RYR2 Channel Inhibition Is the Principal Mechanism of Flecainide Action in CPVT

The class Ic antiarrhythmic drug flecainide prevents ventricular tachyarrhythmia in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), a disease caused by hyperactive RyR2 (cardiac ryanodine receptor) mediated calcium (Ca) release. Although flecainide inhibits single RyR2 ch...

Full description

Saved in:
Bibliographic Details
Published in:Circulation research 2021-02, Vol.128 (3), p.321-331
Main Authors: Kryshtal, Dmytro O, Blackwell, Daniel J, Egly, Christian L, Smith, Abigail N, Batiste, Suzanne M, Johnston, Jeffrey N, Laver, Derek R, Knollmann, Bjorn C
Format: Article
Language:English
Subjects:
Action Potentials
Animals
Anti-Arrhythmia Agents - pharmacology
Calcium Channel Blockers - pharmacology
Calcium Signaling
Calsequestrin - genetics
Calsequestrin - metabolism
Disease Models, Animal
Female
Flecainide - pharmacology
Heart Rate - drug effects
HEK293 Cells
Humans
Male
Mice
Mice, Knockout
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - metabolism
Phosphorylation
Ryanodine Receptor Calcium Release Channel - drug effects
Ryanodine Receptor Calcium Release Channel - metabolism
Sarcoplasmic Reticulum - drug effects
Sarcoplasmic Reticulum - metabolism
Sheep, Domestic
Tachycardia, Ventricular - genetics
Tachycardia, Ventricular - metabolism
Tachycardia, Ventricular - physiopathology
Tachycardia, Ventricular - prevention & control
Voltage-Gated Sodium Channel Blockers - pharmacology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The class Ic antiarrhythmic drug flecainide prevents ventricular tachyarrhythmia in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), a disease caused by hyperactive RyR2 (cardiac ryanodine receptor) mediated calcium (Ca) release. Although flecainide inhibits single RyR2 channels in vitro, reports have claimed that RyR2 inhibition by flecainide is not relevant for its mechanism of antiarrhythmic action and concluded that sodium channel block alone is responsible for flecainide's efficacy in CPVT. To determine whether RyR2 block independently contributes to flecainide's efficacy for suppressing spontaneous sarcoplasmic reticulum Ca release and for preventing ventricular tachycardia in vivo. We synthesized N-methylated flecainide analogues (QX-flecainide and -methyl flecainide) and showed that -methylation reduces flecainide's inhibitory potency on RyR2 channels incorporated into artificial lipid bilayers. -methylation did not alter flecainide's inhibitory activity on human cardiac sodium channels expressed in HEK293T cells. Antiarrhythmic efficacy was tested utilizing a Casq2 (cardiac calsequestrin) knockout (Casq2-/-) CPVT mouse model. In membrane-permeabilized Casq2-/- cardiomyocytes-lacking intact sarcolemma and devoid of sodium channel contribution-flecainide, but not its analogues, suppressed RyR2-mediated Ca release at clinically relevant concentrations. In voltage-clamped, intact Casq2-/- cardiomyocytes pretreated with tetrodotoxin to inhibit sodium channels and isolate the effect of flecainide on RyR2, flecainide significantly reduced the frequency of spontaneous sarcoplasmic reticulum Ca release, while QX-flecainide and -methyl flecainide did not. In vivo, flecainide effectively suppressed catecholamine-induced ventricular tachyarrhythmias in Casq2-/- mice, whereas -methyl flecainide had no significant effect on arrhythmia burden, despite comparable sodium channel block. Flecainide remains an effective inhibitor of RyR2-mediated arrhythmogenic Ca release even when cardiac sodium channels are blocked. In mice with CPVT, sodium channel block alone did not prevent ventricular tachycardia. Hence, RyR2 channel inhibition likely constitutes the principal mechanism of antiarrhythmic action of flecainide in CPVT.
ISSN:0009-7330
1524-4571
DOI:10.1161/circresaha.120.316819