Optical Mapping of the Onset of Ventricular Arrhythmias

描述（由申请人提供）：由室性心动过速引起的心源性猝死每年导致数十万人死亡。拟议的研究将集中在这些心律失常发病的机制上。本项目将研究心律失常常发生的两种情况：(1)由冠状动脉突然闭塞引起的急性局部缺血；(2)非缺血性心力衰竭。该项目将侧重于涉及心脏宏观和微观解剖以及电和机械功能之间相互作用的机制。广泛的长期目标是澄清室性心律失常发病时的事件，并提出预防猝死的新治疗策略。具体目标有三个：在急性局部缺血时，确定缺血边界区机械拉伸与室性早搏之间的关系。这一目的的广泛假设是，在急性局部缺血期间，室性早搏是由缺血区边缘高度拉伸的组织引起的。该假设将使用一种新的光学方法来同时成像整个孤立心脏的电和机械功能。如果这一假设得到证实，它可能为抑制心律失常的发生提供新的治疗靶点。具体目标2。确定右心室插入在心衰患者从电性室性心动过速到心室颤动的转变中的作用。心力衰竭患者的猝死通常以快速但有组织的室性心动过速开始，并很快分解为心室颤动。这一目的的广泛假设是，破裂最可能发生在右心室插入隔膜的地方，可能是因为该区域的显微解剖结构复杂。这一假设将在分离的猪心脏中进行测试，这些猪的心脏是由快速起搏引起的。主要的实验工具是膜电位全景光学成像和心脏微结构扩散张量成像。我们还将测试通过压迫或延迟传导阻滞来防止心室颤动发作的干预措施。具体目标3。确定右心室插入在心脏除颤阈值附近电击失败后VF重新启动中的作用。在除颤阈值附近的休克后的第一个休克后激活通常来自快速聚焦。有时这些激活消退，允许窦性心律恢复，但有时先发生波破，开始一系列进一步的波破事件，使心脏回到室颤。Aim 3的研究将与Aim 2的研究平行，但将侧重于右心室插入处休克后局灶波阵面破裂的机制。许多非缺血性心力衰竭患者现在接受植入式除颤器作为猝死的一级预防，这突出了在这种情况下提高对除颤失败理解的重要性。

DESCRIPTION (provided by applicant): Sudden cardiac death caused by ventricular tachyarrhythmia claims hundreds of thousands of victims each year. The proposed research will focus on the mechanisms that underlie such arrhythmias at their onset. This project will study two settings in which arrhythmias commonly occur: (1) acute regional ischemia caused by the sudden occlusion of a coronary artery and (2) nonischemic heart failure. The project will focus on mechanisms that involve the macro and microscopic anatomy of the heart and interactions between electrical and mechanical function. The broad long-range goal is to clarify events at the onset of ventricular arrhythmias and to suggest novel therapeutic strategies for preventing sudden death. There are three specific aims: Specific Aim 1. During acute regional ischemia, determine the relationship between mechanical stretch in the ischemic border zone and premature ventricular beats. The broad hypothesis of this aim is that premature ventricular beats during acute regional ischemia arise from highly stretched tissue along the border of the ischemic zone. The hypothesis will be tested using a novel optical method for simultaneously imaging electrical and mechanical function in whole isolated hearts. If the hypothesis is validated, it may suggest new therapeutic targets to suppress arrhythmia initiation. Specific Aim 2. Determine the role of the insertions of the right ventricle in the transition from electrically induced ventricular tachycardia to ventricular fibrillation in failing hearts. Sudden death in hear failure patients frequently begins with a rapid, yet organized, ventricular tachycardia that soon breaks down into ventricular fibrillation. The broad hypothesis of this aim is that the breakdown is most likely to occur where the right ventricle inserts into the septum, possibly because of the complex microanatomy of this region. The hypothesis will be tested in isolated swine hearts in which heart failure has been induced with rapid pacing. The main experimental tools will be panoramic optical imaging of membrane potential and diffusion tensor imaging of cardiac microstructure. We will also test interventions that attempt to prevent the onset of ventricular fibrillation by sup- pressing or delaying propagation block in this region. Specific Aim 3. Determine the role of the right ventricular insertions in the reinitiation of VF following failed shocks near the defibrillation threshold in failing hearts. The first postshock activations followig a shock near the defibrillation threshold typically emanate from a rapid focus. Sometimes these activations subside, allowing the resumption of sinus rhythm, but sometimes wavebreak occurs first, starting a cascade of further wavebreak events that sends the heart back into VF. The studies of Aim 3 will parallel those of Aim 2, but will focus on the mechanisms of the breakdown of post shock focal wavefronts at the right ventricular insertions. Many patients with nonischemic heart failure are now receiving implantable defibrillators for primary prevention of sudden death, highlighting the importance of improved understanding of defibrillation failure in this setting.