Synergistic Effect of Dofetilide and Mexiletine on Prevention of Atrial Fibrillation.

Abstract

BACKGROUND:

Although atrial fibrillation (AF) is the most common abnormal heart rhythm and its prevalence continues to rise, there is a marked paucity of effective and safe antiarrhythmic drugs for AF. This study was done to test whether combined use of dofetilide and mexiletine exhibits not only a synergistic effect on AF suppression but also a safer profile in drug-induced ventricular proarrhythmias.

METHODS AND RESULTS:

The effects of dofetilide plus mexiletine on atrial effective refractory period (ERP), AF inducibility, QT, and QT-related ventricular arrhythmias were studied using the isolated arterially perfused rabbit atrial and ventricular wedge preparations. Dofetilide or mexiletine alone mildly to moderately prolonged atrial ERP, but their combined use produced a markedly rate-dependent increase in atrial ERP. Dofetilide (3 nmol/L) plus mexiletine (10 μmol/L) increased the ERP by 28.2% from 72.2±5.7 to 92.8±5.9 ms (n=9, P<0.01) at a pacing rate of 0.5 Hz and by 94.5% from 91.7±5.2 to 178.3±12.0 ms (n=9, P<0.01) at 3.3 Hz. Dofetilide plus mexiletine strongly suppressed AF inducibility. On the other hand, dofetilide at 10 nmol/L produced marked QT and Tp-e prolongation, steeper QT-BCL and Tp-e-BCL slopes, and induced early afterdepolarizations and torsade de pointes in the ventricular wedges. Mexiletine at 10 μmol/L reduced dofetilide-induced QT and Tp-e prolongation, QT-BCL and Tp-e-BCL slopes, and abolished early afterdepolarizations and torsade de pointes.

CONCLUSIONS:

In rabbits, combined use of dofetilide and mexiletine not only synergistically increases atrial ERP and effectively suppresses AF inducibility, but also markedly reduces QT liability and torsade de pointes risk posed by dofetilide alone.

• Authors: Guizhi Liu, Xiaolin Xue, Chuanyu Gao, Jiaqi Huang, Datun Qi, Yanzhou Zhang, Jian-Zeng Dong, Chang-Sheng Ma, Gan-Xin Yan
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 6 Issue 5 (May 18 2017) ISSN: 2047-9980 [Electronic] England
• PMID: 28522677 (Publication Type: Journal Article)
• Copyright: © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Chemical References

• Anti-Arrhythmia Agents
• Phenethylamines
• Sulfonamides
• Mexiletine
• dofetilide

Topics

• Action Potentials
• Animals
• Anti-Arrhythmia Agents (pharmacology, toxicity)
• Atrial Fibrillation (metabolism, physiopathology, prevention & control)
• Drug Synergism
• Drug Therapy, Combination
• Female
• Heart Atria (drug effects, metabolism, physiopathology)
• Heart Rate (drug effects)
• Heart Ventricles (drug effects, physiopathology)
• In Vitro Techniques
• Long QT Syndrome (chemically induced, physiopathology)
• Male
• Mexiletine (pharmacology, toxicity)
• Phenethylamines (pharmacology, toxicity)
• Rabbits
• Refractory Period, Electrophysiological
• Risk Assessment
• Sulfonamides (pharmacology, toxicity)
• Time Factors
• Torsades de Pointes (chemically induced, physiopathology)