Advances in the Pharmacological Treatment of Atrial Fibrillation.

Atrial fibrillation (AF) is a growing clinical problem that is associated with increased morbidity and mortality rates. There are two principal options for the management of AF: rate and rhythm control. The rhythm control strategy aims to maintain sinus rhythm, or to restore rhythm when required, using antiarrhythmic drugs (AADs), catheter ablation, electrical cardioversion, or surgical techniques. AADs are also used to maintain sinus rhythm following catheter ablation or cardioversion. Rate control, in which fibrillation remains in the atrium, is focused on preventing the detrimental effects of rapid activation of the atria on the ventricles. Such effects include the development of cardiomyopathy and heart failure (HF). Depending on their CHADS (congestive HF, hypertension, age, diabetes mellitus, and prior stroke or transient ischemic attack) score, patients undergoing rate or rhythm control may require anticoagulation therapy to reduce the risk of stroke. Data from multicenter, randomized, prospective clinical trials suggest that rhythm control strategies with currently available AADs are not superior to rate control strategies in terms of survival rates (for a review see [1]). A common interpretation of these data is that the adverse effects of using AADs, secondary to extra-cardiac toxicity and ventricular proarrhythmia, exceed the benefit derived from their limited capability to maintain sinus rhythm [1]. However, AF patients with maintained sinus rhythm (with or without AADs) have a better survival rate and quality of life than those in whom AF persists [2,3]. Although the use and efficacy of catheter ablation-based approaches in AF treatment have increased significantly over the past decade, pharmacological agents remain the first-line therapy for rhythm management of AF [4]. It has been speculated that rhythm control using AADs would be preferable for the treatment of most AF patients if safer and more effective AADs were available [1,5]. Most AADs in current clinical use, and those that are under development, exert their anti-AF actions exclusively or primarily via modulation of cardiac ion-channel activity. However, AF is commonly associated with both atrial electrical and structural abnormalities as well as with a number of, often overlapping, intracardiac and extra-cardiac diseases (including HF, hypertension, coronary artery disease, and myocardial infarction). These abnormalities and diseases may significantly modulate the safety and anti-AF efficacy of AAD therapy. Therefore, development of anti-AF agents is focused on alteration of ion-channel activity and targeting upstream intracardiac and extracardiac, non-electrical factors that promote AF (Figure 1). Investigational approaches for pharmacological AF treatments that alter gap junctions or intracellular calcium activity have yielded some positive data but these agents remain far from clinical testing [6]. Figure 1 Current prominent investigational strategies for rhythm control of AF.