University of Groningen. Atrial electrical remodeling from barn to bedside Tieleman, Robert George

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1 University of Groningen Atrial electrical remodeling from barn to bedside Tieleman, Robert George IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 1999 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Tieleman, R. G. (1999). Atrial electrical remodeling from barn to bedside: experimental and clinical studies on tachycardia-induced changes in atrial electrophysiology Groningen: s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 Pathophysiological Mechanisms of Atrial Fibrillation 2 chapter

3 pathophysiological mechanisms of AF Multiple-wavelet reentry Today, the general accepted theory of the electrophysiologic mechanism behind AF is the Multiple Wavelet hypothesis, which was originally described by Moe and colleagues around It was the result of an evolution of ideas which started with the observation of circus movement in the jelly-fish ring preparation by Mayer in Inspired by this, Mines 5 and Garrey 6 performed animal experiments demonstrating circular contractions in cardiac tissue. Mines identified that slow conduction and a short refractory period favored the induction of reentry around an anatomical obstacle, which could be initiated and terminated using a single extrastimulus, 5 while Garrey recognized the importance of tissue mass, shifting areas of local conduction block and multiple circulating wavelets during atrial fibrillation. 6 In 1921, Lewis 7 described electrocardiographic observations in humans with AF and concluded from the shifting atrial electrical axis that AF, like flutter, was the result of a single circulating wavelet, but without the constant course which it pursued in atrial flutter. Almost 4 decades later, Moe and colleagues 1-3 designed experiments to study the initiation and self-perpetuating nature of AF. The results of these studies, together with the previous observations, led to the Multiple Wavelet hypothesis, in which multiple independent wavelets circle randomly through the atria, around constantly changing areas of local conduction block. After initiation, typically by a premature atrial activation, the original wave front becomes fractionated and breaks up due to strands of refractory tissue around which the new wavelets can re-initiate themselves or each other, making AF a self-sustaining arrhythmia. Only when all independent wavelets run into inexcitable tissue at the same time, the arrhythmia terminates and sinus rhythm can resume. The chance for this to occur decreases when an increasing number of wavelets are present in the atria at the same time. The number of wavelets that fit into the atria depends on the atrial mass, the conduction velocity and the atrial refractory period. 1-3 Allessie and co-workers 8 confirmed this hypothesis in 1985 by mapping the atria of isolated Langendorff perfused canine hearts in which AF was induced by acetylcholine application. They demonstrated that during AF, multiple independent wavelets activated the atria in a random reentrant way. Individual wavelets could brake-up, fuse or collide with each other, and wavelets would extinct if they reached the border of the atria or met refractory tissue. From time to time a varying number of wavelets was present in the atria and the duration of each individual wavelet lasted only several hundreds of milliseconds. They showed that indeed the number of wavelets that fit into the atria determined the perpetuation of AF. Below a critical number of wavelets (between 3 and 6), there was a considerable chance for the wavelets to die out all at the same time. In case more than 6 independent wavelets were present, the arrhythmia would not convert spontaneously anymore. 8 During the last decade, mapping studies in humans with AF have further confirmed the multiple wavelet theory. 9,10 16 CHAPTER 2 Pathophysiological Mechanisms of Atrial Fibrillation

4 Alternative mechanisms of AF Opposed to the circus movement theory of Lewis and the multiple wavelet theory of Garrey and Moe was the ectopic focus theory by Engelmann, 11 later confirmed by Scherf. 12,13 This theory postulated a single rapid firing focus with a rate so high, that uniform 1:1 excitation to the surrounding atrial tissue was no longer possible. The circular wavefront would brakeup and a fibrillatory conduction would ensue. In the experiments by Scherf et al 12,13 aconitine injection in the wall of the atrial appendage resulted in AF due to a rapid firing focus at the site of aconitine application. Cooling of this site immediately terminated AF in the atrium, illustrating that both the initiation and perpetuation of AF were due to the rapid firing focus. Moe and colleagues repeated the experiments by Scherf, but they showed that in case of vagal stimulation AF continued in the atria, despite clamping off the appendage at which aconitine was administered, demonstrating the self-perpetuating character of AF. This demonstrated that in the right circumstances (vagal stimulation shortens the refractory period, which shortens the wavelength, see below) AF did not depend on the rapid firing focus any more, which convinced people that AF was a reentry arrhythmia. 1 However, recently, Jais and colleagues 14 demonstrated a focal mechanism in patients with AF similar to the experiments by Scherf. In these patients a fast firing focus, typically originating from one of the orifices of the pulmonary veins, causes fibrillatory conduction to the surrounding atrial tissue with identical electrocardiographic characteristics as the more classical forms of multiple wavelet AF. However, patients with this so-called focal AF can be cured by ablating the single fast firing focus, 14 whereas patients with AF based upon multiple wavelet reentry do not benefit from ablation of a single site. Therefore, in focal AF, the induction and perpetuation of AF is different from the mechanisms explaining the initiation and perpetuation of multiple wavelet AF, which are described below. The percentage of patients with AF that could be cured by this focal approach is not known. Finally, AF could also be the result of a single small reentrant circuit or multiple unstable reentrant circuits with a very short cycle length with fibrillatory conduction to the rest of the atria. 15,16 Single reentrant circuits have indeed been demonstrated during intraoperative mapping of the atria in patients with AF. 9,10 However, in the opinion of these investigators, the small reentrant circuits were just one end of the continuous spectrum of complexity of atrial activation during AF. To bring order into chaos, Konings et al 10 categorized AF into 3 subclasses. In type I AF, there is quite organized atrial activation with 1 broad wavefront propagating at a normal speed with small areas of slow conduction or block. Type II AF is characterized by 2 waves, or single waves but longer or multiple lines of conduction block or slow conduction. More complex activation occurs in type III AF, with 3 or more independent wavelets and multiple areas of local conduction slowing or block. 10 Determinants of AF vulnerability As mentioned above, the number of wavelets that fit into the atria depends on the atrial refractory period and the con- Atrial Electrical Remodeling From Barn To Bedside 17

5 duction velocity. This relation which is of general importance for all reentry arrhythmias is described by the wavelength of excitation. This wavelength is the distance traveled by the activation front of the wavelet during its refractory period (wavelength=conduction velocity x refractory period). 17,18 Reentry arrhythmias around fixed obstacles perpetuate when the circuit length of the arrhythmia exceeds the wavelength, so that the activation front does not run into its tail of refractory tissue. During AF, reentry does not occur exclusively around fixed obstacles, but small differences in refractory period or conduction velocity already can cause small areas of local conduction block, around which the activation front can circle. In this functional reentry of the leading circle type, the activation front will reenter its own relative refractory tail, and the circuit size will be approximately the same size as the wavelength, leaving no or only a small excitable gap. 19 When the refractory period is short or the conduction velocity is low, the wavelength will be short. As a result, more independent wavelets will fit into atria of a certain size, increasing the perpetuation of AF. As was demonstrated by Rensma et al, 20 the wavelength was also of importance for the induction of atrial arrhythmias including AF. In chronically instrumented conscious dogs, the inducibility of AF was tested by delivering single premature stimuli. The wavelength was changed using a variety of drugs (acetylcholine, propafenone, lidocaine, ouabain, quinidine, d-sotalol). It was demonstrated that the refractory period or the conduction velocity were bad predictors for the induction of AF, whereas the wavelength was a strong predictor. 20 Likewise, the action of various anti-arrhythmic drugs in converting AF can be explained by their ability to increase the atrial wavelength Random reentry (and also fibrillation-like conduction) only occurs in the setting of heterogeneous electrophysiologic properties of the atria, such as dispersion of the refractory periods, 24,25 anisotropic tissue properties, 26,27 or a decrease of the negative membrane potential as in diseased or dilated atria These regional differences in repolarization or conduction cause areas of local conduction delay or block, around which the initiating activation front can reenter its circuit. 31,32 In animal experiments, an increased dispersion of refractoriness is associated with an increased inducibility 23,33 and maintenance of AF. 34 Furthermore, patients with paroxysmal AF seemed to express shorter refractory periods and an increased dispersion of refractoriness when compared with controls. 35 The autonomic nervous system and AF vulnerability One of the oldest models to induce sustained AF is applying vagal stimulation. The resulting increased parasympathetic tone will shorten the atrial refractory period through opening of the acetylcholine-dependent potassium channels (I kach ). 36 Furthermore, due to inhomogeneous distribution of the vagal nerve endings, the spatial dispersion in refractoriness will increase In this way, AF will persist after induction with premature stimuli or atrial burst pacing as long as the parasympathetic system is stimulated, either by vagal nerve stimulation or by acetylcholine application. Interestingly, also sympathetic activation shortens the atrial refractory period, due to 18 CHAPTER 2 Pathophysiological Mechanisms of Atrial Fibrillation

6 camp-dependent shortening of the plateau phase. However, this effect is less pronounced and sympathetic activation by epinephrine administration in isolated strips of atrial tissue from rabbit hearts resulted in either an increase in wavelength at slow heart rates or no change at high heart rates. 41 On the other hand, in the clinical situation sympathetic stimulation may increase the number of spontaneous premature atrial activations due to increased automaticity or triggered activity, which may increase the incidence of AF. This may especially be true in patients after cardiac surgery, and explains the significant efficacy of beta-adrenergic blocking drugs in preventing post-operative AF Finally, experimentally induced regional sympathetic denervation facilitates sustained AF, possibly by increasing dispersion of refractoriness. 46 electrophysiologic properties of Healthy and Diseased Atrial tissue The Atrial Action Potential The atrial action potential has a high negative resting membrane potential, a steep upstroke, and a repolarization phase which is generally shorter than repolarization in ventricular myocardium (figure 1). 47 The phase 0 depolarization is caused by a rapid inflow of sodium ions through the voltage-gated and time-dependent Na-channels. 48,49 Furthermore, a more slowly depolarizing current is provided by the influx of calcium through the L-type calcium channels. This last current is thought to be at least partly responsible for the plateau phase during repolarization and initiates calcium release from the sarcoplasmic reticulum which binds to the contractile filaments of the myocardial cell, causing contraction. 50 Phase 1 of repolarization is caused by the Ito-current. This current ends depolarization and lasts only very short, but has important consequences for the action potential duration by its influence on other repolarizing currents. It consists of 2 components; a calcium-independent current which can be blocked with 4 aminopyridine (I to1 ), and a calcium-dependent chloride current which is activated by calcium and blocked by verapamil (I to2 or I Cl(Ca) ) During phase 2 of repolarization, outward potassium currents such as I ks,i kr, and I kach compete with the inward calcium current, which results in formation of the plateau phase. During phase 3 the action potential returns to its transmembrane resting potential, which remains at that level during phase 4 of the action potential until the cell becomes re-activated. Furthermore, the sodium-potassium ATPase-pump and the reversed mode of the sodium-calcium exchanger also contribute to repolarization (the current flows to where the sodium goes). The main difference between atrial and ventricular myocardial action potentials is the distribution and magnitude of the ionic currents responsible for the resting Atrial Electrical Remodeling From Barn To Bedside 19

7 Figure 1 Plateau-shaped action potential with a graphic illustration of the individual currents. (From the Sicilian Gambit 68 ) membrane potential and action potential repolarization. 47 The inward rectifier current I k1, responsible for maintenance of the resting membrane potential, is smaller in atrial cells compared with ventricular cells. 54,55 On the other hand, the acetylcholinedependent potassium current I kach is very important in maintaining and hyperpolarizing the resting membrane potential in atrial cells, while not present in ventricular cells. 55 It is this current which is responsible for hyperpolarization and shortening of the atrial action potential during parasympathetic stimulation. Types of Atrial Action Potentials Apart from the calciumdependent, slowly depolarizing cells of the SA- and AV-node, with their characteristic spontaneous diastolic depolarization (pacemaker activity), there are 2 different kinds of atrial action potentials. Some cells have action potentials with a distinct plateau phase, while other cells have more triangular-shaped action potentials with a shorter action potential duration. 56,57 Histological examination revealed that both action 20 CHAPTER 2 Pathophysiological Mechanisms of Atrial Fibrillation

8 potentials originate from ordinary atrial myocardial cells. 57 Escande et al 58 showed in human atrial tissue that with an increase in age the morphology of the atrial action potentials changes from a triangular shape to a plateau phase action potential (figure 2). It is therefore suggested that the triangular-shaped action potential resembles the early developmental stage of the atrial cell. Furthermore, examination of strips of atrial tissue obtained from patients with AF identified atrial cells with short refractory periods, and with a significant increase in the percentage of triangular shaped action potentials This was in agreement with other studies which demonstrated short refractory periods in AF patients after electrical cardioversion. 62,63 Furthermore, an absence of rate adaptation of the atrial refractory period was demonstrated in patients vulnerable for atrial arrhythmias 64,65 and in strips of atrial tissue from AF patients. 59 At that time, these electrophysiologic abnormalities were all considered to be an important cause of AF. Electrical remodeling of the atria In 1995, 2 studies performed at the same time by separate groups reported on the induction of chronic AF by rapid atrial pacing or repeated induction of AF. Morillo et al 66 demonstrated that 6 weeks of rapid atrial pacing induced chronic AF in a significant number of previously healthy dogs. After this period a shortened atrial refractory period and a marked atrial dilatation explained the increased vulnerability for AF. The other study by Wijffels and colleagues from the group of Allessie described how AF itself can cause the atria to become more vulnerable for reinduction and perpetuation of AF. 67 Using healthy chronically instrumented goats, they repetitively induced AF by burst pacing. Generally, the induced episodes of AF lasted only a few seconds before converting spontaneously to sinus rhythm. An automatic fibrillation pacemaker which was able to recognize the absence of AF after spontaneous conversion then re-induced AF by another burst-pace. Using this experimental Pen recordings of atrial transmembrane action potentials. The left action potential is recorded in a 22 month-old boy with a ventricular septum defect. The right recording is from a 30 year-old woman with syphilic aortitis. Driving rate 1 Hz. (From Escande et al 58 ) Figure 2 Atrial Electrical Remodeling From Barn To Bedside 21

9 Figure 3 Prolongation of the duration of electrically induced episodes of AF after maintaining AF for respectively 24 hours and 2 weeks. The 3 tracings show a single atrial electrogram recorded from the same goat during induction of AF by a 1 second burst stimulus (50 Hz). In the upper tracing the goat had been in sinus rhythm all the time and AF self-terminated within 5 seconds. The second tracing was recorded after the goat had been connected to the fibrillation pacemaker for 24 hours, showing a clear prolongation of the duration of AF to 20 seconds. The third tracing was recorded after 2 weeks of electrically maintained AF. After induction of AF this episode became sustained and did not terminate any more. (From Wijffels et al 67 ) protocol, they were able to sustain AF 24 hours a day, 7 days a week. This artificial maintenance of AF prolonged the duration of the induced episodes, the longer the arrhythmia was sustained, until it eventually became chronic, ie did not convert spontaneously any more (figure 3). The time till the development of chronic AF varied widely among different goats between 2 days and 2 weeks. When they investigated the electrophysiologic changes which occurred during their experiments, it appeared that with a prolonged duration of the experimental protocol, the atrial refractory period shortened significantly, with loss of the physiologic rate adaptation. Since the conduction velocity did not change significantly, the calculated wavelength decreased, which explained the increased vulnerability for AF. Of interest, after cardioversion of AF that had been present for 2 to 4 weeks, this so-called atrial electrical remodeling appeared to be completely reversible within one week after restoration of sinus rhythm. 67 Modulation of Electrical Remodeling In an attempt to unravel the initiating mechanisms behind this newly discovered electrophysiological phenomenon, we administered various drugs during rapid atrial pacing and evaluated the time course of atrial electrical remodeling and recovery from remodeling. 22 CHAPTER 2 Pathophysiological Mechanisms of Atrial Fibrillation

10 Furthermore, modulation of atrial electrical remodeling may have several clinical effects. Drugs which can reduce electrical remodeling during AF may have a beneficial influence on the arrhythmia prognosis by reducing the fibrillation-induced decrease in wavelength. On the other hand, drugs which help to normalize the atrial electrophysiology during recovery from electrical remodeling may increase maintenance of sinus rhythm after successful cardioversion of AF. Therefore the studies presented in the following chapters do not only give insight into the mechanisms of atrial electrical remodeling, they also may initiate new therapeutic approaches to patients with AF. references 1. Moe GK, Abildskov JA: AF as a self-sustaining arrhythmia independent of focal discharge. Am Heart J 1959;58: Moe GK: On the multiple wavelet hypothesis of AF. Arch Int Pharmacodyn Ther 1962;140: Moe GK, Rheinboldt WC, Abildskov JA: A computer model of AF. Am Heart J 1964;67: Mayer AG: Rhythmical pulsation in scyphomedusa (Thesis) 5. Mines GR: On dynamic equilibrium in the heart. J Physiol 1913;46: Garrey WE: The nature of fibrillation contraction of the heart; its relation to tissue mass and form. Am J Physiol 1914;33: Lewis T, Drury AN, Iliescu CC: A demonstration of circus movement in clinical fibrillation of the auricles. Heart 1921;8: Allessie MA, Lammers WJEP, Bonke FIM, Hollen SJ: Experimental evaluation of Moe s multiple wavelet hypothesis of atrial fibrillation, in Zipes DP, Jalife J (eds): Cardiac Electrophysiology and Arrhythmias. New York, Grune & Stratton, 1985,pp Cox JL, Canavan TE, Schuessler RB, Cain ME, Lindsay BD, Stone C, Smith PK, Corr PB, Boineau JP: The surgical treatment of atrial fibrillation. II. Intraoperative electrophysiologic mapping and description of the electrophysiologic basis of atrial flutter and atrial fibrillation. J Thorac Cardiovasc Surg 1991;101: Konings KT, Kirchhof CJ, Smeets JR, Wellens HJ, Penn OC, Allessie MA: Highdensity mapping of electrically induced atrial fibrillation in humans. Circulation 1994;89: Engelmann TW: Über den Einfluss der Systole auf die Motorische Leitung in der Herzkammer, mit Bemerkungen zur Theorie Allorhythmischer Herzstörungen. Arch f d ges Physiol 1896;62: Scherf D: Studies on auricular tachycardia caused by aconitine administration. Proc Soc Exp Biol Med 1947;64: Atrial Electrical Remodeling From Barn To Bedside 23

11 13. Scherf D, Romano FJ: Experimental studies on auricular flutter and auricular fibrillation. Am Heart J 1948;36: Jais P, Haissaguerre M, Shah DC, Chouairi S, Gencel L, Hocini M, Clementy J: A focal source of atrial fibrillation treated by discrete radiofrequency ablation. Circulation 1997;95: Schuessler RB, Grayson TM, Bromberg BI, Cox JL, Boineau JP: Cholinergically mediated tachyarrhythmias induced by a single extrastimulus in the isolated canine right atrium. Circ Res 1992;71: Kumagai K, Khrestian C, Waldo AL: Simultaneous multisite mapping studies during induced atrial fibrillation in the sterile pericarditis model. Insights into the mechanism of its maintenance. Circulation 1997;95: Lewis T: The Mechanism and Graphic Registration of the Heart Beat. London, Shaw & Sons, 1925, 18. Wiener N, Rosenblueth A: The mathematical formulation of the problem of conduction of impulses in a network of connected excitable elements, especially in cardiac muscle. Arch Inst Cardiol Mex 1946;16: Allessie MA, Bonke FI, Schopman FJ: Circus movement in rabbit atrial muscle as a mechanism of tachycardia. III. The leading circle concept: a new model of circus movement in cardiac tissue without the involvement of an anatomical obstacle. Circ Res 1977;41: Rensma PL, Allessie MA, Lammers WJ, Bonke FI, Schalij MJ: Length of excitation wave and susceptibility to reentrant atrial arrhythmias in normal conscious dogs. Circ Res 1988;62: Wang Z, Page P, Nattel S: Mechanism of flecainide s antiarrhythmic action in experimental atrial fibrillation. Circ Res 1992;71: Wang J, Bourne GW, Wang Z, Villemaire C, Talajic M, Nattel S: Comparative mechanisms of antiarrhythmic drug action in experimental atrial fibrillation. Importance of use-dependent effects on refractoriness. Circulation 1993;88: Wang Z, Feng J, Nattel S: Idiopathic atrial fibrillation in dogs: electrophysiologic determinants and mechanisms of antiarrhythmic action of flecainide. J Am Coll Cardiol 1995;26: Allessie MA, Bonke FI, Schopman FJ: Circus movement in rabbit atrial muscle as a mechanism of tachycardia. II. The role of nonuniform recovery of excitability in the occurrence of unidirectional block, as studied with multiple microelectrodes. Circ Res 1976;39: Sato S, Yamauchi S, Schuessler RB, Boineau JP, Matsunaga Y, Cox JL: The effect of augmented atrial hypothermia on atrial refractory period, conduction, and atrial flutter/fibrillation in the canine heart. J Thorac Cardiovasc Surg 1992;104: Spach MS, Dolber PC, Heidlage JF: Influence of the passive anisotropic properties on directional differences in propagation following modification of the sodium conductance in human atrial muscle. A model of reentry based on anisotropic 24 CHAPTER 2 Pathophysiological Mechanisms of Atrial Fibrillation

12 discontinuous propagation. Circ Res 1988;62: Spach MS, Josephson ME: Initiating reentry: the role of nonuniform anisotropy in small circuits. J Cardiovasc Electrophysiol 1994;5: Ten Eick RE, Singer DH: Electrophysiological properties of diseased human atrium. I. Low diastolic potential and altered cellular response to potassium. Circ Res 1979;44: Hordof AJ, Edie R, Malm JR, Hoffman BF, Rosen MR: Electrophysiologic properties and response to pharmacologic agents of fibers from diseased human atria. Circulation 1976;54: Mary Rabine L, Albert A, Pham TD, Hordof A, Fenoglio JJ, Jr., Malm JR, Rosen MR: The relationship of human atrial cellular electrophysiology to clinical function and ultrastructure. Circ Res 1983;52: Lammers WJ, Schalij MJ, Kirchhof CJ, Allessie MA: Quantification of spatial inhomogeneity in conduction and initiation of reentrant atrial arrhythmias. Am J Physiol 1990;259:H Lammers WJ, Kirchhof C, Bonke FI, Allessie MA: Vulnerability of rabbit atrium to reentry by hypoxia. Role of inhomogeneity in conduction and wavelength. Am J Physiol 1992;262:H Satoh T, Zipes DP: Unequal atrial stretch in dogs increases dispersion of refractoriness conducive to developing atrial fibrillation. J Cardiovasc Electrophysiol 1996;7: Wang J, Liu L, Feng J, Nattel S: Regional and functional factors determining induction and maintenance of atrial fibrillation in dogs. Am J Physiol 1996;271:H Misier AR, Opthof T, van Hemel NM, Defauw JJ, de Bakker JM, Janse MJ, van Capelle FJ: Increased dispersion of refractoriness in patients with idiopathic paroxysmal atrial fibrillation. J Am Coll Cardiol 1992;19: Giles W, Noble SJ: Changes in membrane currents in bullfrog atrium produced by acetylcholine. J Physiol (Lond) 1976;261: Alessi R, Nusynowitz M, Abildskov JA, Moe GK: Nonuniform distribution of vagal effects on the atrial refractory period. Am J Physiol 1958;194: Ninomiya I: Direct evidence of nonuniform distribution of vagal effects on dog atria. Circ Res 1966;19: Zipes DP, Mihalick MJ, Robbins GT: Effects of selective vagal and stellate ganglion stimulation of atrial refractoriness. Cardiovasc Res 1974;8: Schuessler RB, Rosenshtraukh LV, Boineau JP, Bromberg BI, Cox JL: Spontaneous tachyarrhythmias after cholinergic suppression in the isolated perfused canine right atrium. Circ Res 1991;69: Smeets JL, Allessie MA, Lammers WJ, Bonke FI, Hollen J: The wavelength of the cardiac impulse and reentrant arrhythmias in isolated rabbit atrium. The role of heart rate, autonomic transmitters, temperature, and potassium. Circ Res 1986;58: Atrial Electrical Remodeling From Barn To Bedside 25

13 42. Roffman JA, Fieldman A: Digoxin and propranolol in the prophylaxis of supraventricular tachydysrhythmias after coronary artery bypass surgery. Ann Thorac Surg 1981;31: White HD, Antman EM, Glynn MA, Collins JJ, Cohn LH, Shemin RJ, Friedman PL: Efficacy and safety of timolol for prevention of supraventricular tachyarrhythmias after coronary artery bypass surgery. Circulation 1984;70: Vecht RJ, Nicolaides EP, Ikweuke JK, Liassides C, Cleary J, Cooper WB: Incidence and prevention of supraventricular tachyarrhythmias after coronary bypass surgery. Int J Cardiol 1986;13: Fuller JA, Adams GG, Buxton B: Atrial fibrillation after coronary artery bypass grafting. Is it a disorder of the elderly? J Thorac Cardiovasc Surg 1989;97: Olgin JE, Sih HJ, Hanish S, Jayachandran JV, Wu J, Zheng QH, Winkle W, Mulholland GK, Zipes DP, Hutchins G: Heterogeneous atrial denervation creates substrate for sustained atrial fibrillation. Circulation 1998;98: Whalley DW, Wendt DJ, Grant AO: Basic concepts in cellular cardiac electrophysiology: Part I: Ion channels, membrane currents, and the action potential. Pacing Clin Electrophysiol 1995;18: Gettes LS, Reuter H: Slow recovery from inactivation of inward currents in mammalian myocardial fibres. J Physiol (Lond) 1974;240: Weidmann S: The effect of the cardiac membrane potential on the rapid availability of the sodium-carrying system. J Physiol 1955;127: Fabiato A: Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum. Am J Physiol 1983;245:C Coraboeuf E, Carmeliet E: Existence of two transient outward currents in sheep cardiac Purkinje fibers. Pflugers Arch 1982;392: Tseng GN, Hoffman BF: Two components of transient outward current in canine ventricular myocytes. Circ Res 1989;64: Zygmunt AC, Gibbons WR: Calcium-activated chloride current in rabbit ventricular myocytes. Circ Res 1991;68: Giles WR, Imaizumi Y: Comparison of potassium currents in rabbit atrial and ventricular cells. J Physiol (Lond) 1988;405:123-45: Heidbuchel H, Vereecke J, Carmeliet E: Three different potassium channels in human atrium. Contribution to the basal potassium conductance. Circ Res 1990;66: Gelband H, Bush HL, Rosen MR, Myerburg RJ, Hoffman BF: Electrophysiologic properties of isolated preparations of human atrial myocardium. Circ Res 1972;30: Tranum-Jensen J, Janse MJ: Fine structural identification of individual cells subjected to microelectrode recording in perfused cardiac preparations. J Mol Cell Cardiol 1982;14: Escande D, Loisance D, Planche C, Coraboeuf E: Age-related changes of action potential plateau shape in isolated human atrial fibers. Am J Physiol 1985;249:H CHAPTER 2 Pathophysiological Mechanisms of Atrial Fibrillation

14 59. Boutjdir M, Le Heuzey JY, Lavergne T, Chauvaud S, Guize L, Carpentier A, Peronneau P: Inhomogeneity of cellular refractoriness in human atrium: factor of arrhythmia? Pacing Clin Electrophysiol 1986;9: Le Heuzey J, Boutjdir M, Gagey S, Lavergne T, Guize L: Cellular aspects of atrial vulnerability. in Attuel P, Olsson SB, Schlepper M (eds): The Atrium in Health and Disease. Mount Kisco; NY, Futura Publishing, 1989,pp Le Heuzey JY, Le Grand B, Hatem S, Lavergne T, Guize L: Cellular electropharmacology of human atrium: effects of antiarrhythmic drugs. Cardiologia 1991;36: Olsson SB, Cotoi S, Varnauskas E: Monophasic action potential and sinus rhythm stability after conversion of atrial fibrillation. Acta Med Scand 1971;190: Cotoi S, Gavrilescu S, Pop T, Vicas E: The prognostic value of right atrium monophasic action potential after conversion of atrial fibrillation. Eur J Clin Invest 1972;2: Attuel P, Childers R, Cauchemez B, Poveda J, Mugica J, Coumel P: Failure in the rate adaptation of the atrial refractory period: its relationship to vulnerability. Int J Cardiol 1982;2: Attuel P, Childers R, Haissaguerre M, Leclercq J, Mugica J, Coumel P: Failure in the rate-adaptation of the atrial refractory periods: new parameter to assess atrial vulnerability. Pacing Clin Electrophysiol 1984;7: Morillo CA, Klein GJ, Jones DL, Guiraudon CM: Chronic rapid atrial pacing. Structural, functional, and electrophysiological characteristics of a new model of sustained atrial fibrillation. Circulation 1995;91: Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA: Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation 1995;92: The Sicilian Gambit: a new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms. Task Force of the Working Group on Arrhythmias of the European Society of Cardiology. Circulation 1991;84: Atrial Electrical Remodeling From Barn To Bedside 27

15 28 CHAPTER 2