Therapeutic Microlesioning by Contrast Echocardiography for Myocardial Reduction

描述(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，每500人中就有1人发生。对于一些年轻患者来说，第一个症状是猝死。室间隔肥厚导致左室流出道梗阻，约三分之一的梗阻患者在药物治疗后仍有症状。目前可用于减少梗阻的治疗方法有心内直视手术、间隔肌切开术和经导管间隔酒精消融术。不幸的是，无水酒精消融术创伤较小，严重并发症发生率高，未得到广泛应用。对于肥厚性心肌病和潜在的其他心肌肥大，迫切需要一种全新的非侵入性组织减少术。本项目的目的是为肥厚性心肌病创造一种更安全、更温和的心肌缩小方法。心肌声学造影(MCE)通过成像来自造影剂微泡的强回声，使心肌灌注可视化成为可能。对于高幅值的MCE，造影剂微泡的间歇性破坏被证明通过空化机制对心肌细胞造成致命性损伤，从而导致组织学上随机分布的微小病变。推动这一项目的中心假设是，在诊断MCE中看到的微损伤效应可以增强，以达到治疗有效的心脏减少。超声心动图和心电图是肥厚性心肌病诊断和治疗随访的金标准。为治疗性MCE(TMCE)融合增强型诊断性MCE与受控微损伤的潜在突破，为该项目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)通过监测空化排放来加强MCE的微循环，以有效地减少心肌梗死；(2)开发具有TMCE能力和治疗反馈的超声系统；(3)在现实的猪模型中证明TMCE治疗心肌减少的安全性和有效性。尽管在2005年可以设想使用MCE治疗肥厚性心肌病的可能性，但为了使这一想法成为现实，三项发展结合在一起：开发综合空化发射作为累积生物效应的监测方法，实现心电中过早的复合波报告微损伤阈值而不考虑原位衰减，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种安全有效的TMCE方案，一种融合成像和治疗的超声波机器，并证明了这一突破性疗法的原则。这个项目的总体影响将是一种微创的新工具的出现，用于心肌缩小治疗。这项创新技术将推动医学超声波的发展，并显著改善威胁生命的心肌肥厚患者的预后。

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.