Transitions among atrial fibrillation, atrial flutter, and sinus rhythm during procainamide infusion and vagal stimulation in dogs with sterile pericarditisl PIERREL.



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Departments of' Surgery and Phumcolsgy, H6pitaE du Sacri-Coeur, and klniversit&de Msntr&al, Montr&krl, Qud , Canada Received April 11, 1990 PAGB,P. L., HASSANALIZADEH, H.,and CARDINAL, R. 1991. Transitions among atrial fibrillation, atrial flutter, and sinus rhythm during procainamide infusion and vagd stimulation in dogs with sterile pericarditis. Can. J. Physiol. Pharmacol. 69: 15-24. The mechanism of atrial flutter and fibrillation induced by rapid pacing in 22 dogs with 3-day-old sterile pericarditis was investigated by computerized epicardial mapping of atrial activation before and after administration of agents h o w n to modify atrid electrophysiologic properties: procainamide, isoproterenol, and electrical stimulation of the vagosympathetic trunks. Before the administration of any of these agents, a total of 38 episodes of sustained atrial flutter ( > 1 min duration, monomorphic; regular cycle length, 127 f 12 ms, mean f SD) was induced in 15 out of 22 dogs and 9 episodes sf unstable atrial flutter (duration, < 1 min; cycle length, 129 $ 34 ms; monomorphic, alternating with fibrillation) were induced in' the remaining 7 preparations. In the latter, administration of procainamide transformed unstable atrial flutter and atrial fibrillation to sustained atrial flutter (cycle length, 142 $ 33 ms; n = 9 episodes). During control atrial flutter, atrial maps displayed circus movement of excitation in the right atrial free wall with faster conduction parallel to the orientation of intra-atrial myocardial bundles. Vagal stimulation changed atrial flutter to atrial fibrillation in 32 of 73 trials; this was associated with acceleration of conduction in the lower right atrium, leading to fragmentation of the major wave front. IsoproterenoI produced a 6 -25 % increase of the atrial rate in 6 out of 14 trials of atrial flutter and induced atrial fibrillation in 4. After procainamide, the reentrant pathway was lengthened and conduction was slowed further in the right atrium. Maps obtained during unstable atrial flutter showed incomplete circuits involving the right atrium. Following prmainapmide infbsion, the area of functional dissociation or block was enlarged and a stable circus movement pattern, which was similar to the pattern seen in control atrial flutter, was established in the right atrium. We conclude that (1) the transitions among atrial fibrillation, atrial flutter, and sinus rhythm occur between different hnctional states sf the same circus movement substratum primarily located in the lower right atrial free wall, and (2) the anisotropic conduction properties of the right atrium may contribute to these reentrant arrhythmias and may be potentiated by acute pericarditis. Key words: atria9 flutter, atrial fibrillation, atrial mapping, antian-hythmic drugs, vagal stimulation. PAG&P. L., HASSANALIZADEH, H., et CARDINAL, W. 1991. Transitions among atrial fibrillation, atrial flutter, and sinus rhythm during procainamide infusion and vagal stimulation in dogs with sterile pericarditis. Can. J. Physiol. Pharmacol. 69 : 15-24. k e mCcanisme du flutter et de la fibrillation auriculaires, induits par une stimulation rapide chez 22 chiens avec une pCricardite stCrile de 3 jours, a CtC examink par cartographie Cpicardique de l'activation auriculaire, avant et aprbs l'administration d'agents modifiant les propriCtCs Clectrophysiologiques auriculaires : prwai'namide, isoprotkrCno1 et stimulation klectrique des troncs vagosympathiques. Avant tout emploi de l'un ou l'autre de ces agents, un total de 30 Cpisodes de flutter auriculaire soutenu (durk > 1 min, rnonomorphe, longueur du cycle 127f 12 ms, moyeme f ET) a CtC induit chez 15 de 22 chiens et 9 Cpisdes de flutter auriculaire instable (durCe, < 1 f i n ; longueur du cycle, 129 f 34 ms; monomorphe, alterwant avec la fibrillation) ont 6tC induits &ins les 7 prCparatioms restantes. Bans le dernier cas, l'administration de procaynamide a trmsfomC le flutter auriculaire instable et la fibrillation auriculaire en flutter auriculaire soutenu (longueur du cycle, 142 f 33 ms, n = 9 kpisdes). Burant le flutter auriculaire tCmoin, les cartes auriculaires ont prksentk un mouvement circulaire d'excitation dans h paroi libre de l'oreillette droite, avec une conduction plus rapide parallble i l'orientation des faisceaux myocardiques intra-auriculaires. La stimulation vagale a transform6 le flutter auriculaire en fibrillation auriculaire dans 32 des 73 essais; ceci a CtC associC 2 I'accClCration de la conduction h n s l'oreillette droite infirieure, menant h la fragmentation de l'onde de front principale. L'isoprot6rinol a produit une augmentation de 6 2 25% de la frkquence auriculaire dans 6 de 14 des essais de flutter auriculaire et induit une fibrillation auriculaire dans 4 cas. Aprbs la perfusion de procai'namide, la voie rCentrante a 6. allongie et la conduction dans l'oreillette droite davantage ralentie. Les cartes obtenues durant ran flutter auriculaire instable ont montrC l'existence de circuits incsmplets impliquant l'oreillette droite. Aprbs la perfaesion de procaharmnide, la zone de dissociation fonctionnelle ou de blocage a CtC agrandie et un patron de mouvements circulaires stables, s i d a i r e B celui ob%ewCdans le flutter auriculaire tCmoin, a kt6 Ctabli dans l'oreillette droite. Nous concluons que (1) les transitions entre fibrillation auriculaire, flutter auriculaire et rythme sinusal se produisent entre diffkrents $tats fonctisnnels du meme substrat de mouvement circulaire essentiellement localis6 dans la paroi libre de l'oreillette droite infkrieure et 42) les propri6tCs de conduction anisotrope de 190reillettedroite pourraient contribuer B ces arythmies reemantes et pourraient Ctre potentialisees par une pdricardite aigue. Mots cle's : flutter auriculaire, fibrillation auriculaire, cartographie auriculaire, antiarythrnisants, stimulation vagale. [Traduit par la Ridaction]

"Pkis work was supported by the Quebec Heart Foundation, the Medical Research Council of Canada and le Fonds de la recherche en santi du QuCbec. 'Author to whom correspondence may be sent at the following address: Centre de recherche, Hbpital du SacrC-Coeur, 5488 Gouin Blvd. West, MontrCal, QuC., Canada H4J 1C5. Printed in Canada / IrnpsimC au Canada

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Introduction Atrid flutter is seen most often in patients with atrial enlargement (Josephson et al. 19'97) or after open heart surgery (Waldo and MacLean 1980). This frequent arrhythmia probably results from a complex interaction of multiple factors (Boineau 1985; AUessie et al. 1987): the greater the involvement of these factors in a given a n i d preparation, the more stable the atrial Butter will be. Although important in elaborating concepts, experimental methods of producing atrid flutter by atrial incisions (Rosenblueth and Garcia-Ramos 1947; Hayden et d. 1947; Boineau et al. 1986; F r m e et d. 1986) or pharmacologic actions (Scherf 1947; Nlessie et al. 1984) have little in c s m o n with the pathophysiology of atrial flutter that occurs in humans. Two animal models relevant to clinical circumstances have been developed: first, right atrid enlargement induced by trieuspid insufficiency and pulmonary artery banding in dogs (Boyden and Hoffman B981), and second, postpericardiotomy pericarditis in dogs. In previous reports, we demonstrated that reproducible atrial flutter could be induced by programmed electrical stimulation 2 -4 days after the production of pericarditis (Pag6 et d. 1983, 1986). Other studies have provided some evidence in favor of intra-atrial reentry as the mechanism of atrid flutter in this model (PagC et d. 1983; Okumura et al. 1984, 1985a, 1985b; Schoels et d. 1989; Shimizu et d. 1990). Furthermore, it was suggested that the circus movement involved a functional dissociation of tissue in the center of the circuit (Obmura et al. 1984, 1985; Schoels et d. 1990; Shimizu et d. 1990). In fact, it is becoming apparent that hnetiond alterations as well as anisotropic tissue organization of the atrium may be important for the stability of reentrant atrial arrhythmias (Boineau 1985; Alessie et d. 1987; Boyden 1988). The present study was designed to assess to what extent the reentrant substratum of atrid fibrillation and stable or unstable atrid flutter induced in dogs with sterile pericardibs may be functionally or stmcturdly determined. We studied the effects on atrid arrhythmias of agents h o w n to modify atrial electrophysiologic properties: procainamide, a class IA antiarrhythmic drug that increases atrid refractoriness and decreases iaatra-atrid conduction; isoproterenol; and electrical stimaalation of the vagosympathetic trunks, an intervention that decreases atrial refractoriness. These effects were studied by epicardid atrial mapping using a computer-based data acquisition system.

Methods Surgery Sterile pericarditis was created in 22 mongrel dogs weighing 25 30 kg by a procedure described previously (Page et al. 1986). In brief, the atrial surfaces were generously dusted with sterile talcum powder through a right thoracotomy. A single layer of gauze was put on the right and left atrial free walls. Three pairs sf stainless steel wire electrodes insulated with Teflon except for the tip were sutured at selected atrial sites and exteriorized posteriorly in the neck for closed chest studies. Three days after the induction of the pericarditls, each dog was anesthetized with 25 mg/kg sodium thiopenthal (Pentothal) i.v., supplemented with a-chBoralose (100 mg/kg) and ventilated with room air by a Harvard respirator. The vagosympathetic trunks were isolated via bilateral neck incisions. Befinitions of atria1 arrhythmias We defined as stable atrialfitter those episodes lasting more than B min with constant beat-to-beat amplitude, polarity and configuration of atrial electrsgrams, and slight variations (less than 10 ms) in

the atria5 cyde length* The nonsustained episodes (less than 1 min duration) &ring which short mm of atrial Kbrillation were occasionOthers have defined ally seen were defined as unstable atrialflutfe~.. the latter as atrial "flitter9' or 66fibrillo-flutter'9(Lewis et al. 1920; Boyden and Hoffman 1981 ; Boineau 1985). Atrial fibrillation was characterized by an atrial cycle length shorter than 100 ms and an irregular amplitude and morg>hology of atrial electrograms.

Induction of atrial arrlzythma'as As described previously (PagC et al. 1986), the dogs were subjected to two protocols of atrial programed electrical stimulation: one to three extrastimuli and (or) burst pacing with decreasing pacing intervds until one-to-one atrial capture was lost or an atrial arrhythmia was precipitated. The stimuli were constant-current pulses of 3 ms duration and 10 mA amplitude (BM-SCP programable stimulator, Institut de g6nie biom6dial, Ecole polytechnique, UniversitC de Montreal). If pacing at any site precipitated sustained atrial flutter (> 1 min), then a low dose (3 mg/kg) of procainamide was administered and the pacing protocol was repeated to assess drug effect on the inducibility of atrid flutter. Intewentions VagosympatB~efic sfizulatisn The denervated cervical vagal nerves were stimulated separately and then simultaneously with two programmable stimulators (SB-9, Grass Inc.) at a frequency of 10 Hz. The stimuli were of 5 ms duration and the strength was set between 2 and 20 V to reduce basal sinus rate by at least 20%. The stimulation was then repeated with the same protocol during atrial flutter. &Adrenep.gie stimkk!abion Isoproterenol (Sigma Chemical Co., St. Louis, MO) was administered as a bolus of 0.5 -0.75 yglkg during normal sinus rhythm to increase the sinus rate by at least 20%'0; administration of the drug was repeated rat the same dose after precipitation of atrial flutter. Class 6 . mtiarrl~ythmicCCCCg Procainamide (Squibb, Montrkd, QuC.) was administered in a b l u s of 20 mglkg i.v. (four dogs) or by successive doses of 3 mg/kg every 3 min (six dogs) until atrial flutter was converted to sinus rhythm or until it could be initiated by programed stimulation in those preparations in which only unstable atrial flutter was inducible in the bas& state. After termination of atrial flutter, the administration of procainamide was interrupted and we attempted to reinduce atrial flutter with the previous8y successhl programmed stimulation protocol. Plasma Bevels of prscainamide (immunofluorescence, TDx amly sor, Abbott Labs. Ltd. ) were determined in six animals i m e d i ately after the resumption of sinus rhythm and when atrial flutter became inducible again. Atrial mapping A median stemstomy was performed in 14 amimds for the purpose of direct atrial mapping: 12 of these were pericarditis preparations and two were sham-operated dogs not subjected to prior pericarditis procedure. The pericardium was genfly peeled from the adherent epicardium and the heart was cradled in the pericardlum. The activation sequence of both atria were obtained from 63 unipolar recording electrodes which were fixed to five flexible templates m d e of double layers of reinforced sheeting (Silastic, Dow Corning). Five such templates were shaped to fit the epicardium of the right atrial free wall, the posteroinferior wall of the left atrium and coronary sinus, the posterior aspect of left atrium (template inserted after division of the left inferior pulmonary vein), the left atrial free wall, and the interatrial band. The distribution of electrodes and the anatomic mapping grid are shown in Fig. 1. We used,a @-channel data acquisition system (Hnstitut de genie biomedical, Ecsle polytechnique, UniversitC de Montreal) described in previous reports (Bonneau et d. 1987). The 63 atrial unipolar signais, referenied to Wilson's central terminal, were simultaneously recorded dong with a surface ECG (lead H), amplified by programmable-gain amplifiers, filtered with a band pass of 0.05-200 Hz, multiplexed, sampled at 500 Hz, and converted to

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FIG. 1. Anatomic grid for atrial epicardial mapping. The atrial surfaces are viewed from a posterior projection. The dots indicate the psition of the recording sites s f 63 unipolar electrograms. The curved dashed lines represent schematically the position of the sulcaas terminalis (ST, overlying the crista terminalis) and the region of the pectinate muscle (P). st, cut edge of the left atrial free wall. b, unfolded edge of the interatrial band (IAB, Bachmann's bundle) and posterior atrid appendages. c, orientation of muscle layers in the right atrium from the crista terminalis to the IAB. AS, interatrial groove overlying atrial septum. AV, right atrioventricular groove. CS, cc~mmhgrsinus. CS,, distal coromry sinus. CS,, proximal coronary sinus. NC, inferior vena cava. LAA, left atrial appendage. PV, pulmonary veins. U A , right atrial appendage. SVC, superior vena cava .

a 10-bit digital format. Data processing was done during the expriment on a PBP l l i 2 3 computer (Digital Equipment Corporation, Maynard, MA). Local excitation times were automatically detected by the program as the point of most rapid decrease in potential with a maximum negative slope in excess of -0.3 mV/ms. Each electrogram was displayed on a video terminal with local excitation times indicated by vertical cursors. It was sometimes necessary that the program operator edit the automatically detected excitation times either tu correct an artifact (motion, p o r electrode contact, electrical noise), to interpret a low amplitude unipolar wave f o m recorded in a critical part of the right atrial free wall, or more often to delete a cursor detecting ventricular activation. Since ventricular contractions usually occurred in a one-to-two relationship, many atrial electrograms had fallen into the ventricular QRS complex, thus preventing adequate signal interpretation. Therefore the time wind6_sws were selected to only include atrial cycles completely separated from ventricular QRS complexes. Finally, isochronal activation m p s w e r e constructed from the activation times detected during the selected time window. The earliest excitation detected by the electrode array was used as the time reference (t = 8). AnilPysis The inducibility of atrial arrhythmias, their type, and atrial rate were examined both before and after the three interventions, and atrial mapping was performed during n o d sinus rhythm and atrial flutter as wdl.

Results Studies during sinus rhythm In the two sham-operated animals, the maps obtained during normal sinus rhythm showed activation sequences in agree-

ment with previously published data ( h e c h et d. 1954; Boineau et d. 1980; Allessie et d.1984). In preparations with pericarditis, the mean atrial sinus cycle length was 436 f 79 ms (n = 12) and the total atrial activation time was 62 f 9 ms. The atrial activation pattern (Fig. 2A) did not differ from that observed in the preparations with normal atrium. In brief, the impulse originating in the vicinity of sinoatrial node activated the right atrium along the pathway of the crista termindis underlying the sulcus termindis, m d it activated the left atrium dong the pathway of the interatrial band. The site of latest activation was l o c d i ~ dnear the coronary sinus (70 ms isochrsne). In d l instances, here was no evidence sf slow conduction or conduction block and all of the electrsgrams displayed a clear intrinsic deflection in spite of the pericarditis. After procainmide infusion, the sinus cycle length was prolonged to 565 f 112 ms (n = 12) and the total epicardid activation time was prolonged to 78 f 1 1 ms ( p < 0.05), but the activation pattern was not modified (Fig. 2B). The administration of isoproterenol decreased the sinus cycle length to 342 59 ms (n = 12), enlarged the area of early activity (Fig. 2@),and decreased the total epicardid activation time to 49 & 13 ms (.-I < 0.01). Bilateral vagal nerve stimulation prolonged the sinus cycle length to 989 f 349 ( p < 0.001) and produced a downward shift of the site of early activation (5 out of 12 preparations, Fig. 2D); it changed the locdization sf the site of latest activation, but had no effect on the total epicardial activation time. Right vagd nerve stirnulation produced an augmentation of the sinus cycle length to 1175 9 752 ms ( p 6 8.001) and shifted the pacemaker site in 6 out of 12 preparations. Stimulation of the left vagal nerve produced an augmentation of the sinus cycle length to 1164 $_ 752 ms ( p < 0.801)and dso induced a shift in pacemaker site in 5 out of 12 cases, as previously reported (Meek and Eyster 1914; Wabnabe et d. 1985). Induction of atrial flutter and jbrillation Sustained atrial flutter was induced in 15 of 22 pericarditis preparations under control conditions. In the remaining seven preparations, infusion sf prscainamide facilitated the initiation of atrial flutter by allowing spontaneous unstable atrial flutter to become sustained. The mean cycle length of atrial flutter induced under control conditions was 127 -t- 12 ms (n = 30) and 142 f 33 ms (n = 9) in those episodes induced after prscaimnaide administration. Only atrial fibrillation with a cycle length less &an 188 ms could be induced in the sham preparations. Eficts of w g a l sti.~'mulatisn Stimulation of the vagd nerves separately or sirnultanesusly was done in eight dogs with atrial flutter induced under control conditions (10 episodes; cycle length, 130 -t- 34 ms) and in five dogs with flutter induced after procainamide administration (seven episodes; cycle length, 15 1 f 26 ms) . The data are detailed in Table 1 . Atrial fibrillation was precipitated in 10 out of 40 trids in the first group and in 23 out of 33 trids in the second group ( p 6 0.001, chi-square). Note that the stimulation of the right vagus produced atrid fibrillation more often than the stimulation of the left vagus, but the difference was not statistically significant. In all instances in which parasympathetic stimulation produced a transition into atsid fibrillation, a slight reduction in the atrial cycle length was observed B - 8 beats after the onset of stimulation (see below, and tracing in upper panel of Fig. 6).






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FIG.2. Atrial activation maps obtained during sinus rhy%hm. The isochronal lines are drawn at 10-m intervals and the numbers refer to the activation time (ms) of each isochrsne. The maps were obtained 3 days after the creation of a sterile pericarditis, before administration of pharaacologic agents, cycle length of 534 ms (A); after procainamide administration, cycle length of 596 ms, plasma level sf 43.1 yglmL @); after adrninistration of 0.75 pglkg of isoproterenol, cycle length of 400 ms (C); and during bilateral vagal nerve stimulation; cycle length of 6W ms (B).

Efleets sf p-adrelaergic stirnulation The administration of isoproterenol during atrid flutter (14 episodes; cycle length, 137 33 ms) produced a 6 -25 % (mean 15.2%) reduction of the atrial cycle length in six trials, changed atrid flutter to atrial fibrillation in three, converted atrid flutter to sinus rhythm in one trial, and had ws effect in four tria%s.


Efleets of procailaamkde In four dogs, procainamide was administered by an intravenous bolus injection sf 20 mglkg during atrial flutter. It was converted to sinus rhythm in all four animals at the point of maximal increase in the atrial cycle length, 24 -64 s after drug administration. In 12 dogs, the dmg was administered in repeated doses of 3 mglkg . In these animals, the atrial cycle length s f flutter increased from 129 _+ 24 ms to 2 18 _+ 59 ms ( p < 0.001, Table 2). In d l instances, 1- 36 doses sf procainarnide interrupted atrial flutter after a prolongation o i the atrid cycle length. Plasma levels of procainamide were determined in six preparations (Table 3). Atrial flutter was precipitated prior to


administration of procainarnide in three of these. A plasma Bevel of 22 6 pglmE was required for atrial Wutter to be induced in the remaining three dogs. In five of six dogs, the plasma level of procainarnide was higher at the time of spontaneous termination of atrial flutter than at the time of its induction. In the other preparation (dog E in Table 31, only atrid fibrillation was precipitated by atrial pacing under contrsl conditions; sustained atrial flutter became inducible when a level of 28 pglmL of procainamide was reached and was converted to sinus rhythm when the level fell to 8 pg/mL. These data illustrate sa consistent response to procainamide administration related to changes in its p l a s m concentration, although the absolute vdues varied from one preparation to another. The delay between the last dose of procainamide and reinduction of atrial flutter varied from 3 to 120 min depending on the cumulative doses of procainarnide. Activarion sequence during atrial flutter Seventeen episodes of atrial flutter (cycle length range, 105-248 ms) were induced by atrial pacing and mapped in nine preparations. Activation mapping demonstrated a circus

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P A G ET ~ AL.

PIG. 3. Counterclockwise circus movement of excitation during atrial flutter. Left panel: atrial activation map obtained during stable atrial flutter (cycle length, 133 ms) in a pericarditis preparation under control conditions. Hsochrones and numbers are as in Fig. 1 . Arrows indicate the direction of the wave front*Right panel: umipolar electrograms from selected sites A to E as shown on the map. ECG, surface electrocardiographic lead IH showing a 2: 1 AV conduction pattern. Vertical dotted lines indicate the limits of the mapping window corresponding to a complete atrial cycle. Oblique arrows indicate the detection of local activation, and the numbers are activation times (ms) from the beginning s f the window (0).

TABLE1. Effect of right, Heft, and bilateral vagal nerve stimulation on atrial flutter

Preparation Group I

Group 11


Site of stimulation

No. of trials

TABLE 2. Effect of procainamide on atrial cycle length of sustained atrial flutter

Effect observed Fibrillation


No effect

Right Left Bilateral Overall Right Left Bilateral Overall All sites


Dose (3 mg kg-' 3 min-I)

Aerial cycle length (ms) Control


NOTE:NSR, n o d sinus rhythm. Group I: ratrial flutter induced under basal csnditions, i.e., withut procainamide (10 episodes of atrial flutter; cycle length, 130 f 34 ms). Group 11: atrid flutter induced after dministration of procainamide (7episodes; cycle kngth, 151 k 25 ms). *Atrial fibrillation respnse in group I vs. group 11: p < 0.05 by chi-square test. -


movement of excitation in the right atrium in 14 sf the 17 episodes. The center of the circus movement was located in the mid-right atrium in six episodes (see Figs. 3 and 4), in the high right atrium in four episodes (see below, Fig. 61, and in the low right atrium in six (not shown). As viewed posteriorly, the impulse rotated in a clockwise direction in 11 instances and in a counterclockwise direction in 5. In the other episode, a circus movement pattern could not be clearly identified. Figure 3 shows a representative example obtained during atrial flutter with a cycle length sf 133 ms. The earliest activation occurred in the right atrial free wall (site A); the impulse spread superiorly towards the base of the right atrial appendage (site B), then inferiorly along the crista terminalis (sites C and D) and finally circulated back towards site E, next to the site of earliest activation in the anterior right atrium. Assuming slow conduction from site E to A or propagation in a rim of tissue between the recording template and the tricuspid annulus, there was a "missed" time interval of 47 ms (35 % of the flutter cycle length of 133 ms) between the latest activa-







< 0.001 by Student's t-test for paired values.

tion (local deflection indicated by arrow at 86 ms s n electrogram E) and the beginning of the next atrial flutter cycle (electrogram A). The left atrium was activated by a centrifugal wave front propagating across the interatrid septum, away from the counterclockwise circus movement. During another episode of atriaH flutter induced in the same preparation (Fig. 4): a circus movement of excitation occurred in the same region of the right atrium, but in a clockwise direction and with a shorter cycle length (123 ms). The portion of the cycle during which local deflections were recorded was of 86 ms, as in the previous example; however, only 37 ms were left unaccounted for by actual recording (for a ' kissed' ' time interval of 30%). Note that this gap between the latest and the earliest activations was localized in the same area as in Fig. 3. EDct ofprocainamide on the activation sequence during atrial Putter The map in Fig. 5A was obtained during unstable atrial flut-


TABLE3. Plasma levels s f procainamide

Cycle length of atrid flutter (ms)

Brscainamide Bevel (pglmL)

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Dog Baseline Procainamide Induction Termination Reinductisn Noninducible

NOTE:AF, atrial fibrillation.








D E ECG PIG. 4. C B ~ c b i s ecircus movement of excitation during atrid flutter. Left panel: atrial activation map obtained during atrial flutter in the same dog as in Fig. 3 (cycle length, 123 ms). Isschrones and numbers are as in previous figures. Right panel: unipolar electrsgrams displayed as in Fig. 3.

ter with a cycle length of 112 ms. The earliest activation occurred on the intereavd band (Q), but the pattern suggested that the right atrium was activated in an upward direction from the region of the lower right atrium, which was activated 12 16 ms later than the interatrial bmd. In the lower right atrial free wall, a delayed electrogram (88 ms) was consistently recorded next to sites activated much earlier (12 ms) suggesting functional dissociation (thick line). After procainamide administration (plasma Bevel of 16.8 pg/mL), an area of block appeared adjacent to the site where a delayed electrogram was recorded in the previous map, and a clockwise circus movement pattern became apparent in the lower right atrid free wall, spanning 93 5% of the atrial flutter cycle (130 ms). There was a progressive return to the same activation pattern as in Fig. 5A as this episode of atrial flutter lasted and the plasma level of prmaimrnide fell. Efect sf lagal ~timukationon the activation sequence during atrial flutter Figure 6 (left upper, atrid electrogram (AEG) tracing) shows the change from atrid flutter to atrial fibrillation during bilateral vagd nerve stimulation. The map obtained during Butter (Fig. 6A, beat A on AEG tracing) suggested the rotation of an impulse around the superior vena cava: the reentrant impulse started in the region of the interatrial band (01, propagated downward on the right atrial free wall where it was

slowed in the transverse direction relative to the orientation of the sulcus terminalis, and activated the interatrid septum at 110 ms. Propagation back to the interatrial band region remains hypothetical, but may have occurred through the limbus of the fossa ovdis, as displayed schematically in Fig. 6B (broken arrows). In this example, the left atrium was activated secondarily from the regions adjacent to the interatrid septum, i .e., the interatrial band superiorly and the proximal coronary sinus inferiorly. Then the wave front propagating in the upper left atrium from the interatrid band region collided with the one propagating in the lower left atrium from the proximal coronary sims region. A 26-m delay between the s e p d portion of the reentrant circuit (1 18 ms) and the epicardial recording site of the proximal part of the coronary sinus (CS,) may explain why this area displayed early activation (130/0 ms, Fig. 6B). When bilateral vagd nerve stimulation was started, eonduction was modified in the lower right atrium and the activation sequence was broken up into multiple wave fronts as shown in Pig. 6C (corresponding to beat C on the upper AEG tracing). This arrhythmia corresponded to the definition of atrid fibrillation, since the tracing displayed a cycle length less than 100 ms and polymorphic atrid electrcsgrams. The administration of 20 mglkg of proeainamide during this episode changed atrial fibrillation back to atrial flutter (Fig. 6D). The activation pattern was similar to &at seen in



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FIG.5. Effect of prmaimmide on activation pattern during atria1 flutter. (A) Mag obtained during unstable atrial flutter with a cycle length of 112 ms without administration sf any agents. The right atrium was activated in an upward direction from sites activated 12- 16 ms after activation of the interatrial band. A delayed electrogram (88 ms) was consistently recorded from the lower right atrial free wail. The thick bar indicates a small area sf hnctisnal dissociation. (B) After procainmide admilaistratioam (plasma level of 16.8 pgIrnE), the cycle length was 138 ms and an area sf block appeared adjacent to the site where a delayed electrograim was recorded in the previous map. m e broken arrow indicates a hypothetical pathway in a rim of tissue between the electrode template and the tricuspid valve annulus. Isochrones and numbers are as in previous figures.

Fig. 6A, but with slower conduction in the right atrid free wdl leading to an increase in the atrid flutter cycle length to 220 ms. In contrast, the presumed conduction time (broken a m w ) between the atrid septum (206) ms) and the interatrial band (220/0) was similar to the one w n in the Fig. 6 8 map (1 18 to B 3010' ms) .

Discussion The present study confirms previous observations (Bag6 et d.1983; Bhmura et d.1985a, 198587; Schoels et al. 1990) that atrial flutter induced in dogs with sterile pericarditis m y be caused by circus movement of excitation located primarily in h e right atrium. Figures 3 md 4 show such a circus movement in the mid right atrid free wall around an area of fumctiond block or dissociation. Apart from this inexcitable central boundary, it appears that the circuit was protected by the following peripheral boundaries: superiorly, the insertion of the right atrid appendage; medicdilly, the superior vena cava; caudally, the inferior vena cava; and internally, the tricuspid ring. The 'kissed" time interval encompassed up to 38% sf the flutter cycle length and was probably related to our epicardial mapping technique, which did not allow recording of the endocardial myocardial band adjacent to the tricuspid orifice. A mapping approach including endocardial recordings would help to clarify this issue. However, global endocardid mapping of both atria necessitates the introduction of eggshaped electrodes in isolated heart preparations (ABBessie et al. 1984, 1987; Boyden 1988), a technique that we believe would have significantly altered the atrial electrophysioHogicd properties and wodd have prevented the use of vagal stimulation. In addition, most of the tissues critically involved in the mechanism of atrial flutter are those affected by the inflama-

tory process of the pericarditis md are accessible to epiczudid patch electrodes.

Funcfiomk versus anatomical factors of reentry The hnctiond nature of the central area of block is supported by the following observations. The atrid activation sequence during sinus rhythm was not modified by the pericarditis process (Fig. 2) when compared with sham-operated dogs in which direct electrical stimulation provoked rapid unstable rhythms only. Areas of inexcitability or slow conduction were not observed in sinus rhythm and the electrographie characteristics of signals recorded during sinus rhythm remained unaltered by the pericarditis; Hocal electrogrms displayed '6n~rHlaI"morphologies similar to the one displayed at the top of Fig. 6 (beat A). On the other hand, complex electrograrns were seen in criticd areas during flutter (see tracings C and D of Figs. 3 and 4). Eiectrogram with double potentials were recorded by others in the critical zone of atrid flutter induced in the same animal model (Ohlaaura et al. 1985a; Shimizu et d. 1990). Mapping studies during rapid atrid pacing suggested that these double potentials might be due to functional block rather than slowed conduction through the center of the reentry circuit (Shimizu et d. 1990). We have demonstrated previously (Pag6 et id. 1986) that neither atrid excitability, intra-atrial conduction time, nor atrid refiactorhess as determined by pacing and recording from a fixed atrial site predicted the inducibility of atrid flutter in this model. However, it was shown that a nonhomogeneous refractory field was necessary to the induction of reentry in isolated rabbit myocardium (Allessie et d. 1976). Furthermore, a nonhomogeneous distribution of refractory periods was shown in a dog with abnormal right atrid free wdl (Boineaaa et al. 1988). Although detailed spatid distribution of


continuous AEG

t A

C vagal stimulation -4



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FIG.6. Transitions between atrid flutter and atrial fibrillation during vagal stimulation and procainamide injection. Upper panel: continuous recording of an atrial electrograrn ( M G ) during the change from atrial flutter (beat A) to atrial fibrillation (beat C). The beginning and the end of bilateral vagal nerve stimulation are indicated. The map obtained during beat A of atrial flutter (panel A) suggested the rotation of an impulse around the superior vena cava. Conduction was slowed in the direction perpendicular to the orientation of the crista terminalis (compare with Fig. 2A in relation to the anatomical landmarks shown in Fig. 1). (El) Schematic representation of the reentry pathway. The right atrium is viewed from the right side. The k l l arrows indicate the impulse coursing in the right atrium. The open arrows indicate the hypothetical pathway of an impulse circulating back to the HAB through the limbus of the fossa ovalis (FO) with a centrifugal wave conducting downward to the coronary sinus through the lower interatrid septum. Numbers indicate activation times (in ms). TV, annulus of the tricuspid valve. Other abbreviations as in Fig. 1. (C) A map obtained during beat C of a run of atrial fibrillation induced by bilateral vagal nerve stimulation. (D) A map obtained during atrial flutter with a cycle length s f 220 ms (tracing not shown) produced after administration s f 20 mg/kg of procairaamide during the nsninterrupted episode of atrial fibrillation shown above; an activation pattern similar to that seen in panel A was displayed, but with slower conduction in the region of the pectinate muscle of the right atrial free wall. The assumed conduction time (broken arrow) between the atrial septum (isochrone 200) and the IAB (220/0) was similar to the one seen in the panel A map (20 ms).

atrid refractory periods was not determined in our in-vivo study, the response of atrial flutter to the administration of agents h o w n to modify atrial refractoriness and conduction provides mother line of evidence in favor of the functional

nature of tissue dissociation, slow conduction, and block in pericarditis preparations. Procainamide prolongs the atrial refractory period and decreases the atrial conduction velocity (Hordof et al. 1976; Boyden 6986; Watanabe et d. 1985). In

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our study9 it produced an augmentation of the atrid flutter cycle length. Ohmura and Waldo (1987) have shown similar effects of quinidine, another class IA antiarrhythmic agent, in the same model. Previous observations that the effects of class IA antiarrhythmic drugs are more pronounced at higher rates (Hondeghem and Katzung 1988; Carson et al. 1986) and on pathologically affected cells (Kugersmith 1975; Cardinal et al. 1981) may explain why these effects were not seen in the sinus rhythm maps. At a low dose, procainamide facilitated the induction of sustained atrial flutter in preparations in which only unstable atrial flutter could be induced under control conditions. These observations fit the concept developed by Rensma et al. (1988) on the relationship between the wavelength of the atrial impulse and the susceptibility to reentrant atrial arrhythmias. They have shown that the refractory periods and conduction velocity were poor predictors of specific atrial arrhythmias, whereas the wavelength, as determined by the product of hese two parameters predicted the induction of atrial arrhythmias correctly in 95 % of the cases. Procainamide should produce a slight prolongation of the wavelength, since its marked effect on refractoriness is counterbalanced by a depression s f conduction. This change in the wavelength m y nevertheless be sufficient to explain the transition from atrial fibrillation to stable atrid flutter under the influence of procainamide. Conversely, it is likely that vagd stimulation provoked atrial fibrillation by inducing wavelength shortening, mainly because of its negative effect on refractory periods. In the map shown in Fig. 5A, a circus movement was not clearly apparent, but the delayed signal recorded in the lower right atrium suggested the possibility of a small reentry circuit beyond the resolution of our electrode array. This signal was recorded in the same region where a complete reentry circuit occurred after procainamide (Fig. 5B). Thus, refractory period prolongation by procainamide may have enlarged the reentry circuit, thereby producing a pattern of activation similar to those shown in Figs. 3 and 4. Conversely, when isoproterenol was administered or vagal stimulation was done during flutter, the shortening of refractory periods, which these interventions are well h o w n to produce in atrial tissue, appeared to have destabilized and fragmented the circus movement and produced atrial fibrillation. In the example illustrated in Fig. 6A, the impulse seemed to rotate around the superior vena cava. The functional portion of the circuit was formed by a slow conduction zone in the downward limb of the pathway. The "missed" time interval in this example occurred between the atrial septum and the interatrial band through the limbus of the fossa ovalis as displayed schematically in Fig. 6B. This is a deeper region which was probably not affected by the pericarditis. Despite slower conduction and a larger reentrant pathway displayed in Fig. 6D, the ""missed9' time interval remained constant (28 ms) . In contrast, the change in the atrid flutter cycle length from the Fig. 3 example to the Fig. 4 example was due to a change in the "missed" time interval, suggesting that slow conduction occurred only in tissue affected by the pericarditis. Thus, the tissues of the thin right atrial free wall appeared to be more affected by pharmacologic interventions than the tissues either little or not affected by the inflammatory process of pericarditis, such as the atrial septum. Mjocaadial discontinuities In addition to the functional alterations associated with the pericarditis, the maps suggest the contribution of natural

myocardial discontinuities and anisotropic conduction related to fiber orientation in the right atrium. The anisotropic nature of ventricular myocardium has k e n invoked as a determinant in the mechanism of ventricular tachycardia occurring in ischemic myocardium (Wit et al. 1987; Cardinal et al. 1988). The myocardial discontinuities of the canine atrium were shown to be essential for the induction of reentry in atrial tissue (Spach et al. 1982) or of atrial flutter in dogs with normal or abnormal atrium (Boineau 1985; Boheau et alC1980). Hn Fig. 2, impulse conduction during sinus rhythm was faster in the direction parallel to the fiber axis of the crista terminalis and interatrial band as shown by the ellipsoidal pattern typical of anisotropic conduction. In maps obtained during atrial Wutter, conduction was always slower perpendicular to the axis of thick myocardial bundles (see Fig. 6A). Perhaps the structural complexities of the canine sight atrium (Spach et al. 1982) predispose to the induction of atrial flutter after tissue alteration by pericarditis or other right atrial abnormalities, such as chronic enlargement (Boyden and Hoffman 1981). In the latter model, reentrant circuits were also found to be confined to the right atrium and to involve an arc of hnctiond block in their center (Boyden 1988). On the other hand, in isolated heart preparations perfused with acetylcholine and without abnormal tissue, Allessie et al. (1984) found that functionally determined intra-atrial reentry circuits could occur anywhere in the right or left atrium, provided that the atrial mass was large enough to accommodate the circuit. In the normal atrium, the size and location of the natural orifices are inadequate to accommodate reentrant circuits. The present study therefore suggests that the substratum for atrial reentry circuits is provided by the combination of functional boundaries (produced by pericarditis and potentiated by procainamide) and existing natural anatomical boundaries. In summary, agents h o w n to modifj atrial refractoriness altered the right atrial activation sequence and produced transitions among atrial fibrillation, unstable atrial flutter, stable atrial flutter, and sinus rhythm. We conclude that the transition between these atrial rhythms occur between different functional states of the same circus movement substratum primarily located in the right atrial free wall. Secondly, the anisotropic conduction properties of the right atrium may contribute to these reentrant arrhythmias and m y be potentiated by acute pericarditis . ALLESSIE, M. A., BONKE, E I. M., and SCHOPMAN, F. J. G . $976. Circus movement in rabbit atrial muscle as a mechanism of tachycardia: 11. The role of nonuniform recovery of excitability in the occurrence of unidirectional block, as studied with multiple rnicroelectrodes. Circ. Wes. 39: 168- $77. ALLBSIE,M. A., LAMMERS, W- J. E. P*, BONKE,F. I. M., and HOLLEN, J. 1984. Intra-atrial reentry as mechanism for atrial flutter induced by acetylcholine and rapid pacing in the dog. Cirsulation, 70: 823 - 53%. ALLE~SIE, M. A., LAMMEWS, WoJ. E. P.?RENSMA, P. L., and BONKE, E I. M. 1987. Flutter and fibrillation in experimental models: what has been learned that can be applied to humans. In Cardiac arrhythmias: where to go from here. Eiiteck by P*Bmgada and H.9. 9. Wellens. Futura Publishing Co., Mount Kisco, NYYpp. 67 - $2. BOINEAW, J. P- 1985. Atrial flutter: a synthesis of concepts. Circulation, 72: 249-257. BOINEAU, J. p, SCHUESSLER, R. B., MOONEY, C. R., MILLER, @. B., ~ Y L BA. S ,@., HUDSON, W. D., BOWREMANS, y. M., 8nd BWWKUS, C. W. 1980. Natural and evoked atrial flutter due to circus movement in dogs. Am. J. Cardiol. 45: '1 167 - 118 1. BONNEAU, G . , TREMBLAY, G., SAVARD, P., GUARIBO, W., EEBLANC,

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Transitions among atrial fibrillation, atrial flutter, and sinus rhythm during procainamide infusion and vagal stimulation in dogs with sterile pericarditis.

The mechanism of atrial flutter and fibrillation induced by rapid pacing in 22 dogs with 3-day-old sterile pericarditis was investigated by computeriz...
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