SK current and ventricular arrhythmias.

SK 电流和室性心律失常。

• 批准号: 10164095
• 负责人: PENG-SHENG CHEN
• 金额: $ 56.18万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164095
• 关键词: Action Potentials; Acute; Amines; Anatomy; Apamin; Arrhythmia; Atrioventricular Block; Cardiac; Cell model; Cells; Clinical; Computer Models; Computer Simulation; Coupling; Development; Electric Countershock; Electrocardiogram; Electrophysiology (science); Female; Functional disorder; Goals; Heart failure; Human; Hypokalemia; Isoproterenol; Knowledge; Long QT Syndrome; Membrane Potentials; Modeling; Oryctolagus cuniculus; Phase; Potassium; Prevention; Process; Public Health; Purkinje Cells; Recurrence; Research; Research Project Grants; Role; Shock; Site; Sudden Death; Syndrome; Testing; Tissue Model; Tissues; Torsades de Pointes; Up-Regulation; Ventricular; Ventricular Arrhythmia; Ventricular Fibrillation; base; clinically relevant; design; experimental study; human model; insight; male; natural hypothermia; preservation; prevent; simulation; sudden cardiac death

The broad and long term goal of this research project is to explore the roles of small conductance Ca2+- activated K (SK) channels in the mechanisms of ventricular arrhythmogenesis. We hypothesize that the SK current upregulation is an endogenous compensatory mechanism to protect the heart from arrhythmias related to reduced repolarization reserve, but under some conditions can result in excess repolarization reserve and proarrhythmic effects. The SK channel became a focus of our research after we discovered that the apamin- sensitive potassium current (IKAS, or SK current) is increased in both the rabbit and human ventricles with heart failure (HF). We also discovered that SK current is acutely increased in normal ventricles with hypokalemia, in a manner that depends on the ventricular activation sequence. These findings raise the intriguing possibility that SK current is a rescue current that compensates for the electrophysiological effects of increased intracellular Ca2+ load. While maintaining repolarization reserve in HF may be antiarrhythmic, we also found that excessive or heterogeneous shortening of the APD by SK current may be proarrhythmic. Our recent preliminary results indicate that IKAS is activated by isoproterenol, and that female rabbit ventricles express more SK current during early phase 2 than male ventricles. CyPPA activation of SK2 and SK3 causes ECG J point elevation, heterogeneous APD distribution, phase 2 reentry and spontaneous VF in normal rabbit ventricles. The latter finding suggests that SK current may also contribute to proarrhythmia in certain clinical conditions by creating excess repolarization reserve, such as in the J-wave syndromes. The incorporation of IKAS in computer models will generate important new insights into the dynamical effects of IKAS in ventricular repolarization. A combined mapping and computer simulation approach will be needed to fully understand the importance of IKAS in cardiac arrhythmogenesis, including both the proarrhythmic and antiarrhythmic potentials. We propose the following specific aims: Aim 1: Antiarrhythmic and proarrhythmic mechanisms of SK current in rabbit ventricles. The Aim 1A is designed to study the Purkinje cells (PCs) in both normal and failing rabbit ventricles to test the hypothesis that the SK current is increased in PCs and that blocking the SK current decreases the Ca2+-membrane potential coupling gain and promotes Ca2+ induced arrhythmias. The Aim 1B is designed to study SK current and J-wave syndrome. We hypothesize that (a) SK current is in part responsible for J-wave elevation and VF during hypothermia, and apamin reverses these proarrhythmic effects and (b) heterogeneous SK current activation can cause J wave elevation and spontaneous VF through heterogeneous shortening of APD and phase 2 reentry. Aim 2: Antiarrhythmic and proarrhythmic mechanisms of SK current in computer simulation. Aim 2A will systematically investigate the mechanisms of SK currents as a rescue mechanism preventing arrhythmias under QT prolongation and as a proarrhythmic mechanism under early repolarization. Aim 2B will extend and validate the hypotheses tested in the rabbits to human models.

该研究项目的广泛而长期的目标是探索小电导Ca2+ - 的作用。 激活的K（SK）通道在心室心律失常发生的机理中。我们假设SK 当前的上调是一种保护心脏免受心律不齐相关的内源补偿机制 减少复极储备，但在某些条件下会导致过度的重极化储备和 心律失常。在我们发现apamin-之后，SK频道成为我们研究的重点 兔子和人心室的敏感钾电流（IKA或SK电流）都增加 失败（HF）。我们还发现，患有低钾血症正常心室的SK电流在 取决于心室激活序列的方式。这些发现提出了有趣的可能性 SK电流是一种补偿增加的电生理影响的救援电流 细胞内Ca2+负载。在维持HF中的复极储备可能是抗心律失常的同时，我们还发现 SK电流对APD的过度缩短或异质缩短可能是心律失常的。我们最近 初步结果表明IKA被异丙肾上腺素激活，而雌性兔心室表达 在第二阶段早期，SK电流多于男性心室。 SK2和SK3的CYPPA激活导致ECG J 点升高，异质APD分布，正常兔子中的第2阶段重新进入和自发VF 心室。后一个发现表明，SK电流也可能导致某些临床上的促心律 通过产生过量的复极储备，例如在J-Wave综合征中。掺入 计算机模型中的IKA将产生对IKA在心室的动态影响的重要新见解 复极化。需要采用合并的映射和计算机仿真方法，以充分了解 IKA在心律失常发生中的重要性，包括心律不齐和抗心律失常电位。 我们提出以下具体目的：目标1：SK电流的抗心律失常和心律失常机制 兔子心室。 AIM 1A旨在研究正常和失败的兔子的Purkinje细胞（PC） 心室以测试以下假设，即PC中SK电流增加并且阻塞SK电流 减少Ca2+膜电势耦合增益并促进Ca2+诱导的心律不齐。目标1B是 设计用于研究SK电流和J波综合征。我们假设（a）SK电流部分负责 在体温过低期间的J波升高和VF，Apamin逆转了这些主心律感的作用，并且（b） 异质SK电流激活会导致J波升高和自发VF通过异质性 APD和第2阶段的缩短。 AIM 2：SK电流的抗心律失常和心律失常机制 计算机模拟。 AIM 2A将系统地研究SK电流的机制作为营救 在QT延长下预防心律不齐的机制，并作为早期的动脉心律失常机制 复极化。 AIM 2B将扩展并验证兔子在人类模型中测试的假设。