The mechanisms underlying the dynamics of vortex-like reentrant arrhythmias are poorly understood. The overall objective of this project is to determine the ionic basis of wave propagation during sustained three- dimensional (3D) vortex-like reentry (scroll waves) in the mouse heart. We use the mouse heart because of the availability of transgenic mouse models of altered integral membranes which are important in cardiac excitation and repolarization. The specific hypotheses to be tested are: 1) manipulations of the transient outward (Ito) and sodium-calcium exchanger (I/NA-Ca) currents will significantly affect the sensitivity of conduction velocity to changes in wave front curvature; 2) the spatial distribution of action potential duration (APD) during vortex-like reentry will be affected by over-expression of Ina-Ca but not by altering Ito; 3) the stability of 3D vortex-like reentry in the anisotropic ventricle of the mouse heart depends on the kinetics of the very early phase of the activation front; 4) reduction of Ito leads to meandering of the cortex core filament but this effect is prevented by partial blockade of the sodium channel; and 5) APD prolongation resulting from over-expression of in the periphery the increased APD leads to wave front-wave tail interactions, thus resulting in the formation of new reentrant waves and eventually fibrillatory activity. To test the above hypotheses, the project will be divided into three specific aims: 1) to determine the role of specific transmembrane currents in wave front curvature-velocity relationships, as well as the influence of a local sink current on the spatial distribution of APD; 2) to study the ionic mechanisms and dynamics of stabilization of stabilization of reentrant excitation in an anatomically determine the roles of specific transmembrane currents in the dynamics of vortex-like reentry in the mouse heart. To accomplish these specific aims we will use a combination of numerical and experimental models. Computer simulations will be carried out using realistic 2- and 3-D ionic models of the mouse heart. We will carry out optical mapping and patch clamp experiments using normal mouse hearts, as well as hearts from two subunit specifically targeted to the heart dominantly inhibits Ito; and ii) a mouse over-expressing the Na+-Ca2+ exchanges specifically in cardiac muscle (ONA-Ca). The results derived from the proposed studies should shed light on the ionic mechanisms that govern the dynamics of reentry in the heart and ultimately give basis for a more rational approach to the management of complex ventricular rhythms.
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