between. Such cadences are strongly reminiscent of QRS behavior in torsade de pointes (Fig. 1). The low atrial voltage interlude is not due to a spatial shift in the f wave vector but is due to intramyocardial cancellation. The shift from one polarity to its reverse is probably related to the accession of a new major wavelet. The pattern carries no predictive elements as to arrest of the fibrillation. When the rate of f spikes approaches 300 but remain irregular, the rhythm is often unusefully called flutterfibrillation. The latter has been attributed to dissimilar rhythms in the two atria, or in the right atrium, wherein one of them is regular.10 More recently, the notion of simultaneous flutter and fibrillation has been entertained.11 If flutter waves can be attributed entirely to right atrial events, then the phenomenology in the left atrium is, even under usual circumstances, concealed from us.12 Maybe uniatrial fibrillation is more common than we think. Flutter is frequently simulated by artifact and by parkinsonian tremor. Discussion of the electrocardiographic aspects of clockwise and counterclockwise cavo-tricuspid isthmus-dependent right atrial flutter, atypical flutter, and left atrial flutter would require a separate paper. The frequent long-short R-R cadences in fibrillation idealize the opportunities for aberrant ventricular conduction, most commonly with functional right bundle branch block but with any of the known intraventricular conduction defects, incomplete or complete, single or in combination. Sustained aberration, simulating ventricular tachycardia, is

generally recognizable by morphological features and with rate and irregularity not greatly different from adjacent narrow QRS clusters.13 Because fibrillation involves a collectively abnormal electric state of the atrial myocyte population, it is appropriate to review how such a state can be gradually or suddenly induced—spontaneously or iatrogenically. The period of maximal expression of vagal nerve tone occurs at night. The minimum heart rate is then attained, and it might be presumed that at this critical time, the vagal form of atrial fibrillation is initiated. However, studies of this relatively uncommon form of intermittent fibrillation relate it to young males who get the paroxysms after meals,14 at night, but not at especially slow heart rates.15 The phenomenon has been studied by time and frequency domain analysis.16 Although the vagal impact on both heart rate and AV nodal conduction is entirely familiar, there is less clinical awareness of its other effects. It hyperpolarizes atrial resting membrane potential, thus increasing the dV/dT of the action potential that is shortened as is the duration of the refractory period. In addition, the vagus reduces contractility, thus weakening the atrial dkick.T An indirect demonstration of this physiologic phenomenon is seen in Fig. 2 when carotid massage achieves massive vagotonic effect in atrial flutter. At the moment of maximal AV block, the atrial rate increases from 264 to 300 bpm. The latter change might imply that the rate was determined by each right atrial reentrant wave front chewing the heels or refractory wake of the antecedent one. The action potentials and hence the atrial refractory periods are abbreviated by the vagal effect. When fibrillation shifts abruptly to flutter, the ventricular rate is always faster. Flutter often ddegeneratesT to fibrillation before changing to sinus rhythm. Digitalis in high therapeutic

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Fig. 2. Atrial flutter. Carotid stimulation causes marked AV block with long pauses and accelerates the atrial rate from 264 to 300 bpm.

doses will convert flutter to fibrillation in 70% of cases. Paroxysmal flutter is probably more often associated with an intra-atrial conduction defect (widened sinus P wave) than paroxysmal atrial fibrillation.17 In 50% of (generally younger) people, such fibrillation returns to sinus rhythm within 24 hours, whereas in 20%, it returns within 2 days. However, in 25%, it becomes permanent. Paroxysmal fibrillation is often dloneT and self-terminating18; if not, it is increasingly described as persistent: the arrhythmia is converted by drugs or cardioversion and remains as infrequent or frequent as the truly paroxysmal form. Permanent atrial fibrillation means the chronic form where cardioversion or drug conversion is likely to be entirely unsuccessful. The issue of left atrial enlargement and whether atriopathy is instrumental in

promoting both enlargement and thrombus formation remains problematic. The impact of cardioversion on the canine heart has been studied. DC shock instantly depolarizes sympathetic and vagal nerve terminals in the heart, releasing norepinephrine in the myocardia of both chambers and acetylcholine in the atrium and sinus node.19 The atrial action potential and refractory period are abruptly shortened (Fig. 3). There is a brief increase in atrial excitability signaled by the successful excitation of subthreshold pulses. AV nodal block is promoted. There is an efflux of potassium from the myocardium. Acetylcholine release also reduces atrial contractility. All these changes are transient, but one cannot avoid noting that they are the very features that, if persistent, would

Fig. 3. DC shock in the dog. This atrial suction electrogram shows immediate shortening of the action potential. Note the brief pulseless postshock ventricular tachycardia before the return of sinus rhythm.

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typify an atrium that is likely to return to the fibrillatory state. It is known for instance that the stronger the postconversion atrial kick, the more likely sinus rhythm will be retained. The transient postshock shortening of the atrial refractory period explains why the same acceleration of atrial rate was seen when the shock fails to convert atrial flutter.20 In the canine fibrillating heart, vagal stimulation (which dramatically reduces the visible squirm of the atria) is sometimes successfully used to restore sinus rhythm. The latter atrial fibrillation (AF) returns after abruptly arresting the vagal train of stimuli. It is postulated that the simultaneous mass dissolution of the released acetylcholine permits the cells to line up in some fashion preparatory for organized depolarization. Exactly the same method has been rarely but successfully used in humans.21,22 The first complete description of cardiac involvement in hyperthyroidism is that of the Irish physician Robert Graves.23 The mechanism by which atrial fibrillation results has been demonstrated: rabbits fed thyroid over several weeks show, in the perfused Langendorff preparation, a profound shortening of action potential duration in the atrium and a high percentage of instant fibrillation when paced or prematurely stimulated.24 What is happening within the sinus node during atrial fibrillation? The number of atrial impulses penetrating this structure is dependent on the refractory period of the sinoatrial junction or node itself. More cogently: how easily can this refractory period contract with a greatly increased input frequency? Amid a plenitude of rabbit atria studies in the tissue bath,25 there is a paucity of information on this issue in the intact mammal. The refractory period contracted sluggishly with rate in one of our studies.26 If sinoatrial and atriosinal block preceded the fibrillation, it is possible that few impulses enter the node. Such was the case in the studies of Bonke et al.27 Following atrial pacing trains, at increasing rates, the sinus escape time remains constant so long as the pacing does not lower blood pressure. By way of contrast in the sick sinus syndrome, the faster the rate, bthe longer the wait.Q In the tachycardia-bradycardia syndrome,28 an atrial tachyarrhythmia, most commonly atrial fibrillation, stops abruptly with profound delay in the appearance of the first sinus escape—or indeed of any escape—atrial, junctional, or idioventricular: this is a generalized disorder of automaticity. In the case of the junction and ventricle, the delay is probably due to overdrive suppression of these subsidiary pacemakers by the rapid ventricular response to the fibrillation. The profound delay in the first sinus escape may in some cases be due to overdrive suppression of the sinus node by penetrating fibrillatory impulses. It is well established that QRS voltage varies greatly on a daily basis.29 From the point of view of electrocardiographic diagnostics, this diurnal variation is essentially inconsequential. Although P wave or f wave amplitude can vary perhaps for the same reasons as that of the QRS, selective low voltage of P waves and other atrial deflections is a known but neglected event. Its simplest expression is the computer call of junctional rhythm in a tracing with scarcely visible presystolic P waves. When the low voltage of fibrillatory

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f waves or flutter F waves is so marked as to render them invisible, there can be major diagnostic consequences. Digitalis intoxication causes the complete loss of atrial oscillations. Excess glycoside causes the closing down of gap junctions.30 Under such circumstances, atrial fibrillation with complete AV nodal block can, in the emergency department, be mistakenly regarded as simple junctional rhythm. The causes of selective voltage reduction of atrial deflections have not as yet been explored beyond these common clinical scenarios: extreme chronicity of the arrhythmia (decades), digitalis intoxication, advanced hyperkalemia, extreme sinus bradycardia, and advanced multiorgan disease states. The fate of myriad atrial impulses entering the AV node was demonstrated by Neil Moore.31 For as far as they go, impulses dying within the node leave a refractory wake that blocks the next in line, which is a process of repetitive concealment. One cannot discuss vulnerability to fibrillation without reviewing the pioneering work of Wiggers and Wegria,32 who defined the vulnerable phase of the ventricle when strong shocks induced ventricular fibrillation. But at current strengths just short of the dfibrillation threshold,T they obtained salvos of polymorphic ventricular tachycardia. These were called ventricular multiple responses.33 Attending the start of atrial fibrillation are the equivalent atrial multiple responses. The number inscribed may depend on slight millisecond variations in the prematurity of the first premature beat. One presumes that the atrial vulnerable period has been encroached upon when these multiple responses appear. The nonconduction of the multiple responses is due to the repeatedly concealed conduction and failure within the AV node, each penetration leaving a refractory wake that blocks the subsequent impulse. The issue of what causes fibrillation to be sustained or not to be sustained is problematic. In a 1981 clinical study, transient atrial pacing was performed on 39 subjects; Attuel and I found that failure of the atrial refractory period to adapt to changing frequency was associated with much longer periods of atrial fibrillation.34,35 The importance of this dmaladaptationT was later emphasized by Alessie et al36,37 who also cited a short wavelength (slow conduction and a short refractory period) as a major factor maintaining or sustaining the arrhythmia.37 Fibrillation can sometimes be induced by rapid atrial pacing, presumably from rapid remodeling.38 Just as the prolonged abnormal QRS activation by an artificial ventricular pacemaker anamnestically alters the repolarization of the captured native QRS, the equivalent phenomenon of memory is atrial remodeling. Although sinus rhythm may be restored, atrial repolarization seems to remember its specific features when atrial fibrillation was maintaining an atrial rate of close to 400. The remodeled atrium maintains this shortened refractory period and rate maladaptation even when the sinus rate is slow. The effect, which develops quickly during fibrillation, lasts as long as a week after sinus restoration.39 This shortened recovery feature invites return of the fibrillation. The hope that verapamil calcium blockade could modify or oppose the remodeling phenomenon has not been realized.40

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The mechanism of fibrillation is still in question. Most agree that it involves both completing and noncompleting micro and macro reentrant loops. Independent wavelets with changing patterns of excitation confront elements at differing termination.41 The postulated mechanisms of fibrillation include a single focus premature atrial activation with changing spread of excitation and multiple wandering wavelets, a critical number of which are required for the rhythm to be sustained (one suggestion, 4-6).42 As Moe43 invoked, fibrillation requires a critical mass of atrial myocardium; it is seldom sustained in small children or puppies. In a minority of instances, fibrillation emerges not from an atrial premature ectopic but straight out of paroxysmal atrial tachycardia or atrial flutter,44 although in the latter instance, a premature atrial excitation may be the vehicle for change.45 In most instances, the triggering geographical source of the premature impulse(s) that induce fibrillation is known to be in the orifices of the pulmonary vein(s)46,47 that may have refractory periods shorter than those of the left atrial roof.48 Anatomically, some cases of atrial fibrillation or atypical atrial flutter may be associated with coronary sinuses circumferentially ensheathed in the myocardium connected to the left atrium.49 Examination of the 12-lead electrocardiographic features of such atrial premature ectopy is hampered by their placement in the T wave of the previous sinus beat. Digital subtraction of the T wave50 can further our knowledge in this respect. The yield of the 12-lead Holter51 in this context is also disappointing. It is essential to discriminate between truly originating pulmonary venous and bystander foci. The correlation of 12-lead P wave configuration with site of origin of an ectopic impulse, or the site of its atrial arrival, is problematic. When P comes first as with sinus, ectopic atrial, or primary pacemaker complex52 rhythm, the shape may be modified by the fusion of 2 close but competing wave fronts. The role of the internodal tracts of James53 whether true specialized fibers (with unique features such as supernormal excitability54) or simply pathways seeking to avoid atrial orifices55 is still controversial. The 12-lead shapes of true transnodal retrograde P waves versus those that arrive via an accessory tract are extremely similar. Further study would require signal-averaged QRS and T wave subtraction during circus tachycardia with the full geographic range of tract locations. Electrocardiography per se has thus far been disappointing as a tool for recognizing the precise trigger location of atrial fibrillation. Atrial fibrillation conducted down the accessory pathway in the WPW syndrome is potentially fatal. The anatomically normal atrioventricular conduction system consists of a series of downstream regional refractory periods. Those of the AV node and trifascicular system have the longest durations. Teleologically, as Moe suggested,56 the latter can be regarded as hurdles that, by means of delay or conduction block, prevent a premature atrial impulse from making a QRS land on the apex of the T wave, causing ventricular fibrillation. In the WPW syndrome, the aforesaid hurdles are missing. Conduction down the accessory pathway can result in ventricular rates approaching 300 per

minute. A long-short cadence can induce an R-on-T phenomenon when the accessory pathway has a very short refractory period. R-R intervals 250 ms or less are specific markers for ventricular fibrillation.57 Atrial fibrillation is seen in one third of the WPW syndrome.58 When the accessory pathway is antegrade and unidirectional, atrial fibrillation may be the only arrhythmic problem encountered. The degree of preexcitation in sinus rhythm has no bearing on the likelihood of either fibrillation or sudden death. The high frequency of the arrhythmia in this syndrome appears to be related to the frequency with which the atrium is subject to the rapid rates of circus tachycardia, causing a modeled abbreviation of the atrial refractory period, with its fibrillatory propensity.36 The actual triggering could be the retrograde confrontation of the atrial vulnerable period, via the accessory tract, by a premature ventricular ectopic impulse.59 In conclusion, it is worth remembering that vulnerability to fibrillation in either the atrium or ventricle is of little significance if the patient remains entirely free of premature depolarizations.

References 1. Adams R. Cases of diseases of heart accompanied with pathological observations. Dublin Hosp Rep 1827;4:353. 2. Hering HE. Analyse des Pulses irregularis perpetuus. Prag Med Wechenschr 1903;38:377. 3. Rothenberger CJ, Winterberg H. Vorhofflimmern und arrhythmia perpetuus. Wien Klin Wochenschr 1909;22:839. 4. Lewis T. Auricular fibrillation: a common clinical condition. BMJ 1909;2:1528. 5. Patel AM, Westveer DC, Man KC, et al. Treatment of underlying atrial fibrillation: paced rhythm obscures recognition. J Am Coll Cardiol 2000;36:784. 6. Halat R, Halphen C, Stoltz JP, Leroy G, Sousana C. Auricular fibrillation: a cause of reversible myocardiopathy. Ann Cardiol Angeiol 1987;36:417. 7. Lown B, Perlroth MG, Kaidbey S. bCardioversionQ of atrial fibrillation. A report on the treatment of 65 episodes in 50 patients. N Engl J Med 1963;269:325. 8. Tsikouris JP, Kluger J, Song J, White CM. Changes in P-wave dispersion and P-wave duration after open heart surgery are associated with the peak incidence of atrial fibrillation. Heart Lung 2001;30:466. 9. Mihalick MJ, Fisch C. Electrocardiographic findings in the aged. Am Heart J 1974;87:117. 10. Leier CV, Schaal SF. Biatrial electrograms during coarse atrial fibrillation and flutter-fibrillation. Am Heart J 1980;99:331. 11. Horvath G, Goldberger JJ, Kadish AH. Simultaneous occurrence of atrial fibrillation and atrial flutter. J Cardiovasc Electrophysiol 2000;11:849. 12. Winter JB, Crijns HJGM. Atrial flutter and atrial fibrillation: two sides of a coin or one coin? J Cardiovasc Electrophysiol 2000;11:859. 13. Sandler JA, Marriott H. Differential morphology of anomalous ventricular complexes of RBBB type in lead V1 ventricular ectopy versus aberration. Circulation 1965;31:551. 14. Coumel P, Attuel P, Lavalle JP, Flammang JD, Leclerq JF, Slama R. Syndrome d’arrhythmie auriculaire d’origine vagale. Arch Mal Coeur Vaiss 1978;71:645. 15. Hnatkova K, Gallagher MM, Murgatroyd FD, et al. Analysis of the cardiac rhythm preceding episodes of paroxysmal atrial fibrillation. Am Heart J 1998;135:1010. 16. Sopher SM, Waktare JEP, Hnatkova K, et al. Influence of time of onset on paroxysmal atrial fibrillation duration. Arch Mal Coeur Vaiss 1998;91(Suppl 3):283.

R. Childers / Journal of Electrocardiology 39 (2006) S174–S179 17. Leier CV, Meacham JA, Schaal SF. Prolonged atrial conduction: a major predisposing factor for the development of atrial flutter. Circulation 1978;57:213. 18. Gallagher MG, Camm AJ. Classification of atrial fibrillation. Pacing Clin Electrophysiol 1997;20:1603. 19. Arnsdorf MF, Rothbaum DA, Childers RW. The effect of direct current countershock on atrial and ventricular electrophysiological properties and myocardial potassium efflux in the thoracotomized dog. Cardiovasc Res 1977;11:324. 20. Shalan LJ, Lyon AF. Paradoxical acceleration of atrial flutter after cardioversion. Am Heart J 1965;69:684. 21. Lown B, Levine SA. The carotid sinus. Clinical value of its stimulation. Circulation 1961;23:766. 22. Bollmann A, Wodarz K, Esperer HD, Toepffer I, Klein HU. Response of atrial fibrillatory activity to carotid sinus massage in patients with atrial fibrillation. Pacing Clin Electrophysiol 2001;24:1363. 23. Graves RJ, Clinical Lectures London M@ SJ 1835;7:516. 24. Arnsdorf MF, Childers RW. Atrial electrophysiology in experimental hyperthyroidism in rabbits. Circ Res 1970;26:575. 25. Prinzse FJ, Bouman LN. The cellular basis of intrinsic sinus node recovery time. Cardiovasc Res 1991;25:546. 26. Childers RW, Arnsdorf MF, de la Fuente DJ, Gambetta M, Svenson R. Sinus nodal echoes. Am J Cardiol 1973;31:220. 27. Bonke FIM, Kirchof CJHJ, Allessie MA. Sinus node reentry. In: Zipes D, Jalife J, editors. Cardiac electrophysiology. 1st ed. 1990. p. 529 [chapter 57]. 28. Kaplan BM, Langendorf R, Lev M, Pick A. Tachycardia-bradycardia syndrome (so-called bsick sinus syndromeQ). Pathology, mechanisms and treatment. Am J Cardiol 1973;31:497. 29. Simonson E. Differentiation between normal and abnormal in electrocardiography. St Louis7 Mosby; 1961. p. 160. 30. Weingart R. The actions of ouabain on intercellular coupling and conduction velocity in mammalian ventricular muscle. J Physiol 1977; 264:341. 31. Moore EN. Observations on concealed conduction in atrial fibrillation. Circ Res 1967;21:201. 32. Wiggers SJ, Wegria R. Ventricular fibrillation due to single localized induction and condenser shocks applied during the vulnerable phase of ventricular systole. Am J Physiol 1940;128:500. 33. Matta RJ, Verrier RL, Lown B. The repetitive extrasystole as an index of vulnerability to ventricular fibrillation. Am J Physiol 1976; 230:1469. 34. Attuel P, Childers RW, et al. Failure in the rate adaptation of the atrial refractory period. Its relationship to vulnerability. Int J Cardiol 1982;2:179. 35. Attuel P, Childers RW, Haissaguere M, et al. Failure in the rate adaptation of the atrial refractory periods: new parameter to assess atrial vulnerability. PACE 1984;7:1382. 36. Tieleman RG, Van Gelder IC, Crijns HJGM, et al. Early recurrences of atrial fibrillation after electrical cardioversion: a result of fibrillationinduced electrical remodelling of the atria? J Am Coll Cardiol 1998;31:167. 37. Alessie MA, Rensma PL, Brugada J, Smeets LRM, Penn O, Kirchof CJHJ. Pathophysiology of atrial fibrillation. In: Zipes DP, Jalife J, editors. Cardiac electrophysiology. 1st ed. Philadelphia7 W.B. Saunders; 1990. p. 574 [Chapter 60]. 38. Gaspo R, Bosch RF, Talajic M, et al. Functional mechanisms underlying tachycardia-induced sustained atrial fibrillation in a chronic dog model. Circulation 1997;96:4027.

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39. Wijffels MC, Kirchof CJ, Dorland R, Alessie MA. Atrial fibrillation begets atrial fibrillation. Circulation 1995;92:1954. 40. Bertaglia E, d’Este D, Zanocco A, Zerbo F, Pascotto P. Effects of pretreatment with verapamil on early recurrences after electrical cardioversion of persistent atrial fibrillation: a randomised study. Heart 2001;85:578. 41. Surawicz B. Electrophysiologic basis of ECG and cardiac arrhythmias. Baltimore7 Williams and Wilkins; 1995. 42. Allessie MA, Lammers WJEP, Bonke FIM, et al. Experimental evaluation of Moe’s multiple wavelet hypothesis of atrial fibrillation. In: Zipes DP, Jalife J, editors. Cardiac arrhythmias. Orlando7 Grune and Stratton; 1985. p. 265. 43. Moe GK. On the multiple wavelet hypothesis of atrial fibrillation. Arch Int Pharmacodyn 1962;140:183. 44. Killip T, Gault JH. Mode of onset of atrial fibrillation in man. Am Heart J 1965;70:172. 45. Allessie MA, Konings K, Kirchoff CJHJ, Wijffels M. Electrophysiologic mechanisms of perpetuation of atrial fibrillation. Am J Cardiol 1996;77:100. 46. Haissaguerre M, Jais P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339:659. 47. Chen SA, Hsieh MH, Tai CT, et al. Initiation of atrial fibrillation by ectopic beats originating from the pulmonary veins. Electrophysiologic characteristics, pharmacologic responses, and effects of radiofrequency ablation. Circulation 1999;100:1879. 48. Adragao AP, Santos KR, Aguiar C, et al. Atrial fibrillation and effective refractory period of the pulmonary vein ostia. Rev Port Cardiol 2002;10:1125. 49. Kasai A, Anselme F, Saoudi N. Myocardial connections between left atrial myocardium and coronary sinus musculature in man. J Cardiovasc Electrophysiol 2001;12:981. 50. Shah D, Yamane T, Choi K-J, Haissaguerre M. QRS subtraction and the ECG analysis of atrial ectopics. Ann Noninvasive Electrocardiol 2004;9:389. 51. Kolb C, Nurnberger S, Ndrepepa G, Zrenner B, Schomig A, Schmitt C. Modes of initiation of paroxysmal fibrillation from analysis of spontaneously occurring episodes using a 12 lead Holter monitoring system. Am J Cardiol 2001;88:853. 52. Boineau JP, Canavan TE, Schuessler RB. Demonstration of a widely distributed atrial pacemaker complex in the human heart. Circulation 1988;77:1221. 53. James T. The connecting pathways between the sinus node and the A-V node and between the right and left atrium in the human heart. Am Heart J 1963;66:498. 54. Childers RW, Merideth J, Moe GK. Supernormality in Bachmann’s bundle. Circ Res 1968;22:363. 55. Anderson RH, Becker AE, Brechenmacher C, Davies MY, Rossi L. The human atrioventricular junctional area. A morphological study of the A-V node and bundle. Eur J Cardiol 1975;3:47. 56. Preston JB, McFadden S, Moe GK. Atrioventricular transmission in young mammals. Am J Physiol 1959;197:236. 57. Klein GJ, Bashore TM, Sellers TD. Ventricular fibrillation in the WolffParkinson-White syndrome and atrial fibrillation. N Engl J Med 1979;301:1080. 58. Wellens HJ, Durrer D. Wolff-Parkinson-White syndrome and atrial fibrillation. Am J Cardiol 1974;34:777. 59. Shen EN, Sung RJ. Initiation of atrial fibrillation by spontaneous ventricular premature beats in concealed Wolff-Parkinson-White syndrome. Am Heart J 1982;103:911.