Mechanisms underlying pro-arrhythmic abnormalities arising from Pitx2-induced electrical remodelling: an in silico intersubject variability study

BACKGROUND: Electrical remodelling as a result of the homeodomain transcription factor 2 (Pitx2)-dependent gene regulation induces atrial fibrillation (AF) with different mechanisms. The purpose of this study was to identify Pitx2-induced changes in ionic currents that cause action potential (AP) shortening and lead to triggered activity. METHODS: Populations of computational atrial AP models were developed based on AP recordings from sinus rhythm (SR) and AF patients. Models in the AF population were divided into triggered and untriggered AP groups to evaluate the relationship between each ion current regulated by Pitx2 and triggered APs. Untriggered AP models were then divided into shortened and unshortened AP groups to determine which Pitx2-dependent ion currents contribute to AP shortening. RESULTS: According to the physiological range of AP biomarkers measured experimentally, populations of 2,885 SR and 4,781 AF models out of the initial pool of 30,000 models were selected. Models in the AF population predicted AP shortening and triggered activity observed in experiments in Pitx2-induced remodelling conditions. The AF models included 925 triggered AP models, 1,412 shortened AP models and 2,444 unshortened AP models. Intersubject variability in I(Ks) and I(CaL) primarily modulated variability in AP duration (APD) in all shortened and unshortened AP models, whereas intersubject variability in I(K1) and SERCA mainly contributed to the variability in AP morphology in all triggered and untriggered AP models. The incidence of shortened AP was positively correlated with I(Ks) and I(K1) and was negatively correlated with I(Na), I(CaL) and SERCA, whereas the incidence of triggered AP was negatively correlated with I(Ks) and I(K1) and was positively correlated with I(Na), I(CaL) and SERCA. CONCLUSIONS: Electrical remodelling due to Pitx2 upregulation may increase the incidence of shortened AP, whereas electrical remodelling arising from Pitx2 downregulation may favor to the genesis of triggered AP.