Membrane current kinetics in dynamics of vortex-like reentry

涡状折返性心律失常的动力学机制知之甚少。本项目的总体目标是确定在小鼠心脏中持续的三维（3D）涡旋样再入（涡卷波）期间波传播的离子基础。我们使用小鼠心脏，因为可获得在心脏兴奋和复极化中重要的改变的完整膜的转基因小鼠模型。实验假设：1）瞬时外向电流（Ito）和钠钙交换器（I/NA-Ca）电流的调控会显著影响传导速度对波前曲率变化的敏感性：2）漩涡样折返时动作电位时程（APD）的空间分布受Ina-Ca过度表达的影响，但不受Ito改变的影响;（3）在小鼠各向异性心室中，三维涡旋状折返的稳定性取决于激活前沿的极早期动力学，（4）Ito的降低导致皮层核心丝的弯曲，但这种作用可通过部分阻断钠通道而被阻止;（5）APD延长，这是由于APD在外周的过度表达，增加的APD导致波前-波尾相互作用，从而导致新的折返波的形成并最终导致反射活动。为了验证上述假设，本项目将分为三个具体目标：1）确定特定跨膜电流在波前曲率-速度关系中的作用，以及局部汇电流对APD空间分布的影响;（二）研究重入激发稳定化的离子机制和动力学，在解剖学上确定特定跨膜的作用，电流在小鼠心脏的涡旋状折返动力学。为了实现这些具体目标，我们将使用数值和实验模型的组合。计算机模拟将进行使用现实的2-和3-D离子模型的小鼠心脏。我们将进行光学映射和膜片钳实验，使用正常小鼠心脏，以及心脏从两个亚基特异性靶向心脏显性抑制Ito;和ii）小鼠过表达的Na+-Ca 2+交换，特别是在心肌（ONA-Ca）。从拟议的研究中得出的结果应该阐明离子机制，管理在心脏折返的动力学，并最终为更合理的方法来管理复杂的心室节律的基础。

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.