Myocardial Ablation by Ultrasound Histotripsy: Microbubble Facilitation

项目摘要 心律失常的导管消融，通常使用射频（RF）能量进行， 在医学难治性病例中，但由于消融深度较浅且未能选择性地 靶向异质性瘢痕中的持续传导心肌。组织摧毁术是一种新型的超声（US） 一种深度聚焦高振幅短超声脉冲以机械分解的消融方法 组织，形成界限分明的病变。空化核以稳定的包裹形式存在， 微泡（MB）降低了产生组织坏死所需的能量。本提案的总体目标是 评估组织摧毁术是否可以产生具有更有效地治疗所需的聚焦深度的大病灶， 消融术我们还假设，血管内微束将通过降低 组织破坏阈值，特别是在传导活性心肌的区域， 不均匀，有疤痕。目的1将使用离体心肌和体内猪模型来评估 非造影剂组织摧毁术能够产生大的、深的、集中的心肌病变。高通量前- 体内模型将允许我们有效地测试改变组织破坏声学参数（峰值 负压、脉冲持续时间和频率），并同时评估负责的声学响应 通过被动空化检测（PCD）进行消融。然后将在体内对最佳候选物进行前瞻性测试。 目的2将定义静脉注射MB在使用各种US增强组织破坏中的益处， 参数，以测试空化阈值是否降低以及病变是否更大和更多 与非造影组织活检相比，其均质。一旦定义了理想条件， 将进行显微镜检查，同时进行PCD，以确定对比度下的生物学事件- 在体内大鼠提睾肌模型中实时增强的组织破坏。为了进一步阐明机制，我们 将研究MB成分变化（脂壳和气核）对空化倾向的影响。 目标3将使用猪心肌梗死模型评估输注MB靶向消融的能力 在疤痕的异质区域内持续灌注和传导“通道”， 患者体内的致癌源。这些目标将建立在消融的范式转变， 能量直接针对维持心律失常的病理性但持续传导的心肌。 通过这个项目，Nazer博士建立在他的生物医学工程和治疗背景之上。 超声研究，并已确定了一个翻译研究课题，这是兼容他的临床工作， 心脏电生理学家他认识到医生科学家在程序上面临的挑战， 导向的领域，但已经组装了必要的保护研究时间，转化研究的重点， 机构的承诺和资源，以及指导和合作者团队，以最大限度地提高他的机会， 作为一名独立的翻译物理学家和科学家。

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.