Glenn Kabell

Comparative assessment of ibutilide, D-sotalol, clofilium, E-4031, and UK-68,798 in a rabbit model of proarrhythmia.

Summary Class III agents have been associated with development of a polymorphic ventricular tachycardia (PVT) known as torsades de pointes. We compared the class III agent ibutilide, which prolongs repolarizatipn through enhancement of an inward sodium current, with the potassium channel blockers E-4031, UK-68,798, clofilium, and D-sotalol for proarrhythmic effects in an anesthetized rabbit model. In these animals, prolongation of repolarization during a, stimulation with methoxamine produces early afterdepolarizations (EADs) and a pause-dependent torsades de pointes-like PVT. Agents were compared over dosage ranges that produced maximal increases in QTc interval and monophasic action potential duration (MAPD). PVT typically developed after atrioventricular (A-V) conduction block and slowing of heart rate (HR), and was preceded by development of repolarization arrhythmias characterized by EADs and triggered activity producing extrasystolic beats. Ibutilide administration resulted in significantly lower EAD amplitudes and a lower incidence of repolarization arrhythmias and PVT as compared with administration of other class HI agents. The percentage of rabbits developing PVT for each agent was ibutilide 12%, D-sotalol 70%, E-4031 56%, UK-68,798 69%, and clofilium 80%. Rabbits receiving saline vehicle instead of a class HI agent never developed conduction or repolarization abnormalities or PVT. Under the conditions of this study at doses that generate maximal class HI effects, ibutilide produces lesser increases in QTc interval and MAPD, and EADs of lower amplitude, resulting in a lower incidence of repolarization arrhythmias and PVT as compared with other class III agents.

Antiarrhythmic and electrophysiologic effects of ibutilide in a chronic canine model of atrial flutter.

We studied the effects of orally administered ibutilide, a class III antiarrhythmic agent, in a model of reentrant atrial flutter in conscious dogs. After baseline determination of atrial effective refractory period (AERP) and demonstration of reproducible induction of atrial flutter by rapid atrial pacing, 8 dogs received either placebo or one of six doses of ibutilide ranging from 0.1 to 5 mg/ kg. Refractory periods and the ability to induce atrial flutter were then assessed at periodic intervals for 8 hours. Ibutilide produced dose-related increases in AERP which were well correlated with prevention of initiation of atrial flutter after doses ≥ 0.25 mg/kg. Placebo and 0.1 mg/kg ibutilide had no effect on AERP or the ability to induce atrial flutter. Doses of 0.25 to 1.0 mg/kg ibutilide significantly increased AERP and prevented induction of atrial flutter for 4–6 h. After treatment with 2.5 or 5 mg/kg ibutilide, significant increases in AERP and prevention of induction of atrial flutter persisted throughout the 8-h study period. The cycle length of inducible atrial flutter was significantly increased after administration of 5 mg/ kg ibutilide. The results demonstrate oral efficacy of ibutilide with rapid onset of action (in 30–60 min), resulting in increased AERP and prevention of induced atrial flutter in this model.

Effects of ibutilide on spontaneous and induced ventricular arrhythmias in 24-hour canine myocardial infarction: a comparative study with sotalol and encainide.

Summary The electrophysiologic and antiarrhythmic effects of ibutilide, sotalol, and encainide were compared in dogs 24 h after myocardial infarction. Ibutilide (0.03 to 0.3 mg/kg i.v.) prevented the induction of ventricular arrhythmias in 100% of the dogs that had demonstrated inducible ventricular arrhythmias prior to treatment. This antiarrhythmic action was associated with significant increases in ventricular refractoriness and monophasic action potential duration. Sotalol (1.0 to 10.0 mg/kg i.v.) increased the ventricular refractory period and monophasic action potential duration and prevented the induction of ventricular arrhythmias in 75% of the dogs that demonstrated inducible ventricular tachyarrhythmias at baseline. Although 10 mg/kg of sotalol was required to prevent the initiation of ventricular tachycardia, this dose produced marked cardiovascular depression and hypotension in 50% of the dogs tested. Neither ibutilide nor sotalol significantly decreased the incidence of spontaneous ventricular arrhythmias. The class IC agent encainide (0.3 to 3.0 mg/kg i.v.) was successful in preventing the induction of ventricular arrhythmias in only 20% of the dogs tested. However, in contrast to ibutilide and sotalol, encainide significantly reduced spontaneous arrhythmias. Atrial and ventricular refractoriness were significantly increased only after the highest dose of encainide tested (3.0 mg/kg). Over the dose ranges studied, the relative efficacy for prevention of pacing-induced ventricular arrhythmias was ibutilide > sotalol ± encainide. For suppression of spontaneous ventricular arrhythmias, the relative efficacy was encainide ± ibutilide = sotalol. These results are consistent with the concept that spontaneous and pacing-induced ventricular arrhythmias result from different mechanisms and that class III agents are more effective in suppressing induced ventricular tachycardia due to reentry than spontaneous arrhythmias that may be due to nonre-entrant mechanisms.

Acute Intravenous Conversion of Canine Atrial Flutter: Comparison of Antiarrhythmic Agents

We studied the acute intravenous (i.v.) effects of the antiarrhythmic agents ibutilide, sematilide, lidocaine, and encainide in a canine Y-shaped right atrial incision model of atrial flutter. After baseline determination of atrial effective refractory period (AERP), sustained atrial flutter (AFL) was initiated by atrial pacing in 25 dogs. Each dog then received placebo, followed by sequential doses of a particular agent every 5 min until AFL was terminated or the highest dose was administered. Ibutilide increased AFL cycle length (CL: 26 +/- 6 ms) before termination of AFL in 8 of 8 dogs in 1 min after the effective dose (6 +/- 1 micrograms/kg). AERP determined immediately after termination of AFL was significantly increased (44 +/- 7 ms). AFL could not be reinitiated after termination with ibutilide. Sematilide increased AFL CL 12 +/- 6 ms, significantly increased AERP 25 +/- 6 ms, and terminated AFL in 4 of 8 dogs (0.6 +/- 0.2 mg/kg). After sematilide or pacing-induced termination, AFL was reinducible in only 1 dog. Lidocaine terminated AFL in 2 of 5 dogs (2.0 +/- 0.5 mg/kg). AERP was unchanged in both animals, and AFL CL increased by 37 +/- 3 ms. AFL was reinducible in all 5 lidocaine-treated dogs after AFL was terminated. Encainide terminated AFL in 3 of 4 dogs after a dose of 3.0 +/- 0.0 mg/kg. AERP was significantly increased 77 +/- 10 ms, and AFL CL was markedly increased by 226 +/- 11 ms. AFL could not be reinitiated after termination of AFL by encainide.(ABSTRACT TRUNCATED AT 250 WORDS)

Ventricular arrhythmias following one-stage and two-stage coronary reperfusion: Evidence for both reentry and enhanced automaticity*

We studied the effects of reperfusion in 60 dogs following a 30-45 minute period of left anterior descending coronary artery occlusion using electrocardiograms and composite electrogram recordings. One-stage reperfusion in 14 of 15 dogs produced ventricular arrhythmias which degenerated into ventricular fibrillation within 60 seconds. The onset of ventricular arrhythmias was associated with continuous electrical activity in epicardial and intramural electrograms recorded from the reperfused zone. Vagal slowing during reperfusion (64 +/- 8/min) did not prevent ventricular fibrillation (eight of eight dogs) and escape beats were often followed by one or more coupled ectopic beats associated with continuous electrical activity. Rapid atrial pacing (270/min) also did not prevent the appearance of ventricular arrhythmia with associated continuous electrical activity and ventricular fibrillation (six of six dogs) nor did 4 mg/kg lidocaine (15 of 16 dogs). In another group of 15 dogs reperfusion was performed in two stages resulting in no ventricular fibrillation but in 8 of 15 dogs ventricular arrhythmias were observed beginning within two minutes after reperfusion and lasting 20-30 minutes. These ventricular arrhythmias were not associated with continuous electrical activity in any of the recorded leads. Atrial pacing suppressed ventricular arrhythmias and idioventricular rate averaged 157 +/- 10/min versus 55 +/- 10/min pre-reperfusion control. The earliest site of activation indicated automatic foci arising in the subendocardium of the reperfused zone. Lidocaine (2-4 mg/kg) rapidly (less than 90 sec) restored normal sinus rhythm and suppressed automaticity (72 +/- 11/min) as did left anterior descending artery reocclusion (52 +/- 6/min). We conclude that both reentry and enhanced automaticity play a role in ventricular arrhythmias due to reperfusion. Lidocaine (2-4 mg/kg) suppresses automatic but not reentrant ventricular arrhythmias in this experimental setting.

Effects of adenosine on wavelength of premature atrial complexes in patients without structural heart disease

Intravenous adenosine produced slight decreases in conduction times for premature atrial complexes but proportionally greater shortening of the functional refractory period. Decreased wavelength may provide a basis for transient atrial fibrillation, which is sometimes observed after adenosine administration.

Effects of Adenosine on Local Stimulus-Response Latency and Induction of Atrial Fibrillation by Premature Stimuli

Premature atrial stimuli delivered during the relative refractory or “vulnerable” period exhibit increased local stimulus‐response latency and may occasionally induce atrial arrhythmias. The use of adenosine to treat supraventricular tachycardias may also provoke atrial arrhythmias. In this study we investigated the effects of adenosine on the latency of premature complexes in relation to repolarization and induction of atrial arrhythmias in 14 patients without structural heart disease. A monophasic action potential catheter was used for recording in the right atrium and introducing premature stimuli (S2) at twice diastolic threshold after eight paced (S1) complexes. At short coupling intervals, S2 latency increased relative to S1 latency. S2 was delivered repeatedly at a fixed coupling interval (producing maximal local response latency) and adenosine (6 mg) was given intravenously. Adenosine decreased S2 latency significantly (23 ± 5 to 11 ± 3 ms, P < 0.01), to values similar to S1 latency. However, despite the decrease in S2 latency, the combination of adenosine and S2 more often resulted in transient atrial arrhythmias (11 of 14 patients vs 2 of 14 patients without adenosine, P < 0.05). Adenosine had no effect on S1 latency (9 ± 2 vs 9 ± 2 ms) but decreased monophasic action potential duration from 202 ± 37 to 158 ± 38 ms (P < 0.01). Adenosine was also given to 10 patients S2 introduced at a coupling interval 40–50 ms less than the baseline effective refractory period. This resulted in a decrease in atrial refractoriness and capture of S2 in all cases. Latency for S2 was significantly greater than S1 latency (21 ± 12 vs 9 ± 2 ms, P < 0.01) and transient atrial arrhythmias were induced in 9 of 10 patients. We conclude that for a given S2 coupling interval, adenosine decreases local stimulus–response latency but increases atrial vulnerability to transient atrial arrhythmias. Decreased latency may be related to a shift in the zone of relative refractoriness associated with an adenosine‐mediated decrease in monophasic action potential duration. Induction of atrial arrhythmias in the presence of adenosine occurs independently of increased latency and is therefore not dependent on S2 falling within the relative refractory period at the site of stimulation.

Ventricular arrhythmias and regional blood flow in acute and subacute myocardial infarction: effects of the carboxylic ionophore monensin.

Summary: The effects of monensin (75 μg/kg, i.v.) on regional myocardial blood flow and ventricular arrhythmias were studied in 15 anesthetized dogs following ligation of the left anterior descending coronary artery (LAD). During the acute stages of ischemia (n = 7), atrial pacing at a constant rate (224 ± 8 min 1) resulted in fractionation and delay of potentials recorded from the epicardial surface of the ischemic zone which preceded the onset of ventricular tachycardia (VT). The progression of ischemic zone conduction delay and the time to appearance of ventricular arrhythmias were reproducible with repeated occlusions (173 ± 13 see). Blood flow in the subepicardium of the LAD region decreased following occlusion (174 ± 27 to 13 ± 3 ml/min/100 g). and was not significantly affected by monensin (75 μg/kg.i.v). although blood flow in the normal zone increased markedly (156 ± 16 to 519 ± 70 ml/min/100 g). In this series of experiments. monensin accelerated the progression of conduction delay in the ischemic zone and decreased the time to onset of VT (138 ± 12 sec, p < 0.05). possibly as a result of increased metabolic demand. In dogs studied 4 days after LAD ligation, atrial pacing and/or atrial pacing with long-short cycle sequences produced ventricular ectopic beats (VEBs) associated with fractionation and delay of potentials recorded from the epicardial surface of the infarction zone. In contrast to the situation immediately following LAD ligation, blood flow in viable subepicardium was more substantial and increased following monensin (52 ± 6 to 70 ± 7 ml/min/100 g < 0.05). However, there was no change in the ability to induce VEBs. The results indicate that although both types of arrhythmias are due to reentry in subepicardial muscle, those in the later stages of infarction are associated with more stable alterations in electrophysiological properties, as well as greater, although still subnormal, blood flow. The degree of collateral development 4 days after coronary ligation suppears to be an important factor in the ability of monensin to increase perfusion of the LAD region. However, increased blood flow to infarction zone sub epicardium was associated with no change in conduction or the-incidence of ventricular arrhythmias.

Ischemia-induced conduction delay and ventricular arrhythmias: comparative electropharmacology of bethanidine sulfate and bretylium tosylate.

Summary: Bretylium tosylate and bethanidine sulfate were studied in two models of experimental myocardial ischemia. In anesthetized dogs, left anterior descending coronary artery occlusion during rapid atrial pacing (180–200 min−1) produced ventricular tachycardia and fibrillation within 5 min in 9 of 11 dogs studied. In all cases, arrhythmias were preceded by and appeared to be temporally related to progressive fractionation and delay of electrograms recorded from the ischemic zone. In four dogs, bretylium (10 mg/kg) did not alter the time course of electrogram changes nor the time to onset of arrhythmia. However, in five dogs bethanidine (10 mg/kg) markedly exacerbated conduction changes in the ischemic zone and decreased the time to onset of ventricular arrhythmias (173 ± 35 vs. 262 ± 34 s control, mean ± SEM, p < 0.05). Bethanidine administration also facilitated ischemia-induced ventricular tachycardia and fibrillation in two dogs that did not exhibit ischemia-induced arrhythmias before receiving the drug. In isolated perfused rabbit hearts, global ischemia produced conduction slowing, depolarization of resting membrane potential, and decreases in amplitude and Vmax that were reproducible in serial 10 min ischemic episodes. Bretylium (10 mg/L) did not affect these parameters under either perfused or ischemic conditions. Although bethanidine (10 mg/L) also did not affect these parameters during perfusion, conduction slowing and depression of Vmax during ischemia were accelerated without affecting the time course of change in resting membrane potential. Both bretylium and bethanidine prolonged action potential duration under perfused conditions, but after 10 min of ischemia this effect was no longer evident. The results demonstrate that differences in the electrophysiologic effects of bretylium and bethanidine are markedly accentuated in the setting of acute ischemia. Although both these agents have been demonstrated to have antifibrillatory effects in other experimental settings, under the conditions of this study, bretylium failed to protect against ischemia-induced arrhythmias and acute bethanidine administration produced a proarrhythmic effect in association with an exacerbation of ischemia-induced conduction changes.

Effects of adenosine on retrograde refractoriness of accessory atrioventricular connections

Ventricular premature stimuli were used to demonstrate adenosine-mediated decreases in the retrograde refractoriness of accessory atrioventricular connections. This response is consistent with the concept that accessory atrioventricular connections have electrophysiologic properties that are similar to those of atrial myocardium.