Optical Mapping of the Onset of Ventricular Arrhythmias

描述(申请人提供)：由室性快速性心律失常引起的心脏性猝死每年造成数十万人死亡。拟议的研究将集中在这种心律失常发生时的机制上。本项目将研究两种常见的心律失常情况：(1)冠状动脉突然闭塞引起的急性区域性缺血和(2)非缺血性心力衰竭。该项目将重点研究心脏的宏观和微观解剖以及电和机械功能之间的相互作用的机制。广泛的长期目标是阐明室性心律失常发生时的事件，并为预防猝死提出新的治疗策略。具体目的有三个：一、急性局部缺血时，确定缺血区机械牵张与室性早搏的关系。这一目标的广泛假设是，急性区域性缺血期间的室性早搏是由缺血区边缘高度拉伸的组织引起的。这一假说将使用一种新的光学方法进行验证，该方法可以同时对整个分离心脏的电和机械功能进行成像。如果这一假说被证实，它可能会提出新的治疗靶点来抑制心律失常的发生。明确目的2.确定右室插入物在衰竭心脏从电诱导性室性心动过速向室颤转变过程中的作用。心力衰竭患者的猝死通常始于快速但有组织的室性心动过速，很快就会分解为室颤。这一目标的广泛假设是，右室最有可能发生在右心室插入间隔的地方，这可能是因为该区域的复杂显微解剖。这一假说将在用快速起搏诱发心力衰竭的猪心中进行检验。主要的实验工具将是膜电位的全景光学成像和心脏微结构的扩散张量成像。我们还将测试试图通过抑制或延迟该区域的传播阻断来预防室颤发作的干预措施。具体目的3.确定右室附着点在衰竭心脏除颤阈值附近的失败电击后重新启动室颤中的作用。在除颤阈值附近的电击之后的第一次震后激活通常是从快速聚焦发出的。有时这些激活消退，允许恢复窦性心律，但有时首先发生波形中断，开始一连串的进一步波形中断事件，将心脏送回室颤。目标3的研究将与目标2平行，但将重点放在右心室附着点的震后焦点波阵面破裂的机制上。许多非缺血性心力衰竭患者现在正在接受植入式除颤器作为猝死的一级预防，这突显了在这种情况下提高对除颤失败的认识的重要性。

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.