Azd7009: a new antiarrhythmic drug with predominant effects on the atria effectively terminates and prevents reinduction of atrial fibrillation and flutter in the sterile pericarditis model

Abstract

Introduction: We tested the hypothesis that AZD7009 terminates induced atrial fibrillation (AF) and flutter (AFL) and prevents their reinduction, and that effects on refractoriness, conduction, and excitability are predominantly on the atria.

Methods and results: Thirty-eight electrophysiologic studies were performed during AZD7009 infusion in 11 dogs with sterile pericarditis. The effects of AZD7009 on refractoriness, conduction, and capture threshold were studied and its antiarrhythmic efficacy tested. Simultaneous multisite biatrial mapping was performed in 7 dogs to assess arrhythmia termination. AZD7009 prolonged arrhythmia cycle length (CL) from 121 +/- 7.8 to 157 +/- 9.7 msec (P < 0.001) before terminating 23 of 23 AF/AFL episodes. Mapping demonstrated that AF/AFL CL prolonged and then terminated in area(s) of slow conduction in a reentrant circuit. Arrhythmia reinduction failed in 19 of 20 attempts. At 400-msec CL, atrial and ventricular refractoriness and QT interval increased 33%, 17% (P < 0.001 vs atrial refractoriness), and 9%, respectively. Atrial capture threshold increased in a CL-dependent manner: 1.8 +/- 0.3 to 2.2 +/- 0.3 mA (CL 400 msec); 2.1 +/- 0.3 to 2.8 +/- 0.5 mA (CL 300 msec), and 2.2 +/- 0.3 to 5.3 +/- 0.8 mA (CL 200 msec). Only minor nonsignificant changes occurred in the ventricles: 0.95 +/- 0.05 to 0.98 +/- 0.06 mA (CL 400 msec), and 1.14 +/- 0.12 to 1.16 +/- 0.13 mA (CL 333 msec). Atrial conduction time increased 8 +/- 1.4 msec (CL 400 msec), 8.3 +/- 1.5 msec (CL 300 msec), and 13.2 +/- 1.6 msec (CL 200 msec, all P < 0.001), but ventricular conduction time was unchanged.

Conclusion: AZD7009 is highly efficacious in terminating AF/AFL and preventing reinduction in this model. It exhibits marked effects on atrial electrophysiology but has only modest effects on the ventricle.