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A Controlled Septal Ablation for Inoperable Hypertrophic Cardiomyopathy

无法手术的肥厚型心肌病的可控室间隔消融术

基本信息

批准号：
10514872
负责人：
Jun Liao
金额：
$ 43.31万
依托单位：
UNIVERSITY OF TEXAS ARLINGTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10514872
关键词：
3-Dimensional Ablation Alcohols Arteries Atrioventricular Block Biomechanics Cardiac Cardiac Myocytes Cardiac Surgery procedures Cardiotoxicity Catheterization Cells Clinical Collagen Complication Control Groups Cyanoacrylates Dangerousness Data Diffuse Diffusion Doxorubicin Drug usage Echocardiography Emulsions Endothelin-1 Extracellular Matrix Funding Genetic Diseases Glues Glycolates Goals Gold Harvest Heart Heart Block Hispanic Histology Human Hypertrophic Cardiomyopathy Hypertrophy In Vitro Injections Institutes Left Measures Modeling Mouse Strains Mus Muscle Muscle Cells Myocardium Myofibroblast Nature Necrosis Obstruction Operative Surgical Procedures Outcome Patients Penetration Pharmaceutical Preparations Pharmacologic Substance Procedures Reporting Research Safety Sampling Surface System Tachycardia Techniques Texas Thoracotomy Time Tissues Treatment Effectiveness United States National Institutes of Health Ventricular Ventricular Fibrillation base collagenase design dosage experience heart function improved innovation mechanical properties minimally invasive mortality mouse model nanoparticle necrotic tissue novel reduce symptoms scaffold sham surgery translational potential undergraduate student

项目摘要

Project Summary Hypertrophic cardiomyopathy (HCM) is a genetic disease that results in abnormal thickening of ventricular heart muscle, particularly the septum, causing left ventricular outflow tract (LVOT) obstruction. When medication alone is not sufficient to relieve symptoms, the current gold standard, septal myectomy, is performed to surgically remove excess muscle with an open heart surgery. Unfortunately, many patients are poor surgical candidates and require less invasive treatment options. In these cases, cardiologists treat the patients with a minimally invasive catheterization technique called alcohol septal ablation (ASA), in which 1-4 mL of pure alcohol is injected into the septum via a septal perforator (artery) to destroy part of the septal muscle by triggering necrosis. However, the diffusive nature of pure alcohol causes dangerous uncontrollable necrosis and a very high complication profile for a minimally invasive technique. Risky complications of ASA, with a periprocedural mortality rate of ~2%, include atrioventricular block, ventricular fibrillation/tachycardia, and complete heart block due to lack of control of alcohol localization and indiscriminate tissue destruction. To answer the unmet clinical need, recently cyanoacrylate (super glue) was investigated as a replacement for pure alcohol but experienced challenges in efficacy and long-term safety. To overcome those limitations, our goal is to design a novel ablation system to replace the pure alcohol in ASA and achieve a controllable, localized septal tissue shrinkage and hence a safer ablation. Based on our preliminary data, we hypothesize that the delivery of a collagenase-coated, doxorubicin-loaded, degradable nanoparticles (NPs) will allow for localized doxorubicin-induced destruction of the hypertrophic cardiomyocytes, and this single dosage delivery will lead to regression of the overgrown HCM septal tissue. Doxorubicin was recently found to be responsible for the clearance of unwanted hypertrophic cardiac tissue, and the proposed single dosage delivery can avoid cardiac toxicity often caused by repeat exposure. Three aims will thus be pursued to better understand HCM septal tissue and develop this novel treatment approach: (1) Determine the biomechanical and microstructural abnormalities of human HCM septal tissues and develop a biomimicking in vitro 3D HCM model; (2) Develop a collagenase-coated, doxorubicin- loaded, biodegradable nanoparticle ablation system and optimize the ablation system using the in vitro 3D HCM model; (3) Validate the safety and efficacy of the newly developed ablation system in an HCM mouse model. The proposed research paves a new avenue to improve the safety and efficacy of septal ablation in inoperable HCM patients. The impacts are (i) the innovative concept and design of a controllable, localized ablation to replace the unpredictable, diffusive pure alcohol ablation, and (ii) the promising translational potential. This AREA project will also provide valuable NIH-funded research opportunities to our underrepresented undergraduate students at UT Arlington, a Hispanic-Serving Institute in Northern Texas.

项目概要肥厚型心肌病 (HCM) 是一种导致心室异常增厚的遗传性疾病肌肉，特别是隔膜，导致左心室流出道（LVOT）阻塞。单独用药时不足以缓解症状，目前的金标准是间隔肌切除术，通过手术进行通过心脏直视手术去除多余的肌肉。不幸的是，许多患者不适合接受手术并需要侵入性较小的治疗方案。在这些情况下，心脏病专家会用最低限度的治疗来治疗患者。称为酒精间隔消融 (ASA) 的侵入性导管技术，其中注入 1-4 mL 纯酒精通过间隔穿支（动脉）进入间隔，通过触发坏死来破坏部分间隔肌。然而，纯酒精的扩散性质会导致危险的、无法控制的坏死和非常高的酒精浓度。微创技术的并发症概况。 ASA 的危险并发症，围手术期死亡率约 2%，包括房室传导阻滞、心室颤动/心动过速和完全性心脏传导阻滞由于缺乏对酒精定位的控制和不加区别的组织破坏。解答临床未满足的问题需要，最近研究氰基丙烯酸酯（强力胶）作为纯酒精的替代品，但经验丰富功效和长期安全性方面的挑战。为了克服这些限制，我们的目标是设计一种新颖的消融术系统替代 ASA 中的纯酒精，实现可控的局部间隔组织收缩和因此更安全的消融。根据我们的初步数据，我们假设胶原酶涂层的递送，负载阿霉素的可降解纳米粒子（NP）将允许局部阿霉素诱导的破坏肥大的心肌细胞，这种单剂量给药将导致过度生长的 HCM 消退间隔组织。最近发现阿霉素负责清除不需要的肥大细胞心脏组织，并且所提出的单剂量给药可以避免经常由重复引起的心脏毒性接触。因此，我们将追求三个目标，以更好地了解 HCM 间隔组织并开发这种新型药物。治疗途径：（1）确定人HCM房间隔的生物力学和微观结构异常组织并开发仿生体外 3D HCM 模型； (2) 开发胶原酶包被的阿霉素- 负载的、可生物降解的纳米颗粒消融系统，并使用体外 3D HCM 优化消融系统模型; (3) 在 HCM 小鼠模型中验证新开发的消融系统的安全性和有效性。拟议的研究为提高不能手术的房间隔消融的安全性和有效性开辟了一条新途径肥厚型心肌病患者。影响是（i）可控、局部消融的创新概念和设计取代不可预测的、扩散的纯酒精消融，以及（ii）有希望的转化潜力。这个区域该项目还将为我们代表性不足的本科生提供宝贵的 NIH 资助的研究机会德克萨斯大学阿灵顿分校的学生，这是德克萨斯州北部的一所西班牙裔服务学院。