Membrane current kinetics in dynamics of vortex-like reentry

旋涡样重入性心律失常的动力学机制尚不清楚。该项目的总体目标是确定在小鼠心脏中持续三维（3D）涡旋式再入（涡旋波）期间波传播的离子基础。我们之所以使用小鼠心脏，是因为在心脏兴奋和复极化中起重要作用的整膜改变转基因小鼠模型的可用性。需要验证的具体假设是：1)瞬态外向（Ito）和钠钙交换器（I/NA-Ca）电流的操纵会显著影响传导速度对波前曲率变化的敏感性；2)动作电位持续时间（APD）的空间分布受Ina-Ca过表达的影响，而不受Ito改变的影响；3)小鼠心脏各向异性心室三维涡状再入的稳定性取决于激活锋极早期的动力学；4) Ito的减少导致皮层核丝的弯曲，但这种影响可以通过部分阻断钠通道来阻止；5)外周APD的过度表达导致APD延长，APD的增加导致波前波尾相互作用，从而导致新的重入波的形成，最终导致纤颤活动。为了验证上述假设，本项目将分为三个具体目标：1)确定特定跨膜流在波前曲率-速度关系中的作用，以及局部汇流对APD空间分布的影响；2)研究离子机制和再入兴奋稳定的动力学，解剖确定特定的跨膜电流在小鼠心脏漩涡状再入动力学中的作用。为了实现这些具体目标，我们将使用数值和实验模型相结合的方法。计算机模拟将使用逼真的2- d和3-D离子模型的老鼠心脏。我们将使用正常小鼠心脏，以及来自两个亚基的心脏进行光学作图和膜片钳实验，这些亚基专门针对心脏的主要抑制Ito；ii)小鼠心肌中Na+-Ca2+交换特异性过表达（ONA-Ca）。从所提出的研究中得出的结果应该阐明控制心脏再入动力学的离子机制，并最终为复杂心室节律的更合理的管理方法提供基础。

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.