OPTO-ELECTRIC MAPPING OF ACTION POTENTIALS

描述（由申请人提供）：心律失常每年夺去300- 400，000美国人的生命。现有疗法主要基于药理学、外科手术、消融和植入式器械方法。诊断中的主要障碍之一是无法无创地记录人类患者的动作电位（AP）。唯一可用的技术是侵入性心内MAP导管，其从单个部位提供高保真度记录，迄今为止尚未被用于高分辨率标测。或者，光学标测技术允许记录来自心外膜或心内膜的数万个AP，但它仅用于体外研究，尚未转化为临床电生理学（EP）实验室。目前的临床EP研究依赖于电描记图，电描记图是由许多细胞产生的动作电位的空间整合电特征。因此，在复杂的传导和复极化情况下，它们不容易解释。基于逆问题解决方案的心电图成像（ECGi）的出现，提供了一个令人兴奋的机会，从体表电描记图映射和使用CT或MRI的整个胸部成像开始，无创地映射心外膜电描记图。然而，该方法仅提供电描记图而不提供动作电位。此外，体表电位标测模式迄今不能重建心内膜电描记图，这需要侵入性经静脉球囊或篮状导管标测。我们开发了一种新的AP ECGI方法，其目的是基于体表电图测量和逆问题解决方案无创重建动作电位。然而，关键问题是如何验证这些方法，因为没有高分辨率的映射技术可用于直接映射的动作电位在体内。在本项目中，我们将开发一个离体验证平台，使用电描记图和光学动作电位的同步映射，可以直接比较所有现有的ECG方法和我们的新AP ECGi。我们将创建一个离体3D模型的人胸腔周围Langendorff灌注的人或兔的心脏。该系统将模拟人体胸腔中的活体心脏，并允许同时采集（i）240个胸腔表面电描记图和（ii）使用电压敏感染料的心外膜光学动作电位全景标测。我们的新方法将允许现有的非侵入性临床心脏电生理设备的AP ECGi的验证显着进步。此外，我们将这些数据集提供给其他研究小组和公司，他们有兴趣验证他们自己的竞争ECGi方法。 公共卫生相关性：心脏节律紊乱每年夺去30 - 40万美国人的生命。现有疗法主要基于药理学、外科手术、消融和植入式器械方法。诊断中的主要障碍之一是无法无创地记录人类患者的动作电位（AP）。目前的临床EP研究依赖于电描记图，电描记图是由许多细胞产生的动作电位的空间整合电特征。因此，在复杂的传导和复极化情况下，它们不容易解释。基于逆问题解决方案的心电图成像（ECGi）的出现，提供了一个令人兴奋的机会，从体表电描记图映射和使用CT或MRI的整个胸部成像开始，无创地映射心外膜电描记图。然而，该方法仅提供电描记图而不提供动作电位。我们开发了一种新的AP ECGI方法，其目的是基于体表电图测量和逆问题解决方案无创地构建动作电位。在本项目中，我们将开发一个离体验证平台，使用电描记图和光学动作电位的同时映射，可以直接比较所有现有的ECGi方法和我们的新型AP ECGi。我们的新方法将使现有的非侵入性临床心脏电生理设备的显着进步。此外，我们将把这些数据集提供给其他研究小组和公司，这些研究小组和公司有兴趣验证他们自己的非侵入性动作电位成像患者的竞争方法。

DESCRIPTION (provided by applicant): Heart rhythm disorders claim 300-400,000 lives of Americans annually. Existing therapies are primarily based on pharmacological, surgical, ablative, and implantable device approaches. One of the major impediments in diagnostics is the inability to record action potentials (AP) in human patients noninvasively. The only available technique is an invasive intracardiac MAP catheter, which provides high fidelity recording from a single site and thus far has not been adopted for high resolution mapping. Alternatively, optical mapping technology permits recordings of tens of thousands of APs from the epicardium or endocardium, yet it has been used solely for in vitro studies and has not yet been translated to the clinical electrophysiology (EP) laboratory. Current clinical EP studies rely on electrograms, which are the spatially integrated electrical signatures of action potentials produced by numerous cells. Hence, they are not easily interpretable in complex conduction and repolarization cases. The advent of electrocardiographic imaging (ECGi) based on inverse problem solution, has provided an exciting opportunity to map epicardial electrograms noninvasively starting from the body surface electrogram mapping and whole thorax imaging using CT or MRI. However, this method provides only electrograms and not the action potentials. Moreover, body surface potential mapping modalities thus far cannot recreate endocardial electrograms, which requires invasive transvenous balloon or basket catheter mapping. We have developed a novel AP ECGi methodology which aims to noninvasively reconstruct action potentials based on body surface electrogram measurement and inverse problem solution. However, the critical issue is how to validate these methodologies, because there is no high resolution mapping technique available for direct mapping of action potentials in vivo. In this project we will develop an ex vivo validation platform against which all existing ECG methodologies and our new AP ECGi can be directly compared, using simultaneous mapping of electrograms and optical action potentials. We will create an ex vivo 3D model of the human thorax surrounding Langendorff-perfused human or rabbit hearts. The system will simulate a living heart in a human thorax and allow the simultaneous acquisition of (i) 240 thorax surface electrograms and (ii) panoramic mapping of optical action potentials from the epicardium using voltage-sensitive dyes. Our novel method will allow significant advancement of the existing noninvasive clinical cardiac electrophysiology armamentarium by validation of AP ECGi. Moreover, we will make these data sets available to other research groups and companies that are interested in validation of their own competing ECGi methods. PUBLIC HEALTH RELEVANCE: Heart rhythm disorders claim 300-400,000 lives of Americans annually. Existing therapies are primarily based on pharmacological, surgical, ablative, and implantable device approaches. One of the major impediments in diagnostics is the inability to record action potentials (AP) in human patients noninvasively. Current clinical EP studies rely on electrograms, which are the spatially integrated electrical signatures of action potentials produced by numerous cells. Hence, they are not easily interpretable in complex conduction and repolarization cases. The advent of electrocardiographic imaging (ECGi) based on inverse problem solution, has provided an exciting opportunity to map epicardial electrograms noninvasively starting from the body surface electrogram mapping and whole thorax imaging using CT or MRI. However, this method provides only electrograms and not the action potentials. We have developed a novel AP ECGi methodology which aim to noninvasively construct action potentials based on body surface electrogram measurement and inverse problem solution. In this project we will develop an ex vivo validation platform against which all existing ECGi methodologies and our novel AP ECGi can be directly compared, using simultaneous mapping of electrograms and optical action potentials. Our novel method will allow significant advancement of the existing noninvasive clinical cardiac electrophysiology armamentarium. Moreover, we will make these data sets available to other research groups and companies that are interested in validation of their own competing methods of noninvasive action potential imaging of patients.