Atrial-Selective Drugs for the Management of Atrial Fibrillation

Abstract

Development of safe and effective pharmacological treatments for atrial fibrillation (AF) is one of the greatest unmet medical need facing our society today. Currently available anti-arrhythmic drugs for rhythm control of AF are far less than optimal. Ion channel inhibition remains the principal strategy for suppression of AF. Recent studies have focused on development of atrial-selective potassium ion channels blockers, taking advantage of the presence of an ultra-rapid delayed rectifier current (IKur) in atria but not ventricles. However, practical clinical experience indicates that multi-ion channel blockers are generally more effective for rhythm control of AF compared to ion channel-selective blockers. Recent experimental studies have identified atrial-selective sodium channel current (INa) blockers, which can effectively suppress AF, while exerting little or no effects in the ventricles. Chronic amiodarone and ranolazine have been shown to be atrial-selective sodium channel blockers, capable of producing atrial-selective depression of excitability and conduction as well as post-repolarization refractoriness and are thus effective in suppressing AF and preventing its re-induction in experimental models as well as in the clinic. The combination of amiodarone and ranolazine as well as dronedarone and ranolazine produce potent synergistic effects resulting in potent use-dependent atrial-selective depression of sodium channel-dependent parameters and very effective suppression of AF. While the remarkable synergism exerted by the atrial-selective drug combination holds great promise for safe and effective management of AF, a number of critical questions remain to be answered.