Clinical Research
Heart Rhythm Disorder
Synergistic Effect of the Combination of Ranolazine and Dronedarone to Suppress Atrial Fibrillation

https://doi.org/10.1016/j.jacc.2010.08.600Get rights and content
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Objectives

The aim of this study was to evaluate the effectiveness of a combination of dronedarone and ranolazine in suppression of atrial fibrillation (AF).

Background

Safe and effective pharmacological management of AF remains one of the greatest unmet medical needs.

Methods

The electrophysiological effects of dronedarone (10 μmol/l) and a relatively low concentration of ranolazine (5 μmol/l) separately and in combination were evaluated in canine isolated coronary-perfused right and left atrial and left ventricular preparations as well as in pulmonary vein preparations.

Results

Ranolazine caused moderate atrial-selective prolongation of action potential duration and atrial-selective depression of sodium channel–mediated parameters, including maximal rate of rise of the action potential upstroke, leading to the development of atrial-specific post-repolarization refractoriness. Dronedarone caused little or no change in electrophysiological parameters in both atrial and ventricular preparations. The combination of dronedarone and ranolazine caused little change in action potential duration in either chamber but induced potent use-dependent atrial-selective depression of the sodium channel–mediated parameters (maximal rate of rise of the action potential upstroke, diastolic threshold of excitation, and the shortest cycle length permitting a 1:1 response) and considerable post-repolarization refractoriness. Separately, dronedarone or a low concentration of ranolazine prevented the induction of AF in 17% and 29% of preparations, respectively. In combination, the 2 drugs suppressed AF and triggered activity and prevented the induction of AF in 9 of 10 preparations (90%).

Conclusions

Low concentrations of ranolazine and dronedarone produce relatively weak electrophysiological effects and weak suppression of AF when used separately but when combined exert potent synergistic effects, resulting in atrial-selective depression of sodium channel–dependent parameters and effective suppression of AF.

Key Words

antiarrhythmic drugs
arrhythmias
electrophysiology
pharmacology
sodium-channel blockers

Abbreviations and Acronyms

ACh
acetylcholine
AF
atrial fibrillation
AP
action potential
APD
action potential duration
CL
cycle length
DAD
delayed afterdepolarization
DTE
diastolic threshold of excitation
ERP
effective refractory period
INa
sodium channel current
LV
left ventricular
PRR
post-repolarization refractoriness
PV
pulmonary vein
RA
right atrial
Vmax
maximal rate of rise of the action potential upstroke

Cited by (0)

This study was supported by grants from Gilead Sciences, the National Institutes of Health (grant HL-47678 to Dr. Antzelevitch), and the New York State and Florida Grand Lodges of Free and Accepted Masons. Dr. Antzelevitch received research support from Gilead Sciences, AstraZeneca, Merck, and Cardiome; and consulting support from Gilead Sciences and AstraZeneca. Dr. Belardinelli is an employee of Gilead Sciences. All other authors have reported that they have no relationships to disclose.