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.

该研究项目的广泛和长期目标是探索小电导 Ca2+- 的作用 室性心律失常发生机制中激活的 K (SK) 通道。我们假设 SK 电流上调是一种内源性代偿机制，可保护心脏免受心律失常的影响 减少复极储备，但在某些情况下可能会导致复极储备过多， 促心律失常作用。在我们发现 apamin- 后，SK 通道成为我们研究的焦点。 兔子和人的心室中敏感钾电流（IKAS 或 SK 电流）均增加 失败（高频）。我们还发现，在低钾血症的正常心室中，SK 电流急剧增加， 取决于心室激活顺序的方式。这些发现提出了一个有趣的可能性 SK电流是一种救援电流，可以补偿增加的电生理效应 细胞内Ca2+负荷。虽然在心衰时维持复极储备可能具有抗心律失常作用，但我们还发现 SK 电流对 APD 的过度或不均匀缩短可能会导致心律失常。我们最近的 初步结果表明IKAS被异丙肾上腺素激活，雌性兔心室表达 第 2 相早期 SK 电流高于男性心室。 CyPPA 激活 SK2 和 SK3 导致心电图 J 正常兔的点抬高、APD 分布不均匀、2 期折返和自发性 VF 心室。后一个发现表明 SK 电流也可能导致某些临床中的致心律失常。 通过产生过多的复极储备来治疗疾病，例如 J 波综合征。纳入 计算机模型中的 IKAS 将为 IKAS 对心室动力学效应产生重要的新见解 复极化。需要结合绘图和计算机模拟方法来充分了解 IKAS 在心律失常发生中的重要性，包括促心律失常和抗心律失常的潜力。 我们提出以下具体目标： 目标 1：SK 电流的抗心律失常和促心律失常机制 兔子的心室。 Aim 1A 旨在研究正常和衰竭兔子的浦肯野细胞 (PC) 心室以检验 PC 中 SK 电流增加以及阻断 SK 电流的假设 降低 Ca2+-膜电位耦合增益并促进 Ca2+ 诱导的心律失常。目标 1B 是 旨在研究 SK 电流和 J 波综合征。我们假设 (a) SK 电流是部分原因 对于低温期间的 J 波抬高和心室颤动，apamin 可以逆转这些致心律失常效应，并且 (b) 异质 SK 电流激活可通过异质引起 J 波抬高和自发性 VF APD 和第二阶段再入的缩短。目标 2：SK 电流的抗心律失常和促心律失常机制 计算机模拟。 Aim 2A将系统地研究SK电流的救援机制 QT 延长时预防心律失常的机制以及早期心律失常的机制 复极化。目标 2B 会将在兔子身上测试的假设扩展到人体模型并进行验证。