Ultrasound Targeted Microbubble Cavitation to Treat Coronary Microvascular Obstruction

超声靶向微泡空化治疗冠状动脉微血管阻塞

• 批准号: 10181828
• 负责人: John J Pacella
• 金额: $ 70.07万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-17 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10181828
• 关键词: 5' -AMP-activated protein kinase; Acoustics; Acute; Acute myocardial infarction; Address; Age; Alteplase; Animal Model; Arteries; Behavior; Biological Availability; Blood Tests; Blood Vessels; Cell Adhesion; Clinical; Clinical Trials; Congestive Heart Failure; Coronary; Coronary artery; Data; Diagnostic; Distal; EFRAC; Endothelial Cells; Erythrocytes; Failure; Funding; Gases; Goals; Hindlimb; Hypotension; Incidence; Infarction; Inflammatory; Intravenous; Ischemia; Lipids; Mechanics; Mediating; Methods; Microbubbles; Microcirculation; Microvascular Permeability; Modeling; Myocardial; Myocardium; Nitric Oxide; Nitric Oxide Donors; Nitrites; Obstruction; Outcome; Output; Oxidative Stress; Oxides; Pathway interactions; Patient-Focused Outcomes; Patients; Perfusion; Physiologic pulse; Physiological; Plasminogen Activator Interaction; Platelet aggregation; Rattus; Regulatory Pathway; Reperfusion Therapy; Rodent; Rodent Model; Role; Safety; Signal Pathway; Site; Sodium Nitrite; Speed; Stents; Swelling; Techniques; Technology; Testing; Therapeutic; Therapeutic Embolization; Thrombus; Time; Translating; Translations; Treatment Efficacy; Trees; Ultrasonic Therapy; Ultrasonography; Vascular Patency; Vasospasm; Viscosity; Work; adverse outcome; clinical translation; clinically relevant; comparative efficacy; effective therapy; heart damage; improved; in vitro Model; indexing; insight; mortality; novel; percutaneous coronary intervention; porcine model; protective effect; shear stress; standard of care; synergism; targeted delivery; treatment strategy

With the introduction of reperfusion therapy, mortality from acute myocardial infarction (AMI) has decreased markedly, from 20% in 1980 to 5% in 2008, but has plateaued, despite the fact that our time to reperfusion is more rapid. Now, post AMI congestive heart failure (CHF) is increasing due to reduced myocardial salvage and greater infarct size; the leading cause is microvascular obstruction (MVO). Its presence, independent of age, infarct size, and ejection fraction, is associated with worse clinical outcomes. It results in lower post AMI ejection fraction and is felt to be the single most important contributor to post AMI CHF. In my first R01 (ESI status), we demonstrated that ultrasound targeted microbubble cavitation (UTMC) can relieve MVO via sonoreperfusion (SRP), and that specific mechanical mechanisms underly this phenomenon. Importantly, we also showed that nitric oxide (NO) is a crucial part of this reperfusion efficacy, evidenced by a more than 50% reduction in reperfusion during blockade of NO. NO has multi-level therapeutic potential, specifically for MVO, owing to its crucial role in numerous signaling and regulatory pathways. Moreover, there is abundant data showing that increasing NO bioavailability during AMI promotes myocardial salvage. Our preliminary data shows that UTMC can be used to increase NO bioavailability and leveraged for optimization of the therapeutic efficacy of SRP by: (1) stimulating endogenous NO release from both endothelial cells and red blood cells; (2) using intravascular microbubbles to deliver focal payloads of an exogenous NO donor, sodium nitrite, to the obstructed microvasculature that result in synergistic NO output and markedly enhanced NO bioavailability. Our ultimate goal is to use UTMC adjunctively, post PCI, to maximize microvascular perfusion and minimize oxidative stress in order to attain the highest level of myocardial salvage. Accordingly, in AIM 1, we will tune UTMC to optimize endogenous NO output from both endothelial cells and red blood cells. In AIM 2, we will develop a novel nitrite-loaded microbubble to enhance targeted delivery of exogenous NO. We will perform mechanistic cellular studies to determine whether the synergy observed between UTMC and nitrite is mediated through the AMPK pathway. Finally, in AIM 3, we will determine whether NO-optimized UTMC with nitrite-loaded microbubbles will enhance SRP efficacy in a clinically relevant porcine model of AMI and MVO. For clinical translation, we will compare reperfusion efficacy of this optimized UTMC regime to a treatment strategy utilizing diagnostic high mechanical index UTMC with commercially available microbubbles, currently being explored in clinical trials. This strategy of using SRP adjunctively following PCI is promising and represents a paradigm shift in our treatment of AMI. It provides a means to offer patients complete vascular patency, not just of the epicardial culprit artery with stenting, but also of the microcirculation, which is crucial to effect maximal salvage. By further optimization of UTMC, we will attain the highest level of safety and efficacy, and improve patient outcome.

随着再灌注疗法的引入，急性心肌梗死（AMI）的死亡率下降 显然，从1980年的20％到2008年的5％，但尽管我们的再灌注时间更快，但仍处于平稳状态。 现在，AMI充血后的心力衰竭（CHF）由于心肌挽救和梗塞大小的增加而增加。 主要原因是微血管阻塞（MVO）。它的存在，独立于年龄，梗塞大小和射血 分数与较差的临床结局有关。它导致较低的AMI射出分数，并认为是 AMI CHF后最重要的贡献者。在我的第一个R01（ESI状态）中，我们证明了超声波 靶向微气泡气氮（UTMC）可以通过SonorePerfusion（SRP）缓解MVO，并且该特定的机械 这种现象的基础机制。重要的是，我们还表明一氧化氮（NO）是关键的部分 再灌注功效，在NO期间封锁期间再灌注降低了50％以上。没有 多层治疗潜力，特别针对MVO，是由于其在众多信号传导中至关重要的作用 监管途径。此外，有大量的数据表明，在AMI期间没有增加生物利用度 促进心肌挽救。我们的初步数据表明，UTMC可用于不增加生物利用度 并利用了SRP的治疗功效的优化：（1）刺激内源性无释放 来自内皮细胞和红细胞。 （2）使用血管内微泡提供焦点有效载荷 外源的无供体硝酸钠对阻塞的微脉管系统导致协同无输出 并且明显增强了没有生物利用度。我们的最终目标是辅助使用UTMC，后PCI，以最大化 微血管灌注并最大程度地减少氧化应激，以达到心肌救助的最高水平。 因此，在AIM 1中，我们将调整UTMC以优化两个内皮细胞的内源性输出 和红细胞。在AIM 2中，我们将开发一种新型亚硝酸盐的微泡以增强目标输送 外源号。我们将进行机械性细胞研究，以确定是否观察到协同作用 UTMC和亚硝酸盐之间通过AMPK途径介导。最后，在AIM 3中，我们将确定是否 带有亚硝酸盐的微泡的未优化UTMC将增强临床相关猪的SRP功效 AMI和MVO的模型。对于临床翻译，我们将比较此优化UTMC的再灌注功效 利用诊断性高机械指数UTMC的治疗策略的制度 微泡，目前正在临床试验中探索。 遵循PCI辅助使用SRP的这种策略是有希望的，代表了我们的范式转变 AMI的处理。它提供了一种为患者提供完整血管通畅的方法，而不仅仅是心外膜 罪魁祸首带有支架，但也具有微循环，这对于影响最大救助至关重要。进一步 优化UTMC，我们将获得最高水平的安全性和功效，并改善患者的结果。