Short Communication: Flecainide Exerts an Antiarrhythmic Effect in a Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia by Increasing the Threshold for Triggered Activity

• Published in: Circulation research Vol. 109; no. 3; pp. 291 - 295
• Main Authors: Liu, Nian, Denegri, Marco, Ruan, Yanfei, Avelino-Cruz, José Everardo, Perissi, Andrea, Negri, Sara, Napolitano, Carlo, Coetzee, William A, Boyden, Penelope A, Priori, Silvia G
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 22.07.2011; Lippincott Williams & Wilkins
• Subjects: Animals; Anti-Arrhythmia Agents - pharmacology; Biological and medical sciences; Calcium Signaling - drug effects; Calcium Signaling - physiology; Cardiac dysrhythmias; Cardiology. Vascular system; Disease Models, Animal; Extracellular Space - drug effects; Extracellular Space - physiology; Flecainide - pharmacology; Fundamental and applied biological sciences. Psychology; Gene Knock-In Techniques; Heart; Isoproterenol - pharmacology; Medical sciences; Mice; Mice, Mutant Strains; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - physiology; Patch-Clamp Techniques; Ryanodine Receptor Calcium Release Channel - genetics; Ryanodine Receptor Calcium Release Channel - physiology; Sarcoplasmic Reticulum - drug effects; Sarcoplasmic Reticulum - physiology; Sodium Channels - physiology; Sympathomimetics - pharmacology; Tachycardia, Ventricular - drug therapy; Tachycardia, Ventricular - genetics; Tachycardia, Ventricular - prevention & control; Vertebrates: cardiovascular system; Animal model; Arrhythmia; Rodentia; Ryanodine receptor; Cardiovascular disease; Ventricular tachycardia; Ionic channel; Vertebrata; Mammalia; Sodium; Mouse; sodium channel; Heart disease; Genetics; Circulatory system; Flecainide
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.111.247338

RATIONALE:Flecainide prevents arrhythmias in catecholaminergic polymorphic ventricular tachycardia, but the antiarrhythmic mechanism remains unresolved. It is possible for flecainide to directly affect the cardiac ryanodine receptor (RyR2); however, an extracellular site of action is suggested because of the hydrophilic nature of flecainide. OBJECTIVE:To investigate the mechanism for the antiarrhythmic action of flecainide in a RyR2 knock-in mouse model of catecholaminergic polymorphic ventricular tachycardia. METHODS AND RESULTS:Flecainide prevented catecholamine-induced sustained ventricular tachycardia in RyR2 mice. Cellular studies were performed with isolated RyR2 myocytes. Isoproterenol caused the appearance of spontaneous Ca transients, which were unaffected by flecainide (6 μmol/L). Flecainide did not affect Ca transient amplitude, decay, or sarcoplasmic reticulum Ca content. Moreover, it did not affect the frequency of spontaneous Ca sparks in permeabilized myocytes. In contrast, flecainide effectively prevented triggered activity induced by isoproterenol. The threshold for action potential induction was increased significantly (P<0.01), which suggests a primary extracellular antiarrhythmic effect mediated by Na channel blockade. CONCLUSIONS:Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in RyR2 mice; however, at variance with previous reports, we observed minimal effects on intracellular Ca homeostasis. Our data suggest that the antiarrhythmic activity of the drug is caused by reduction of Na channel availability and by an increase in the threshold for triggered activity.