Antiarrhythmic effect of vernakalant in electrically remodeled goat atria is caused by slowing of conduction and prolongation of postrepolarization refractoriness

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• 作者：Arne van Hunnik ; BSc ; Dennis H. Lau ; MBBS ; PhD ; FHRS ; Stef Zeemering ; MSc ; Marion Kuiper ; BSc ; Sander Verheule ; PhD ; Ulrich Schotten ; MD ; PhD ; FHRS ; ^{schotten@maastrichtuniversity.nl" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Vernakalant ; Atrial fibrillation ; Remodeling ; Antiarrhythmic drugs ; In vivo model ; Flecainide ; AVE0118
• 刊名：Heart Rhythm
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：13
• 期：4
• 页码：964-972
• 全文大小：477 K

文摘

Vernakalant inhibits several potassium currents and causes a rate- and voltage-dependent inhibition of the sodium current.

Objective

The aim of this study was to evaluate the antiarrhythmic mechanism of vernakalant in normal and electrically remodeled atria.

Methods

Fourteen goats were instrumented with electrodes on both atria. Drug effects on refractory period (ERP), conduction velocity (CV), and atrial fibrillation cycle length (AFCL) were determined in normal goats (control) and after 2 (2dAF) or 11 (11dAF) days of pacing-induced atrial fibrillation (AF) in awake goats. To evaluate the contribution of changes in conduction and ERP, the same experiments were performed with flecainide and AVE0118. In a subset of goats, monophasic action potentials were recorded during anesthesia.

Results

Vernakalant dose-dependently prolonged ERP and decreased CV in CTL experiments. Both effects were maintained after 2dAF and 11dAF. After 11dAF, conduction slowed down by 8.2 ± 1.5 cm/s and AFCL increased by 55 ± 3 ms, leading to AF termination in 5 out of 9 goats. Monophasic action potential measurements revealed that ERP prolongation was due to enhanced postrepolarization refractoriness. During pacing, vernakalant had comparable effects on CV as flecainide, while effect on ERP was comparable to AVE0118. During AF, all compounds had comparable effects on median AFCL and ERP despite differences in their effects on CV during pacing.

Conclusion

The antiarrhythmic effect of vernakalant in the goat, at clinically relevant plasma concentrations, is based on both conduction slowing and ERP prolongation due to postrepolarization refractoriness. These electrophysiological effects were not affected by long-term electrical remodeling of the atria.