title: Inhibition of cardiac Ca2+ release channels (RyR2) determines efficacy of class I antiarrhythmic drugs in catecholaminergic polymorphic ventricular tachycardia.
abstract: 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.
  
  
  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, P<0.05). 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 β-blockers.
authors.affiliation: Oates Institute for Experimental Therapeutics, Vanderbilt University School of Medicine, Division of Clinical Pharmacology, Nashville, TN 37232-0575, USA.
authors.forename: Hyun Seok
authors.initials: HS
authors.lastname: Hwang
authors.forename: Can
authors.initials: C
authors.lastname: Hasdemir
authors.forename: Derek
authors.initials: D
authors.lastname: Laver
authors.forename: Divya
authors.initials: D
authors.lastname: Mehra
authors.forename: Kutsal
authors.initials: K
authors.lastname: Turhan
authors.forename: Michela
authors.initials: M
authors.lastname: Faggioni
authors.forename: Huiyong
authors.initials: H
authors.lastname: Yin
authors.forename: Björn C
authors.initials: BC
authors.lastname: Knollmann
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002155:Calsequestrin / Q000172:deficiency / Q000235:genetics; D017147:Defibrillators, Implantable; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004554:Electric Countershock / Q000295:instrumentation; D004562:Electrocardiography; D005424:Flecainide / Q000494:pharmacology*; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D011342:Procainamide / Q000494:pharmacology; D011405:Propafenone / Q000494:pharmacology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D017180:Tachycardia, Ventricular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors; D055815:Young Adult; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D002155:Calsequestrin; D019837:Ryanodine Receptor Calcium Release Channel; D026941:Sodium Channel Blockers; C514388:casq2 protein, mouse; D011405:Propafenone; D008012:Lidocaine; D005424:Flecainide; D011342:Procainamide