The efficacy of class III anti-arrhythmic drugs in 3D canine atrial models: Is the blockade of IKCa pro- or anti-arrhythmic?

Small conductance calcium-activated potassium channel current, I_KCa, has recently been characterized in atrial tissue and linked with atrial arrhythmogenesis. As I_KCa does not contribute significantly to the ventricular action potential, there is great interest in developing pharmacological agents targeting these channels. However, experimental data so far have presented conflicting evidence as to whether I_KCa inhibition is pro- or anti-arrhythmic. We have created a new formulation for I_KCa, which we included in recently developed heterogeneous and anisotropic 3D canine atrial models. These were applied to investigate the effect of I_KCa blockade compared to inhibition of other potassium currents: I_Kr and I_Kur. Blocking I_KCa led to the termination of AF in the 3D atrial model, in contrast to blockades of I_Kur or I_Kr. Blocking I_KCa prolonged action potential duration, APD, by at least 20 ms in all atrial cell types, whereas I_Kr or I_Kur blocks did not increase APD by more than 10 ms, thus explaining I_KCa's effectiveness in terminating AF. Nevertheless, the blockade of I_KCa also led to an increase in APD dispersion, which is expected to be pro-arrhythmic. In cases when the APD dispersion effects dominate over the APD prolongation, the blockade of I_KCa is expected to be pro-arrhythmic, as seen in experimental models of non-remodelled canine atria.