Fibrin-targeted phase shift microbubbles outperform fibrin-targeted microbubbles for the treatment of microvascular obstruction

Abstract

Introduction: Mortality from AMI has decreased in recent years; however, microvascular obstruction (MVO) occurs frequently, ultimately limits myocardial salvage, is associated with rising post-AMI CHF, and has no definitive therapy. To address this urgent unmet need, we have developed an image-guided acute therapy, termed “sonoreperfusion” (SRP), that resolves MVO via ultrasound-targeted microbubble cavitation (UTMC). We previously used standard MBs with fibrin-targeting and demonstrated enhanced reperfusion compared to standard MBs with non-targeting. However, phase shift microbubbles are much smaller than standard MBs. Thus, we compared the SRP efficacies of fibrin-targeted phase shift microbubbles (FTPSMB) to standard size fibrin-targeted microbubbles (FTMBs). Methods: MVO of the rat hindlimb was created by injecting microthrombi into the left femoral artery under contrast-enhanced ultrasound (CEUS) guidance. DEFINITY® MBs were infused (2 ml/h) through the right external jugular vein for CEUS. Following 10 min of stable MVO, a transducer was positioned vertically above the hindlimb to deliver therapeutic US pulses during concomitant administration of FTMBs/FTPSMBs (3 ml/h). Results and conclusion: FTPSMB treatment resulted in a greater increase in the blood volume (dB) and flow rate (dB/sec) than FTMB after each 10-minute treatment session owing to their small size and more effective thrombus penetration. Studies to explore the underlying molecular mechanisms associated with SRP treatments are underway