Towards prospective in-silico trials in atrial fibrillation: the case of polypharmacological SK and K2P channel block

BackgroundVirtual evaluation of medical therapy through human-based modelling and simulation can accelerate and augment clinical investigations. Treatment of the most common cardiac arrhythmia, atrial fibrillation (AF), requires novel approaches. ObjectivesTo prospectively evaluate and mechanistically explain novel pharmacological therapies for atrial fibrillation through in-silico trials, considering single and combined SK and K2P channel block. MethodsA large cohort of 1000 virtual patients was developed for simulations of AF and pharmacological action. Extensive calibration and validation with experimental and clinical data support their credibility. ResultsSustained AF was observed in 654 (65%) virtual patients. In this cohort, cardioversion efficacy increased to 82% (534 of 654) through combined SK+K2P channel block, from 33% (213 of 654) and 43% (278 of 654) for single SK and K2P blocks, respectively. Drug-induced prolongation of tissue refractoriness, dependent on the virtual patients ionic current profile, explained cardioversion efficacy (atrial refractory period increase: 133.0{+/-}48.4 ms for combined vs. 45.2{+/-}43.0 and 71.0{+/-}55.3 for single SK and K2P block, respectively). Virtual patients cardioverted by SK channel block presented lower K2P densities, while lower SK densities favoured the success of K2P channel inhibition. Both ionic currents had a crucial role on atrial repolarization, and thus, a synergism resulted from the polypharmacological approach. All three strategies, including the multi-channel block, preserved atrial electrophysiological function (i.e., conduction velocity and calcium transient dynamics) and thus, its contractile properties (safety). ConclusionIn-silico trials identify key factors determining efficacy of single vs combined SK+K2P channel block as effective and safe strategies for AF management.