Computational analysis of the effect of KCNH2 L532P mutation on ventricular electromechanical behaviors

The KCNH2 L532P mutation is an alteration in the I_Kr channel that is associated with short QT syndrome and atrial fibrillation in zebrafish. In preliminary studies, the electrophysiological effects of the hERG L532P mutation were investigated using a mathematical model in a single-cell and 2D sheet medium. The objective of this study was to quantify the effects of the KCNH2 L532P mutation on the 3D ventricular electrophysiological behavior and the mechanical pumping responses. We used a realistic three-dimensional ventricular electrophysiological-mechanical model, which was adjusted into two conditions: the wild-type (WT) condition, i.e., the original case of the Tusscher et al. model, and the L532P mutation condition, with modification of the original I_Kr equation. The action potential duration (APD) in the mutant ventricle was reduced by 73% owing to the significant increase of the I_Kr current density. In the 3D simulation, the L532P mutation maintained the sustainability of reentrant waves; however, the reentry was terminated in the WT condition. The contractility of the ventricle with L532P mutation was significantly reduced compared with that in WT which results in sustain shivering heart during reentry condition. The reduction of the contractility was associated with the shortening APD which simultaneously shortened the duration of the Ca²⁺ channel opening. In conclusion, the ventricle with KCNH2 L532P mutation is prone to reentry generation with a sustained chaotic condition, and the mutation significantly reduced the pumping performance of the ventricles.