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: 10406302
• 负责人: John J Pacella
• 金额: $ 71.36万
• 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/10406302
• 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; 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; ultrasound

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