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Current pharmacological therapy against atrial fibrillation (AF), the most common cardiac arrhythmia, is limited by moderate efficacy and adverse side effects including ventricular proarrhythmia and organ toxicity. One way to circumvent the former is to target ion channels that are predominantly expressed in atria vs. ventricles, such as K V 1.5, carrying the ultra-rapid delayed-rectifier K +  current (I Kur ). Recently, we used an  in silico  strategy to define optimal K V 1.5-targeting drug characteristics, including kinetics and state-dependent binding, that maximize AF-selectivity in human atrial cardiomyocytes in normal sinus rhythm (nSR). However, because of evidence for I Kur  being strongly diminished in long-standing persistent (chronic) AF (cAF), the therapeutic potential of drugs targeting I Kur  may be limited in cAF patients. Here, we sought to simulate the efficacy (and safety) of I Kur  inhibitors in cAF conditions. To this end, we utilized sensitivity analysis of our human atrial cardiomyocyte model to assess the importance of I Kur  for atrial cardiomyocyte electrophysiological properties, simulated hundreds of theoretical drugs to reveal those exhibiting anti-AF selectivity, and compared the results obtained in cAF with those in nSR. We found that despite being downregulated, I Kur  contributes more prominently to action potential (AP) and effective refractory period (ERP) duration in cAF vs. nSR, with ideal drugs improving atrial electrophysiology (e.g., ERP prolongation) more in cAF than in nSR. Notably, the trajectory of the AP during cAF is such that more I Kur  is available during the more depolarized plateau potential. Furthermore, I Kur  block in cAF has less cardiotoxic effects (e.g., AP duration not exceeding nSR values) and can increase Ca 2+  transient amplitude thereby enhancing atrial contractility. We propose that  in silico  strategies such as that presented here should be combined with  in vitro  and  in vivo  assays to validate model predictions and facilitate the ongoing search for novel agents against AF.

In Silico Assessment of Efficacy and Safety of IKur Inhibitors in Chronic Atrial Fibrillation: Role of Kinetics and State-Dependence of Drug Binding