Original Articles
Inhibition of Cardiac Ca
2
Release Channels (RyR2)
Determines Efficacy of Class I Antiarrhythmic Drugs in
Catecholaminergic Polymorphic Ventricular Tachycardia
Hyun Seok Hwang, PhD; Can Hasdemir, MD; Derek Laver, PhD; Divya Mehra, BPharm;
Kutsal Turhan, MD; Michela Faggioni, MD; Huiyong Yin, PhD; Björn C. Knollmann, MD, PhD
Background—Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations in the cardiac ryanodine
receptor (RyR2) or calsequestrin (Casq2) and can be difficult to treat. The class Ic antiarrhythmic drug flecainide blocks RyR2
channels and prevents CPVT in mice and humans. It is not known whether other class I antiarrhythmic drugs also block RyR2
channels and to what extent RyR2 channel inhibition contributes to antiarrhythmic efficacy in CPVT.
Methods and Results—We first measured the effect of all class I antiarrhythmic drugs marketed in the United States
(quinidine, procainamide, disopyramide, lidocaine, mexiletine, flecainide, and propafenone) on single RyR2 channels
incorporated into lipid bilayers. Only flecainide and propafenone inhibited RyR2 channels, with the S-enantiomer of
propafenone having a significantly lower potency than R-propafenone or flecainide. In Casq2
-/-
myocytes, the
propafenone enantiomers and flecainide significantly reduced arrhythmogenic Ca
2+
waves at clinically relevant
concentrations, whereas Na
+
channel inhibitors without RyR2 blocking properties did not. In Casq2
-/-
mice, 5 mg/kg
R-propafenone or 20 mg/kg S-propafenone prevented exercise-induced CPVT, whereas procainamide (20 mg/kg) or
lidocaine (20 mg/kg) were ineffective (n=5 to 9 mice, P0.05). QRS duration was not significantly different, indicating
a similar degree of Na
+
channel inhibition. Clinically, propafenone (900 mg/d) prevented ICD shocks in a 22-year-old
CPVT patient who had been refractory to maximal standard drug therapy and bilateral stellate ganglionectomy.
Conclusions—RyR2 cardiac Ca
2+
release channel inhibition appears to determine efficacy of class I drugs for the
prevention of CPVT in Casq2
-/-
mice. Propafenone may be an alternative to flecainide for CPVT patients symptomatic
on -blockers. (Circ Arrhythm Electrophysiol. 2011;4:128-135.)
Key Words: class I antiarrhythmic drugs
propafenone
RyR2
catecholaminergic polymorphic ventricular tachycardia
flecainide
ranolazine
tetrodotoxin
quinidine
procainamide
disopyramide
lidocaine
mexiletine
C
atecholaminergic polymorphic ventricular tachycardia
(CPVT) is an inherited arrhythmia syndrome character-
ized by physical or emotional stress-induced bidirectional or
polymorphic ventricular tachycardia.
1
The more common
autosomal-dominant form has been linked to mutations in the
gene encoding the cardiac Ca
2+
release channel (RYR2).
2
A
less common but more severe autosomal-recessive form is
caused by mutations in the gene encoding cardiac calsequestrin
(CASQ2),
3,4
the major Ca
2+
-binding protein in the sarcoplasmic
reticulum (SR).
5
Ventricular myocytes isolated from mouse
models of both forms of CPVT exhibit catecholamine-induced
premature SR Ca
2+
release and spontaneous Ca
2+
waves that
trigger delayed afterdepolarizations (DADs) and premature
beats.
6,7
Thus, the spontaneous opening of SR Ca
2+
release
channels elicited by catecholaminergic stress are the likely
culprit for triggering ventricular arrhythmias in CPVT.
8
Clinical Perspective on p 135
Although significantly reduced, cardiac events remain
unacceptably high in CPVT patients treated with -blockers.
9
Even implantable cardioverter-defibrillators (ICDs) are not
necessarily effective, because defibrillation shocks can cause
catecholamine release and electrical storm, and deaths have
been reported in CPVT patients with ICDs.
10 –12
Thus, there is
a need for better drug therapy in CPVT. We recently found
that the class Ic antiarrhythmic drug flecainide directly targets
the molecular defect in CPVT by open-state block of RyR2
channels
13
and prevents CPVT in mice and humans.
14
How-
Received July 28, 2010; accepted January 13, 2011.
From the Oates Institute for Experimental Therapeutics (H.S.H., M.F., B.C.K.), Vanderbilt University School of Medicine, Division of Clinical
Pharmacology, Nashville, TN; the Department of Cardiology (C.H.) and Department of Thoracic Surgery (K.T.), Ege University School of Medicine,
Izmir, Turkey; the School of Biomedical Sciences and Pharmacy (D.L., D.M.), University of Newcastle and HMRI, Callaghan, Australia; and the
Department of Pharmacology and Chemistry (H.Y.), Vanderbilt University School of Medicine, Nashville, TN.
Drs Hwang, Hasdemir, and Laver contributed equally to this work.
The online-only Data Supplement is available at http://circep.ahajournals.org/cgi/content/full/CIRCEP.110.959916/DC1.
Correspondence to Bjo ¨rn C. Knollmann, MD, PhD, Oates Institute for Experimental Therapeutics, Vanderbilt University School of Medicine, Medical
Research Building IV, Room 1265, 2215B Garland Ave, Nashville, TN 37232-0575. E-mail bjorn.knollmann@vanderbilt.edu
© 2011 American Heart Association, Inc.
Circ Arrhythm Electrophysiol is available at http://circep.ahajournals.org DOI: 10.1161/CIRCEP.110.959916
128 by guest on May 16, 2016 http://circep.ahajournals.org/ Downloaded from by guest on May 16, 2016 http://circep.ahajournals.org/ Downloaded from by guest on May 16, 2016 http://circep.ahajournals.org/ Downloaded from by guest on May 16, 2016 http://circep.ahajournals.org/ Downloaded from by guest on May 16, 2016 http://circep.ahajournals.org/ Downloaded from