Dr. Horikawa opened by noting that researchers have long believed that the antiarrhythmic effects of class 1c drugs on atrial fibrillation (AF) arise from prolongation of atrial effective refractory period and reduction of conduction velocity within the atrium; however, drug effects on the pulmonary vein (PV) and PV-left atrial junction had not been explored prior to the current research.

The investigators had previous experience with atrial arrhythmias in a dog model: They had shown that an application of aconitine to a branch of one PV can induce a regular atrial tachycardia (called PV tachycardia) that can be converted into AF in the majority of dogs with use of vagal nerve stimulation.

The current work used the same open chest dog model to look for possible drug effects of pilsicainide on substrates of AF that originate in either the left or right PV. In a total of 27 dogs, induction of AF was done with use of bilateral stimulation of the cervical vagal nerves after application of aconitine on a main branch of the right or left PV (20 and 7 dogs, respectively).

Electrophysiologic studies were conducted before and after intravenous administration of pilsicainide at 1 mg/kg/5 min; study setup involved electrodes in the atria and PVs, as well as a mapping plaque with 128 electrodes placed on the surface of the right atrium.

・	Needle type electrodes were inserted into the atria, PV and ventricle.
・	A 128 polar plaque electrode was placed on the right atrial free wall to measure the atrial conduction velocity.

Sustained AF originating from the aconitine-treated PV (cycle length, 61.2 ms) was induced in 21 of 27 dogs, and PV tachycardia that did not convert to AF was induced in the remaining 6 dogs.

*	VS converted AT into sustained AF in 21 of 27 dogs, and in the remaining 6 dogs sustained AF was not induced.
**	Administration of pilsicainide terminated AF in 20 of 21 dogs.

Intracardiac electrograms were demonstrated when AF was terminated by pilsicainide. Activation intervals of atria and PVs were prolonged and the waves organized before AF was converted into PV tachycardia.

The findings expected for a class 1c drug were also noted: Atrial effective refractory period increased from 90.0 ms to 107.5 ms, and conduction velocity decreased from 73.2 cm/s to 55.2 cm/s.

Attempts to reinduce arrhythmia with atrial burst pacing produced sustained AF in 3 of the 20 dogs in which pilsicainide had terminated the arrhythmia; nonsustained AF was produced in 12 of the 20 dogs. In 6 of the 36 dogs, investigators noted PV-left atrium (LA) dissociation before conversion to normal rhythm.

Intracardiac recordings during re-induced AF after pilsicainide administration demonstrate rapid PV activation and slower atrial activation.

Rapid PV activation was noted in all 3 dogs in which sustained AF was reinduced, but it was observed in only 1 of the 12 dogs in which nonsustained AF was induced. The mean plasma concentration of pilsicainide achieved with intravenous administration was significantly higher than the therapeutic range (2.13 μg/mL compared with 0.3 -0.9 μg/mL).

*	Atrial pacing provoked rapid PV activation only in 4 dogs, which showed AF (sustained 3, non-sustained 1).
**	Rapid PV activation was not provoked in the remaining 16 dogs, in which sustained AF was not induced.

The research demonstrates in the dog model that a class 1c drug (namely, pilsicainide) can terminate AF originating from a PV, with antiarrhythmic effects in a variety of tissues including the atria, PVs, and PV-LA junctions. Future research should take these pharmacologic effects seen with AF of PV origin into account when considering the activity of antiarrhythmic agents.