An integrative model of mouse cardiac electrophysiology from cell to torso

Abstract

Although the transgenic mouse has become an important new tool in the study of human diseases and the design of new therapies, a complete picture of cardiac electrophysiology in the mouse, from genome to body surface, is lacking. A computational model of the mouse heart is presented, which is used to study the impact of ion-channel and structural manipulations on the distributions of extracellular potentials on the heart and body surface. A model of the mouse heart anatomy, fibre organization and torso geometry was constructed from DTMRI images. An anisotropic bidomain model, with a modified Pandit et al. model for the ionic currents, was used to represent the electrical properties of the tissue. Spatial heterogeneity in the ion currents was introduced by modulating the transient outward current. A sinus beat was simulated in hearts with different tissue and membrane properties and the extracellular potentials were computed at both the heart and body surface. The simulated transmembrane patterns in the heart, and the timing and morphology of the simulated ECG waveforms were consistent with experimental measurements. In addition, the patterns of activation and recovery and the waveforms of the corresponding ECG were found to be relatively insensitive to changes in cell type distribution and tissue anisotropy. Because of the small size of the heart, an integrative model of mouse electrophysiology can be simulated from cell to torso, enabling a new tool to study how extracellular signals might be used to detect molecular changes underlying an arrhythmogenic substrate.