In silico assessment of genetic variation in KCNA5 reveals multiple mechanisms of human atrial arrhythmogenesis
A(i) In the presence of ISO, EADs were produced by Y155C and P488S, but not in WT or D469E in RA; (ii) EADs were induced by D469E in CT but not in PM. B Under uniform application of ISO in a 1D strand model with D469E, EADs in the CT but not PM induced conduction block at an S2 of 689 ms (i) and success at 690 ms (ii). C 1D conduction patterns under mutations and application of ISO in various configurations. On the left of each panel is a breakdown of the regions in the 1D model and an illustration of the anatomical conduction pathway to which they correspond; on the right is the regions of tissue to which ISO was applied. (i) Regular conduction pattern under WT and uniform ISO application; (ii) Under uniform application of ISO, D469E led to alternating bidirectional conduction block due to EADs in the CT; (iii) D469E and non-uniform ISO can lead to unidirectional conduction block, resulting from EADs in the CT regions with ISO; (iv) Unidirectional block can also be attained through a different pathway to the PM, in which the CT on one side of the SAN is of insufficient extent to develop significant EADs. In the simulations effects of beta-adrenergic stimulation was modelled by simulated application of ISO (1 μM).