Table of ContentsThe Challenges of Spatial Scales in Modeling and Understanding Cardiac Fibrillation Theme Will a particular antiarrhythmic drug alter either the fibrillation or defibrillation thresholds? The Ultimate Forward Problem: How can we use knowledge of the protein sequence for voltage-gated ion channels to predict numerically the electrocardiogram during a long episode of fibrillation? The characteristics of cardiac fibrillation are set by the spatial scale of the entire heart 10 nanometers: Ion channels are in control 1 nanometer: Pore in a gated ion channel Two extremes: Models of cardiac activity The problem of scales: The characteristic lengths and times in biological systems span MANY orders of magnitude. The Ultimate Forward Problem: Start with the DNA sequence for a potassium channel… Assemble the proteins And we solve the protein folding problem… Insert the folded proteins into the membrane Compute how the protein conformation depends upon voltage or ligand binding See which drugs block the channel Compute the channel kinetics to determine the switching behavior Compute the time-dependent channel conductance Stochastically activate the channels PPT Slide Sprinkle the channels and their currents onto a family of virtual cardiac cells Divide each cell into a numerically stable subunit Assemble the cells into small regions of cardiac tissue PPT Slide Assemble the regions into a whole heart Compute 10 seconds of fibrillation … The computer runs forever…. Look at the model The Problem of Scale: Numerical Models Discussion Solutions to the Ultimate Forward Problem Characterizing the Cardiac State What do you do with all the data? Visualizing Fibrillation And the Third Dimension… Understanding Cardiac Dynamics |
Author: John P. Wikswo
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