Abstract 12110: First Direct Comparison of the Late Sodium Current Blocker Ranolazine to Established Antiarrhythmic Agents in an Ischemia/Reperfusion Model
Introduction: There are few safe antiarrhythmics for ischemic heart disease. Whereas ranolazine (R) is a promising late INa blocker with anti-arrhythmic effects, and devoid of pro-arrhythmic properties, there are no direct comparisons between R and other anti-arrhythmic agents in an ischemia/reperfusion setting.
Hypothesis: Our hypothesis was that R was an equally effective antiarrhythmic in the setting of ischemia/reperfusion, compared to approved agents.
Methods: Anesthetized rats were subjected to 5 minutes of proximal left coronary artery occlusion plus 5 minutes of reperfusion, a model that reliably causes severe reperfusion ventricular arrhythmias. At 21 minutes prior to coronary occlusion, rats were randomized to receive sotalol (S) IV bolus 5 mg/kg, 10 mg/kg/hr infusion; lidocaine (L) IV bolus 2.5 mg/kg, 2.5 mg/kg/hr infusion; R IV bolus 3.3 mg/kg, 3.2 mg/kg/hr infusion (∼4 µM plasma concentration) or matched saline control (C, n = 20 rats in each group). Drug doses approximated middle of therapeutic range.
Results: The incidence of ventricular arrhythmias in the S, L, R, C groups was 7/20, 10/20, 9/20, and 16/20, respectively (p = 0.01 S vs. C, p = 0.10 L vs. C, and p = 0.048 R vs. C). Duration of ventricular tachycardia (VT) episodes was reduced from 15.5 ± 6.9 sec in C to 1.3 ± 1.1 sec in S (p = 0.02 vs. C), 1.4 ± 0.9 sec in L (p = 0.15) and 0.09 ± 0.05 sec in R (p = 0.03). The number of rats with any (≥ 10 sec) sustained VT was 3 in C versus 1, 0, and 0 in the S, L and R groups, respectively. Two rats in C had reversible ventricular fibrillation versus 0 in the S, L, and R groups. The number of VPBs was 10.9 ± 3.5 in C, 2.3 ± 1.2 in S (p = 0.002 vs. C); 4.9 ± 2.5 in L (p = 0.04 vs. C); and 5.7 ± 2.8 in R (p = 0.03 vs. C). P = NS for R vs. L or S for all analyses.
Conclusion: In this first head to head comparison of R to other antiarrhythmic agents in an ischemia/reperfusion model, R (which lacks pro-arrhythmic effects) at a dose that inhibits late INa was as effective for reperfusion induced ventricular arrhythmias as the established antiarrhythmics S and L.
- © 2010 by American Heart Association, Inc.