Sonoreperfusion with fibrin-targeted phase shift microbubbles for the treatment of microvascular obstruction

Abstract

More than 1 million Americans yearly have a new or recurrent acute myocardial infarction (AMI). Although the mortality rate from AMI has decreased in recent years, post-MI congestive heart failure is increasing due to microvascular obstruction (MVO), ultimately limiting myocardial salvage. We aim to address this unmet need by devising an image-guided therapy called sonoreperfusion (SRP) to resolve MVO by ultrasound-targeted microbubble cavitation (UTMC). In this study, we hypothesized that fibrin-targeted phase shift microbubbles (FTPSMBs; ∼200 nm) (Microvascular Therapeutics, Inc) would improve SRP efficacy compared to fibrin-targeted microbubbles (FTMBs; 1–3 μm) to treat MVO owing to the smaller size and more efficient microthrombi penetration. A rat hindlimb model of MVO was created by directly injecting freshly prepared porcine microthrombi into the left femoral artery under contrast-enhanced ultrasound imaging (CEUS) guidance, and treated with UTMC (1 MHz, 1.5 MPa, 5 ms pulse duration, 5-sec pulse interval) with concomitant administration of FTPSMBs/FTMBs (3 mL/hr). The treatment effect was accessed with CEUS. UTMC with FTPSMBs caused more rapid and complete reperfusion of rat hindlimb following MVO compared with FTMB, likely owing to their small size and more effective thrombus penetration. Studies to explore the underlying molecular mechanisms associated with SRP treatments are underway.