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

基本信息

批准号：
10610782
负责人：
John J Pacella
金额：
$ 71.55万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
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/10610782
关键词：
5&apos -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 Ischemia Legal patent 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 Vascular Patency Vasospasm Viscosity Work adverse outcome clinical translation clinically relevant comparative efficacy effective therapy heart damage improved in vitro Model indexing insight intravenous administration mortality novel percutaneous coronary intervention porcine model protective effect shear stress standard of care synergism targeted delivery treatment strategy ultrasound vibration

项目摘要

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.

随着再灌注治疗的引入，急性心肌梗死（AMI）的死亡率有所下降明显地，从 1980 年的 20% 下降到 2008 年的 5%，但已趋于稳定，尽管事实上我们的再灌注时间更快。现在，由于心肌抢救减少和梗塞面积扩大，AMI 后充血性心力衰竭 (CHF) 正在增加；主要原因是微血管阻塞（MVO）。它的存在与年龄、梗塞大小和射血无关分数，与较差的临床结果相关。它会导致 AMI 后射血分数降低，并且被认为 AMI 后 CHF 的最重要贡献者。在我的第一个 R01（ESI 状态）中，我们证明了超声靶向微泡空化 (UTMC) 可以通过声灌注 (SRP) 缓解 MVO，并且该特定机械这一现象背后的机制。重要的是，我们还表明一氧化氮 (NO) 是这一过程的重要组成部分。再灌注疗效，通过阻断 NO 期间再灌注减少 50% 以上来证明。没有多层次的治疗潜力，特别是 MVO，因为它在许多信号传导和监管途径。此外，有大量数据表明，AMI 期间 NO 生物利用度的增加促进心肌挽救。我们的初步数据表明 UTMC 可用于提高 NO 生物利用度并通过以下方式优化 SRP 的治疗效果：(1) 刺激内源性 NO 释放来自内皮细胞和红细胞； (2)利用血管内微泡来传递焦点有效载荷外源性 NO 供体亚硝酸钠，作用于阻塞的微血管，导致协同 NO 输出并显着提高NO的生物利用度。我们的最终目标是在 PCI 之后辅助使用 UTMC，以最大限度地提高微血管灌注并最大限度地减少氧化应激，以达到最高水平的心肌挽救。因此，在 AIM 1 中，我们将调整 UTMC 以优化内皮细胞的内源性 NO 输出和红细胞。在 AIM 2 中，我们将开发一种新型载有亚硝酸盐的微泡，以增强靶向递送外源性NO。我们将进行机制细胞研究，以确定是否观察到协同作用 UTMC 和亚硝酸盐之间的相互作用是通过 AMPK 途径介导的。最后，在 AIM 3 中，我们将确定是否具有负载亚硝酸盐的微泡的 NO 优化 UTMC 将增强临床相关猪的 SRP 功效 AMI 和 MVO 模型。对于临床转化，我们将比较这种优化的 UTMC 的再灌注功效利用诊断性高机械指数 UTMC 和市售产品的治疗策略方案微泡，目前正在临床试验中进行探索。这种在 PCI 之后辅助使用 SRP 的策略是有前途的，代表了我们的范式转变。 AMI 的治疗。它提供了一种为患者提供完全血管通畅的方法，而不仅仅是心外膜的通畅通过支架置入罪魁祸首动脉，同时也影响微循环，这对于实现最大程度的挽救至关重要。通过进一步 UTMC 的优化，我们将达到最高水平的安全性和有效性，并改善患者的治疗结果。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effect of Ultrasound Pulse Length on Sonoreperfusion Therapy.

超声脉冲长度对超声灌注治疗的影响。

DOI：
发表时间：
2023-01
期刊：
影响因子：
2.9
作者：
Yu, François T H;Amjad, Muhammad Wahab;Mohammed, Soheb Anwar;Yu, Gary Z;Chen, Xucai;Pacella, John J
通讯作者：
Pacella, John J

Dynamic Behavior of Polymer Microbubbles During Long Ultrasound Tone-Burst Excitation and Its Application for Sonoreperfusion Therapy.

聚合物微泡在长超声猝发激励过程中的动态行为及其在超声灌注治疗中的应用。