R01HL157497

Ultrasound Targeted Microbubble Cavitation to Treat Coronary Microvascular Obstruction

With the introduction of reperfusion therapy, mortality from acute myocardial infarction (AMI) has decreased markedly, from 20% in 1980 to 5% in 2008. However, despite the fact that our time to reperfusion is more rapid, the mortality rate has plateaued. Now, post-AMI congestive heart failure (CHF) is increasing due to reduced myocardial salvage and greater infarct size, with the leading cause being microvascular obstruction (MVO). The presence of MVO, independent of age, infarct size, and ejection fraction, is associated with worse clinical outcomes. It results in a lower post-AMI ejection fraction and is felt to be the single most important contributor to post-AMI CHF.

In our first R01 (ESI status), we demonstrated that ultrasound targeted microbubble cavitation (UTMC) can relieve MVO via sonoreperfusion (SRP), and that specific mechanical mechanisms underlie 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.

University Of Pittsburgh - Of The Commonwealth System Of Higher Education

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Pennsylvania United States

State-Wide

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 395% from $700,687 to $3,464,986.