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: 10818081
• 负责人: Babak Nazer
• 金额: $ 61.93万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-09 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10818081
• 关键词: 3-Dimensional; Ablation; Acoustics; Alcohols; Anatomy; Animal Experimentation; Animals; Arrhythmia; Arteries; Atrioventricular Block; Award; Bundle-Branch Block; Cardiac ablation; Catheters; Chest Pain; Cicatrix; Clinical; Complication; Coronary artery; Custom; Development; Devices; Disease; Documentation; Dyspnea; Echocardiography; Electrophysiology (science); Endocardium; Ensure; Family suidae; Feasibility Studies; Femur; Fibrosis; Frequencies; Genetic Diseases; Gold; Health Services Accessibility; Heart Septum; Heart failure; Histology; Hypertrophic Cardiomyopathy; Hypertrophy; Image; Incidence; Laboratories; Left; Lesion; Location; Maps; Mechanics; Methods; Modeling; Morbidity - disease rate; Myocardial; Myocardial perfusion; 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; Risk Reduction; 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; ex vivo perfusion; fabrication; 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 efficacy; 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.

项目概要 梗阻性肥厚型心肌病 (HCM) 由于左心室异常导致明显的症状和发病率 心室流出道梗阻（LVOTO）。 LVOTO 室间隔 (IVS) 复位手术 例如酒精间隔消融术和手术心肌切除术可以缓解症状并降低猝死风险，但是 由于围手术期风险、解剖学限制、 并发症（特别是房室（AV）传导阻滞）和有限的疗效。我们的实验室开发了一种 IVS 减少疗法 (SRT) 的有吸引力的方法，并使用高通量获得了初步的大动物数据。 强度超声 (HIU) 导管系统用于治疗 oHCM、严重 LVOTO 及其后果。 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) 选择性消融心肌中部，同时保留心内膜下层（其中含有组氨酸） 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学可用性。 该提案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后续奖项。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，以确认 换能器-组织接触，实时跟踪导管位置，并确认 HIU 后 IVS 消融有效 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 存活 30 天以上的 IVS 厚度（和局部心肌力学）。 组建的团队包括超声治疗、声学物理学、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 帮助这项工作最终转化为首次人体研究。监管顾问将确保动物 研究以符合良好劳工和实践 (GLP) 的方式进行，使我们的团队能够 早期可行性研究的研究设备豁免及后续奖励。