Efficacy of azimilide and dofetilide in the dog right atrial enlargement model of atrial flutter

INTRODUCTION: Azimilide dihydrochloride blocks both the rapid (I(Kr)) and slow (I(Ks)) components of the delayed rectified K+ current; dofetilide blocks only I(Kr). Their efficacies were assessed on atrial flutter reentrant circuits in dogs with surgically induced right atrial enlargement. METHODS AND RESULTS: Multiple biopsies of the tricuspid valve and banding of the pulmonary artery in male mongrel dogs made them susceptible, about 3 weeks postoperatively, to stimulation-induced sustained (5 min or longer) atrial flutter. Azimilide 3 mg/kg administered intravenously (i.v.) terminated flutter in 8 of 8 dogs, but a slower, nonsustained arrhythmia could be reinduced in 5. In these 5 dogs, azimilide 10 mg/kg terminated flutter and prevented reinduction. This dose increased effective refractory period significantly more in the slow conduction zone (25%) than in the normal zone (17%) and increased flutter cycle length (37%). Termination followed progressive conduction delay in the slow zone of the reentrant circuit. Dofetilide 1 microg/kg i.v. terminated flutter in 6 of 6 dogs, but the arrhythmia could be reinduced. At 3 microg/kg, flutter terminated in all dogs and could not be reinduced. Dofetilide also increased the effective refractory period significantly more in the slow zone (17%) than in the normal zone (12%) and increased cycle length (33%), leading to interruption of the arrhythmia circuit. CONCLUSION: In the canine right atrial enlargement model of circus movement atrial flutter, both azimilide 10 mg/kg i.v. and dofetilide 3 microg/kg i.v. were 100% effective in terminating flutter and preventing reinduction. Efficacy relied on a similar mechanism of differentially prolonged refractoriness in the slow conduction component of the reentrant circuit where drug-induced termination occurred.     

Role of anatomic architecture in sustained atrial reentry and double potentials.

To determine the role of anatomic architecture in atrial flutter, electrophysiologic findings were correlated with anatomic features in a modified model of atrial flutter with ligation of the crista terminalis. Crista ligation in the middle right atrium prolonged intraatrial conduction time in a rate-dependent manner in 12 dogs, particularly in the low right atrium. With burst atrial pacing, unidirectional block occurred either in the low right atrium or in the interatrial septal region near the superior vena cava, leading to initiation of atrial flutter. Atrial activation mapping revealed a slow conduction area in the low right atrium where conduction had been delayed by crista ligation. On the intact tissues between the venae cavae, double potentials were recorded, a finding indicative of functional block in the center of the reentrant circuit. The interdeflection time of double potentials changed with the activation sequence of atrial flutter. This change could be explained by assuming that the functional center of the reentrant circuit leaned on the right atrial free wall side. Anatomic study demonstrated that areas of slow conduction, unidirectional block, and functional block in the center of the reentrant circuit were closely related to the location of the intact crista terminalis. In conclusion, the intact portion of the crista terminalis played an important role in the genesis of atrial flutter after blockage of longitudinal conduction through the crista.     

Circus movement atrial flutter in the canine sterile pericarditis model. Differential effects of procainamide on the components of the reentrant pathway

To evaluate the mechanisms of action of procainamide on the components of the reentrant pathway, drug-induced changes in activation patterns, effective refractory periods (ERPs), and stimulation thresholds were analyzed in nine dogs with sterile pericarditis and sustained atrial flutter. Activation maps were based on 127 close bipolar recordings from a special "jacket" electrode. From the control map, 22 +/- 2 sites covering the slow zone and the normal zone of the reentrant circuit were selected to measure ERPs and thresholds. The excitable gap was estimated from the longest ERP during pacing at the tachycardia cycle length. During atrial flutter, epicardial activation proceeded as a single wave around an arc of functional conduction block in the proximity of the atrioventricular (AV) ring or around a combined functional/anatomic obstacle, with the arc being contiguous with one of the venae cavae. An area of slow conduction, which accounted for 53 +/- 15% of the revolution time within 35 +/- 15% of the total length of the reentrant pathway, was bordered by the arc of block and the AV ring or a caval vein and the AV ring, respectively. Procainamide (5-10 mg/kg i.v.) prolonged the cycle length of atrial flutter from 144 +/- 17 to 190 +/- 24 msec (p less than 0.05) and then terminated the arrhythmia in all studies. The increase in cycle length was due to an increase in conduction time in the slow zone by 37 +/- 11 msec (86 +/- 17% of the total cycle length increase). During the last reentrant beat, conduction failed in the slow zone, with the arc of block joining the AV ring. At termination, procainamide had prolonged conduction time, stimulation threshold, and ERP in the normal zone by 11 +/- 18%, 40 +/- 80%, and 5 +/- 15%, respectively, compared with 51 +/- 16%, 86 +/- 93%, and 14 +/- 21%, respectively, in the slow zone (p less than 0.05 for all three parameters). The duration of the excitable gap did not change significantly. We conclude that procainamide preferentially affected the slow zone of single loop reentrant circuits. The drug terminated circus movement atrial flutter without abolishing the excitable gap, and its effect on conduction seemed the major determinant of the antiarrhythmic action.     

Onset of induced atrial flutter in the canine pericarditis model

To test the hypothesis that induced atrial flutter evolves from a transitional rhythm, the onset of 99 episodes of induced atrial flutter (mean cycle length 135 +/- 18 ms) lasting greater than 5 min in 40 dogs with sterile pericarditis was first characterized. In 85 (86%) of the 99 episodes, atrial flutter was preceded by a brief period (mean 1.4 +/- 0.9 s, range 0.4 to 42) of atrial fibrillation. Then, in 11 open chest studies, atrial electrograms were recorded simultaneously from 95 pairs of right atrial electrodes during the onset of 18 episodes of induced atrial flutter (mean cycle length 136 +/- 16 ms). Atrial flutter was induced by a train of eight paced atrial beats, followed by one or two premature atrial beats (7 episodes) or rapid atrial pacing (11 episodes). A short period of atrial fibrillation (mean cycle length 110 +/- 7 ms) induced by atrial pacing activated the right atrium through wave fronts, which produced a localized area of slow conduction. Then unidirectional conduction block of the wave front occurred for one beat in all or a portion of the area of slow conduction. This permitted the unblocked wave front to turn around an area of functional block and return through the area of slow conduction that had developed the unidirectional conduction block, thereby initiating the reentrant circuit. The location of the unidirectional block relative to the direction of the circulating wave fronts determined whether the circus movement was clockwise or counterclockwise. The area of slow conduction and unidirectional conduction block occurred where the wave front crossed perpendicular to the orientation of the atrial muscle fibers, suggesting a role for anisotropic conduction. These areas included the high right atrial portion of the sulcus terminalis (10 episodes), the low right atrial portion of the sulcus terminalis (4 episodes) and the pectinate muscle region (4 episodes). It is concluded that the development of a localized area of slow conduction in the right atrium followed by unidirectional conduction block in this area produced during a short period of atrial fibrillation or rapid atrial pacing is necessary for atrial flutter to occur in this model.     

Antiarrhythmic and Electrophysiologic Effects of Intravenous Ibutilide and Sotaloi in the Canine Sterile Pericarditis Model

Ibutilide, Sotalol, and Atrial Flutter. Introduction: Atrial arrhythmias are a frequent clinical complication following open heart surgery. We compared the Class III agents d,I-sotalol and ibutilide fumarate in an intravenous cross-over study using the canine atrial sterile pericarditis model. Methods and Results: We studied pacing-induced sustained atrial flutter over a 7-day post-surgical period in conscious dogs, alternating analysis of ibutilide (1.0 to 30.0 μg/kg) and d,I-sotalol (0.1 to 3.0 mg/kg). Ibutilide significantly increased atrial flutter cycle length (AFL CL) II ± 2 msec and atrial effective refractory period (AERP) 13 ± 2 msec, and terminated atrial flutter in all cases (n = 12) following a mean dose of 6 ± 2 μg/kg. Plasma concentrations of ibutilide were 53 ± 13 ng/mL. Ventricular effective refractory period (VERP) was not signiflcantly affected (4 ± 2 msec). Following termination with ibutilide, atrial flutter could he reinitiated in 1 of 12 trials, and was nonsustained (40-sec duration). Sotalol significantly increased AFL CL 23 ± 3 msec and terminated atrial flutter in 8 of 12 trials following a mean dose of 1.5 ± 0.4 mg/kg. AERP and VERP were significantly increased 20 ± 6 and 12 ± 2 msec, respectively. The incidence of reinduced atrial flutter was 9 of 12 trials (P ≥ 0.05 vs ibutilide) (7 nonsustained 57 ± 7 sec duration, and 2 sustained). Sotalol failed to terminate atrial flutter in two dogs on days 1 and 5, despite increases in AFL CL (21 ± 8 msec) and AERP (16 ± 9 msec), whereas on day 3, ibutilide (20 ± 7 μg/kg) terminated atrial flutter in those two dogs while increasing AFL CL and AERP 18 ± 6 and 15 ± 0 msec, respectively. Conclusion: Both sotalol and ibutilide terminate atrial flutter in this model. Ibutilide converted atrial flutter in dogs in which sotalol was not successful. Following atrial flutter termination, ibutilide had a lower incidence of reinduced arrhythmias compared to sotalol. Ibutilide produced atrial antiarrhythmic effects while having no significant electrophysiologic effects on the ventricle.     

Atrial activation sequence during atrial flutter in the canine pericarditis model and its effects on the polarity of the flutter wave in the electrocardiogram

Stable atrial flutter induced in both conscious and open chest states was studied in 30 mongrel dogs after production of sterile pericarditis. During the conscious state studies, induced atrial flutter (mean cycle length 128 +/- 15 ms) was always sustained greater than 15 min and was stable. Three types of flutter wave polarity were noted in electrocardiogram (ECG) lead II: positive in 16 dogs, negative in 3 and flat or slightly positive in 11. Sequential site atrial mapping during atrial flutter (mean cycle length 133 +/- 18 ms) in the open chest state showed either clockwise (18 dogs) or counterclockwise (12 dogs) circus movement in the right atrium. In 19 of 30 dogs, the circus movement clearly did not require any naturally existing anatomic obstacle; in 11, the orifice of the superior vena cava probably was also involved. Double potentials were recorded from the center of the reentrant circuit during atrial flutter, and fractionated electrograms were recorded from a pivot point of the reentrant wave front. A positive flutter wave in ECG lead II (12 dogs with counterclockwise circus movement) was associated with early activation of the Bachmann's bundle region compared with the posteroinferior left atrium and activation of the left atrium mainly in a superoinferior direction. A negative flutter was associated with the early activation of the posteroinferior left atrium compared with Bachmann's bundle and activation of a considerable portion of the left atrium in an inferosuperior direction. A flat or slightly positive flutter wave (14 of 18 with clockwise circus movement) was associated with activation of the left atrium almost simultaneously by two wave fronts coming from both these sites. In conclusion, atrial flutter in this dog model is due to circus movement in the right atrium, the center of which does not necessarily require an anatomic obstacle. Although atrial flutter is generated by circus movement in the right atrium, the flutter wave polarity in the ECG is determined primarily by the activation sequence of the left atrium.     

Natural and evoked atrial flutter due to circus movement in dogs: Role of abnormal atrial pathways, slow conduction, nonuniform refractory period distribution and premature beats

Natural atrial flutter was discovered In a dog. Two forms of the arrhythmia resembling the human counterparts of typical and atypical atrial flutter were noted. The Observations in this dog led to studies in a series of normal dogs in which the extrastimulus technique was used to evoke runs of repetitive activity simulating but unlike true atrial flutter. Epicardial atrial activation maps were made from 72 to 96 bipolar complexes recorded during the arrhythmias. Multiple effective refractory periods were determined and these values were used to construct maps of the refractory period distribution. Dog 1, with true atrial flutter, demonstrated a complex form of circus motion characterized by unidirectional block and one-way conduction. Abnormal slowing of the unblocked circus wave stabilized and maintained the repetition by permitting more time for recovery of a uniform state of excitability ahead of the wave. The slow conduction in this dog was associated with right atrial hypoplasia and discontinuity in the preferential atrial conduction pathways. The circus activation patterns in the dogs with evoked flutter were similar to those in true flutter; however, the cycle lengths were shorter and the circus wave conducted faster. In evoked flutter the regional differences in refractory period duration determined the one-way block and circus conduction patterns. The circus pattern was caused by a nonuniform bimodal refractory state of the atrium that simultaneously exerted a blocking effect while permitting conduction and complex shaping of the unblocked wave, which was routed back to its site of origin. Thus atrial flutter was the result of three Interacting factors: (1) an atrial premature beat, (2) nonuniform distribution of atrial refractory periods, and (3) slow conduction of the circus wave initiated by factors 1 and 2.     

Variations in Human Atrial Flutter Cycle Length Induced by Ventricular Beats: Evidence of a Reentrant Circuit with a Partially Excitable Gap

Variations in Atrial Flutter Cycle Length. Introduction : The purpose of this investigation was to study the mechanisms responsible for small variations in atrial flutter cycle lengths. Methods and Results : In a study group of 11 patients with common atrial flutter, atrial electrograms were recorded from an intraesophageal lead together with a surface lead (V₁). Upon the onset of the QRS complex, atrial flutter intervals consistently increased by an average of 1.8% (SD± 0.9; P <0.01) and subsequently decreased by 2.1% (SD ± 0.8; P <0.01) before returning to the average flutter rate. Carotid sinus massage, which temporally prevented ventricular activation, markedly reduced the variations in atrial flutter intervals. Ventricular pacing at different rates clearly demonstrated that the pattern in atrial flutter intervals was coupled to the moment of ventricular contraction. The hypothesis was formulated that these periodic variations in atrial flutter intervals following a ventricular contraction were caused by the influence of stretch of the atrial myocardium on the conduction properties of a circulating impulse in the atrium. The secondary decrease in flutter rate could be explained if a partial excitable gap is assumed between head and tail of the circus movement. This hypothesis was tested in a simulation study, which revealed that the alternation in intervals as found in patients could only be reproduced if the excitable gap in the circus movement was partially excitable. Conclusion : In conclusion, the analysis of variations in atrial flutter cycle lengths points to a mechanism of circus movement with a partially excitable gap in common atrial flutter.     

Antiarrhythmic drugs preferentially produce conduction block at the area of slow conduction in the re-entrant circuit of canine atrial flutter: comparative study of disopyramide, flecainide, and E-4031

STUDY OBJECTIVE--The aim was to test whether antiarrhythmic drugs preferentially suppressed conduction in the area of slow conduction in the re-entrant circuit. DESIGN--Intravenous disopyramide [n = 8, plasma concentrations: 1.4 (SEM 0.2) micrograms.ml-1], flecainide [n = 8, 0.6(0.1) micrograms.ml-1], and E-4031, a new class III antiarrhythmic drug [n = 8, 5.6(1.0) ng.ml-1], were investigated for their effects on atrial flutter due to re-entry in dogs with intercaval crush. In three dogs, detailed atrial activation sequence during atrial flutter was determined with a hand held bipolar electrode and an epicardial isochronal map was drawn. EXPERIMENTAL MATERIAL--24 anaesthetised adult mongrel dogs were used. MEASUREMENTS AND MAIN RESULTS--There was an area of slow conduction during atrial flutter in the low right atrium. Atrial flutter was terminated in all dogs except for one treated with flecainide. In 92% of the dogs, conduction block occurred in the low right atrium in which the area of slow conduction was located. Increase in local conduction time was greater in the area of slow conduction than other parts of the atria (percent ratio to the increase in cycle length of atrial flutter: 63% with disopyramide, 52% with flecainide, and 99% with E-4031). CONCLUSION--These data suggested antiarrhythmic drugs preferentially suppressed conduction at the area of slow conduction in the re-entrant circuit leading to termination of atrial flutter in this canine model, irrespective of electrophysiological effects of antiarrhythmic drugs.     

Role of anisotropy in determining the selective action of antiarrhythmics in atrial flutter in the dog.

OBJECTIVE: The aim was to clarify the electrophysiological and anatomical features of the preferential site of action of antiarrhythmic drugs in the re-entrant circuit of canine atrial flutter. METHODS: Electrophysiological and anatomical findings were correlated in 17 anaesthetised adult mongrel dogs with atrial flutter associated with an intercaval anatomical obstacle, before and after intravenous administration of disopyramide (2 mg.kg-1) and flecainide (2 mg.kg-1). RESULTS: Before drug injection, a rate dependent prolongation of conduction time occurred in the low right atrium where the conduction was slow during atrial flutter. Disopyramide (n = 8 dogs) and flecainide (n = 9 dogs) terminated atrial flutter, with conduction block occurring in this slow conduction area in the low right atrium. Although the degree of drug induced prolongation of refractoriness in this particular area was similar to those in other areas of the right atrium, conduction was depressed to a greater extent in this region. Anatomical study revealed that a thick pectinate muscle that branched from the crista or crista terminalis itself ran perpendicular to the wavefront of the pacing impulse and atrial flutter in this slow conduction area. CONCLUSIONS: These data indicated that slow conduction might be attributed, at least in part, to anisotropic conduction over the thick muscle bundle in the low right atrium, and that antiarrhythmic drugs preferentially produced conduction block in this area. Anisotropic conduction in the low right arium is an anatomical substrate for slow conduction in the re-entrant circuit and for the site preference of antiarrhythmic drugs in the present canine model.     

Azimilide for Atrial Fibrillation: Clinical Trial Results and Implications

Azimilide dihydrochloride (or azimilide) is a class III antiarrhythmic drug currently under investigation that has been tested in atrial fibrillation in four randomized, placebo-controlled clinical trials to assess efficacy and dose range. These investigational trials showed that doses of azimilide 100 and 125 mg once daily prolonged the time to symptomatic arrhythmia recurrence in patients with a history of symptomatic atrial fibrillation, atrial flutter or both. Doses of 75 mg or less were not useful in this indication. Safety of azimilide has been examined in several different types of studies. In a large randomized clinical trial of post-infarct patients, azimilide neither increased nor decreased mortality risk. In patients with supraventricular arrhythmias, the most common adverse effects reported by patients on azimilide were approximately equal in frequency with those on placebo: headache, asthenia, infection, diarrhea and dizziness. Infrequent cases of torsade de pointes and severe neutropenia were reported in patients taking azimilide. Azimilide is an investigational antiarrhythmic drug that has shown efficacy in patients with atrial fibrillation.     

Circus movement atrial flutter in the canine sterile pericarditis model: Relation of characteristics of the surface electrocardiogram and conduction properties of the reentrant pathway

Objectives. This study was designed to elucidate the basis for the electrocardiographic (ECG) appearance of atrial flutter in the canine sterile pericarditis model.Background. During atrial flutter, the surface ECG may show typical F waves or isolated P waves of any polarity.Methods. Electrocardiographic leads II, III and aVF and epicardial atrial activation maps constructed from 127 simultaneously recorded bipolar electrograms were compared in 20 dogs with sterile pericarditis and inducible atrial flutter.Results. In 10 dogs with F wave atrial flutter, single loop reentry occurred around combined functional/anatomic obstacles that included one or both caval veins and a vertically oriented arc of functional conduction block. In 10 dogs with P wave atrial flutter, a merely functional (n = 4) or combined (n = 6) obstacle involving any atrial vessel and more vertically (n = 5) or more horizontally (n = 5) oriented arcs of block was present. The isoelectric interval between P waves corresponded to the conduction time within the slow zone of the reentrant circuit (96 ± 27 vs. 100 ± 24 ms, mean ± SD). Slow conduction accounted for 65 ± 8% of the cycle length in P wave atrial flutter, but for only 29 ± 7% in F wave atrial flutter (p < 0.05). Slow conduction was usually associated with activation of fewer than five epicardial electrodes per 10-ms isochronal interval, reflecting only a small amount of atrial tissue. The polarity of P or F waves was determined by the direction of the major wave front activating the most electrodes per 10-ms isochronal interval, irrespective of whether the right or the left atrium was activated.Conclusions. The F waves result from reentrant activation at a relatively constant speed around a vertically oriented functional/ anatomic obstacle involving one or both caval veins. The P waves occur when the circuit contains a marked area of slow conduction.     

Antiarrhythmic effects of azimilide in atrial fibrillation: efficacy and dose-response. Azimilide Supraventricular Arrhythmia Program 3 (SVA-3) Investigators

OBJECTIVES: The purpose of this study was to assess the effectiveness of azimilide, a class III antiarrhythmic drug, in reducing the frequency of symptomatic arrhythmia recurrences in patients with atrial fibrillation, atrial flutter or both. BACKGROUND: Atrial fibrillation is an increasingly common disorder of the heart rhythm, and most patients with this problem are identified because they have symptoms associated with their arrhythmia. New antiarrhythmic therapies are needed to treat patients with this problem. METHODS: A total of 384 patients with a history of atrial fibrillation, atrial flutter or both were randomly assigned to receive once daily doses of placebo or azimilide; recurrent symptomatic arrhythmias were documented using transtelephonic electrocardiogram (ECG) recording. Azimilide 50 mg, 100 mg or 125 mg was tested; the primary efficacy analysis compared the time to first symptomatic recurrence in the combined azimilide 100 mg and 125 mg dose groups with that in the placebo group using the log-rank test. RESULTS: In the primary efficacy analysis, the time to first symptomatic arrhythmia recurrence was significantly prolonged in the combined azimilide 100 mg and 125 mg daily dose group compared with the placebo group (chi-square 7.96, p = 0.005); the hazard ratio (placebo: azimilide) for this comparison was 1.58 (95% confidence interval [CI] = 1.15, 2.16). In comparisons between individual doses and placebo, the hazard ratio for the 50 mg daily dose was 1.17 (95% CI = 0.83, 1.66; p = 0.37); for the 100 mg group, dose was 1.38 (95% CI = 0.96, 1.98; p = 0.08), and for the 125 mg group, dose was 1.83 (95% CI = 1.24, 2.70; p = 0.002). CONCLUSIONS: Azimilide significantly lengthened the symptomatic arrhythmia-free interval in patients with a history of atrial fibrillation, atrial flutter or both.     

Activation patterns in experimental canine atrial flutter produced by right atrial crush injury.

OBJECTIVES. This study was designed to localize and characterize the atrial flutter reentrant circuit and the electrophysiologic effects of right atrial crush injury in a new canine model. BACKGROUND. In previous studies sustained atrial flutter was induced in the canine heart by rapid atrial pacing after a linear crush injury was placed in the right atrial free wall. METHODS. Eight dogs (group 1) with three electrode plaques on the right and left atria and Bachmann's bundle and seven dogs (group 2) with a single high density electrode plaque on the right atrium were studied with use of a 64-channel computerized mapping system. RESULTS. At baseline, during sinus rhythm and right and left atrial pacing, activation spread uniformly without areas of slow conduction. Crush injury produced marked conduction delay or complete block during sinus rhythm, increasing the mean difference in activation times across the injury compared with control values (group 1, 31 +/- 4 vs. 14 +/- 5 ms, p less than 0.01; group 2, 28 +/- 10 vs. 7 +/- 2 ms, p less than 0.01). Rapid atrial pacing (S1S1 200 ms) above and below the crush injury revealed a line of complete block across which adjacent electrodes recorded markedly different activation times (33 +/- 5 and 38 +/- 12 ms difference, respectively) and around which activation wave fronts proceeded, colliding opposite the stimulating electrodes. The mean atrial flutter cycle length of 11 episodes induced in group 1 and 14 episodes in group 2 was 157 +/- 16 and 140 +/- 16 ms, respectively (p = NS). Activation mapping revealed a reentrant circuit in the right atrium around the crush injury in all episodes. Although the reentrant circuit did not contain a discrete area of slow conduction, activation time below was longer than that above the crush injury (92 +/- 14 vs. 66 +/- 8 ms and 82 +/- 12 vs. 59 +/- 9 ms in groups 1 and 2, respectively, p less than 0.01 for both). Rapid atrial pacing or premature stimuli produced progressive conduction delay and unidirectional block between the crush injury and the tricuspid anulus, inducing atrial flutter directly in 9 of 25 episodes. In 16 episodes, atrial flutter developed after transient induction of atrial fibrillation. CONCLUSIONS. 1) Atrial flutter in this model is due to reentry in the right atrium; 2) the crush injury functions as an anatomic obstacle around which reentry may occur; and 3) the reentrant circuit does not contain a discrete area of slow conduction but, rather, generally slower conduction below the crush injury.     

Demonstration of macroreentry and feasibility of operative therapy in the common type of atrial flutter

Two patients are described who had recurrent and long-standing atrial flutter of the common type and were referred for electrophysiologic testing and surgical management. In both patients, atrial flutter could be initiated and terminated by programmed stimulation. Atrial endocardial mapping showed earliest activation during flutter at the orifice of the coronary sinus, with activity proceeding to the low atrial septum, high lateral right atrium and low right atrium, respectively. Programmed atrial extrasystoles from the high right atrium at a time when the atrial septal region was refractory advanced atrial flutter in proportion to prematurity of the extrastimulus, while maintaining the low to high activation sequence. Intraoperatively, epicardial atrial mapping revealed a large right atrial reentrant circuit beginning in the posteroseptal region and proceeding superiorly and laterally through the right atrial free wall before returning to its starting point. The narrowest part of the circuit and that showing relatively slow conduction during atrial flutter was observed in the low right atrial tissue between the tricuspid valve ring and the orifices of the inferior vena cava and proximal coronary sinus, respectively. Cryosurgical ablation around the orifice of the coronary sinus and surrounding atrial wall has prevented recurrent atrial flutter over short term follow-up in both patients, although 1 of the patients has required antiarrhythmic therapy for postoperative atrial fibrillation.     

High-resolution mapping of tachycardia originating from the superior vena cava: evidence of electrical heterogeneity,slow conduction,and possible circus movement reentry

Superior Vena Cava Reentry. High-resolution mapping of a tachycardia originating from the superior vena cava (SVC) in a patient with atrial fibrillation is described. Unidirectional circuitous repetitive activation encompassing the full tachycardia cycle length was documented around a line of block within the myocardial sleeve of the SVC. Intermittent conduction to the right atrium resulted in an irregular atrial tachycardia. Evidence of electrical heterogeneity and slow conduction persisted in sinus rhythm and was exaggerated by premature stimulation but did not reproduce the activation pattern during tachycardia. All the available evidence is best compatible with circus movement reentry within the SVC, with marked slow and anisotropic conduction responsible for the restricted dimensions of the reentrant circuit. These findings may suggest a similar substrate and arrhythmia mechanism in the myocardium of the pulmonary veins.     

The interrelationship between atrial fibrillation and atrial flutter

For a long time, it has been known that atrial fibrillation and atrial flutter have a close clinical interrelationship. Recent electrophysiological studies, especially mapping studies, have significantly advanced our understanding of this interrelationship. Regarding the relationship of atrial fibrillation with atrial flutter: Atrial fibrillation of variable duration precedes the onset of atrial flutter in almost all instances. During the atrial fibrillation, the functional components needed to complete the atrial flutter reentrant circuit, principally a line of block between the venae cavae, are formed. If this line of block does not form, classical atrial flutter does not develop. If this line of block shortens or disappears, classical atrial flutter disappears. In fact, it is fair to say that the major determinant of whether atrial fibrillation persists or classical atrial flutter develops is whether a line of block forms between the venae cavae. Regarding the relationship of atrial flutter with atrial fibrillation: Studies in experimental models and now in patients have demonstrated that a driver (a rapidly firing focus or a reentrant circuit of very short cycle length) can cause atrial fibrillation by producing fibrillatory conduction to the rest of the atria. When the driver is a stable reentrant circuit of very short cycle length, it is, in effect, a very fast form of atrial flutter. There probably is a spectrum of reentrant circuits of short cycle length, i.e., "atrial flutter," that depend, in part, on where the reentrant circuit is located. When the cycle length of the reentrant circuit is so short that it will only activate small portions of the atria in a 1:1 manner, the rest of the atria will be activated rapidly but irregularly, i.e., via fibrillatory conduction, resulting in atrial fibrillation. In short, there are probably several mechanisms of atrial fibrillation, one of which is due to a very rapid atrial flutter circuit causing fibrillatory conduction. In sum, atrial fibrillation and atrial flutter have an important interrelationship.     

Activation sequence during atrial flutter in dogs with surgically induced right atrial enlargement: I. Observations during sustained rhythms

The atrial activation sequences during 15 episodes of sustained atrial flutters were determined in the isolated hearts of four dogs with surgically induced right atrial enlargement (TI/PS dogs). These sequences were compared with the activation sequences of six episodes of nonsustained atrial tachyarrhythmias induced in three control hearts. Total endocardial activation of both atria during normal sinus rhythm and during the arrhythmias was determined first by recording simultaneously from 192 pairs of recording electrodes positioned into egg-shaped electrode arrays, and then by determining the moment of activation from each of the recorded electrograms. Isochronal maps of total activation were constructed by computer. Nonsustained atrial rhythms inducible in control hearts were due to circus movement excitation either in the left atrium (two episodes) or in the right atrium (four episodes). On the other hand, all 15 episodes of sustained atrial flutter induced and mapped in the TI/PS dog hearts were due to reentrant excitation in the enlarged right atrium. The reentrant pattern could be in a clockwise or counterclockwise pattern. In these episodes of stable flutter an area of functional block was an essential component to the reentrant excitation.     

Termination of a tachyarrhythmia by flunarizine is not a specific marker for a triggered mechanism

BACKGROUND: Prior studies have indicated that tachyarrhythmia termination by flunarizine demonstrates a triggered mechanism. This concept was not confirmed in atrial tachyarrhythmias. OBJECTIVE: The purpose of this study was to test the hypothesis that flunarizine will not terminate reentrant atrial flutter (AFL). METHODS: We administered flunarizine (2 mg/kg intravenously over 2 minutes) in 11 episodes of reproducibly inducible, sustained AFL in eight canines with sterile pericarditis. If flunarizine terminated AFL, we studied AFL reinducibility. We also studied pacing thresholds, refractoriness, and intra-atrial conduction time during closed-chest studies and pacing at selected cycle lengths (CLs) from selected sites before and after flunarizine administration. Atrial mapping (510 electrodes) assessed the epicardial activation sequence during AFL and its termination in six episodes. Four AFL episodes were studied in the closed-chest state. RESULTS: Flunarizine increased AFL CL in all episodes (mean 21 ms; range 7-49 ms), which is explained by slowing conduction in the AFL reentrant circuit, principally in the area of slow conduction. AFL was terminated in 10/11 episodes after drug initiation (mean 3.7 minutes; range 0.5-6.5 minutes) by block in the area of slow conduction. AFL was then not immediately reinducible until >20 minutes after drug administration. Flunarizine had no meaningful effect on atrial pacing thresholds for capture or refractoriness and only affected conduction time in the area of slow conduction in the reentrant circuit. CONCLUSIONS: Flunarizine (1) causes progressive slowing and block in the area of slow conduction of the AFL reentrant circuit in the canine sterile pericarditis model and (2) is effective in terminating reentrant AFL and so is not a specific marker for a triggered mechanism.