Fig. 5.

Dofetilide. A: Experimental evidence of Dofetilide-induced abnormalities recorded in human trabeculae at 1 Hz pacing (A1: EADs, figure reproduced with permission from Page et al. (2016)) and human myocytes paced at 0.25 Hz (A2: EADs, figure reproduced from O’Hara et al. (2011) as allowed by the CC-BY licence) and 1 Hz (A3: aftercontractions, figure reproduced from Nguyen et al. (2017) as allowed by the CC-BY licence). B: Single cell and tissue simulations of Dofetilide exposure. B1-B2: Single cell comparison between ToR-ORd+Land (B1) and ORd+Land (B2) model predictions. Dofetilide-induced AP prolongation favours a persistent ICaL current, which mediates positive inotropic effects at low doses and EADs formation for the highest ones. B3-B5: 3D tissue simulations at 1.25 Hz pacing. 0.1 μM of Dofetilide induces EADs (B3) that trigger aftercontractions (B4). Contractility escapes indicated by horizontal arrows. AP and z displacements recorded at the free surface opposite stimulation. B5: AP time course in a line connecting two opposite corners. Arrows highlight APs propagation failure. The inset reports the AP time course at the stimulus site. Results in B3-B5 obtained with the ORd+Land model.