Mechanisms Responsible for Ultrasound-accelerated Fibrinolysis in the Presence and Absence of Optison

摘要

Ultrasound at frequencies greater than 1 MHz is known to accelerate clot dissolution by fibrinolytic agents. It is speculated that ultrasound accelerates enzymatic fibrinolysis primarily through non-thermal mechanisms by increasing transport of drug molecules into the clot. To elucidate the mechanisms of ultrasound-accelerated enzymatic fibrinolysis, the role of both stable and inertial cavitation were investigated during in vitro fibrinolysis by ultrasound in combination with recombinant tissue plasminogen activator (rt-PA) in the presence and absence of Optison. Methods: A unique treatment configuration was used in which ultrasound, rt-PA, and contrast agent were all applied to the interior of a plasma clot. rt-PA was injected directly into the clot at a concentration of 5,000 IU/mL. Optison was dispersed throughout the clot at a concentration of 2.6×10{sup}6 bubbles/mL. The ultrasound exposure consisted of 1.7 MHz pulsed ultrasound with 1.5 MPa spatial-peak peak-negative pressure applied for 30 minutes by a transducer-tipped catheter. Lysis efficacy was measured as clot weight reduction. Cavitational mechanisms were investigated by passively monitoring acoustic emissions from the clot using a focused broadband hydrophone, and quantifying levels of subharmonic emission and broadband noise, indicators for stable and inertial cavitation, respectively. Results and Conclusions: In the absence of Optison, ultrasound plus rt-PA resulted in 45 ± 19% lysis enhancement relative to lysis from rt-PA alone. Cavitation signals were not detected in the corresponding radiated acoustic signal, indicating a role for non-cavitational mechanical effects of ultrasound. The addition of Optison significantly increased lysis enhancement to 88 ± 25%. Broadband noise elevation was present only at the start of the exposure, while low-level subharmonic emissions persisted throughout. Additional experiments suggested that the lysis enhancement in the presence of Optison was correlated to the subharmonic emission rather than the broadband noise, indicating a role for stable cavitation. Mechanisms related to stable cavitation, such as microstreaming near oscillating bubbles, may enhance fibrinolysis by promoting local mass transfer and thus increasing the rate of penetration of rt-PA throughout the clot matrix.