In silico investigation of short QT syndrome-linked potassium channel mutations on electro-mechanical function of human atrial cells

Short QT syndrome (SQTS) patients are prone to atrial arrhythmias. However, the link between SQTS gene mutations and atrial pro-arrhythmia is not well understood. This study investigated the functional impact of two SQTS-related gain-of-function potassium channel mutations on the electro-mechanical activities of human atrial cells. A contemporary human atrial action potential (AP) model was coupled to the Rice et al. mechanics model. Markov formulations of the rapid and slow delayed rectifier currents, iKr and iKs, the a subunits of which are encoded by the hERG and KCNQJ genes, respectively, were implemented in wild type (WT), N588K-hERG (SQTJ), and V307L-KCNQJ (SQT2) conditions. The Markov models were validated against experimental data through simulated voltage and AP clamp experiments. The N588K-hERG and V307L-KCNQJ mutations were found to accelerate atrial repolarisation by increasing outward potassium currents during phase 3 of the AP, which reduced action potential duration at 90% repolarisation (APD₉₀). Secondary effects of the mutations resulted in impaired contractile force, an effect which was lessened when stretch-activated channels (SACs) were incorporated.