Ultrasound Targeted Microbubble Cavitation to Treat Coronary Microvascular Obstruction

随着再灌注治疗的引入，急性心肌梗死（AMI）的死亡率降低 从1980年的20%下降到2008年的5%，但已经趋于平稳，尽管我们的再灌注时间更快。 目前，AMI后充血性心力衰竭（CHF）由于心肌挽救减少和梗死面积增大而日益增多; 主要原因是微血管阻塞（MVO）。其存在与年龄、梗死面积和射血无关 分数与更差的临床结局相关。它导致AMI后射血分数降低， 是AMI后CHF的唯一最重要因素。在我的第一个R 01（ESI状态）中，我们证明了超声 靶向微泡空化（UTMC）可通过声灌注（SRP）缓解MVO， 这一现象背后的机制。重要的是，我们还表明，一氧化氮（NO）是其中的一个重要组成部分。 再灌注功效，通过在NO阻断期间再灌注减少超过50%来证明。 多水平的治疗潜力，特别是MVO，由于其在许多信号转导和 调控途径。此外，有大量的数据表明，在AMI期间增加NO的生物利用度 促进心肌挽救。我们的初步数据表明，UTMC可用于增加NO的生物利用度 并通过以下方式优化SRP的治疗功效：（1）刺激内源性NO释放 从内皮细胞和红细胞;（2）使用血管内微泡递送局部有效载荷， 一个外源性NO供体，亚硝酸钠，阻塞的微血管，导致协同NO输出 显著提高NO生物利用度。我们的最终目标是在PCI后连续使用UTMC， 微血管灌注和最小化氧化应激，以达到最高水平的心肌挽救。 因此，在AIM 1中，我们将调整UTMC以优化两种内皮细胞的内源性NO输出， 和红细胞。在AIM 2中，我们将开发一种新型的亚硝酸盐载药微泡，以增强靶向给药 我们将进行机制细胞研究，以确定是否观察到的协同作用， 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 NO优化的UTMC与亚硝酸盐加载的微泡将提高SRP在临床相关猪中的功效 AMI和MVO模型。对于临床翻译，我们将比较这种优化的UTMC的再灌注疗效 治疗策略采用诊断性高机械指数UTMC， 微泡，目前正在临床试验中探索。 这种在PCI后连续使用SRP的策略是有希望的，代表了我们的研究范式的转变。 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 支架植入术不仅可以保护罪犯动脉，而且还可以保护微循环，这对实现最大限度的挽救至关重要。通过进一步 通过优化UTMC，我们将达到最高水平的安全性和有效性，并改善患者的预后。

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.