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 tachyarrhythmias and sudden cardiac death.

Objective: To examine whether low-dose ranolazine and/or dronedarone can protect against vulnerability to atrial fibrillation (AF) and ventricular tachyarrhythmias.

Methods: In 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).

Results: Before 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).

Conclusions: Combined 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.