Depth-resolved imaging of myocardial excitation

描述(由申请人提供)：心脏传播电生理标测的先进技术的发展是最近在心律失常机制的基本了解和临床应用(如标测引导的射频消融)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对隐藏在心肌壁内的异常传导致心律失常区域的标测。这项建议的最终目标是开发一种利用新型近红外(NIR)电压敏感染料的微创3D断层成像光学标测技术，这将显著增强人们研究心肌壁内电刺激的能力。在之前的支持期间，我们进行了广泛的建模和实验研究，表明了我们方法的可行性。下一步将是实施、验证和评估这项新技术的潜力，用于正常心肌和生理相关的致心律失常缺血基质的3D标测。该建议的具体目的是：1)建立一个快速光学层析成像系统，用于隔离冠状动脉灌注的室壁标本的壁内电波的时间分辨3D成像。2)对Tyrode灌流和血液灌流的猪室壁标本进行室壁内电激发波三维重建。3)在模拟致心律失常底物(缺血缘、梗死疤痕)不均匀染色模式的条件下，测试重建的准确性。4)利用新的技术来确定灌注区域的三维几何形状在急性局部缺血时心律失常发生中的作用。我们将检验这样一种假设，即给定冠状动脉的灌注区的解剖结构定义了缺血区的几何形状，并且是决定该动脉闭塞后出现的电传播模式的主要因素。成功完成所提出的特定目标将在正常和临床相关条件下产生、验证和测试一种用于心肌内兴奋的3D光学成像的快速新的断层成像方法。它还将提供有关灌注区解剖和缺血相关传导异常之间联系的新的机制信息。公共卫生相关性：拟议研究的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来源。这种来源出现在供应心肌的动脉阻塞时，通常会导致心脏性猝死。这项新技术将有助于了解这些来源的启动机制，这是开发有效的抗心律失常治疗和预防心脏性猝死的关键。

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.