High-Intensity Ultrasound Ablation for Septal Reduction Therapy of Hypertrophic Cardiomyopathy

项目摘要 梗阻性肥厚型心肌病（HCM）由于左心室肥厚， 心室流出道梗阻（LVOTO）。LVOTO的室间隔（IVS）复位手术 如酒精室间隔消融术和外科肌切除术可缓解症状并降低猝死风险，但 由于围手术期风险、解剖限制， 并发症（特别是房室（AV）传导阻滞）和疗效有限。我们的实验室开发了一种 有吸引力的方法，IVS减少治疗（SRT），并获得了初步的大型动物数据，使用高- 用于治疗oHCM、严重LVOTO及其后果的高强度超声（HIU）导管系统。 HIU与现有SRT方法相比具有明显的优势，因为它： 1)侵入性较小（通过股静脉途径输送至右心室（RV））。 2)选择性地消融中层心肌，同时保留内膜下（其包含His- 浦肯野系统），从而降低房室传导阻滞的风险。 3)不依赖于不可预测的间隔穿支冠状动脉分支的解剖可用性。 该提案将通过优化病变尺寸和深度，避免 近场内膜下，跟踪导管位置/方向/接触，确认有效形成非 侵入性，并启动监管工作，使我们能够进行首次人体研究，并获得随后的奖项。在 目标1，我们将使用声学模拟来设计，制造和验证最佳的HIU换能器和导管 在离体模型中。Aim 2将开发和测试几种先进的导管设计功能， 传感器-组织接触，真实的时间跟踪导管位置，并在HIU后确认有效的IVS消融 进行超声处理。目标3将在体内研究完全开发的HIU导管，以确定减少 30天生存期内的IVS厚度（和局部心肌力学）。 该小组包括治疗超声，声学物理，超声心动图， 心脏MRI，大型动物研究方法，研究超声医师和HCM临床研究人员， 帮助最终将这项工作转化为首次人体研究。监管顾问将确保动物 研究是在良好的劳动和实践（GLP）的合规性的方式进行，定位我们的小组， 早期可行性研究的试验用器械豁免及后续奖励。

PROJECT SUMMARY Obstructive hypertrophic cardiomyopathy (HCM) causes significant symptoms and morbidity due to left ventricular outflow tract obstruction (LVOTO). Interventricular septal (IVS) reduction procedures for LVOTO such as alcohol septal ablation and surgical myectomy relieve symptoms and reduce sudden death risk, but are often initiated late in the disease process due to their peri-operative risk, anatomic constrains, complications (particularly atrio-ventricular (AV) block) and limited efficacy. Our laboratory has developed an attractive approach to IVS reduction therapy (SRT) and obtained preliminary large animal data using a high- intensity ultrasound (HIU) catheter system for the treatment of oHCM, severe LVOTO and its consequences. HIU has distinct benefits over existing SRT methods in that it: 1) is less invasive (delivered via a femoral venous approach to the right ventricle (RV)). 2) selectively ablates the mid-myocardium while sparing the sub-endocardium (which contains the His- Purkinje system), thereby reducing risk of AV block. 3) does not rely on unpredictable anatomic availability of septal perforator coronary artery branches. This proposal will further develop HIU IVS reduction by optimizing lesion size and depth, avoiding the near-field subendocardium, tracking catheter location/orientation/contact, confirming effective formation non- invasively, and initiating regulatory work to position us for first-in-human studies with a subsequent award. In Aim 1, we will use acoustic simulations to design, fabricate and validate optimal HIU transducers and catheters in ex-vivo models. Aim 2 will develop and test several advanced catheter design features that will confirm transducer-tissue contact, track catheter location in real time, and confirm effective IVS ablation after HIU sonication is performed. Aim 3 will study fully-developed HIU catheters in-vivo to determine ability to reduce IVS thickness (and local myocardial mechanics) over 30 day survival. The assembled team includes exerts in therapeutic ultrasound, acoustic physics, echocardiography, cardiac MRI, large animal research methods, research sonographer, and an HCM clinical researcher who will help with eventual translation of this work to first-in-man studies. Regulatory consultants will ensure that animal studies are performed in a Good Labor and Practices (GLP)-compliant manner, positioning our group for an Investigational Device Exemption for an Early Feasibility Study with subsequent awards.