Advanced Ultrasound Ablation Therapy for Atrial Fibrillation

描述(申请人提供)：该项目的最终目标是开发有效和安全的HIFU消融技术，通过术中或胸腔镜手术治疗心房颤动(AF)。房颤是最常见的持续性心律失常，其特征是心房活动不协调，导致心房机械功能恶化。它会增加患者中风的风险，并对生活质量产生重大负面影响。这是一个重大的公共卫生问题，导致了巨额的医疗费用。目前房颤的药物治疗是暂时的、昂贵的，并且有公认的局限性，如相对较低的疗效和通常较差的疗效。 耐受全身副作用。消融技术已经被利用来复制切割缝合迷宫程序，用消融的线代替切口处。虽然导管消融或手术消融的最佳选择是基于患者的解剖和病史，但能量外科房颤消融有几个优点，包括心外膜入路具有更高的安全性，这对房颤消融程序至关重要，而且心外膜消融可以在更短的时间内完成。射频消融、微波消融、超声消融和冷冻消融已经被用于房颤消融，但目前的消融技术对于心外膜消融并不是最理想的，主要是因为它们在产生所需的线形跨壁损伤和最小附带损伤方面的能力有限。高强度聚焦超声(HIFU)的焦点很容易深入到地下部位，因此有可能克服现有技术的局限性，实现更好的消融效果。然而，仍然存在着阻碍HIFU房颤消融发展的主要问题。本项目旨在解决这些问题，以开发成功的高强度聚焦超声消融治疗房颤。本项目的具体目标是：1.开发用于监测HIFU消融的创新成像技术，包括用于评估HIFU暴露中组织变化的高分辨率超声光谱成像和基于红外(IR)热像的新型断层温度成像；2.表征HIFU心脏消融中的电生理、物理和细胞变化。这些基于机理的综合剂量-反应研究将研究HIFU消融的时空电生理效应，并将这些效应与温度相关联， 使用隔离的朗宁多夫灌流的犬心制剂和体外移植的人的心脏，病变大小和组织学变化。3.研制一种用于心外膜消融的图像引导HIFU阵列系统，为心脏不停跳心外膜消融提供安全有效的能量沉积。任务包括：1)开发HIFU阵列系统，能够产生电子控制的通用波束轮廓和可变焦深；2)集成组织温度和病变形成的成像技术；3)展示原型HIFU系统在体内用于受控心外膜消融的能力。 公共卫生相关声明(申请人提供)：房颤(房颤)是最常见的持续性心律失常。这是一个重大的公共卫生问题，发生在大约1%的总人口和超过10%的老年患者中。 80多年，特别是在人口老龄化的情况下，产生了巨大的医疗费用。房颤的特点是心房活动不协调，导致心房机械功能恶化，导致卒中风险增加，患者生活质量下降。房颤的主要治疗方法是药物治疗，它是暂时的、昂贵的，而且有公认的局限性，包括相对较低的疗效和往往耐受性较差的全身副作用。通过外科COX迷宫手术直接介入治疗房颤仍是治疗和治愈房颤的金标准，有效率超过90%。但该手术尚未得到广泛应用，因为该手术在技术上具有挑战性，需要创建一套复杂的手术切口和重建心房，并与显著的发病率和死亡率有关。使用高强度聚焦超声(HIFU)在心房制造热损伤的消融治疗可以极大地简化外科消融治疗房颤的过程。本项目旨在开发一种创新、有效、安全的治疗房颤的超声消融疗法。

DESCRIPTION (provided by applicant): The ultimate goal of this project is to develop efficient and safe HIFU ablation technology for treating atrial fibrillation (AF) by the means of intraoperative or thoracoscopic operations. AF is the most common sustained cardiac arrhythmia, characterized by uncoordinated atrial activation with consequent deterioration of atrial mechanical function. It increases a patient's risk of stroke and has a significant negative impact on quality of life. It is a significant public health problem incurring substantial health care costs. Current pharmacotherapy of AF is temporary, expensive, and has well-recognized limitations such as relatively low efficacy and often poorly tolerated systemic side effects. Ablation techniques have been exploited to replicate the cut-and-sew maze procedure by replacing the incisions with lines of ablation. While the choice of catheter or surgical ablation is best determined based on patient anatomy and history, energy surgical AF ablation has several advantages including the fact that the epicardial approach has a higher safety profile which is essential for AF ablation procedures, and that epicardial ablation can be performed in a much shorter period of time. Radiofrequency (RF), microwave, ultrasound, and cryo-therapy have been exploited for AF ablation, but current ablation technologies are not optimal for epicardial ablation, mainly due to their limited ability to create desired set of linear transmural lesions with minimum collateral damage. With its focus readily placed at depth to reach subsurface sites, high intensity focused ultrasound (HIFU) has the potential to overcome the limitations of current technologies to achieve better ablation outcome. However, major problems remain that have hindered the development of HIFU AF ablation. This project seeks to address these very problems in order to develop successful HIFU ablation therapy for AF. The specific aims of this project are: 1. To develop innovative imaging techniques for monitoring of HIFU ablation including high resolution ultrasound spectral imaging to assess tissue changes in HIFU exposures and a novel tomographic temperature imaging based on infrared (IR) thermography; 2. To characterize the electrophysiological, physical, and cellular changes in HIFU cardiac ablation. These mechanism-based comprehensive dose-response studies will investigate the spatiotemporal electrophysiological effects of HIFU ablation and correlate these effects with the temperature, lesion size, and histological changes in tissue using isolated Langendorff-perfused canine heart preparations and explanted human hearts in vitro. 3. To develop an image-guided HIFU array system for controlled epicardial ablation for effective and safe energy deposition for epicardial ablation on a beating heart. Tasks include: 1) to develop a HIFU array system capable of generating an electronically controlled versatile beam profile and variable focal depth; 2) to integrate imaging techniques for tissue temperature and lesion formation; 3) to demonstrate the ability of the prototype HIFU system for controlled epicardial ablation in vivo. Public Health Relevance Statement (provided by applicant): Atrial Fibrillation (AF) is the most common sustained cardiac arrhythmias. It is a significant public health problem, occurring in approximately 1% of the general population and in more than 10% of patients aged more than 80 years, incurring significant health care costs especially as the population ages. AF is characterized by uncoordinated atrial activation with consequent deterioration of atrial mechanical function, leading to increased risk of stroke and reduction of quality of life for patients. The primary treatment for AF is pharmacotherapy, which is temporary, expensive, and has well-recognized limitations including relatively low efficacy and often poorly tolerated systemic side effects. The direct interventional therapy of AF by the surgical Cox-maze procedure remains the gold standard to treat and cure AF with over 90% efficacy. But the procedure has not gained wide spread application because the operation is technically challenging, requiring the creation of complex set of surgical incisions and reconstruction of the atria, and is associated with significant morbidity and mortality. Ablation therapy using high intensity focused ultrasound (HIFU) to create thermal lesions in the atriums could greatly simply surgical ablation procedure to treat AF. This project aims to develop an innovative, effective and safe ultrasound ablation therapy for treating AF.