In Vitro Evaluation of Ultrasound-Assisted Thrombolysis Using a Targeted Ultrasound Contrast Agent

Abstract

Shear wave elasticity imaging (SWEI) was employed to track acoustic radiation force impulse (ARFI)-induced shear waves in the mid-myocardium of the left ventricular free wall (LVFW) of a beating canine heart. Shear waves were generated and tracked with a linear ultrasound transducer that was placed directly on the exposed epicardium. Acquinsition was ECG-gated arid coincided with the mid-diastolic portion of the cardiac cycle. Axial displacement profiles consistent with shear wave propagation were clearly evident in all SWEI acquisitions (i.e., those including an ARFI excitation); displacement data from control cases (i.e., sequences lacking an ARFI excitation) offered no evidence of shear wave propagation and yielded a peak absolute mean displacement below 0.31 μm after motion filtering. Shear wave velocity estimates ranged from 0.82 to 2.65 m/s and were stable across multiple heartbeats for the same interrogation region, with coefficients of variation less than 19% for all matched acquisitions. Variations in velocity estimates suggest a spatial dependence of shear wave velocity through the mid-myocardium of the LVFW, with velocity estimates changing, in limited cases, through depth and lateral position.

Sonothrombolysis with Magnetically Targeted Microbubbles

“…To the best of the authors' knowledge, this is the first report of magnetically targeted microbubbles as a method to accelerate sonothrombolysis. Targeted sonothrombolysis has been previously investigated in vitro and in vivo using various "biological" microbubble targeting methods (e.g., antibody conjugation) (Alonso et al 2009;Chen et al 2009;Culp et al 2004;Wu et al 1998;Xie et al 2009b). Higher plasma D-dimer levels have been reported in rats treated with pulsed 2-MHz US and platelet-specific, abciximab-coated immunobubbles, compared with the non-specific immunobubble control group.…”

Sonothrombolysis

“…They concluded instead that strong inertial cavitation shielded the acoustic energy from the thrombus. Although strong inertial activity appears to enhance thrombolysis in some cases (Chen et al 2009; Maxwell et al 2009), sustained bubble activity is difficult (Prokop et al 2007), potentially due to the destruction of cavitation nuclei (Datta et al 2006). …”

“…These studies confirm thrombolytic efficacy using ultrasound and microbubbles alone, emphasizing the importance of cavitation activity. Several groups have developed thrombus-specific microbubbles with the ability to target clots for both imaging (Unger et al 1998; Chen et al 2009) and therapy (Alonso et al 2009; Hagisawa et al 2013) (Fig. 19.6).…”

“…However, there was no significant difference in the infarct volume if targeted or non-targeted microbubbles were used. Several additional studies demonstrated enhanced thrombolytic efficacy in-vitro (Unger et al 1998; Chen et al 2009) and in-vivo (Alonso et al 2009; Hagisawa et al 2013) using targeted microbubbles. It should be noted that the treatment parameters employed in several other studies did not produce appreciable thrombolytic efficacy with ultrasound alone (Frenkel et al 2006; Datta et al 2006; Prokop et al 2007; Shaw et al 2008; Petit et al 2012a) or with microbubbles (Datta et al 2008; Petit et al 2012a; Bader et al 2015).…”

Diagnosis and treatment of platelet hyperactivity in relation to thrombosis in dogs and cats

“…The results showed that tirofiban had a dose‐dependent antithrombotic effect but also a dose‐dependent increase in bleeding time from 3.5 minutes in controls to 13 minutes at the lowest tested drug concentration and >30 minutes at the highest concentration . Interestingly, tirofiban has also been used to target ultrasound contrast to the site of thrombus formation in dogs …”