Optical Mapping of the Onset of Ventricular Arrhythmias

描述（由申请人提供）：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发病时这种心律失常的机制。本计画将研究两种心律不齐常见的情形：（1）冠状动脉突然闭塞所造成的急性区域性缺血;（2）非缺血性心力衰竭。该项目将侧重于涉及心脏的宏观和微观解剖结构以及电气和机械功能之间的相互作用的机制。广泛的长期目标是澄清室性心律失常发作时的事件，并提出预防猝死的新治疗策略。具体目标有三个：一是具体目标。在急性局部缺血期间，确定缺血边缘区机械牵拉和室性早搏之间的关系。该目的的广泛假设是，急性局部缺血期间的室性早搏是由沿缺血区边缘沿着高度拉伸的组织引起的。该假设将使用一种新的光学方法进行测试，同时成像的电和机械功能在整个隔离的心脏。如果这一假设得到验证，它可能会提出新的治疗目标，以抑制心律失常的启动。具体目标2。确定右心室附着点在衰竭心脏中电诱导室性心动过速向室颤转变中的作用。心力衰竭患者的猝死通常开始于快速但有组织的室性心动过速，很快就会转变为心室颤动。这一目标的广泛假设是，破裂最有可能发生在右心室插入室间隔的位置，可能是因为该区域复杂的显微解剖结构。将在用快速起搏诱导心力衰竭的离体猪心脏中检验该假设。主要的实验工具将是膜电位的全景光学成像和心脏微观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滞来预防室颤发作的干预措施。具体目标3。确定右心室插入在衰竭心脏除颤阈值附近电击失败后VF重新启动中的作用。在除颤阈值附近的电击之后的第一次电击后激活通常源自快速聚焦。有时这些激活消退，允许恢复窦性心律，但有时首先发生波断，开始进一步的波断事件的级联，将心脏送回VF。目标3的研究将与目标2的研究平行，但将侧重于右心室插入处电击后局灶性波前的击穿机制。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，突出了在这种情况下提高对除颤失败的理解的重要性。

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.