The Right Stuff in the Right Place-The Quest for Atrial Selective Antiarrhythmic Agents

Atrial fibrillation, the most common arrhythmia requiring medical attention, has frustrated pharmacologists and clinicians for almost 100 years. The basis for this frustration is the failure to develop an agent significantly more efficacious for its prevention, excepting only Amiodarone, than the prototype agent quinidine introduced in 1918.1 Agents now in common use have supplanted quinidine not because of greater efficacy but because they are better tolerated with fewer adverse extra cardiac effects, again excepting Amiodarone. The agents considered first line for therapy block INa or IKr or both in therapeutic doses, except Amiodarone which blocks multiple channels, including INa, ICal, and multiple potassium channels including IKr and Ito. The scourge of life-threatening ventricular proarrhythmia, first identified with the prototype quinidine2 has accompanied all the current successor agents in the treatment of atrial fibrillation although the problem is less severe with Amiodarone. Block of INa and slowing of conduction in diseased ventricular myocardium can promote reentrant ventricular tachycardia and ventricular fibrillation; excessive block of IKr can induce early after depolarizations, torsade de pointes, and ventricular fibrillation. In the publication of the discovery of IKur in human atrial cells in 1993, the authors suggested that block of this current, which is not present in ventricular myocytes, could be an atrial selective antiarrhythmic action devoid of the risk of ventricular proarrhythmia.3 Nearly a decade later, agents that block IKur were initially synthesized and evaluated in the laboratory.4 In general, agents developed to block IKur that also blocks other currents including Ito, IK-ACh, INa, and IKr.5 Atrial selectivity with these agents has been relative, not absolute. Recently, there has been reported an experiment of nature in which IKur is selectively reduced due to loss-of-function mutation in KCNA5.6 Contrary to expectation, the selective reduction of IKur predisposed to atrial fibrillation. Block of a specific current may have diverse effects depending on preexisting conditions that apply not only to the specific current blocked but also to other ion currents. Because ion currents and ion channels are voltage and time dependent, the temporal changes in voltage caused by blocking a specific current will have time- and rate-dependent effects on other currents. An enhanced potency of sodium channel blockers in ischemic and hypoxic ventricular myocardium is an old observation.7 Recent observations disclosed that relatively selective IKur blockade can paradoxically abbreviate action potentials duration and effective refractory period in atrial myocytes with plateau action potentials presumably because positive shift of the membrane potential early in the action potential affects other currents, possibly IKr to accelerate later phases of repolarization. In contrast, triangular action potentials at certain sites of atrial myocardium under normal conditions or in remodeled atrial myocardium tend to prolong with IKur block possibly because altered amplitudes of other currents, for example, reduction of IKr8 during remodeling may amplify the effect of IKur block. Besides IKur, other potential atrial-specific targets include IK-Ach, constitutively active IK-Ach,9 and connexin 40. In this issue, Burashnikov et al10 pursue a novel theme of atrial selectivity: Atrial selectivity of pharmacologic agents may be achieved not only by engaging atrial-specific targets such as IKur but also by exploiting atrial-specific properties of targets present in both atria and ventricles. Because atrial myocytes generally have less polarized resting potentials and prolonged late-phase 3 tails compared with ventricular myocytes, agents that bind to the inactivated state may in general block INa more potently in atria where more sodium channels would be in the inactivated state. In addition, it was recently shown that the voltage dependence of inactivation is displaced negatively in atrial myocardium compared with ventricular myocardium.11 The authors expand this observation by demonstrating different kinetics of inactivation gating in atrium and ventricle, specifically slower recovery from inactivation in atrium. The bases for the difference in properties of the atrial and ventricular sodium channels with the same alpha subunits are unclear, but one possibility may be the differences in expression in atria and ventricles of beta subunits that modify the behavior of the channel.12 As a result of these differences in the voltage dependence and kinetics of inactivation gating and their interaction with the binding affinities and kinetics of AZD1305 to the different states of the sodium channel, there is a relatively strong selectivity for atrial myocardium in the effects of sodium channel blockade: slowed conduction, reduced excitability, and prolonged postrepolarization refractoriness. AZD1305 also prolongs action potential and refractoriness more in the atrium than in the ventricle, by delaying more the relatively longer late tail of repolarization, an effect shared by most IKr blockers. The IKur blocking action of AZD1305 seems to play little role at therapeutic concentrations. As has been recently demonstrated with ranolazine,13 block of INa by AZD1305, especially the late component, mitigates, perhaps eliminates, the risk of ventricular proarrhythmia. The methodology of these studies is commendable for its vertical integration. The experimental preparations ranged from voltage-controlled isolated myocytes, ruptured patch, and cell attached; to arterially perfused tissues, paced and fibrillating; to whole animals. This comprehensive and complex methodology acknowledges that the actions of antiarrhythmic agents especially those that interact with multiple channels are greatly influenced by the conditions. The validity of conclusions of mechanisms of action and final effects on the abnormal electrophysiologic condition require consolidation of observations at multiple levels of integration of the normal and abnormal conditions. As the authors acknowledge, in the end, the ultimate effect on the abnormal human condition must be tested in patients with atrial fibrillation in all its pathologic varieties.