Recent breakthroughs in the creation and use of transgenic animals have provided an experimental approach to manipulate processes at the protein level and study the consequence on the organ level. Unfortunately, not all variables of interest can be measured in a single preparation. In sufficiently realistic, computer models of heart electrophysiology can play a major role in relating information that can be measured experimentally to information that cannot and, perhaps more importantly, provide linkages across disparate scales. The objective of the proposed project is to develop software tools to advance computer modeling of the heart such that fine-grain changes in structure and membrane properties at the microscopic level can be incorporated properly into large scale-organ models, helping to unlock the molecular basis of arrhythmia. A unified problem solving environment, CARDIOPSE, will be developed for the rapid construction and manipulation of heart models based on image data and by doing so, enable preparation specific simulation, visualization and analysis of electrophysiology from ion-channel to torso. The proposed work will focus on creating the first microscopic and macroscopic integrative computer models of mouse electrophysiology suitable for exploring molecular level changes on global measurements like the ECG. Unlike other heart modeling tools, the proposed software will be designed for efficient simulation of both microscopic discrete models and macroscopic continuous models in 3D.
The specific aims are to 1) develop tools for directly segmenting MRI diffusion tensor imaging data at sub 100 micron resolution and confocal microscopy data at sub-cellular resolution to form preparation specific computational grids of the mouse heart ultrastructure and macroscopic fiber architecture. A library of models will be developed for normal and hypertrophied hearts; 2) create a novel finite-volume based scheme for representing intracellular and extracellular current flow in three-dimensional cardiac ultrastructure of coupled cells embedded in an extracellular matrix. The models will be used to study discrete impulse conduction and extracellular potentials in three-dimensions and to test assumptions used in macroscopic models for normal and diseased states; 3) develop a unified computational framework and tools-set for creating, simulating, visualizing and analyzing preparation specific cardiac electrophysiology from ion-channel to torso.
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