title: 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.
authors.affiliation: Beth Israel Deaconess Medical Center; Harvard Medical School, Boston, Massachusetts 02215, USA. rverrier@bidmc.harvard.edu
authors.forename: Richard L
authors.initials: RL
authors.lastname: Verrier
authors.forename: Vitor P F
authors.initials: VP
authors.lastname: Pagotto
authors.forename: Alexandre F
authors.initials: AF
authors.lastname: Kanas
authors.forename: Marcel F
authors.initials: MF
authors.lastname: Sobrado
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Nearing
authors.forename: Dewan
authors.initials: D
authors.lastname: Zeng
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
mesh_terms: D000083:Acetanilides / Q000493:pharmacokinetics / Q000494:pharmacology*; D000638:Amiodarone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001281:Atrial Fibrillation / Q000517:prevention & control*; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D000077764:Dronedarone; D004359:Drug Therapy, Combination; D004562:Electrocardiography; D006439:Hemodynamics / Q000187:drug effects; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D000069458:Ranolazine; D013552:Swine; D017180:Tachycardia, Ventricular / Q000517:prevention & control*
chemical_list: D000083:Acetanilides; D010879:Piperazines; D000069458:Ranolazine; D000077764:Dronedarone; D000638:Amiodarone