Abstract 18550: Efficacy and Potency of Class 1 Antiarrhythmic Drugs for Suppression of Ca2+ Waves in Permeabilized Calsequestrin Null Myocytes
Background: Ca2+ waves are the underlying events that produce delayed-after-depolarizations and can trigger ventricular arrhythmias such as catecholaminergic-polymorphic ventricular tachycardia (CPVT). The prevention of the Ca2+ waves should decrease the likelihood of the production of the arrhythmia. We recently reported that flecainide, a class 1c antiarrhythmic drug, reduces Ca2+ waves in intact myocytes and prevents CPVT in mice and humans. We hypothesized that other antiarrhythmic drugs may also suppress Ca2+ waves and could be useful in CPVT.
Methods and Results: We tested the effect of all clinically-available class 1 antiarrhythmic drugs in an experimental model of Ca2+ waves using permeabilized myocytes isolated from calsequestrin null mice, a CPVT model. After incubation with internal solution containing the respective drug for 10 min., myocytes were imaged in the line-scan mode using confocal microscopy. Drug effects on wave incidence, amplitude, frequency, and propagation speed were analyzed. These parameters are thought to predict the arrhythmogenicity of Ca2+ waves. Concentration-response curves were constructed for each drug to obtain the IC50 (potency) and the maximum % inhibition (efficacy). Of all drugs tested, flecainide and R-propafenone had the highest efficacy and potency for reducing wave amplitude, wave frequency and propagation speed, resulting in a strong suppression of Ca2+ waves. Although flecainide and R-propafenone had similar efficacy of wave suppression, R-propafenone was about 6 times more potent in preventing Ca2+ waves than flecainide. The table lists the potency and efficacy for each class 1 drug (n = 45 – 105 myocytes per drug; #p<0.05 vs drugs with IC50>100 µM; *p<0.05 vs vehicle).
Conclusions: Only flecainide and R-propafenone inhibit arrhythmogenic Ca2+ waves at concentrations that are likely relevant for clinical use. Based on our results, propafenone should be further evaluated as therapeutic agent in CPVT.
- Arrhythmias, treatment of
- Dose-response relation, drug
- Muscle, cardiac — see Myocardium
- © 2010 by American Heart Association, Inc.