Abstract 14560: Inhibition of Cardiac Ca2+ Release Channels (RyR2) Determines Efficacy of Class I Antiarrhythmic Drugs in Catecholaminergic Polymorphic Ventricular Tachycardia
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. We recently reported that the class Ic antiarrhythmic drug flecainide blocks RyR2 channels and prevents CPVT in mice and humans. Here, we compare the efficacy of all clinically-available class 1 antiarrhythmic drugs in CPVT.
Methods and Results: Class 1 antiarrhythmic drugs and other Na+ channel blockers (Quinidine, Procainamide, Disopyramide, Lidocaine, Mexiletine, Flecainide, Propafenone, Encainide, Ranolazine, and Tetrodotoxin) were compared with vehicle (VEH) in (1) Ca2+ fluorescence recordings in myocytes, (2) single RyR2 channel recordings, (3) ECG recordings in a mouse CPVT model lacking Casq2. The R-enantiomer of propafenone (R-PROP) is not a β-adrenergic receptor blocker and was used for all experiments. At clinically-relevant concentrations, only R-propafenone (R-PROP) and flecainide (FLEC) prevented 1µM of isoproterenol-induced arrhythmogenic Ca2+ waves in Casq2 null myocytes (SCW/s: VEH 1.0±0.19, Procainamide, 15µM 1.59±0.16, Lidocaine 50µM 1.15±0.16, R-PROP 6µM 0.14±0.03*, FLEC 6µM 0.14±0.07*, Ranolazine 15µM 0.91±0.21 n=28–45, *p=0.01 vs. VEH). SR Ca2+ content was not significantly changed by any of the drugs tested. Flecainide and R-PROP had the highest potency for inhibiting RyR2 channels among all class 1 antiarrhythmic drugs tested. In Casq2-/- mice, 5mg/kg R-PROP completed prevented exercise-induced CPVT, whereas higher doses of procainamide (20 mg/kg) or lidocaine (20 mg/kg) were ineffective (n=5–9 mice per group, p<0.05). At the same time, QRS duration was not significantly different, indicating a similar degree of Na+ channel inhibition. Clinically, propafenone (900 mg/day) prevented ICD shocks and exercise-induced VT in a 22 year-old CPVT patient who had received frequent ICD shocks despite maximal standard drug therapy and bilateral stellate ganglionectomy.
Conclusion: RyR2 cardiac Ca2+ release channel inhibition, not Na+ channel block, determines efficacy of class 1 agents for the prevention of CPVT in Casq2 null mice. Propafenone may be a promising mechanism-based drug therapy for CPVT patients.
- © 2010 by American Heart Association, Inc.