New pharmacological targets and treatments for atrial fibrillation Leif Carlsson, Go ¨ ran Duker and Ingemar Jacobson AstraZeneca R&D Mo ¨ lndal, Bioscience, Pepparedsleden 1, S-43183 Mo ¨ lndal, Sweden Atrial fibrillation (AF) is an arrhythmia of growing clinical concern that is increasing in prevalence and is associated with significant morbidity and mortality. Pharmacologi- cal agents remain the first-line therapy for the AF patient, and the potential advantages of sinus rhythm mainten- ance motivate continued efforts to identify novel pharmacological means to restore and maintain sinus rhythm. Traditional antiarrhythmic agents only moder- ately suppress AF and present problematic concerns of proarrhythmia and extracardiac toxicity. Current inves- tigational or recently approved strategies for improving efficacy and safety of anti-AF agents include (i) specific or predominant blockade of atrial ion channels; (ii) ‘‘upstream therapies’’ affecting non-ion channel targets that influence electrical and structural remodeling, inflammation and oxidative stress; (iii) amiodarone derivatives with an improved safety profile; (iv) intra- cellular calcium handling; and (v) therapies aiming at alleviating conduction disturbances (gap junction coupling enhancers). This review provides a succinct overview of some of these strategies. Introduction Atrial fibrillation (AF) is characterized by disorganized atrial electrical activity. It is the most common tachyar- rhythmia encountered in clinical practice and accounts for considerable morbidity and mortality (Box 1) [1]. Although effective non-pharmacological treatment modalities have evolved, drug therapy remains the treatment of choice for most AF patients. Rhythm control aiming at restoring and maintaining sinus rhythm is generally considered prefer- able to a strategy to control ventricular rate while the atria continue to fibrillate. However, several prospective clinical trials failed to demonstrate superiority of rhythm over rate control in terms of survival [1–3]. The lack of benefit of currently available antiarrhythmic drugs for rhythm con- trol can relate to adverse effects such as ventricular proar- rhythmia and long-term organ toxicity, a scarcity that has prompted continued search for improved pharmacological options. A variety of recent advances have opened exciting development options for novel and superior approaches to arrhythmia therapy (Figure 1) [4–6]. Drugs such as dro- nedarone, budiodarone and vernakalant, which target multiple ion channels determining myocardial depolariz- ation and repolarization, have been suggested to partly circumvent efficacy and safety setbacks of older drugs. Based on findings that specific ion channels are predomi- nantly expressed in atrial tissue, several targets for atrial- selective therapy have emerged (Figure 2). Such targets and approaches include the ultra rapid delayed rectifying potassium current (I Kur ), the acetylcholine-regulated and the constitutively active inwardly rectifying potassium current (I KACh and I KAChC ), atrially expressed connexins and atrial-selective/predominant sodium channel blockade [4–6]. Atrial-selective approaches would potentially offer therapy with a substantially lower risk of ventricular- related side effects. During the past decade the understanding of the ionic, structural and electrophysiological remodeling resulting from AF has progressed rapidly. Numerous findings suggest that AF is self-perpetuating, that is the tachyarrhythmia itself can produce electrophysiological changes that contrib- ute to the establishment of permanent AF (‘‘AF begets AF’’) [7]. It is probable that the rapid rates in AF progressively favor a creation of small re-entrant pathways (micro re- entry) by reducing their wavelength through a shortening of the refractory period and reduction of the atrial conduction velocity [8,9]. Hence, an effective therapy to delay or prevent atrial tachycardia-induced remodeling (‘‘upstream therapy’’) would potentially retard the progression of AF. This review describes some potential anti-AF targets as well as imminent and recently approved pharmacological agents that will hopefully improve and diversify currently available strategies for AF treatment. Novel potential targets for AF treatment The ultra-rapid delayed rectifying potassium current The I Kur current carried by Kv1.5 channels has been promoted as a leading candidate target for selective AF therapy. Importantly, in human cardiac tissue this specific ion channel seems selectively expressed in the atria and its blockade can thus predominantly result in atrial repolar- ization delay. However, reports that that loss-of-function mutations in KCNA5 (the gene encoding the a-subunit of the I Kur channel protein) are associated with familial AF have raised safety concerns of Kv1.5 blockers [10]. How- ever, the discovery of a large number of structurally unre- lated Kv1.5 blockers covering a broad spectrum of ion channel selectivity profiles have been reported [11–13]. For example, AVE0118 blocks recombinant human Kv1.5 and Kv4.3/KChIP2.2 (the transient outward potass- ium current, I to ) currents with IC 50 values ranging from 1.1 to 6.2 mM and 1.8 to 3.3 mM, respectively [12]. DPO1 correspondingly blocks Kv1.5 at 0.16 mM without influen- cing Kv4.3/KChIP2.2 at 1 mM. NIP142 is interesting in that it blocks Kv1.5 with an IC 50 value of 4.8 mM and I KACh with an IC 50 value of 0.64 mM (see below). Review Corresponding author: Carlsson, L. (leif.g.carlsson@astrazeneca.com) 364 0165-6147/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tips.2010.05.001 Trends in Pharmacological Sciences 31 (2010) 364–371