Microvascular no reflow in acute MI—Mechanistic studies of sonoreperfusion

Abstract

Congestive heart failure (CHF) following acute myocardial infarction (AMI) is on the rise. Microvascular obstruction (MVO) is the single most important contributor to post-AMI CHF; it occurs in up to 80% of patients with AMI and is associated with worse outcomes. To address this unmet need, we have been developing ultrasound targeted microbubble cavitation (UTMC) to achieve “sonoreperfusion” (SRP) for MVO. During SRP, US is applied to intravenously administered MBs as they transit the coronary microcirculation, which causes MBs to oscillate and generate shear stress. We have previously shown that SRP therapy restores perfusion during MVO through direct mechanical “chiseling” effects of MBs on microthrombi. However, MVO is more than just physical obstruction from microemboli; it is characterized by a milieu of inflammation and oxidative stress, a state of imbalance between the formation of damaging reactive oxygen species (ROS) and antioxidant defenses. One such defense is nitric oxide (NO), which has multi-level therapeutic potential for MVO. We have demonstrated that UTMC releases NO from endothelial cells through mechanotransduction, and that NO is a major contributor to the efficacy of SRP. We are now actively pursuing strategies to optimize SRP, not only through mechanical mechanisms but also by addressing oxidative stress.