Nonpharmacologic rate control of postoperative atrial fibrillation in the canine sterile pericarditis model.

INTRODUCTION: Postoperative atrial fibrillation (POAF) is common following open heart surgery, and is associated with significant morbidity. Medications used for ventricular rate control of POAF may not be effective in controlling rapid ventricular rates during the postoperative period because of increased sympathetic tone. The purpose of this study was to develop nonpharmacologic rate control of POAF by atrioventricular node (AVN) fat pad stimulation using clinically available temporary pacing wires in the canine sterile pericarditis model. METHODS: We studied 10 sterile pericarditis dogs in the closed-chest state on postoperative days 1-3. The AVN fat pad stimulation (amplitude 2-15 mA; frequency 20 Hz; pulse width 0.03-0.2 ms) was performed during sustained POAF (>5 min). We measured ventricular rate and inefficient ventricular contractions during sustained POAF and compared it with and without AVN fat pad stimulation. Also, the parameters of AVN fat pad stimulation to achieve a rate control of POAF were measured over the postoperative days. RESULTS: Eleven episodes of sustained POAF were induced in 5/10 sterile pericarditis dogs in the closed-chest state on postoperative days 1-2. During POAF, the AVN fat pad stimulation decreased the ventricular rate from 178 ± 52 bpm to 100 ± 8 bpm in nine episodes. Nonpharmacologic rate control therapy successfully controlled the ventricular rate and eliminated inefficient ventricular contractions during POAF for the duration of the AVN fat pad stimulation. The AVN fat pad stimulation output remained relatively stable over the postoperative days. CONCLUSION: During sustained POAF, nonpharmacologic rate control by AVN fat pad stimulation effectively and safely controlled rapid ventricular rates throughout the postoperative period.

Validation of a new species for studying postoperative atrial fibrillation: Swine sterile pericarditis model.

BACKGROUND: The canine sterile pericarditis model associated with atrial inflammation is an experimental counterpart of postoperative atrial fibrillation (POAF). However, the use of canines for research is restricted by ethics committees in many countries, and social acceptance is declining. OBJECTIVE: To validate the feasibility of the swine sterile pericarditis model as an experimental counterpart to study POAF. METHODS: Seven domestic pigs (35-60 kg) underwent initial pericarditis surgery. On two or more postoperative days in the closed-chest state, we performed electrophysiological measurements of pacing threshold and atrial effective refractory period (AERP) while pacing from the right atrial appendage (RAA) and the posterior left atrium (PLA). The inducibility of POAF (>5 min) by burst pacing was determined in both the conscious and anesthetized closed-chest state. These data were compared to previously published canine sterile pericarditis data for validation. RESULTS: The pacing threshold increased from day 1 to day 3 (2 ± 0.1 to 3.3 ± 0.6 mA in the RAA, 2.5 ± 0.1 to 4.8 ± 0.2 mA in the PLA). Also, the AERP increased from day 1 to day 3 (118 ± 8 to 157 ± 16 ms in the RAA; 98 ± 4 to 124 ± 2 ms in the PLA, both p < .05). Induction of sustained POAF occurred in 43% (POAF CL range 74-124 ms). All electrophysiologic data from the swine model were consistent with the canine model with respect to (1) the range of both pacing threshold and AERP; (2) the progressive increase in threshold and AERP over time; (3) a 40%-50% incidence of POAF. CONCLUSION: A newly developed swine sterile pericarditis model demonstrated electrophysiologic properties consistent with the canine model and patients after open heart surgery.

An Evaluation of Phase Analysis to Interpret Atrial Activation Patterns during Persistent Atrial Fibrillation for Targeted Ablation.

BACKGROUND: Phase analysis has been used to identify and localize atrial fibrillation (AF) sources for targeted ablation. We previously demonstrated that repetitive wannabe reentry (incomplete reentry) often generated an apparent stable rotor using phase analysis. The misinterpretation caused by phase analysis using atrial electrograms (AEGs) may result from detecting inaccurate time points at phase inversion (π to -π) in the instantaneous phase waveform converted from AEG. The purpose of this study was to evaluate the accuracy of phase analysis to detect atrial activations recorded from the high-density mapping of AF in patients with persistent and long-standing persistent (LSP) AF. METHODS AND RESULTS: During open heart surgery, we recorded activation from both atria simultaneously using 512 electrodes in 7 patients with persistent and LSP AF. The phase analysis was compared to manual measurements during 4 s of data. For the accuracy of activation sequence maps, a successful recording site was defined as having ≤4 mismatched activation times during the 4 s. In all AF episodes, the accuracy of the phase analysis was only 82% of the total number of activation times due to either activation time differences (14.7%), under-sensing (2.7%), or over-sensing (0.6%). Only 67.9% of the total recording sites met the requirement of a successful recording site by phase analysis. In unsuccessful recording sites, AEG characteristics were relatively irregular cycle length (CL), complex AEG, and double potential AEG. CONCLUSION: The phase analysis was less accurate in recording sites with a relatively irregular CL, complex AEG, or double potential AEG. As a result, phase analysis may lead to the misinterpretation of atrial activation patterns during AF. A visual review of the original AEG is needed to confirm the detected AF sources of phase analysis before performing targeted ablation.

Reliable pace termination of postoperative atrial fibrillation in the canine sterile pericarditis model: Implications for atypical atrial flutter.

BACKGROUND: We have identified a reentrant circuit in the pulmonary vein region, which drives the atria, producing fibrillatory conduction, as one mechanism of postoperative atrial fibrillation (POAF) in the canine sterile pericarditis model. OBJECTIVE: In this model, we tested the hypothesis that overdrive pacing from a site at or near such a reentrant circuit would interrupt it and thereby terminate POAF. METHODS: We studied 11 sterile pericarditis dogs on postoperative days 1-4. Atrial electrograms (AEGs) were recorded during POAF, overdrive pacing, and pace termination from 3 sites simultaneously: Bachmann's bundle, posterior left atrium, and right atrial appendage. When recorded AEGs demonstrated regular activation, pace termination was attempted at that site by delivering a drive train starting with 4 consecutive beats at a cycle length (CL) of 2-5 ms shorter than that of the intrinsic CL. RESULTS: Sixteen episodes of sustained POAF (>5 minutes) diagnosed by electrocardiogram were induced. During all episodes of POAF, AEGs recorded from the left atrium exhibited regular activation, ie, constant AEG morphology and CL. When capture of the reentrant circuit by overdrive pacing occurred (mean 13 ± 5, range 5-23 beats), all 16 POAF episodes were successfully terminated. In all termination episodes, at the end of pacing but prior to the return of sinus rhythm, there was disorganized atrial activation in the previously organized sites (mean 2 seconds, range 0.1-8 seconds). However, these beats did not sustain POAF in the absence of a reentrant circuit ("driver"). CONCLUSION: Overdrive pacing from a site demonstrating regular activation during sustained POAF terminated the POAF by interrupting the reentrant circuit.

New Insights Into Understanding Rotor Versus Focal Activation in Patients With Persistent Atrial Fibrillation.

OBJECTIVES: This study was to test the hypotheses that: 1) when using phase analysis, repetitive Wannabe re-entry produces a phase singularity point (i.e., a rotor); and 2) the location of the stable rotor is close to the focal source. BACKGROUND: Recent contact mapping studies in patients with persistent atrial fibrillation (AF) demonstrated that phase analysis produced a different mechanistic result than classical activation sequence analysis. Our studies in patients with persistent AF showed that focal sources sometimes produced repetitive Wannabe re-entry, that is, incomplete re-entry. METHODS: During open heart surgery, we recorded activation from both atria simultaneously using 510 to 512 electrodes in 12 patients with persistent AF. We performed activation sequence mapping and phase analyses on 4 s of mapped data. For each detected stable rotor (>2 full rotations [720°] recurring at the same site), the corresponding activation patterns were examined from the activation sequence maps. RESULTS: During AF, phase singularity points (rotors) were identified in both atria in all patients. However, stable phase singularity points were only present in 6 of 12 patients. The range of stable phase singularity points per patient was 0 to 6 (total 14). Stable phase singularity points were produced due to repetitive Wannabe re-entry generated from a focal source or by passive activation. A conduction block sometimes created a stable phase singularity point (n = 2). The average distance between a focal source and a stable rotor was 0.9 ± 0.3 cm. CONCLUSIONS: Repetitive Wannabe re-entry generated stable rotors adjacent to a focal source. No true re-entry occurred.

Reconsidering the multiple wavelet hypothesis of atrial fibrillation.

BACKGROUND: Moe and Abildskov proposed the multiple wavelet hypothesis of atrial fibrillation (AF) on the basis of observations in the canine vagal nerve stimulation (VNS) AF model. Data from mapping studies in an in vitro canine AF model by Allessie et al (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. Orlando, FL: Grune & Stratton; 1985:265-275.) were used to evaluate the Moe/Abildskov hypothesis, which revealed that a critical number of wavelets sustained AF. OBJECTIVE: The purpose of this study was to reassess VNS mapping data using the same methods used by Allessie to evaluate Moe's multiple wavelet hypothesis. METHODS: Using the canine VNS AF model in 6 dogs, 510 unipolar atrial electrograms were recorded simultaneously from both atria. Activation sequence maps were produced from sustained AF during VNS in each dog. Per Allessie, consecutive 10 ms activation windows were analyzed over a period of 300 ms. Repetitive activation analysis was applied to Moe's canine VNS AF model. RESULTS: The number of wavefronts in each AF episode was 0-8 in Allessie's studies measured by sequential atrial mapping and 0-10 in our biatrial simultaneous mapping studies. In both studies, an electrically silent period was observed in each atrium and was reactivated by wavefronts emanating from focal sources. Allessie postulated that an electrically silent atrium was reactivated by a wavefront propagating from the other atrium. However, in our biatrial simultaneous mapping studies, each electrically silent atrium was reactivated by a distinct focal source. CONCLUSION: Data from both studies showed a similar number of wavefronts, similar AF activation patterns, and periods of electrical atrial silence reactivated by focal sources. Also, in our studies, independent focal sources initiated wavefronts reactivating the atria, thereby explaining the mechanism maintaining AF.

Effect of Lidocaine Injection of Ganglionated Plexi in a Canine Model and Patients With Persistent and Long-Standing Persistent Atrial Fibrillation.

Background This study assessed the effect of blockading neural transmission in the ganglionated plexi by injecting lidocaine into fat pads in the vagal nerve stimulation canine model and patients with persistent atrial fibrillation ( AF ). Methods and Results An efficacy test of lidocaine injection was performed in 7 canines. During vagal nerve stimulation, AF was sustained for >5 minutes. The lidocaine was injected into ganglionated plexi during sinus rhythm and reinduction of AF was attempted. Six patients with persistent AF were studied at open heart surgery. Lidocaine was injected into ganglionated plexi. Atrial electrograms were recorded from 96 epicardial electrodes covering Bachmann's bundle and atrial appendages. In the canine vagal nerve stimulation AF model, AF was not inducible in 4 of 7 after lidocaine injection. In patients with persistent AF , during baseline AF , there was a left atrium ( LA )-to-right atrium ( RA ) frequency gradient ( LA , mean cycle length [ CL ] 175±17 ms; RA , mean CL 192±17 ms; P<0.01). After lidocaine injection, AF persisted in all patients, and the LA -to- RA frequency gradient disappeared ( LA , mean CL 186±13 ms; RA , mean CL 199±23 ms; P=0.08). Comparison of mean CL s before and after lidocaine demonstrated prolongation of LA CL s ( P<0.05) with no effect on RA CL s. Conclusions In the canine vagal nerve stimulation AF model, lidocaine injection decreased inducibility of AF . In patients with persistent AF , atrial electrograms from the LA had shorter CL s than RA , indicating an LA -to- RA frequency gradient. Lidocaine injection significantly prolonged only LA CL s, explaining disappearance of the LA -to- RA frequency gradient. The mechanism of localized atrial electrogram CL prolongation in patients with persistent AF is uncertain.

Characterization of Foci and Breakthrough Sites During Persistent and Long-Standing Persistent Atrial Fibrillation in Patients: Studies Using High-Density (510-512 Electrodes) Biatrial Epicardial Mapping.

BACKGROUND: We previously demonstrated that persistent and long-standing persistent atrial fibrillation is maintained by activation emanating from foci and breakthrough sites of different cycle lengths (CLs). The purpose of this study was to characterize the behavior of focal and nonrandom breakthrough activation identified during high-density mapping of atrial fibrillation in these patients. METHODS AND RESULTS: During open heart surgery, we recorded activation from both atria simultaneously using 510 to 512 epicardial electrodes along with ECG lead II in 12 patients with persistent and long-standing persistent atrial fibrillation. For each patient, analysis of 32 consecutive seconds of activation from identified focal (sustained and/or intermittent) and nonrandom breakthrough sites was performed. Multiple foci (sustained and/or intermittent) of different CLs were present in both atria in 11 of 12 patients; 8 foci were sustained, and 22 were intermittent. Temporal CL behavior of sustained foci varied over time (≤20 ms of the mean CL). For intermittent foci, no activation periods were due to a spontaneous pause (18 of 22) or activation of the focus by another wave front (11 of 22). All patients had breakthrough activation. Seven patients had 12 nonrandom breakthrough sites. Periods of no breakthrough activation were caused by a spontaneous pause (6 of 12 patients) or activation from another wave front (4 of 12) or were uncertain (5 of 12). Focal and nonrandom breakthrough activation sometimes produced repetitive "wannabe" (incomplete) reentry in 6 of 12 patients. CONCLUSIONS: During persistent and long-standing persistent atrial fibrillation, sustained foci manifested variable CLs. Spontaneous pauses or activation from other wave fronts explained the intermittency of foci and nonrandom breakthrough. Focal and nonrandom breakthrough activation occasionally produced wannabe reentry.

Simultaneous Biatrial High-Density (510-512 Electrodes) Epicardial Mapping of Persistent and Long-Standing Persistent Atrial Fibrillation in Patients: New Insights Into the Mechanism of Its Maintenance.

BACKGROUND: The mechanism(s) of persistent and long-standing persistent (LSP) atrial fibrillation (AF) is/are poorly understood. We performed high-density, simultaneous, biatrial, epicardial mapping of persistent and LSP AF in patients undergoing open heart surgery (1) to test the hypothesis that persistent and LSP AF are due to ≥ 1 drivers, either focal or reentrant, and (2) to characterize associated atrial activation. METHODS AND RESULTS: Twelve patients with persistent and LSP AF (1 month to 9 years duration) were studied at open heart surgery. During AF, electrograms were recorded from both atria simultaneously for 1 to 5 minutes from 510 to 512 epicardial electrodes with ECG lead II. Thirty-two consecutive seconds of activation sequence maps were produced per patient. During AF, multiple foci (QS unipolar atrial electrograms) of different cycle lengths (mean, 175 ± 18 ms) were present in both atria in 11 of 12 patients. Foci (2-4 per patient, duration 5-32 s) were either sustained or intermittent, were predominantly found in the lateral left atrial free wall, and likely acted as drivers. Random and nonrandom breakthrough activation sites (initial r or R in unipolar atrial electrograms) were also found. In 1 of 12 patients, only breakthrough sites were found. All wave fronts emanated from foci and breakthrough sites, and largely either collided or merged with each other at variable sites. Repetitive focal QS activation occasionally generated repetitive wannabe reentrant activation in 5 of 12 patients. No actual reentry was found. CONCLUSIONS: During persistent and LSP AF in 12 patients, wave fronts emanating from foci and breakthrough sites maintained AF. No reentry was demonstrated.

Insights into new-onset atrial fibrillation following open heart surgery and implications for type II atrial flutter.

AIMS: Postoperative atrial fibrillation (POAF), new-onset AF after open heart surgery (OHS), is thought to be related to pericarditis. Based on AF studies in the canine sterile pericarditis model, we hypothesized that POAF in patients after OHS may be associated with a rapid, regular rhythm in the left atrium (LA), suggestive of an LA driver maintaining AF. The aim of this study was to test the hypothesis that in patients with POAF, atrial electrograms (AEGs) recorded from at least one of the two carefully selected LA sites would manifest a rapid, regular rhythm with AEGs of short cycle length (CL) and constant morphology, but a selected right atrial (RA) site would manifest AEGs with irregular CLs and variable morphology. METHODS AND RESULTS: In 44 patients undergoing OHS, AEGs recorded from the epicardial surface of the RA, the LA portion of Bachmann's bundle, and the posterior LA during sustained AF were analysed for regularity of CL and morphology. Sustained AF occurred in 15 of 44 patients. Atrial electrograms were recorded in 11 of 15 patients; 8 of 11 had rapid, regular activation with constant morphology recorded from at least one LA site; no regular AEG sites were present in 3 of 11 patients. CONCLUSIONS: Atrial electrograms recorded during sustained POAF frequently demonstrated rapid, regular activation in at least one LA site, consistent with a driver maintaining AF.

Termination of Atrial Flutter and Fibrillation by K201's Metabolite M-II: Studies in the Canine Sterile Pericarditis Model.

INTRODUCTION: K201, a 1,4-benzodiazepine derivative, acts on multiple cardiac ion channels and the ryanodine receptor. We tested whether administration of M-II, the main metabolite of K201, would terminate induced atrial flutter (AFL) or atrial fibrillation (AF) in the canine sterile pericarditis model. METHODS: In 6 dogs, electrophysiologic studies were performed at baseline and after drug administration, measuring atrial effective refractory period (AERP), and conduction time from 3 sites during pacing at cycle lengths (400, 300, and 200 milliseconds) on postoperative days 1-4. In 12 induced episodes of sustained AF/AFL (2/10, respectively), M-II was administered intravenously to test efficacy. Five of the AFL episodes were studied in the open chest state during simultaneous multisite atrial mapping. RESULTS: M-II terminated 2/2 AF and 8/10 AFL episodes, prolonged AERP (P < 0.05), significantly increased atrial pacing capture thresholds but did not significantly change atrial conduction time. AFL CL prolongation was largely explained by prolonged conduction in an area of slow conduction in the reentrant circuit. AFL terminated with block in the area of slow conduction. CONCLUSIONS: M-II was very effective in terminating AFL/AF in the canine sterile pericarditis model. AFL terminated due to block in the area of slow conduction of the reentrant circuit.

Ranolazine terminates atrial flutter and fibrillation in a canine model.

BACKGROUND: Ranolazine has been shown to have antiarrhythmic properties. OBJECTIVE: We tested the hypothesis that intravenous ranolazine would terminate induced atrial flutter (AFL) or atrial fibrillation (AF) in the canine sterile pericarditis model. METHODS: In 6 dogs with sterile pericarditis, we performed electrophysiological measurements of the atrial effective refractory period (AERP) and conduction time (CT) while pacing from the right atrial appendage, Bachmann bundle, and the posteroinferior left atrium at cycle lengths (CLs) of 400, 300, and 200 ms before and after the administration of ranolazine. In 13 induced episodes of AFL (n = 9) and AF (n = 4), ranolazine was administered intravenously as a 3.2 mg/kg bolus, followed by a maintenance infusion of 0.17 mg/(kg·min). Six episodes (4 AFL and 2 AF) were induced in the open-chest state to perform simultaneous, multisite (486 electrodes), epicardial mapping of the arrhythmia and its termination. RESULTS: Ranolazine terminated 7 of 9 AFL and 3 of 4 AF episodes. Ranolazine significantly prolonged the AFL CL by a mean of 43 ms (P < .001) and the AF CL by a mean of 34 ms (P < .01). The AERP was prolonged (P < .05 overall), and the atrial capture threshold increased minimally (P < .01 for all). Ranolazine prolonged CTs (P < .01 overall). During open-chest, multisite mapping, block in the region of slow conduction in the reentrant circuit terminated AFL and interruption of the regular driver terminated AF. CONCLUSION: Ranolazine terminated AFL/AF in our canine sterile pericarditis model by interrupting the regular driver. Ranolazine was found to significantly prolong the AERP, CT, and tachycardia CLs.

An algorithm to measure beat-to-beat cycle lengths for assessment of atrial electrogram rate and regularity during atrial fibrillation.

INTRODUCTION: Experimental models have demonstrated that atrial fibrillation (AF) may be due to one or more rapid drivers (source) producing AF. These drivers may be characterized by rapid and regular cycle lengths (CLs), producing fibrillatory conduction to the rest of the atria. The ability to reliably identify such drivers would be invaluable. The purpose of this study was to develop and validate a CL variability detection (CLVD) analysis capable of accurately determining beat-to-beat CLs of atrial electrograms (AEGs) during AF, and then to compare this analysis with dominant frequency (DF) analysis. METHODS AND RESULTS: We analyzed 6 episodes of AF in 6 dogs (sterile pericarditis model) due either to a single, stable left atrial reentrant circuit, or unstable reentrant circuits causing fibrillatory conduction to the rest of the atria. During AF, AEGs were recorded simultaneously from 400 to 420 electrodes on both atria. CLs from over 20,000 AEGs were manually measured, and compared to CLs detected using both the CLVD and DF analyses. There was significant correlation between (1) CLs measured manually and the CLVD analysis (mean CL: correlation coefficient [CC]= 0.96, standard deviation [SD]: CC = 0.89); and (2) mean CL measured manually and the DF analysis (CC = 0.84). However, there was poor correlation between SD of CLs measured manually and the organization index (OI) by DF analysis (CC =-0.59). CONCLUSION: The CLVD analysis was validated as being accurate for detecting both rate and degree of regularity of AEGs during AF, and more accurate than DF analysis.

High density mapping of atrial fibrillation during vagal nerve stimulation in the canine heart: restudying the Moe hypothesis.

INTRODUCTION: Moe et al. hypothesized that multiple wavelets (random reentry) were the mechanism of atrial fibrillation (AF) based on studies in a vagal nerve stimulation (VNS) canine model and a computer model of AF, but atrial mapping during AF in this model has not been done. We restudied this model using high density, simultaneous site mapping to test the hypothesis that AF was due to multiple wavelets. METHODS AND RESULTS: During pacing induced AF during VNS in 10 dogs, 512 unipolar atrial electrograms were recorded simultaneously from both atria. AF activation maps were produced including through AF termination after VNS cessation. During sustained AF, multiple foci (persistent and transient) of different cycle lengths (CLs) were present in both atria. Persistent foci of short (mean 112 ± 25 milliseconds), regular (standard deviation 5.3 ± 3 milliseconds) CLs were predominantly found in the left atria, near the pulmonary veins and coronary sinus. Both types of foci acted as drivers, and each produced wave fronts that largely resulted in collision or merging with each other at variable sites. No random reentry (multiple wavelets) was demonstrated. Ordered reentry (circus movement with head-tail interaction) was infrequently seen. With cessation of VNS, focal firing slowed and disappeared, followed by resumption of sinus rhythm after a prolonged pause. CONCLUSIONS: In contrast to the prediction of the multiple wavelet hypothesis, during AF in the Moe model, multiple foci drove the atria, producing and maintaining AF. Reentry played little, if any, role.

Oral vanoxerine prevents reinduction of atrial tachyarrhythmias: preliminary results.

BACKGROUND: Vanoxerine is a promising, new, investigational antiarrhythmic drug. The purpose of this study was to test the hypothesis that oral dosing of vanoxerine would first terminate induced atrial flutter (AFL) and atrial fibrillation (AF), and then prevent their reinduction. METHODS: In 5 dogs with sterile pericarditis, on the fourth day after creating the pericarditis, we performed electrophysiologic (EP) studies at baseline, measuring atrial excitability, refractoriness (AERP), and conduction time (CT) when pacing from the right atrial appendage, Bachmann's bundle (BB), and the posteroinferior left atrium at cycle lengths (CLs) of 400, 300, and 200 ms. Then, after induction of AFL or AF, all dogs received hourly oral doses of vanoxerine: 90 mg, followed by 180 mg and 270 mg. Blood was obtained to determine plasma vanoxerine concentrations at baseline, every 30 minutes, when neither AFL nor AF were inducible, and, finally, 1 hour after the 270 mg dose. Then we repeated the baseline EP studies. RESULTS: Four dogs had inducible, sustained AFL, and 1 dog only had induced, nonsustained AF. In 4 AFL episodes, oral vanoxerine terminated the AFL and then rendered it noninducible after an average of 111 minutes (range 75-180 minutes) after the first dose was administered. The mean vanoxerine plasma level at the point of noninducibility was 84 ng/mL, with a narrow range of 76-99 ng/mL. In the dog with induced, nonsustained AF, it was no longer inducible at a drug level of 75 ng/mL. Vanoxerine did not significantly (1) prolong the AERP except at BB, and then only at the faster pacing CLs; (2) change atrial excitability thresholds; (3) prolong atrial conduction time, the PR interval, the QRS complex or the QT interval. CONCLUSIONS: Orally administered vanoxerine effectively terminated AFL and rendered it noninducible. It also suppressed inducibility of nonsustained AF. These effects occurred at consistent plasma drug levels. Vanoxerine's insignificant or minimal effects on measured electrophysiologic parameters are consistent with little proarrhythmic risk.

Characterization of atrial activation (A-A) intervals during atrial fibrillation due to a single driver: do they reflect atrial effective refractory periods?

BACKGROUND: The mean, median, and minimum local atrial activation (A-A) intervals have been used to determine the local atrial effective refractory period (AERP) during atrial fibrillation (AF), the underlying assumption being that AF is due to multiple reentrant wavelets. OBJECTIVE: We tested the hypothesis that when AF is due to a single, rapid, stable reentrant circuit (driver), the minimum and mean local A-A intervals will be similar at sites in the reentrant circuit, but will vary widely at sites with fibrillatory conduction, making these latter intervals unreliable indicators of AERP. METHODS: During sustained AF due to a left atrial (LA) driver in 6 sterile pericarditis dogs, electrograms were recorded from 186 bipolar electrodes from both atria. A-A intervals were measured from each recording site during 1.2 seconds of AF. Minimum A-A intervals as well as temporal (within site) and spatial (between sites) variability were determined from all sites. RESULTS: A-A intervals from each site during AF demonstrated that (1) 90-100% of right atrial (RA) sites and 18-39% of LA sites showed considerable (SD > 6 ms) temporal variability; (2) RA and LA sites with fibrillatory conduction (SD > 6 ms) showed considerable (a) spatial variability (RA: 9-36 ms; LA: 5-27 ms) and (b) variability of the minimum A-A intervals (RA: 14-35 ms; LA 11-28 ms). CONCLUSION: During AF due to a driver, areas with fibrillatory conduction manifested considerable variability in the mean and the minimum A-A intervals. Therefore, it is unlikely that any of the A-A intervals reflect AERP.

Vanoxerine, a new drug for terminating atrial fibrillation and flutter.

BACKGROUND: Vanoxerine produces potent block of cardiac hERG, sodium, and L-type calcium channels. Block is strongly frequency dependent, is unassociated with transmural dispersion of repolarization, and occurs at concentrations safe in humans. Therefore, we proposed that vanoxerine might be antiarrhythmic. In these studies, we tested the hypothesis that vanoxerine would terminate induced atrial fibrillation (AF) and atrial flutter (AFL) in dogs with sterile pericarditis (SP). METHODS AND RESULTS: In 9 SP dogs, 11 episodes each of sustained (>10 minutes) AF and AFL were induced. Electrophysiological studies were performed before and after infusion of vanoxerine, which effectively terminated AF and AFL in 19 of 22 episodes. Simultaneous multisite mapping during 3 AF and 3 AFL episodes demonstrated that termination of each arrhythmia occurred with termination of the driver (a reentrant circuit) following an increase in tachycardia CL. Except for conduction in an area of slow conduction in the driver's reentrant circuit, vanoxerine did not significantly affect intraatrial or atrioventricular conduction time, QRS duration, or QT/QTc intervals. Ventricular refractoriness prolonged minimally during ventricular pacing at 400 and 333 ms (176 +/- 16 ms to 182 +/- 16 ms; 173 +/- 11 ms to 178 +/- 18 ms, respectively). Vanoxerine minimally increased (mean 0.7 mA) atrial stimulus threshold for capture. CONCLUSIONS: Vanoxerine effectively terminated induced, sustained AF and AFL in the canine SP model, and produced insignificant or minimal changes in refractoriness, conduction time, or stimulus threshold, consistent with little proarrhythmic risk.

Frequency analysis of atrial electrograms identifies conduction pathways from the left to the right atrium during atrial fibrillation-studies in two canine models.

UNLABELLED: Studies of atrial fibrillation (AF) have demonstrated that a stable rhythm of very short cycle length in the left atrium (LA) can cause fibrillatory conduction in the rest of the atria. We tested the hypothesis that fast Fourier transform (FFT) analysis of atrial electrograms (AEGs) during this AF will rapidly and reliably identify LA-to-right atrium (RA) conduction pathway(s) generated by the driver. METHODS AND RESULTS: During induced atrial tachyarrhythmias in the canine sterile pericarditis and rapid ventricular pacing-induced congestive heart failure models, 380-404 AEGs were recorded simultaneously from epicardial electrodes on both atria. FFT analysis of AEGs during AF demonstrated a dominant frequency peak in the LA (driver), and multiple frequency peaks in parts of the LA and the most of the RA. Conduction pathways from the LA driver to the RA varied from study-to-study. They were identified by the presence of multiple frequency peaks with one of the frequency peaks at the same frequency as the driver, and traveled (1) inferior to the inferior vena cava (IVC); (2) between the superior vena cava and the right superior pulmonary vein (RSPV); (3) between the RSPV and the right inferior pulmonary vein (RIPV); (4) between the RIPV and the IVC; and (5) via Bachmann's bundle. Conduction pathways identified by FFT analysis corresponded to the conduction pathways found in classical sequence of activation mapping. Computation time for FFT analysis for each AF episode took less than 5 minutes. CONCLUSION: FFT analysis allowed rapid and reliable detection of the LA-to-RA conduction pathways in AF generated by a stable and rapid LA driver.

Fixed intercaval block in the setting of atrial fibrillation promotes the development of atrial flutter.

BACKGROUND: In the canine sterile pericarditis model, typically only atrial fibrillation (AF) is inducible on postoperative day 2. OBJECTIVE: In this model, we tested the hypothesis that on postoperative day 2, placing a fixed line of block (LoB) between the vena cavae critically alters the atrial substrate, favoring the induction of sustained atrial flutter (AFL) instead of AF. METHODS: In 6 sterile pericarditis dogs, sustained AF was induced by rapid atrial pacing. After terminating AF, a fixed LoB between the vena cavae was created (cryoablation), and AF reinduction was attempted. Simultaneous mapping from 400 to 420 electrodes on the right and left atrial epicardium and the interatrial atrial septum was performed during all studies. RESULTS: Before creation of the LoB, in all 6 dogs, rapid atrial pacing induced sustained AF because of a rapid (mean cycle length [CL] 110 +/- 10 ms), regular, left atrial reentrant driver, which caused fibrillatory conduction. After creation of the LoB, in 5 dogs, rapid atrial pacing now induced sustained AFL (mean CL 167 +/- 13 ms). In the 6th dog, AFL failed to develop because the left atrial driver that was induced before the LoB was still reproducibly induced despite the LoB. CONCLUSION: In this model of sustained AF, altering the substrate to create a fixed LoB between the vena cavae creates a substrate favoring the induction of AFL.

Prednisone prevents inducible atrial flutter in the canine sterile pericarditis model.

BACKGROUND: Atrial fibrillation (AF) and atrial flutter (AFL) are common following cardiac surgery and are associated with significant morbidity. We tested the hypothesis that suppression of the inflammatory response with steroids would significantly modify the inducibility of postoperative AF/AFL in the canine sterile pericarditis model. METHODS: Twenty-three dogs were studied daily from creation of pericarditis to the fourth postoperative day: 11 dogs were treated with oral prednisone (PRED) starting 2 days preoperatively until the end of the study; 12 dogs were controls (CON). EP testing was performed daily using epicardial electrodes placed at initial surgery. High-resolution (404 sites) epicardial mapping was performed during the terminal study. Baseline and daily CRP levels were obtained in all dogs. RESULTS: Sustained AFL was absent in PRED (0%) versus CON dogs (91%; P < 0.001); AF induced in the early postoperative course in PRED dogs was of very short CL (mean 66 ms). Tissue inflammation was significantly attenuated in PRED dogs. Thresholds were lower in PRED versus CON dogs, significantly so on postoperative day (POD) 3. There was a trend toward lower ERPs in the PRED group at all CLs. CRP levels were markedly reduced in PRED versus CON dogs (peak CRP 78 +/- 7 mg/L vs 231 +/- 21 mg/L, P < 0.001), and returned to baseline in PRED dogs by POD 4, correlating with a virtual absence of sustained arrhythmia. During open chest mapping studies on POD 4, PRED dogs showed only nonsustained AF/AFL. CONCLUSIONS: Prednisone eliminated postoperative AFL, affected all EP parameters studied, and attenuated the inflammatory response associated with pericarditis.