Prospective in silico trials identify combined SK and K2P channel block as an effective strategy for atrial fibrillation cardioversion.

Key points Virtual 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. This study prospectively evaluates and mechanistically explains three novel pharmacological therapies for AF through <italic>in silico</italic> trials, including single and combined SK and K2P channel block. AF and pharmacological action were assessed in a large cohort of 1000 virtual patients, through 2962 multiscale simulations. Extensive calibration and validation with experimental and clinical data support their credibility. Sustained AF was observed in 654 virtual patients. In this cohort, cardioversion efficacy increased to 82% (535 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 patient's ionic current profile, explained cardioversion efficacy (atrial refractory period increase: 133.0 ± 48.4 ms for combined <italic>vs</italic>. 45.2 ± 43.0 and 71.0 ± 55.3 ms 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 multichannel block. All three strategies, including the multichannel block, preserved atrial electrophysiological function (i.e. conduction velocity and calcium transient dynamics) and thus its contractile properties (safety). <italic>In silico</italic> trials identify key factors determining treatment success and the combined SK+K2P channel block as a promising strategy for AF management. This is a large‐scale <italic>in silico</italic> trial study involving 2962 multiscale simulations. A population of 1000 virtual patients underwent three treatments for atrial fibrillation. Single and combined SK+K2P channel block were assessed prospectively. The multi‐ion channel inhibition resulted in 82% cardioversion efficacy. <italic>In silico</italic> trials have broad implications for precision medicine. [ABSTRACT FROM AUTHOR]