Advanced Ultrasound Ablation Therapy for Atrial Fibrillation

描述（由申请人提供）：本项目的最终目标是开发高效、安全的HIFU消融技术，通过术中或胸腔镜手术治疗房颤（AF）。房颤是最常见的持续性心律失常，其特征是心房激动不协调，从而导致心房机械功能恶化。它增加了患者中风的风险，并对生活质量产生显著的负面影响。这是一个重大的公共卫生问题，导致大量的医疗保健费用。目前AF的药物治疗是暂时的，昂贵的，并且具有公认的局限性，例如相对较低的疗效， 耐受的全身副作用。消融技术已被用于通过用消融线代替切口来复制切割缝合迷宫手术。虽然导管或手术消融的选择最好基于患者解剖结构和病史来确定，但能量外科AF消融具有几个优点，包括心外膜入路具有更高的安全性，这对于AF消融手术至关重要，并且心外膜消融可以在更短的时间内进行。射频（RF）、微波、超声和冷冻治疗已被用于AF消融，但目前的消融技术并不是心外膜消融的最佳选择，主要是因为它们在产生所需的线性透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）的焦点容易放置在深度以到达表面下部位，因此有可能克服当前技术的局限性，以实现更好的消融效果。然而，主要的问题仍然存在，阻碍了高强度聚焦超声消融术的发展。本项目旨在解决这些问题，以发展成功的HIFU消融治疗房颤。开发用于监测HIFU消融的创新成像技术，包括评估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）热成像的新型断层温度成像; 2.旨在表征HIFU心脏消融术中的电生理、物理和细胞变化。这些基于机制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， 病变大小和组织学变化，使用离体Langendorff灌注的犬心脏制备物和体外分离的人心脏。3.开发一种用于受控心外膜消融的图像引导高强度聚焦超声阵列系统，以便在跳动的心脏上进行有效和安全的心外膜消融能量沉积。任务包括：1）开发一种能够产生电子控制的多功能光束轮廓和可变焦深的HIFU阵列系统; 2）整合用于组织温度和损伤形成的成像技术; 3）证明原型HIFU系统用于体内受控心外膜消融的能力。 公共卫生相关性声明（由申请人提供）：房颤（AF）是最常见的持续性心律失常。它是一个重要的公共卫生问题，发生在大约1%的普通人群中，超过10%的年龄大于10岁的患者中。 超过80岁，尤其是随着人口老龄化，会产生大量的医疗保健费用。AF的特征是心房激动不协调，随之而来的心房机械功能恶化，导致卒中风险增加和患者生活质量降低。房颤的主要治疗是药物治疗，这是暂时的，昂贵的，并具有公认的局限性，包括相对较低的疗效和耐受性差的全身副作用。通过外科Cox迷宫手术直接介入治疗AF仍然是治疗和治愈AF的金标准，有效率超过90%。但该手术尚未获得广泛应用，因为该手术在技术上具有挑战性，需要创建一组复杂的手术切口和重建心房，并且与显著的发病率和死亡率相关。利用高强度聚焦超声（HIFU）在心房内产生热损伤的消融治疗可以大大简化外科消融手术治疗房颤。本项目旨在开发一种创新的、有效的和安全的治疗房颤的超声消融治疗方法。

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.