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.

本研究项目的广泛和长期目标是探索小电导Ca 2 +- 激活的K（SK）通道在心室肌发生机制中的作用。我们假设SK 电流上调是一种内源性代偿机制，以保护心脏免受心律失常相关 复极储备减少，但在某些情况下可能导致过度复极储备， 预防作用SK通道成为我们研究的焦点，因为我们发现， 兔和人心室中的敏感钾电流（IKAS或SK电流）均增加 故障（HF）。我们还发现，SK电流在低钾血症的正常心室中急剧增加， 这取决于心室激动顺序。这些发现提出了一种有趣的可能性， 该SK电流是补偿增加的电生理效应的救援电流， 细胞内Ca 2+负荷。虽然维持HF的复极储备可能具有抗心律失常作用，但我们也发现， 由SK电流引起的APD的过度或不均匀缩短可能是预防性的。我们最近 初步结果表明，IKAS被异丙肾上腺素激活，雌兔心室表达IKAS， 在早期阶段2比男性心室SK电流。SK2和SK 3的CyPPA激活导致ECG J 正常家兔的点抬高、不均匀APD分布、2相折返和自发性VF 心室后一项发现表明，SK电流也可能有助于某些临床上的致心律失常。 通过创建过度复极储备，例如在J波综合征中。掺入 计算机模型中的IKAS将产生重要的新的见解IKAS在心室动力学效应 复极化将需要一种结合绘图和计算机模拟的方法来充分了解 IKAS在心脏血管发生中的重要性，包括预防和抗血管生成的潜力。 我们提出以下具体目标：目的1：SK电流的抗肿瘤和促肿瘤机制 兔子心室目的1A研究正常和衰竭家兔的浦肯野细胞（Purkinje cells，PC） 心室测试的假设，SK电流增加PC和阻断SK电流 降低Ca ~（2+）-膜电位耦合增益，促进Ca ~（2+）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电流是部分负责 对于低温期间J波升高和VF，apamin逆转了这些促心律失常作用，以及（B） 异质性SK电流激活可通过异质性介导J波抬高和自发性VF APD缩短和2期折返。目的2：SK电流的抗肿瘤和促肿瘤机制 计算机仿真目的2A将系统地研究SK电流作为拯救的机制 QT延长下预防心律失常的机制以及早期心律失常的致心律失常机制 复极化目的2B将在家兔模型中测试的假设扩展并验证到人类模型。