Low doses of ranolazine and dronedarone in combination exert potent protection against atrial fibrillation and vulnerability to ventricular arrhythmias during acute myocardial ischemia

BackgroundCoronary artery disease carries dual risk for atrial tachyarrhythmias and sudden cardiac death.ObjectiveTo examine whether low-dose ranolazine and/or dronedarone can protect against vulnerability to atrial fibrillation (AF) and ventricular tachyarrhythmias.MethodsIn chloralose-anesthetized, open-chest Yorkshire pigs (n = 15), the proximal segment of left circumflex (LCx) coronary artery was occluded to reduce flow by 75%. An electrode catheter was positioned on the left atrial appendage to measure AF threshold (AFT) before and during LCx coronary artery stenosis before and at 1 hour after dronedarone (0.5 mg/kg intravenous bolus over 5 minutes) and/or ranolazine administration (0.6 mg/kg intravenous bolus followed by 0.035 mg/kg/min).ResultsBefore drug administration, LCx coronary artery stenosis lowered AFT from 25.2±1.7 mA control (mean±SEM) to 4.9±1.0 mA baseline (P<.01). At the low doses, neither ranolazine (plasma concentration 2.4±0.6 μM) nor dronedarone (plasma concentration 20.9±3.5 nM) alone blunted the ischemia-induced reduction in AFT but were effective together (from 25.2±1.7 mA control to 22.0±3.0 mA during stenosis; P = not significant). AF duration (P<.03) and AF inducibility (P = .012) were reduced by ranolazine and dronedarone together but not by either drug alone. Concurrently, combined but not separate administration blunted the ischemia-induced surge in T-wave heterogeneity, a marker of risk for ventricular tachyarrhythmias (from 43.1±11.1 μV control to 149.7±15.1 μV during stenosis, P<.001, compared to 61.7±13.7 μV control to 83.7±15.8 μV during stenosis, P = not significant).ConclusionsCombined administration of low doses of ranolazine and dronedarone exerts a potent antiarrhythmic action on ischemia-induced vulnerability to AF and ventricular tachyarrhythmias due to direct effects on myocardial electrical properties.