title: Inertial Cavitation Ultrasound with Microbubbles Improves Reperfusion Efficacy When Combined with Tissue Plasminogen Activator in an In Vitro Model of Microvascular Obstruction.
abstract: We have previously reported that long-tone-burst, high-mechanical-index ultrasound (US) and microbubble (MB) therapy can restore perfusion in both in vitro and in vivo models of microvascular obstruction (MVO). Addition of MBs to US has been found to potentiate the efficacy of thrombolytics on large venous thrombi; however, the optimal US parameters for achieving microvascular reperfusion of MVO caused by microthrombi, when combined with tissue plasminogen activator (tPA), are unknown. We sought to elucidate the specific effects of US, with and without tPA, for effective reperfusion of MVO in an in vitro model using both venous and arterial microthrombi. Venous- and arterial-type microthrombi were infused onto a mesh with 40-μm pores to simulate MVO. Pulsed US (1 MHz) was delivered with inertial cavitation (IC) (1.0 MPa, 1000 cycles, 0.33 Hz) and stable cavitation (SC) US (0.23 MPa, 20% duty cycle, 0.33 Hz) regimes while MB suspension (2 × 106MBs/mL) was infused. The efficacy of sonoreperfusion with these parameters was tested with and without tPA. Sonoreperfusion efficacy was significantly greater for IC + tPA compared with tPA alone, IC, SC and SC + tPA, suggesting lytic synergism between tPA and US for both venous- and arterial-type microthrombi. In contrast to our previous in vitro studies using 1.5 MPa at 5000 US cycles without tPA, the IC regime employed herein used 90% less US energy. These findings suggest an IC regime can be used with tPA synergistically to achieve a high degree of fibrinolysis for both thrombus types.
authors.affiliation: Center for Ultrasound Molecular Imaging and Therapeutics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Akash
authors.initials: A
authors.lastname: Goyal
authors.affiliation: Center for Ultrasound Molecular Imaging and Therapeutics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Francois T H
authors.initials: FTH
authors.lastname: Yu
authors.affiliation: Center for Ultrasound Molecular Imaging and Therapeutics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Mathea G
authors.initials: MG
authors.lastname: Tenwalde
authors.affiliation: Center for Ultrasound Molecular Imaging and Therapeutics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Xucai
authors.initials: X
authors.lastname: Chen
authors.affiliation: Clinical Biostatistics Core, Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Althouse
authors.affiliation: Center for Ultrasound Molecular Imaging and Therapeutics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Flordeliza S
authors.initials: FS
authors.lastname: Villanueva
authors.affiliation: Center for Ultrasound Molecular Imaging and Therapeutics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. Electronic address: pacellajj@upmc.edu.
authors.forename: John J
authors.initials: JJ
authors.lastname: Pacella
mesh_terms: D000818:Animals; D003131:Combined Modality Therapy / Q000379:methods; D005343:Fibrinolytic Agents / Q000008:administration & dosage; D057086:High-Intensity Focused Ultrasound Ablation / Q000379:methods*; D045423:Microbubbles / Q000627:therapeutic use*; D055806:Microvessels / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D015424:Reperfusion / Q000379:methods*; D013552:Swine; D015912:Thrombolytic Therapy / Q000379:methods*; D013927:Thrombosis / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator
keywords: Microbubbles; Microcirculation; Microvascular obstruction; Myocardial infarction; Sonothrombolysis; Ultrasound; Ultrasound contrast agents