Therapeutic Microlesioning by Contrast Echocardiography for Myocardial Reduction

描述（由申请人提供）：肥厚型心肌病（HCM）是最常见的遗传性心血管疾病，发生率为1/500。对于一些年轻患者来说，第一个征兆就是猝死。室间隔肥大导致左心室流出道梗阻，约三分之一的梗阻患者在药物治疗后仍有症状。目前可用的减少阻塞的治疗方法是心内直视手术进行间隔肌切除术和经导管间隔消融术与酒精。不幸的是，微创酒精消融术严重并发症的发生率很高，并且没有广泛应用。对于HCM和其他潜在的心肌肥厚，迫切需要一种全新的非侵入性组织缩小方法。本项目的目的是为HCM创建一种更安全，更温和的心肌还原方法。心肌造影超声心动图（MCE）通过造影剂微泡的强回声成像实现了心肌灌注的可视化。对于高振幅MCE，造影剂微泡的间歇性破坏已被证明通过空化机制对心肌细胞造成致命损伤，这导致在组织学中观察到随机分散的微病变。驱动该项目的中心假设是，可以增强诊断MCE中观察到的微病变效应，以实现治疗有效的心脏缩小。超声心动图和心电图是HCM诊断和治疗随访的金标准。增强诊断性MCE与控制性微损伤融合所带来的潜在突破，为治疗性MCE（TMCE）创造了一个令人信服的理由。我们的研究策略有三个具体目标：（1）通过监测空化发射来增强MCE的微损伤，以实现有效的心肌缩小，（2）开发具有TMCE功能和治疗反馈的超声系统，（3）在真实的猪模型中证明TMCE治疗性心肌缩小的安全性和有效性。虽然MCE治疗HCM的可能性是可以想象的，在2005年，三个发展已经合并，使这个想法实用：开发集成的空化发射作为一种监测方法，积累的生物效应，实现在心电图中的过早复合报告的微病变阈值，无论在原位衰减，和超声系统开发的新平台的可用性。实现我们目标的预期结果是一种安全有效的TMCE方案，一种将成像与治疗性治疗融合在一起的超声机，以及这种突破性治疗的原理证明。该项目的总体影响将是一种微创心肌缩小治疗新工具的出现。这项创新技术将推动医学超声学的发展，并显着改善患有危及生命的心肌肥大患者的预后。

DESCRIPTION (provided by applicant): Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease, occurring in 1 in 500 people. For some young patients, the first sign is sudden death. Septal hypertrophy leads to obstruction of the left ventricular outflow path and about one-third of patients with obstruction remain symptomatic after pharmacological therapy. Presently available treatments to reduce obstruction are open heart surgery for septal myectomy and transcatheter septal ablation with alcohol. The less invasive alcohol ablation procedure unfortunately has a high incidence of serious complications and is not widely applied. A completely new non-invasive option for tissue reduction is sorely needed for HCM and potentially other myocardial hypertrophies. The objective of this project is to create a safer, gentler method of myocardial reduction for HCM. Myocardial contrast echocardiography (MCE) has enabled visualization of myocardial perfusion by imaging strong echos from contrast-agent microbubbles. For high amplitude MCE, intermittent destruction of contrast microbubbles has been shown to lethally injure cardiomyocytes by the cavitation mechanism, which leads to randomly scattered microlesions seen in histology. The central hypothesis driving this project is that the microlesioning effect seen in diagnostic MCE can be enhanced to achieve therapeutically efficacious cardiac reduction. Echocardiography together with electrocardiography is the gold standard for diagnosis and treatment follow-up for HCM. The potential breakthrough resulting from fusion of enhanced diagnostic MCE with controlled microlesioning, for therapeutic MCE (TMCE), creates a compelling rationale for this project. Our research strategy has three specific aims: (1) enhance microlesioning by MCE for efficacious myocardial reduction with monitoring of cavitation emissions, (2) develop an ultrasonic system with TMCE capability and treatment feedback and (3) demonstrate the safety and efficacy of therapeutic myocardial reduction by TMCE in a realistic porcine model. Although the possibility of MCE for HCM therapy was conceivable in 2005, three developments have coalesced to make the idea practical: the development of integrated cavitation emissions as a monitoring method for accumulated bioeffects, the realization that premature complexes in the ECG report the microlesion threshold regardless of in situ attenuation, and the availability of new platforms for ultrasound system development. The outcomes expected from achieving our aims are a safe and efficacious protocol for TMCE, an ultrasonic machine fusing imaging with therapeutic treatment, and the proof of principle for this breakthrough therapy. The overall impact of this project will be the advent of a minimally invasive new tool for myocardial reduction therapy. This innovative technology will advance medical ultrasonics and improve significantly the prognosis for patients living with life-threatening myocardial hypertrophy.