Membrane current kinetics in dynamics of vortex-like reentry

涡旋状折返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持续的三维涡旋状再入(涡旋波)过程中波传播的离子基础。我们使用小鼠心脏是因为转基因小鼠的整体膜改变的模型是可用的，这在心脏兴奋和复极过程中很重要。需要检验的具体假设是：1)瞬时外向电流(Ito)和钠钙交换器(I/NA-Ca)电流的操纵将显著影响传导速度对波前曲率变化的敏感性；2)涡旋样再入过程中动作电位时程的空间分布将受到Ina-Ca过度表达的影响，但不受Ito改变的影响；3)小鼠各向异性脑室三维涡状再入的稳定性取决于激活前沿非常早期的动力学；4)Ito减少导致皮质核心丝漂移，但这种作用可被部分阻断钠通道所阻止；5)由于外周高表达而导致的时程延长导致波前-波尾相互作用，从而形成新的折返波，最终引起纤颤活动。为了验证上述假设，该项目将分为三个具体目标：1)确定特定的跨膜电流在波前曲率-速度关系中的作用，以及局部汇电流对动作电位的空间分布的影响；2)研究在小鼠心脏中稳定折返兴奋的离子机制和动力学，从解剖学的角度确定特定的跨膜电流在小鼠心脏涡旋状折返动力学中的作用。为了实现这些具体目标，我们将结合使用数值模型和实验模型。计算机模拟将使用真实的小鼠心脏2-D和3-D离子模型进行。我们将使用正常的小鼠心脏以及针对心脏的两个亚单位的心脏进行光学标测和膜片钳实验；以及ii)过度表达特定于心肌(ONA-Ca)的Na+-Ca2+交换的小鼠。这些研究的结果将有助于阐明控制心脏折返动力学的离子机制，并最终为更合理地处理复杂的室性心律失常提供基础。

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.