Enhancement of ultrasound-accelerated thrombolysis by echo contrast agents: dependence on microbubble structure

Abstract

The combination of ultrasound (US) exposure and ultrasound contrast agent (UCA) further increases the amount of drug-mediated thrombolysis. The aim of this study was to examine the efficacy of the combination of US and UCA on tissue plasminogen activator (tPA) thrombolysis, and the dependence on the microbubble structure. A catheter-type transducer capable of US emission (10 MHz, spatial peak temporal average intensity = 1.02 W/cm 2 and peak negative pressure = 0.33 MPa) in the continuous-wave mode was employed. In 28 artificial white thrombi, serial changes in acoustic properties monitored by echography and histopathology during the tPA-mediated thrombolysis were analyzed. The thrombi were assorted to 4 groups; UCA nontreated (Control), sonicated albumin (A)-, SH-U508A (SH)- and dodecafluoropentane emulsion (DDFP)-treated groups. Persistence of microbubble opacification and thrombus weight were also measured. After the sample was suspended in a beaker with tPA (8000U) and 100 mL of saline, the UCA was administered and the mixture exposed to US for 10 min. Weight reduction of the thrombus was greatest in the DDFP Group (−49 ± 8%), and that in the A Group (−8 ± 5%) was not significantly different from that in the Control Group (−5 ± 1%). The persistence of the microbubbles expressed as the decay of the time-intensity curve, was longest in the DDFP Group. The echo intensity of the superficial layer of the thrombus exposed to US was high and weight loss was marked. Multiple cavity formation was observed histopathologically. The stability of the microbubbles was an important factor of the US and UCA enhancement effect on tPA-mediated thrombolysis. This combination therapy has potential for clinical application in patients with thrombotic arterial and venous occlusion and left arterial thrombus.