Computational prediction of the effect of D172N KCNJ2 mutation on ventricular pumping during sinus rhythm and reentry

Abstract

The understanding of cardiac arrhythmia under genetic mutations has grown in interest among researchers. Previous studies focused on the effect of the D172N mutation on electrophysiological behavior. In this study, we analyzed not only the electrophysiological activity but also the mechanical responses during normal sinus rhythm and reentry conditions by using computational modeling. We simulated four different ventricular conditions including normal case of ten Tusscher model 2006 (TTM), wild-type (WT), heterozygous (WT/D172N), and homozygous D172N mutation. The 2D simulation result (in wire-shaped mesh) showed the WT/D172N and D172N mutation shortened the action potential duration by 14%, and by 23%, respectively. The 3D electrophysiological simulation results showed that the electrical wavelength between TTM and WT conditions were identical. Under sinus rhythm condition, the WT/D172N and D172N reduced the pumping efficacy with a lower left ventricle (LV) and aortic pressures, stroke volume, ejection fraction, and cardiac output. Under the reentry conditions, the WT condition has a small probability of reentry. However, in the event of reentry, WT has shown the most severe condition. Furthermore, we found that the position of the rotor or the scroll wave substantially influenced the ventricular pumping efficacy during arrhythmia. If the rotor stays in the LV, it will cause very poor pumping performance. Graphical Abstract A model of a ventricular electromechanical system. This whole model was established to observe the effect of D172N KCNJ2 mutation on ventricular pumping behavior during sinus rhythm and reentry conditions. The model consists of two components; electrical component and mechanical component. The electrophysiological model based on ten Tusscher et al. with the IK1 D172N KCNJ2 mutation, and the myofilament dynamic (cross-bridge) model based on Rice et al. study. The 3D electrical component is a ventricular geometry based on MRI which composed of nodes representing single-cell with electrophysiological activation. The 3D ventricular mechanic is a finite element mesh composed of single-cells myofilament dynamic model. Both components were coupled with Ca2+ concentration. We used Gaussian points for the calcium interpolation from the electrical mesh to the mechanical mesh.

Keywords: D172N KCNJ2 mutation; Electromechanical modeling; Ventricular arrhythmia.