The class III antiarrhythmic drugs dofetilide and sotalol prevent AF induction by atrial premature complexes at doses that fail to terminate AF.

BACKGROUND: Clinical trials suggest that sotalol and dofetilide are much more effective in preventing atrial fibrillation (AF) than in terminating it. This study evaluated potential mechanisms of discordant sotalol and dofetilide effects on AF termination vs. prevention. METHODS: We applied 240-electrode epicardial mapping and programmed stimulation in a vagotonic dog model of AF before and after dofetilide or sotalol. RESULTS: Under control conditions, sustained AF could be induced by single S(2) extrastimuli that caused unidirectional block and macroreentry. Sotalol (2 mg/kg) and dofetilide (0.04 mg/kg) failed to terminate AF in any dog, but prevented AF induction by S(2) stimuli in 19/22 (86%) and 4/5 (80%) of animals, respectively. With sotalol and dofetilide, unidirectional block still occurred, but wavefront reentry failed. The prevention of S(2)-induced reentry was related to large increases in the effective refractory period (ERP) at a BCL of 1000 ms, leading to ERPs that exceeded the conduction delay following S(2). Reverse use-dependent effects resulted in smaller ERP increases at BCLs closer to the AF cycle length. Although the number of zones of reactivation per cycle during sustained AF were decreased by sotalol and dofetilide, the changes were small and insufficient to terminate AF. CONCLUSIONS: Sotalol and dofetilide prevent AF initiation by premature depolarizations at doses that fail to terminate vagotonic AF, by increasing ERP at the basic cycle length beyond the associated conduction delay that leads to reentry.

Polymorphic ventricular tachycardias induced by D-sotalol and phenylephrine in canine preparations of atrioventricular block: initiation in the conduction system followed by spatially unstable re-entry.

OBJECTIVE: Polymorphic ventricular tachycardias (PVT) occur spontaneously in canine hearts under the combination of D-sotalol (S), bradycardia and phenylephrine (PE). We investigated the hypotheses that: (1) the activation patterns of the initial PVT beats would be consistent with an origin in the ventricular conduction system; and (2) the inhomogeneous prolongation of repolarisation intervals can provide refractory barriers for re-entrant activity. METHODS: Unipolar electrograms were recorded from 127 epicardial (EPI) sites with a sock electrode array as well as from intramural and endocardial sites during PVTs. Electrograms were analysed to generate isochronal maps and measure the spatial distribution of activation-recovery intervals (ARI). RESULTS: Under S (9.9-14.5 mg.l-1), spontaneously terminating PVTs (cycle length of 270 +/- 43 ms, n = 45) (mean +/- s.d.) occurred when a PE bolus (10-50 micrograms.kg-1) was injected. The first beat of the PVTs occurred with a coupling interval of several hundred ms to the preceding idioventricular beat (IDV) without any bridging activity and its earliest EPI breakthrough occurred in areas overlying the terminations of the right or left bundle branch. ARI values measured in IDV (295 +/- 47 ms) were significantly prolonged prior to PVT (462 +/- 92 ms). Prolongation was greater in apical than in basal epicardial areas, and at endocardial than epicardial sites (to > 500 ms). Maximum delays > 200 ms developed in the regions of marked ARI prolongation and, in later beats, circus movement re-entry occurred around refractory barriers, shifting between various regions of the ventricles. CONCLUSION: Thus, PVTs occurring spontaneously under conditions of delayed repolarisation originate from shifting sites in the ventricular conduction system and re-entrant activity shifting between various regions of the ventricle may occur in later beats of the more sustained arrhythmias.

Detection of QTc interval prolongation using jacket telemetry in conscious non-human primates: comparison with implanted telemetry.

BACKGROUND AND PURPOSE: During repeat-dose toxicity studies, ECGs are collected from chemically or physically-restrained animals over a short timeframe. This is problematic due to cardiovascular changes caused by manual restraint stress and anesthesia, and limited ECG sampling. These factors confound data interpretation, but may be overcome by using a non-invasive jacket-based ECG collection (JET). The current study investigated whether a jacketed external telemetry system could detect changes in cardiac intervals and heart rate in non-human primates (NHPs), previously implanted with a PCT transmitter. EXPERIMENTAL APPROACH: Twelve male cynomolgus monkeys were treated weekly with vehicle or sotalol (8, 16, 32 mg kg⁻¹) p.o. ECGs were collected continuously for 24 hours, following treatment, over 4 weeks. A satellite group of six NHPs was used for sotalol toxicokinetics. KEY RESULTS: Sotalol attained Cmax values 1-3 hours after dosing, and exhibited dose-proportional exposure. In jacketed NHPs, sotalol dose-dependently increased QT/QTc intervals, prolonged PR interval, and reduced heart rate. Significant QTc prolongation of 27, 54 and 76 msec was detected by JET after 8, 16, and 32 mg kg⁻¹ sotalol, respectively, compared with time-matched vehicle-treated animals. Overall, JET-derived PR, QT, QTc intervals, QRS duration, and heart rate correlated well with those derived from PCT. CONCLUSIONS AND IMPLICATIONS: The current findings clearly support the use of JET to quantify cardiac interval and rhythm changes, capable of detecting QTc prolongation caused by sotalol. JET may be a preferred method compared to restraint-based ECG because high-density ECG sampling can be collected in unstressed conscious monkeys, over several weeks.

Effects of procainamide and propafenone on the composition of the excitable gap in canine atrial reentry tachycardia.

The effects of procainamide and propafenone on the composition of the excitable gap (EG) were studied in a canine model of atrial flutter (AFI) around the tricuspid valve. In 14 open-chest, chloralose-anesthetized dogs, a Y-shaped incision was made in the intercaval area extending to the right atrial appendage. Atrial effective refractory period (ERP) was measured at constant stimulation cycle lengths (CLs) (200 and 300 msec) at each of five recording sites around the tricuspid valve. The EG as defined by the reset-response curve was determined by introducing premature stimuli during AFI induced by burstpacing. Seven dogs each received procainamide or propafenone as a bolus followed by infusion. At constant plasma levels, both drugs increased ERP at constant paced CL and prolonged the reentry CL. In the absence of drug, reset-response curves were mixed, demonstrating an EG composed of both partially (increasing portion) and fully (flat portion) excitable tissue. Procainamide and propafenone shifted the curve upward and to the right and prolonged ERP during AFI, but did not change the duration of the EG. On procainamide, fully excitable tissue was preserved, but on propafenone, in some cases, the fully excitable part of the gap was reduced markedly or even eliminated. In conclusion, both drugs can prolong AFI CL by a direct effect on conduction velocity in fully excitable tissue. In addition, propafenone's effect on refractoriness can contribute significantly in some cases to slowing of AFI.

Effects of procainamide on refractoriness, conduction, and excitable gap in canine atrial reentrant tachycardia.

The effects of procainamide were studied in a model of atrial flutter around the tricuspid valve in seven open chest, chloralose-anesthetized dogs (31 +/- 3 kg). A Y-shaped incision in the intercaval area extending to the right atrial appendage was made and five bipolar electrodes were sutured on the atrial epicardium around the tricuspid valve. Reentry tachycardia was induced in the absence and presence of drug by burst pacing. Procainamide (15 mg/kg bolus followed by 0.075 mg/kg/min infusion) produced stable plasma levels (38 +/- 9 microM) during the study. At a pacing cycle length of 200 msec, mean (+/- SD) diastolic threshold at the five sites increased from 1.6 +/- 1.5 to 2.0 +/- 1.7 mA and mean atrial effective refractory period from 125 +/- 9 to 140 +/- 16 msec on drug (P less than 0.05). Procainamide prolonged the cycle length of atrial flutter from 144 +/- 10 to 160 +/- 13 msec and slowed conduction velocity during atrial flutter around the tricuspid valve from 73 +/- 6 to 66 +/- 6 cm/sec (P less than 0.05). A reset response curve was determined by introducing premature stimuli during atrial flutter. Procainamide prolonged effective refractory period during atrial flutter from 101 +/- 13 to 116 +/- 17 msec but did not change the duration of the excitable gap (38 +/- 9 vs 40 +/- 18 msec). Although the reset response curve was predominantly increasing, in six of seven experiments there was present a flat portion at long coupling intervals approaching the atrial flutter cycle length that comprised 23% +/- 10% of the excitable gap.(ABSTRACT TRUNCATED AT 250 WORDS)

Method for simultaneous epicardial and endocardial mapping of in vivo canine heart: application to atrial conduction properties and arrhythmia mechanisms.

INTRODUCTION: It has been suggested that the three-dimensional structure of the atria may be crucial in arrhythmogenesis; however, previous in vivo atrial activation mapping studies have been limited to either endocardial or epicardial approaches. METHODS AND RESULTS: To investigate the role of endocardial and epicardial structures and their interaction in atrial conduction and arrhythmias, we used five epicardial plaques and two intra-atrial balloon arrays to record a total of 368 unipolar electrograms from the entire epicardial and endocardial surface of both atria. During regular 1:1 pacing from the right atrial appendage, right atrial endocardial activation spread considerably faster than epicardial (total activation time 45+/-12 msec vs 60+/-19 msec, respectively [mean +/- SD]; P < 0.05), pointing to preferential conduction over structures like the crista terminalis and pectinate muscles. No such differences were noted in the left atrium. Transseptal spread occurred via discrete anterior and posterior pathways, causing separate breakthroughs in anterior and posterior atrial regions, respectively. Dissociation between septal pathways played a role in reentry during vagal atrial fibrillation. In 2 of 4 dogs with atrial fibrillation associated with congestive heart failure, single macroreentrant circuits involving endocardial and epicardial components were revealed during the arrhythmia. CONCLUSION: We conclude that activation mapping using simultaneous recording from both epicardial and endocardial surfaces provides potentially important insights into the mechanisms of atrial conduction and arrhythmogenesis.