Coronary thrombosis on a ruptured coronary plaque is the main pathophysiologic event that leads to acute coronary syndromes (ACS). Clinical methods currently utilized to treat this are fibrinolytic agents or percutaneous coronary interventions, combined with anti-platelet agents. Several in vitro and pre-clinical investigations have examined the effect of ultrasound to enhance thrombolysis (termed sonolysis). Transcutaneous high mechanical index (MI) ultrasound and intravenous microbubbles have successfully recanalized peripheral vessel thromboses in animal studies. Our preliminary mechanistic studies have shown that an essential component for effective sonolysis is applying high MI cavitation-inducing impulses only when low MI imaging detects microbubbles as they transit through small micro-channels within the thrombus. The potential for transthoracic sonolysis in ACS is limited by several factors, including attenuation of the ultrasound beam, coronary size and motion relative to the ultrasound field, downstream microvascular flow, and safety factors related to the high MI impulses. The central hypothesis of this study is that coronary recanalization in ACS with sonolysis can be over 90% successful when using three-dimensional high MI impulses guided by low MI pulse sequence schemes which detect microbubbles within the affected coronary artery perfusion bed. In this project we will test the effect of attenuation, insonation angle, and peak negative acoustic pressure on the success rate of thrombus issolution with high MI guided ultrasound. Coronary simulation studies will be performed which examine the effect of these variables, as well as what effect three-dimensional diagnostic ultrasound and microbubble targeting strategies have on increasing the amount of cavitation at the site of a thrombosed vessel during the guided high MI impulses. These findings will then be extended to an open-chest atherosclerotic pig model, where we will examine what effect two- versus three-dimensional high MI impulses have on cavitation within the thrombosed coronary artery and downstream microvasculature, and how this impacts coronary recanalization rates. Finally, we will apply these findings to a closed-chest atherosclerotic pig model. We will prospectively compare the effectiveness of the guided ultrasound approach to conventional fibrinolytic therapy in both a) recantalizing the thrombosed coronary artery and b) improving microcirculatory flow. With the completion of these studies, a Phase I clinical trials could potentially be initiated exploring whether three-dimensional sonolysis could be utilized in the emergency department or pre-hospital setting to treat patients with acute coronary syndromes. Public Health Relevance Statement (provided by applicant): The three-dimensional/microbubble sonolysis could be utilized in the emergency department or pre-hospital setting to treat patients with acute coronary syndromes. It would serve as a more rapid, less costly, and safer approach to acute coronary syndromes than fibrinolytic therapy or emergent percutaneous coronary interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB009050-05
Application #
8323996
Study Section
Special Emphasis Panel (ZEB1-OSR-B (O1))
Program Officer
Lopez, Hector
Project Start
2008-09-30
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$536,911
Indirect Cost
$167,524
Name
University of Nebraska Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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Wu, Juefei; Xie, Feng; Kumar, Tanmay et al. (2014) Improved sonothrombolysis from a modified diagnostic transducer delivering impulses containing a longer pulse duration. Ultrasound Med Biol 40:1545-53
Xie, Feng; Gao, Shunji; Wu, Juefei et al. (2013) Diagnostic ultrasound induced inertial cavitation to non-invasively restore coronary and microvascular flow in acute myocardial infarction. PLoS One 8:e69780
Kutty, Shelby; Wu, Juefei; Hammel, James M et al. (2012) Microbubble mediated thrombus dissolution with diagnostic ultrasound for the treatment of chronic venous thrombi. PLoS One 7:e51453
Porter, Thomas R; Xie, Feng (2012) Can transcranial ultrasound and microbubble therapy ever enter the mainstream in acute stroke therapy? Expert Rev Cardiovasc Ther 10:549-51
Xie, Feng; Slikkerveer, Jeroen; Gao, Shunji et al. (2011) Coronary and microvascular thrombolysis with guided diagnostic ultrasound and microbubbles in acute ST segment elevation myocardial infarction. J Am Soc Echocardiogr 24:1400-8
Xie, Feng; Everbach, E Carr; Gao, Shunji et al. (2011) Effects of attenuation and thrombus age on the success of ultrasound and microbubble-mediated thrombus dissolution. Ultrasound Med Biol 37:280-8
Kutty, Shelby; Xie, Feng; Gao, Shunji et al. (2010) Sonothrombolysis of intra-catheter aged venous thrombi using microbubble enhancement and guided three-dimensional ultrasound pulses. J Am Soc Echocardiogr 23:1001-6