Evolving developments in the therapeutics of atrial fibrillation: addressing an unmet need.

A trial fibrillation (AF) is by far the most common sustained arrhythmia in the population. Its prevalence is highly age-related and is increasing with aging of the population, to the point where the term epidemic has been applied. The presently available therapeutic options all have intrinsic limitations. The most appealing approach to AF therapy would be to achieve and maintain sinus rhythm. This approach is commonly called rhythm control. However, most patients who experience AF will have subsequent recurrences in the absence of additional therapy to maintain sinus rhythm. The classical approach to sinus-rhythm maintenance has been the use of channel-blocking antiarrhythmic agents. Although such agents do promote sinusrhythm maintenance, they also carry a risk of serious adverse effects, the most disturbing of which is the induction of potentially lethal tachyarrhythmias via collateral actions on the ventricles. An alternative approach to controlling the adverse consequences of AF is simply to control the ventricular response rate by reducing the number of atrial impulses that conduct through the atrioventricular node, a method called rate control. Whatever approach is chosen, it is necessary to prevent thromboembolic complications resulting from the prothrombotic atrial stasis that accompanies AF. In theory, perfect sinus rhythm maintenance should prevent such complications; however, perhaps because sinus rhythm maintenance is usually imperfect with present rhythm-control therapies, oral anticoagulants are generally needed to prevent thromboemboli in high-risk AF patients, whether they are managed with rhythm or rate control approaches. Despite the theoretical advantages of sinus-rhythmmaintenance, severalwell-controlled studies have failed to demonstrate superiority of rhythm over rate control approaches, both in the broad AF population and more recently in a heart failure cohort. We are thus left with an apparent paradox; despite the conceptual superiority of sinus rhythm maintenance in AF patients, the available evidence suggests that aiming to maintain sinus rhythm with presently available antiarrhythmic drug approaches is not clinically advantageous for the AF population as a whole. Therefore, the currently accepted treatment strategy is to favor rate control for all patients who have AF that is either asymptomatic or can be rendered asymptomatic with proper rate control. In practice, rate control is not a viable solution for many patients. Significant numbers of patients feel ill during AF, even with adequate rate control. There is evidence that, even with good rate control, AF may impair ventricular function. Finally, some patients cannot achieve adequate rate control or have periods of bradycardia that require permanent ventricular pacemaking. The growing importance of AF as a clinical problem, the inadequacy of presently available pharmacological approaches, and rapid developments in understanding the pathophysiology of AF have led to great ferment in the development of new therapeutic avenues. In recognition of the active evolution of this area, the Journal of Cardiovascular Pharmacology has decided to present a series of review articles dealing with important issues relating to new therapeutic approaches to AF. A schematic diagram of the areas to be covered is presented in Figure 1.