Modelling the functional impact of KCNA5 mutations on the electrical and mechanical activities of human atrial cells

A recent study identified six mutations (three gain-of-function and three loss-of-function mutations) in the KCNA5 channel (encoding for the ultra-rapid delayed rectifiermutations potassium current, I_Kur) associated with lone-atrial-fibrillation. However, the impact of the mutations on atrial electro-mechanical functions is unclear. In this study, we developed a coupled electro-mechanical model of the human atrial cell to investigate such functional impact. Our previously developed human atrial model was updated with a new I_Kur model, and was then coupled with the myofilament model proposed by Rice et al.. A stretch activated current was also incorporated to account for the mechanical feedback. Simulations of isometric and isotonic stretch conditions were performed to study the basic-cycle-length-adaptations of action potential duration and active force. It was shown that these mutations exhibited heterogeneous effects on human atrial electrical and mechanical activities. The gain-of-function mutations induced negative inotropic effects, whereas the loss-of-function mutations enhanced contractile functions. These results are in good agreement with a previous experimental study on effects of I_Kur block. In conclusion, the mutations significantly altered the adaptation properties of action potential and force, which could be pro-arrhythmic.