Myocardial Ablation by Ultrasound Histotripsy: Microbubble Facilitation

项目总结 使用通常使用射频(RF)能量进行的心律失常的导管消融 在医学难治性病例中，但由于消融深度浅和未能选择性地进行治疗，其疗效受到限制 靶点是在异质疤痕中持续传导的心肌。组织诊断学是一种新型的超声(US) 深度聚焦高幅度短超声脉冲机械崩解的消融方法 组织，形成边界清楚的损伤。以稳定包覆形式存在的空化核 微泡(MB)降低了产生组织坏死所需的能量。这项提案的总体目标是 评估组织电切术是否可以产生更有效所需的聚焦深度的大病变 消融。我们还假设，血管内微球滤过率将进一步提高消融效果 组织学阈值特别是在经常交错的存活心肌传导区域 异质性的有疤痕。AIM 1将使用体外心肌和体内猪模型来评估 非对比剂组织检查能够造成大的、深的、有焦点的心肌损害。高吞吐量EX- 活体模型将允许我们有效地测试改变组织摩擦学声学参数(峰值)的效果 负压、脉冲持续时间和频率)，并同时评估负责的声学响应 用于被动空化探测(PCD)的消融。然后，最好的候选人将接受前瞻性的体内测试。 目标2将使用不同的US确定静脉注射MBS在加强组织尿路感染方面的益处 参数，以测试空化阈值是否降低，病变是否更大和更多 均质型与非对比型组织镜检结果比较。一旦定义了理想的条件，那么在生命中 将进行同时进行PCD的显微镜检查，以确定对比不足的生物事件- 在活体大鼠提睾肌模型中增强组织摩擦学的实时研究。为了进一步阐明机理，我们 将研究甲基溴的成分变化(唇壳和气核)对气蚀易感性的影响。 AIM 3将使用猪心肌梗死模型来评估输注的MBS靶向消融的能力 在SCAR的不同区域内持续灌流和传导的“通道”，这代表着 患者心律失常的诱因。这些目标将朝着消融的范式转变而建立， 能量直接针对持续心律失常的病理性持续传导心肌。 通过这个项目，纳泽尔博士在生物医学工程和治疗方面的背景基础上 超声研究，并定义了一个与他的临床工作相兼容的翻译研究主题 心脏电生理学家。他认识到内科科学家在程序上面临的挑战- 面向领域，但已经汇集了必要的受保护的研究时间，翻译研究的重点， 机构承诺和资源，以及导师和合作者团队，以最大限度地提高他的机会 成功地成为一名独立的翻译内科医生兼科学家。

PROJECT SUMMARY Catheter ablation of cardiac arrhythmias, typically performed with radiofrequency (RF) energy, is used in medically refractory cases, but is limited in efficacy by shallow depth of ablation and failure to selectively target persistently conducting myocardium amidst heterogeneous scar. Histotripsy is a novel ultrasound (US) ablation method that deeply focuses short ultrasound pulses with high amplitudes to mechanically disintegrate tissue, forming well-demarcated lesions. The presence of cavitation nuclei in the form of stable encapsulated microbubbles (MB) lowers the power necessary to produce tissue necrosis. The overall goal of this proposal is to evaluate whether histotripsy can generate large lesions with focused depth necessary for more effective ablation. We also hypothesize that intravascular MBs will further improve ablation efficacy by lowering histotripsy threshold specifically in areas of conducting viable myocardium that often interdigitate heterogeneously with scar. Aim 1 will use both ex-vivo myocardium and in-vivo swine models to assess the ability of non-contrast histotripsy to create large, deep, focused myocardial lesions. The high-throughput ex- vivo model will allow us to efficiently test the effects of varying the histotripsy acoustic parameters (peak negative pressure, pulse duration and frequency) and to simultaneously assess acoustic response responsible for ablation by passive cavitation detection (PCD). Best candidates will then be prospectively tested in-vivo. Aim 2 will define the benefit of intravenously-injected MBs in potentiating histotripsy using various US parameters in order to test whether cavitation threshold is reduced and lesions are larger and more homogenous compared with non-contrast histotripsy. Once ideal conditions are defined, then intravital microscopy with simultaneous PCD will be performed to define the biologic events that underly contrast- enhanced histotripsy real-time in an in-vivo rat cremaster muscle model. To further elucidate mechanism, we will study the effect of MB compositional changes (lipd shell and gas core) on the predisposition to cavitation. Aim 3 will use a swine myocardial infarction model to assess the ability of infused MBs to target ablation toward persistently perfused and conducting “channels” within heterogeneous areas of scar, which represent the arrhythmogenic source in patients. These aims will build toward a paradigm shift in ablation whereby energy is targeted directly at pathologic yet persistently conducting myocardium that sustains arrhythmias. With this project, Dr. Nazer builds upon his background in biomedical engineering and therapeutic ultrasound research, and has defined a translational research topic that is compatible with his clinical work as a cardiac electrophysiologist. He is cognizant of the challenges faced by physician-scientists in procedurally- oriented fields, but has assembled the necessary protected research time, translational research focus, institutional commitment and resources, and mentorship and collaborator team to maximize his chance of succeeding as an independent translational physician-scientist.