Depth-resolved imaging of myocardial excitation

描述（由申请人提供）：心脏传播电生理测绘的先进技术的发展已经成为最近在心律失常机制的基本理解和临床应用（如测绘引导射频消融）方面取得成功的决定性因素。然而，基础和临床心脏电生理学的主要挑战之一仍然是隐藏在心肌壁内的异常传导致心律失常区域的定位。本提案的最终目标是利用新型近红外（NIR）电压敏感染料开发一种微创3D层析光学成像技术，这将大大提高研究心肌壁内电激发的能力。在之前的支持期间，我们进行了广泛的建模和实验研究，表明我们的方法的可行性。下一步将是实施，验证和评估新技术的潜力，用于正常心肌和生理相关的心律失常缺血性底物的3D制图。本课题的具体目的是：1)建立一个快速的光学层析成像系统，用于对离体冠状动脉灌注心室壁制剂的壁内电波进行时间分辨的三维成像。2)对tyrode灌注和血灌注猪心室壁制剂的壁内电激发波进行三维重建。3)在模拟致心律失常底物（缺血边界、梗死疤痕）不均匀染色模式的条件下，测试重建的准确性。4)利用新技术确定急性局部缺血时灌注区域三维几何形状在心律失常发生中的作用。我们将检验一个假设，即给定冠状动脉灌注区域的解剖结构定义了缺血区域的几何形状，并且是决定该动脉闭塞后出现的电传播模式的主要因素。成功完成所提出的Specific Aims将在正常和临床相关条件下产生、验证和测试一种快速的新型层析成像方法，用于心肌内兴奋的3D光学成像。它也将为灌注区域的解剖结构和缺血相关的传导异常之间的联系提供新的机制信息。公共卫生相关性：提出的研究目标是开发一种光学成像技术，用于检测隐藏在心肌壁深处的心律失常源。这种来源出现在供血心肌的动脉阻塞时，经常引起心源性猝死。这项新技术将有助于了解这些源的启动机制，这是开发有效的抗心律失常治疗和预防心源性猝死的关键。

DESCRIPTION (provided by applicant): The development of advanced technologies for electrophysiological mapping of cardiac propagation has been a defining factor in recent successes both in basic understanding of arrhythmia mechanisms and clinical applications such as mapping-guided radiofrequency ablation. However, one of the major challenges both in basic and clinical cardiac electrophysiology remains the mapping of abnormally conducting arrhythmogenic regions hidden inside the myocardial wall. The ultimate goal of this proposal is to develop a minimally invasive 3D tomographic optical mapping technique utilizing novel near-infrared (NIR) voltage-sensitive dyes, which will significantly enhance one's ability to study electrical excitation inside the myocardial wall. During the previous period of support, we have conducted extensive modeling and experimental studies that indicate the feasibility of our method. The next step will be to implement, validate, and assess the potential of the new technique for 3D mapping of normal myocardium and physiologically relevant arrhythmogenic ischemic substrates. The Specific Aims of this proposal are: 1) Build a fast optical tomographic system for the time-resolved 3D imaging of intra-mural electrical waves in isolated coronary-perfused ventricular wall preparations. 2) Perform the 3D reconstructions of intramural electrical excitation wave in Tyrode-perfused and blood-perfused pig ventricular wall preparations. 3) Test the accuracy of the reconstructions under conditions simulating non- uniform staining patterns characteristic of arrhythmogenic substrates (ischemic border, infarction scar). 4) Utilize the new techniques to determine the role of 3D geometry of perfusion territories in arrhythmogenesis during acute regional ischemia. We will test the hypothesis that the anatomy of the perfusion territory of a given coronary artery defines the geometry of the ischemic region and is a major factor that determines the pattern of electrical propagation emerging after occlusion of that artery. Successful completion of the proposed Specific Aims will produce, validate, and test both under normal and clinically relevant conditions a fast new tomographic method for the 3D optical imaging of intra-myocardial excitation. It will also provide new mechanistic information regarding the links between the anatomy of perfusion territories and ischemia-related conduction abnormalities. PUBLIC HEALTH RELEVANCE: The goal of the proposed studies is to develop an optical imaging technology for detecting sources of arrhythmia hidden deep inside the myocardial wall. Such sources emerge during the blockage of arteries feeding cardiac muscle and often cause sudden cardiac death. The new technology will help to understand the mechanisms of initiation of such sources, which is the key to developing effective anti-arrhythmic therapies and prevention of sudden cardiac death.