Antiarrhythmic drug therapy for atrial fibrillation: focus on atrial selectivity and safety

Atrial fibrillation (AF) is a highly prevalent arrhythmia and responsible for significant morbidity, mortality and health care cost. The prevalence of AF is expected to increase markedly with the aging population. The use of conventional antiarrhythmic agents has been limited by potentially fatal ventricular proarrhythmia. Rhythm control could become the preferred treatment strategy for AF if antiarrhythmic agents that are similarly or more effective, but safer, than currently approved AF agents become available. A subanalysis of the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) trial data showed that normal sinus rhythm confers a survival benefit in AF, suggesting that rhythm control, if achieved without the adverse effects related to current antiarrhythmic medications, may offer a significant survival advantage over rate control. Considerable work has been performed to explore novel, potentially safer antiarrhythmic drug targets for AF therapy, and some of these drug targets are currently being tested in experimental and clinical proof of concept studies. This article summarizes relevant aspects of the cellular electrophysiology of AF and reviews the actions of pharmacological agents being considered for the prevention and treatment of AF, focusing on atrial selective antiarrhythmic agents. A variety of drugs that inhibit the atrium-specific ultra rapid delayed rectifier potassium current (IKur) are being evaluated pre-clinically, but human experience with these agents is limited. The acetylcholine-activated current (IKACh) is another novel candidate target for atrial-specific drug therapy. The constitutively active form of this current is increased in human AF and pharmacological inhibition might be of therapeutic value. Certain drugs have IKACh blocking properties, but similar to IKur-blockers, none have been shown to have pure selectivity for this current. Newer agents being studied also include gap junction modulators and angiotensin-converting enzyme inhibitors. There is great hope that at least some of these agents will ultimately be available for effective and safer clinical treatment and prevention of AF.