Ultrasound (US) is used for a variety of therapeutic applications and has been proposed for increasing tissue perfusion in ischemic cardiovascular disease. The most important non- thermal bioeffect by which US can increase perfusion is convective motion which increases shear mechanotransduction. Microbubble (MB) contrast agents used in patients to enhance the blood pool can potentially augment shear through microstreaming during acoustic cavitation. We have recently demonstrated that US-mediated MB cavitation can augment limb tissue perfusion by up to 10-fold and that this effect can persist for greater than 24 hours. The overall aim of this proposal is to assemble a multidisciplinary team to optimize the technology of US- mediated MB cavitation and transition it from pre-clinical models to the treatment of patients with severe symptomatic peripheral artery disease (PAD).
In Aim 1 preclinical small animal models will be used to define optimal conditions for augmenting limb perfusion with regards to acoustic pressure, frequency, MB concentration, and pulsing interval which governs the vascular level at which cavitation occurs. Contrast ultrasound perfusion imaging will be used to assess effect and the type of cavitation (stable versus inertial) will be determined from frequency-power spectra in order to understand the physical determinants for flow augmentation.
In Aim 2 we will use large animal models of PAD to spatially characterize and quantify changes in limb perfusion in relation to the volume of tissue in which cavitation is produced. In both of the first two Aims, data will also be generated to define the safety profile for microbubble cavitation. Understanding the biologic determinants for acute and long-term (>24 hour) flow augmentation will be the subject of Aim 3 where we will examine the role of shear- and pressure-dependent mediators of vascular tone. Potential candidate mediators will include NO, adenosine, eicosanoids, and ATP.
In Aim 4, an existing 3-D with optimized acoustic conditions for MB cavitation will be applied to evaluate limb tissue perfusion in (a) healthy human subjects, and (b) patients with PAD and critical limb ischemia. These studies represent the translational steps for development of a non-invasive therapy for severe PAD that can be used to achieve meaningful and immediate increases in perfusion, and that can maintain limb tissue viability in situations where immediate revascularization is either not immediately possible or available.

Public Health Relevance

The major objective of this project is to develop a new therapeutic approach for immediately increasing blood flow in patients with severe peripheral artery disease who have threatened loss of a limb. The technique involves the application of ultrasound to the limb while administering ul rasound contrast agents that cavitate or 'ring' in the ultrasound field thereby stimulating increa ed flow. In this proposal, we will characterize the ideal ultrasound settings for improving bloodflow, develop a custom therapeutic ultrasound probe, and assess the safety and efficacy of the technology.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL130046-04
Application #
9676350
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Danthi, Narasimhan
Project Start
2016-04-12
Project End
2020-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Lindner, Jonathan R; Link, Jeanne (2018) Molecular Imaging in Drug Discovery and Development. Circ Cardiovasc Imaging 11:e005355
Lindner, Jonathan R (2018) Cause or Effect? Microvascular Dysfunction in Insulin-Resistant States. Circ Cardiovasc Imaging 11:e007725
Ozawa, Koya; Packwood, William; Varlamov, Oleg et al. (2018) Molecular Imaging of VWF (von Willebrand Factor) and Platelet Adhesion in Postischemic Impaired Microvascular Reflow. Circ Cardiovasc Imaging 11:e007913
Atkinson, Tamara; Packwood, William; Xie, Aris et al. (2018) Assessment of Novel Antioxidant Therapy in Atherosclerosis by Contrast Ultrasound Molecular Imaging. J Am Soc Echocardiogr 31:1252-1259.e1
Moccetti, Federico; Brown, Eran; Xie, Aris et al. (2018) Myocardial Infarction Produces Sustained Proinflammatory Endothelial Activation in Remote Arteries. J Am Coll Cardiol 72:1015-1026
Lindner, Jonathan R (2018) Microvascular Dysfunction and Clinical Outcomes. Circ Cardiovasc Imaging 11:e008381
Davidson, Brian P; Belcik, J Todd; Landry, Gregory et al. (2017) Exercise versus vasodilator stress limb perfusion imaging for the assessment of peripheral artery disease. Echocardiography 34:1187-1194
Belcik, J Todd; Davidson, Brian P; Xie, Aris et al. (2017) Augmentation of Muscle Blood Flow by Ultrasound Cavitation Is Mediated by ATP and Purinergic Signaling. Circulation 135:1240-1252
Oehler, Andrew C; Minnier, Jessica; Lindner, Jonathan R (2017) Increased Coronary Tortuosity Is Associated with Increased Left Ventricular Longitudinal Myocardial Shortening. J Am Soc Echocardiogr 30:1028-1034.e2
Davidson, Brian P; Hodovan, James; Belcik, J Todd et al. (2017) Rest-Stress Limb Perfusion Imaging in Humans with Contrast Ultrasound Using Intermediate-Power Imaging and Microbubbles Resistant to Inertial Cavitation. J Am Soc Echocardiogr 30:503-510.e1

Showing the most recent 10 out of 21 publications