Minimally Invasive High Intensity Therapeutic Ultrasound for the Treatment of Obstructive Hypertrophic Cardiomyopathy

微创高强度超声治疗梗阻性肥厚型心肌病

• 批准号: 10603460
• 负责人: Howard Levin
• 金额: $ 78.45万
• 依托单位: CORIDEA, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10603460
• 关键词: Ablation; Acceleration; Acoustics; Acute; Adverse effects; Alcohols; Anatomy; Animal Model; Animals; Brain; Cardiac Electrophysiologic Techniques; Cardiac conduction system; Catheters; Certification; Characteristics; Chest Pain; Chronic; Clinical; Clinical Pathology; Clinical Trials; Coronary artery; Critical Illness; Dangerousness; Data; Defibrillators; Development; Devices; Disease; Dyspnea; Elements; Endothelium; Equilibrium; Equipment; Femur; Frequencies; Future; Gel; Geometry; Grant; Health; Heart Block; Heart Diseases; Histopathology; Human; Hypertrophic Cardiomyopathy; Hypertrophy; Industry Standard; Inflammation; Inherited; Injury; International; Irrigation; Laboratories; Left; Lesion; Life; Lung; Medical; Methods; Modality; Nature; Obstruction; Operative Surgical Procedures; Organ; Output; Pacemakers; Pathology; Patients; Performance; Persons; Phase; Physics; Pre-Clinical Model; Preparation; Procedures; Process; Prognosis; Radiation; Refractory; Reporting; Resistance; Resolution; Right ventricular structure; Risk; Risk Reduction; Safety; Small Business Innovation Research Grant; Source; Sterility; System; Techniques; Technology; Testing; Therapeutic; Thick; Thinness; Thrombus; Tissues; Transducers; Ultrasonic Transducer; Venous; Ventricular; Ventricular septum; Work; animal data; atrioventricular node; behavior observation; cardiac magnetic resonance imaging; commercialization; comorbidity; design; design verification; dosimetry; healing; heart rhythm; implantation; improved; manufacturability; manufacture; meetings; minimally invasive; mortality; novel; patient subsets; pre-clinical; preservation; prototype; public health relevance; research clinical testing; response; side effect; tool; ultrasound; ultrasound ablation; verification and validation

Project Summary Obstructive hypertrophic cardiomyopathy (oHCM) is a common inherited heart disease that can cause major limitations to daily acts of living, poor prognosis, and mortality. There are as many as 1.5 M people with HCM in the US alone, 2/3 of whom have the obstructive form of the disease with over 50k remaining refractory to medical management and are candidates for septal reduction therapy (SRT). Despite this, only ~1,200 patients per year of the 50k currently indicated receive SRT, leaving the vast majority of the most severe patients untreated. The reason for is the highly invasive nature of existing SRTs that cause frequency cardiac rhythm abnormalities requiring implantation of a pacemaker or cardioverter defibrillator (ICD) and have unacceptably high rates of peri- and post- procedural mortality (up to 10%). Additionally, many patients are unsuitable for existing SRT procedures due to existing co-morbidities and/or anatomical limitations. This Phase II SBIR proposes development of a novel treatment for oHCM by precisely targeting the source of the obstruction on the interventricular septum (IVS) using a novel high-intensity therapeutic ultrasound (HITU) catheter. Our approach takes a relatively safe, femoral venous approach to the right ventricle (RV) using existing delivery tools and knowhow within cardiac electrophysiology. Treatment focuses on delivery of HITU to selectively ablate the entire mid-myocardium of the IVS while sparing the cardiac conduction system on the sub-endocardium (His-Purkinje), thereby reducing risk of heart block requiring pacemaker or ICD insertion. This proposal builds upon the Phase I-equivalent work in acoustic physics, and pre-clinical proof of concept with a prototype catheter demonstrating that, by generating deep lesions in the mid-septum with a HITU, the IVS thickness can be reduced by approximately 30%. Based on catheter irrigation features and HITU’s natural focusing characteristics sparing the sub- endocardium, heart block can be avoided even in the setting of extensive ablation in this region. The aims of this proposal will focus on maturation of catheter design elements and manufacturing methods to make the prototype device suitable for clinical evaluation, verify the functionality and safety of the system to relevant international safety standards (particularly IEC 60601-2-62 standards), and validate the safety, efficacy, and durability of this therapy in acute and chronic (3-month) preclinical models via clinically accepted modalities (cardiac MRI, TTE, clinical pathology, gross pathology and histopathology). The information obtained in this grant will be used in direct support of early feasibility IDE submission with the FDA as part of a future phase of the grant. Commercialization of our system will bring lifesaving therapy to thousands of critically ill patients every year and eventually expand to treatment of HCM patients in earlier stages of the disease before long- standing obstructive hypertrophy resulted in irreversible health consequences.

项目摘要 阻塞性肥厚型心肌病（oHCM）是一种常见的遗传性心脏病，可导致严重的限制， 日常生活行为、预后差和死亡率。仅在美国就有多达150万人患有HCM，其中2/3的人患有HCM。 患有阻塞性疾病的患者，超过50 k的患者对药物治疗难以治疗， 间隔缩小治疗（SRT）的候选人。尽管如此，目前每年仅约1,200例患者（50 k）适应症 接受SRT，使绝大多数最严重的患者得不到治疗。其原因是， 现有SRT导致需要植入起搏器或心律转复器的频率心律异常 除颤器（ICD），并且具有不可接受的高手术死亡率（高达10%）。此外，许多 患者由于现有的合并症和/或解剖学限制而不适合现有的SRT手术。 该II期SBIR提出通过精确靶向阻塞源来开发oHCM的新型治疗方法 使用新型高强度治疗性超声（HITU）导管在室间隔（IVS）上进行。我们的方法 使用现有的输送工具和技术，采用相对安全的股静脉入路进入右心室（RV） 心脏电生理学中。治疗重点是输送HITU以选择性消融整个中层心肌 同时保留内膜下（希-浦二氏）的心脏传导系统，从而降低 需要植入起搏器或ICD的心脏传导阻滞。 该提案建立在声学物理学的I期等效工作和原型概念的临床前证明基础上 导管证明，通过使用HITU在中间隔产生深部损伤，可以减少IVS厚度 大约30%。基于导管冲洗功能和HITU的自然聚焦特性， 即使在该区域进行广泛消融的情况下，也可以避免心脏传导阻滞。 本提案的目的将侧重于导管设计要素和制造方法的成熟， 适用于临床评价的原型器械，根据相关国际标准验证系统的功能性和安全性 安全标准（特别是IEC 60601-2-62标准），并验证该疗法的安全性、有效性和持久性， 急性和慢性（3个月）临床前模型通过临床上接受的方式（心脏MRI，TTE，临床病理学， 大体病理学和组织病理学）。 本资助中获得的信息将用于直接支持向FDA提交早期可行性IDE， 这是未来阶段的一部分。我们系统的商业化将为成千上万的危重病人带来挽救生命的治疗。 并最终扩展到疾病早期阶段的HCM患者的治疗- 站立阻塞性肥大导致不可逆转的健康后果。