Abstract 9164: Low Doses of Ranolazine and Dronedarone in Combination Exert Potent Protection against Atrial Fibrillation and Vulnerability to Ventricular Arrhythmias during Acute Myocardial Ischemia

Abstract

Background: Coronary artery disease carries dual risk for atrial fibrillation (AF) and sudden cardiac death. We examined whether low-dose ranolazine and/or dronedarone can protect against AF and vulnerability to ventricular tachyarrhythmias. Methods, Results: In chloralose-anesthetized, open-chest Yorkshire pigs (N=19), proximal segment of left circumflex (LCx) coronary artery was occluded to reduce flow by 75%. Electrode catheter was positioned on left atrial appendage to measure AF threshold (AFT) before and during LCx coronary artery stenosis prior to and at one hour after dronedarone (0.5 mg/kg i.v. bolus over 5 min) and/or ranolazine (0.6 mg/kg, i.v. bolus, followed by 0.035 mg/kg/min). Without drugs, LCx coronary artery stenosis lowered AFT from 25.2±1.7 control (mean±SEM) to 4.9±1.0 mA baseline (p<0.01). At these low doses, neither ranolazine (plasma concentration: 2.4±0.6 μ M) nor dronedarone (plasma concentration: 20.9±3.5 nM) alone blunted ischemia-induced reduction in AFT, but combination was effective (from 25.2±1.7 control to 22.0±3.0 mA, NS). Combined but not separate administration blunted ischemia-induced surge in T-wave heterogeneity (TWH), a marker of risk for ventricular tachyarrhythmias. Without drug, TWH increased from 43.1±11.1 control to 149.7±15.1 μ V baseline during stenosis (p<0.001); with both agents, TWH increased only from 61.7±13.7 control to 83.7±15.8 μ V during stenosis (NS) (Fig.). Conclusions: Combined administration of low doses of ranolazine and dronedarone exerts a potent, antiarrhythmic action consistent with synergy due to direct effects on myocardial electrical properties not on coronary flow, which was controlled.