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

Abstract

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, the acetylcholine-activated inward-rectifying Kir3.1/Kir3.4 channel conducting I, the Ca-activated K channels of small conductance (SK) conducting I, 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, I, and I. 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.

Populations of in silico myocytes and tissues reveal synergy of multiatrial‐predominant K+‐current block in atrial fibrillation

“…Inhibition of atrial‐predominant currents, such as I Kur , I K2P , I KCa and I K,ACh , is a promising strategy for anti‐AF pharmacological therapies to limit adverse proarrhythmic (ventricular) effects of antiarrhythmic drugs (Hancox et al, 2016; Ravens, 2017; Voigt & Dobrev, 2016). However, atrial‐predominant‐K + current blockers have not yet been successful in producing significant antiarrhythmic effects in the clinic.…”

Antiarrhythmic drugs for atrial fibrillation: Imminent impulses are emerging

“…Several compounds were investigated in phase 2 trials (e.g. MK-0448, XEN D0101, XEN D0103, BMS-394136, BMS-919373) demonstrating prolonged APD with increased rate and suppression of action potential at higher rates; however, there is a shortening of APD in sinus rhythm with the risk of reinitiating AF [ [31] , [32] , [33] ]. Moreover, there is a strong risk of proarrhythmia with excessive blockade.…”

“…There are contemporary attempts to synthetize a selective TASK-1 blocker deprived of important side-effects (i.e. pulmonary hypertension) [ 17 , 32 ] and one caveat with this approach is that TASK-1 currents are reduced instead of increased in AF patients with heart failure [ 36 ], making it unlikely that inhibition of TASK-1 would be an efficient anti-AF approach in patients with structurally-remodeled atria.…”

“…Flecainide and dronedarone both block this current and although other moderately selective I K,ACh blockers prolong repolarization in humans, their overall efficacy is rather limited [ 17 , 31 , 40 ]. There is an ongoing search for selective I K,ACh blockers deprived of some neurological side effects and general toxicity or excessive proarrhythmogenic APD prolongation at very high frequencies [ 32 ]. Thus like with I Kur , selective targeting of I K,ACh is still a viable option of unproven clinical efficacy.…”

Sex differences in cardiac electrophysiology

“…The high frequency of electrical activity in AF leads to characteristic electrical and structural changes in the atrial tissue (electrical and structural "remodelling"), including changes in atrial APs and tissue morphology. The hallmark of electrical remodelling is the change of the action potential from a spike-and-dome to a typical triangular shape (Figure 3, inset) (Dobrev and Ravens 2003;Ravens 2017;Ravens et al 2015).…”