Broad antiarrhythmic effect of mexiletine in different arrhythmia models.

Abstract

Aims:

Experimental studies and clinical reports suggest antiarrhythmic properties of mexiletine in different arrhythmias. We aimed at investigating mexiletine in experimental models of atrial fibrillation (AF) as well as in long-QT- (LQTS) and short-QT-syndrome (SQTS).

Methods and results:

In 15 isolated rabbit hearts, erythromycin (300 µM) was infused for simulation of long-QT-2-syndrome. In further 13 hearts, veratridine was administered to simulate long-QT-3-syndrome. Both drugs induced a significant QT-prolongation (erythromycin: +87 ms, P < 0.01; veratridine: +19 ms, P < 0.05) and increased dispersion of repolarization (erythromycin: +55 ms, P < 0.01; veratridine +31 ms, P < 0.01). Additional infusion of mexiletine (25 µM) resulted in a significant reduction of dispersion (erythromycin: -43 ms, P < 0.01; veratridine: -26 ms, P < 0.05). Reproducible induction of torsade de pointes was observed in 13 of 15 erythromycin-treated hearts (192 episodes) and 6 of 13 veratridine-treated hearts (36 episodes). Additional infusion of mexiletine significantly reduced ventricular tachycardia (VT) incidence. With mexiletine, only 3 of 15 erythromycin-treated hearts (27 episodes) and 1 of 13 veratridine-treated hearts (2 episodes) presented polymorphic VT. In additional 9 hearts, the IK-ATP-channel-opener pinacidil was employed to simulate SQTS and significantly abbreviated ventricular repolarization (QT-interval: -18 ms, P < 0.05) and enhanced induction of ventricular fibrillation (VF). Mexiletine reversed the effects of pinacidil, increase refractory period (+127 ms, P < 0.01) and significantly suppressed induction of VF. In further 13 hearts AF was induced by combined treatment with acetylcholine/isoproterenol. Mexiletine also increased atrial refractory period (+80 ms, P < 0.01) and thereby effectively suppressed atrial fibrillation.

Conclusion:

Acute infusion of mexiletine significantly reduced the occurrence of polymorphic VT in the presence of pharmacologically simulated LQTS. Furthermore, mexiletine demonstrated potent antiarrhythmic properties in a model of SQTS and in AF.

• Authors: Gerrit Frommeyer, Jonas Garthmann, Christian Ellermann, Dirk G Dechering, Simon Kochhäuser, Florian Reinke, Julia Köbe, Kristina Wasmer, Lars Eckardt
• Journal: Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology (Europace) Vol. 20 Issue 8 Pg. 1375-1381 (08 01 2018) ISSN: 1532-2092 [Electronic] England
• PMID: 29016765 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Anti-Arrhythmia Agents
• Mexiletine

Topics

• Action Potentials (drug effects)
• Animals
• Anti-Arrhythmia Agents (pharmacology)
• Arrhythmias, Cardiac (physiopathology, prevention & control)
• Atrial Fibrillation (physiopathology, prevention & control)
• Disease Models, Animal
• Heart Conduction System (drug effects, physiopathology)
• Heart Rate (drug effects)
• Isolated Heart Preparation
• Long QT Syndrome (physiopathology, prevention & control)
• Mexiletine (pharmacology)
• Rabbits
• Tachycardia, Ventricular (physiopathology, prevention & control)
• Time Factors