Evolving Developments in the Therapeutics of Atrial Fibrillation: Addressing an Unmet Need

Atrial 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.1 The presently available therapeutic options all have intrinsic limitations.2 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.3 The classical approach to sinus-rhythm maintenance has been the use of channel-blocking antiarrhythmic agents. Although such agents do promote sinus-rhythm 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.3 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.4,5 Despite the theoretical advantages of sinus-rhythm maintenance, several well-controlled studies have failed to demonstrate superiority of rhythm over rate control approaches, both in the broad AF population4,5 and more recently in a heart failure cohort.6 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.7 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 AF8 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.FIGURE 1: A schematic of subjects dealt with in the review series on novel therapeutic approaches to atrial fibrillation. Each listing corresponds to one of the articles in the series, with the authors indicated in brackets.The 12 review articles in this series will be published in 4 issues of the Journal. The first issue contains 2 articles dealing with aspects of the currently accepted rate-control/anticoagulation approach. George Wyse addresses important and often overlooked problems in applying rate control therapy, particularly the question of appropriate criteria for assessing the adequacy of rate control.9 Andreas Goette discusses new developments in oral anticoagulation therapy.10 Campbell and Link first discovered dicoumarol as the active anticoagulant in sweet clover in 1941,11 and warfarin was later developed as a rodent poison by the Wisconsin Alumni Research Foundation, whose initials accompanied by the “arin” in coumarin gave the compound its name. Warfarin was considered too toxic for therapeutic use in humans, until the observation of successful survival after a massive overdose.12 Warfarin and related vitamin K antagonist compounds rapidly became the mainstay of oral anticoagulation, which they have remained since the 1950s, but their many limitations, along with important developments in coagulation science, have led to considerable interest in the production of new classes of anticoagulants as reviewed by Dr Goette.10 The last paper in this issue, by Burstein and Nattel, deals with atrial remodeling as a therapeutic target.13 With the recognition of the various problems associated with conventional ion-channel targeting antiarrhythmics, and the discovery that drug therapy can prevent atrial structural remodeling implicated in the AF substrate,14 considerable efforts have been expended to identify drug approaches that can prevent AF by suppressing the substrate. The next 3 articles address novel ionic targets that seek to control AF without ventricular proarrhythmia by producing atrial-selective effects. Ford and Milnes discuss the potential promise of blocking the ultra-rapid delayed rectifier current,15 which is involved in human atrial repolarization but has minimal expression in human ventricles.16-18 Burashnikov and Antzelevitch address the issue of atrial-selective Na+-channel blockade, which they have recently defined as an interesting mechanism for AF therapy.19 Finally, Joachim Ehrlich discusses inward-rectifier K+-currents, including the background current IK1 and the atrial-selective acetylcholine-regulated K+-current, both of which are functionally upregulated in AF,20,21 as AF-selective antiarrhythmic targets.22 The next set of papers deal with new technologies in AF treatment. Rapid improvements in understanding of functional atrial anatomy and energy delivery have placed atrial ablation procedures at the forefront of AF therapeutics, creating the possibility of effective and reliable sinus-rhythm maintenance without ventricular proarrhythmia. Naccarelli and Gonzalez tackle the provocative question of whether further developments in AF ablation will eventually eliminate the need for drug therapy.23 Govindan et al address the expanding role of hybrid therapies involving both pharmacological and non-pharmacological methods for AF management, particularly in patients whose AF is difficult to control.24 Finally, Qin et al discuss the exciting new horizons promised by biological therapies, including cell and gene transfer approaches, for the future of AF therapeutics.25 The final group of papers describes several additional approaches to the development of novel AF therapeutics. Abnormal Ca2+ handling has been identified as a potentially important and poorly understood culprit in the etiology of AF.26,27 Dobrev and Nattel discuss the possible implications for new therapeutic approaches.28 Amiodarone is the most successful presently available drug for sinus rhythm maintenance.29 In the absence of a clear understanding for the basis of its superiority, the development of new compounds that mimic amiodarone's properties, including the ability to block multiple cardiac ion channels, but have improved pharmacokinetic or safety profiles is being pursued actively. This strategy is discussed by Bramah Singh,30 who first described the cellular antiarrhythmic properties of amiodarone almost 40 years ago.31 The final article, by David Van Wagoner, concerns the suppression of oxidative stress and tissue inflammation, which appear to accompany AF in many different experimental and clinical paradigms.32 There is extensive evidence for an important pathophysiological role for oxidative stress and tissue inflammation in AF, as well as for the ability of therapies targeting oxidation/inflammation to prevent the arrhythmia. I am very honored to have been asked to serve as guest editor for this exciting review series, and I wish to express my gratitude to the outstanding group of expert authors who have contributed to its realization. The product certainly does justice to this important and rapidly evolving field.

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