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

高强度超声消融室间隔缩小术治疗肥厚型心肌病

• 批准号: 10339776
• 负责人: Babak Nazer
• 金额: $ 60.29万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10339776
• 关键词: 3-Dimensional; Ablation; Acoustics; Alcohols; Anatomy; Animal Experimentation; Animals; Arrhythmia; Arteries; Award; Bundle-Branch Block; Cardiac ablation; Catheters; Chest Pain; Cicatrix; Clinical; Complication; Coronary artery; Custom; Development; Devices; Disease; Documentation; Due Process; Dyspnea; Echocardiography; Electrophysiology (science); Endocardium; Ensure; Feasibility Studies; Fibrosis; Frequencies; Genetic Diseases; Gold; Health Services Accessibility; Heart Septum; Heart failure; Histology; Hypertrophic Cardiomyopathy; Hypertrophy; Image; Incidence; Investigation; Laboratories; Left; Lesion; Location; Mechanics; Methods; Modeling; Morbidity - disease rate; Myocardial; Myocardium; Obstruction; Operative Surgical Procedures; Pacemakers; Pathology; Patients; Perioperative; Physics; Physiologic pulse; Positioning Attribute; Procedures; Process; Radial; Research; Research Methodology; Research Personnel; Resolution; Right ventricular structure; Risk; Safety; Signal Transduction; Sonication; Statistical Study; Sudden Death; Symptoms; System; Testing; Therapeutic; Thick; Time; Tissues; Transducers; Translating; Translations; Ultrasonic Therapy; Ultrasonic Transducer; Validation; Venous; Ventricular; Ventricular septum; Work; animal data; cardiac magnetic resonance imaging; coronary fibrosis; design; first-in-human; follow-up; heart imaging; high risk; image processing; implantation; improved; in vivo; indexing; mortality; mortality risk; multidisciplinary; novel; novel strategies; porcine model; preclinical safety; prototype; real time monitoring; reduce symptoms; simulation; simulation software; ultrasound; ultrasound ablation

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.

项目总结 梗阻性肥厚型心肌病(HCM)引起明显的症状和发病率，由于左 室流出道梗阻(LVOTO)。室间隔(IVS)减少术治疗LVOTO 例如酒精间隔消融术和外科子宫切除术可以缓解症状，降低猝死风险，但 由于围手术期的风险，解剖限制， 并发症(尤其是房室传导阻滞)和疗效有限。我们实验室已经研制出一种 有吸引力的IVS减量治疗(SRT)的方法，并获得了初步的大型动物数据使用高- 强度超声(HIU)导管系统用于治疗肥厚型心肌病、严重的左心室肥厚及其后果。 与现有的SRT方法相比，HIU具有明显的优势，因为它： 1)侵袭性较小(经股静脉入路进入右室)。 2)选择性地消融中间心肌，保留心内膜下(含有组氨酸- Purkinje系统)，从而降低房室传导阻滞的风险。 3)不依赖于间隔穿支冠状动脉分支的不可预测的解剖可用性。 这项建议将通过优化病变大小和深度来进一步减少HIU IVS，避免 近场心内膜下，跟踪导管位置/方位/接触，确认有效形成非 具有侵入性，并启动监管工作，为我们进行第一次人类研究奠定基础，并随后颁发奖项。在……里面 目标1，我们将使用声学模拟来设计、制造和验证最优的HIU换能器和导管 在体外模型中。Aim 2将开发和测试几个先进的导管设计功能，这些功能将证实 换能器-组织接触，实时跟踪导管位置，并确认HIU后有效的IVS消融 进行超声波治疗。Aim 3将在体内研究完全发育的HIU导管，以确定减少 存活30天以上的IVS厚度(和局部心肌力学)。 组建的团队包括治疗性超声、声学物理、超声心动图、 心脏核磁共振，大型动物研究方法，研究超声波，以及一名将 帮助最终将这部作品转化为亲身研究。监管顾问将确保动物 研究以符合良好劳动和实践(GLP)的方式进行，为我们的团队定位 早期可行性研究的研究设备豁免，并获得后续奖励。