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.