Therapeutic Microlesioning by Contrast Echocardiography for Myocardial Reduction

描述（由申请人提供）：肥厚性心肌病（HCM）是最常见的遗传性心血管疾病，发病率为1 / 500。对于一些年轻病人来说，第一个症状是猝死。室间隔肥厚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。目前可用的治疗方法是心内直视手术切除室间隔肌和经导管酒精消融术。不幸的是，侵入性较小的酒精消融术有较高的严重并发症发生率，并没有得到广泛应用。HCM和潜在的其他心肌肥大急需一种全新的非侵入性组织缩小方法。本项目的目的是为HCM创造一种更安全、更温和的心肌缩小方法。心肌对比超声心动图（MCE）可以通过造影剂微泡产生的强回声来显示心肌灌注。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，导致组织学上可见随机分散的微病变。驱动这个项目的中心假设是，在诊断性MCE中看到的微损伤效应可以增强，以实现治疗有效的心脏复位。超声心动图和心电图是HCM诊断和治疗随访的金标准。在治疗性MCE （TMCE）中，将增强诊断性MCE与可控微病变相融合可能带来突破，这为该项目创造了令人信服的理由。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微损伤以实现有效的心肌减容；(2)开发具有TMCE能力和治疗反馈的超声系统；(3)在现实猪模型上证明TMCE治疗心肌减容的安全性和有效性。尽管在2005年，MCE用于HCM治疗的可能性是可以想象的，但三个发展结合在一起使这一想法成为现实：综合空化发射作为累积生物效应的监测方法的发展，心电图中过早复合物报告微病变阈值而不考虑原位衰减的认识，以及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个安全有效的TMCE方案，超声机融合成像与治疗治疗，以及这一突破性治疗的原理证明。这个项目的总体影响将是一种微创心肌减少治疗的新工具的出现。这项创新技术将推动医学超声技术的发展，并显著改善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.