A Controlled Septal Ablation for Inoperable Hypertrophic Cardiomyopathy

项目摘要 肥厚型心肌病(HCM)是一种导致室性心脏异常增厚的遗传性疾病 肌肉，尤其是间隔，导致左心室流出道(LVOT)阻塞。当单独用药时 不足以缓解症状，目前的黄金标准，隔肌切除术，是通过外科手术进行的 通过心脏直视手术去除多余的肌肉。不幸的是，许多病人都不适合做外科手术。 而且需要更少的侵入性治疗选择。在这些情况下，心脏科医生对患者进行最小限度的 有创性插管技术称为酒精间隔消融术(ASA)，其中注入1-4毫升纯酒精 通过间隔穿支(动脉)进入间隔，通过引发坏死破坏部分间隔肌肉。 然而，纯酒精的扩散性质会导致危险的不可控的坏死和非常高的 微创技术的并发症概况。高风险的ASA并发症，围手术期 死亡率~2%，包括房室传导阻滞、室颤/心动过速和完全性心脏传导阻滞 由于没有控制酒精的定位和不分青红皂白的组织破坏。回答未满足的临床问题 需要，最近氰基丙烯酸酯(强力胶)作为纯酒精的替代品被研究，但经验丰富 在有效性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型的消融 系统取代ASA中的纯酒精，实现可控的、局部的间隔组织收缩和 因此，消融更安全。根据我们的初步数据，我们假设胶原酶涂层的输送， 载阿霉素的可降解纳米粒(NPs)将允许阿霉素诱导的局部破坏 肥大的心肌细胞，这种单次给药将导致过度生长的HCM的消退 隔膜组织。阿霉素最近被发现负责清除不想要的肥大 心脏组织，建议单次给药，可避免经常重复给药造成的心脏毒性 曝光。因此，为了更好地理解HCM间隔组织并开发这部小说，作者将追求三个目标 治疗方法：(1)测定人HCM间隔的生物力学和显微结构异常 (2)建立胶原酶包被的阿霉素-阿霉素A-1胶原酶包被的阿霉素-阿霉素胶原酶包被的人巨噬细胞瘤细胞模型。 负载型、可生物降解纳米粒子消融系统和利用体外3DHCM优化消融系统 (3)在HCM小鼠模型上验证新开发的消融系统的安全性和有效性。 这项研究为提高不能手术的鼻中隔消融的安全性和有效性开辟了一条新的途径。 肥厚型心肌炎患者。其影响是：(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)前景看好的转化潜力。这一地区 该项目还将为我们人数不足的本科生提供宝贵的NIH资助的研究机会 德州大学阿灵顿分校的学生，这是一所位于德克萨斯州北部的拉美裔服务学院。

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.