In silico investigation of the mechanisms underlying atrial fibrillation due to impaired Pitx2
Fig 1
Multi-scale computer models to investigate the mechanism underlying Pitx2-induced AF and the effects of class Ic AAD (flecainide).
a, The computer models incorporated Pitx2-induced electrical and structural remodeling, and flecainide interactions with ion channels. Remodeled targets (magenta circles) included gap junction, IK1, IKs, INa, ICaL, RyR and SERCA. Drug targets of flecainide (red circles) were IKr, INa and RyR. Under the control condition, heterogeneity in Pitx2 expressions (b) and AP (c) between LA and RA was included in the computer models. d, Based on experimental and clinical studies up to date, four Pitx2 deficiency-induced human atrial cell models were developed: Pitx2-1 with remodeled IK1 (green), Pitx2-2 with remodelled IKs and ICaL (magenta), Pitx2-3 with remodelled ICaL, RyR and SERCA (red) and Pitx2-4 with remodelled IK1, IKs, INa, ICaL, RyR and SERCA (blue). Abbreviations: AF–atrial fibrillation; AAD–antiarrhythmic drug; LA–left atrium; RA–right atrium; AP–action potential; RyR–ryanodine receptor; SERCA–calcium transport ATPase.