Atrial-selective K⁺ channel blockers: potential antiarrhythmic drugs in atrial fibrillation?

In the wake of demographic change in Western countries, atrial fibrillation has reached an epidemiological scale, yet current strategies for drug treatment of the arrhythmia lack sufficient efficacy and safety. In search of novel medications, atrial-selective drugs that specifically target atrial over other cardiac functions have been developed. Here, I will address drugs acting on potassium (K⁺) channels that are either predominantly expressed in atria or possess electrophysiological properties distinct in atria from ventricles. These channels include the ultra-rapidly activating, delayed outward-rectifying Kv1.5 channel conducting I_Kur, the acetylcholine-activated inward-rectifying Kir3.1/Kir3.4 channel conducting I_K,ACh, the Ca²⁺-activated K⁺ channels of small conductance (SK) conducting I_SK, and the two-pore domain K⁺ (K2P) channels (tandem of P domains, weak inward-rectifying K⁺ channels (TWIK-1), TWIK-related acid-sensitive K⁺ channels (TASK-1 and TASK-3)) that are responsible for voltage-independent background currents I_TWIK-1, I_TASK-1, and I_TASK-3. Direct drug effects on these channels are described and their putative value in treatment of atrial fibrillation is discussed. Although many potential drug targets have emerged in the process of unravelling details of the pathophysiological mechanisms responsible for atrial fibrillation, we do not know whether novel antiarrhythmic drugs will be more successful when modulating many targets or a single specific one. The answer to this riddle can only be solved in a clinical context.