The theme of this application is the effects of activation sequence on repolarization properties. Parallel animal, isolated tissue and isolated cell studies and computer simulations are proposed. Studies are designed to: 1) define the mechanisms controlling activation sequence induced change in electronic effects on repolarization, 2) determine the effect of activation sequence on the spatial distributions of repolarization properties, and 3) examine the relation between activation sequence induced changes in repolarization and arrhythmia vulnerability. Electrograms will be recorded simultaneously from up to 192 sites in whole canine preparations and refractory periods will be measured during multiple activation sequences and paced cycle lengths in normal and ischemic myocardium. Isolated tissue and cell studies will be done in which the effects of similar interventions on action potential height, duration, area, membrane resistance during repolarization and intracellular Ca will be determined. Computer simulations will include 1D, 2D and 3D models with uniform and nonuniform tissue anisotropy and incorporate membrane equations from Ebihara-Johnson and DiFrancesco-Noble. The results will be analyzed in terms of the relation of activation sequence induced changes in action potential height, membrane resistance during repolarization and conduction velocity to changes in repolarization properties and the spatial distribution of those properties. There is increasing awareness that tissue anisotropy plays a role in reentrant arrhythmias. Emphasis, however, has been on the effects of anisotropy on propagation. Our proposed studies are specifically directed at examining the ways activation perturbs the spatial gradients of repolarization, determining the mechanism for those effects and the role of activation sequence induced changes in repolarization in reentrant arrhythmias. We believe detailed studies of repolarization, as proposed here, are important to understanding and controlling arrhythmias.
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