Ultrasound (US) is used for a variety of therapeutic applications. Over a range of different frequencies and powers, US has been shown to produce to produce modest increases in arterial diameter and tissue perfusion in animal models of limb and myocardial ischemia. In the initial funding period for this award, we described how the combination of US with microbubble (MB) contrast agents that undergo inertial cavitation during high-power contrast-enhanced US (CEU) produces much greater augmentation of limb skeletal muscle perfusion (up to 10-fold) than US alone. Brief CEU cavitation protocols were found to reverse limb ischemia for >24 hrs in animal models, and a clinical trial in patients with peripheral artery disease (PAD) confirmed that MB cavitation increases limb perfusion by several fold. In the course of our studies, optimal conditions for these bioeffects were investigated which mandated us to design novel US pulse schemes and 3-D exposure capability. From a mechanistic standpoint, we carefully mapped pathways responsible for cavitation-induced flow augmentation which rely on shear-mediated ATP release from endothelial cells and erythrocytes, with secondary purinergic vasodilation through downstream mediators (NO, prostaglandins, adenosine). Knowledge of the optimal conditions and mechanistic underpinnings is critical for our current efforts to apply cavitation and activation of ATP channels to treat ischemic disease by augmenting flow or by other potentially beneficial anti-thrombotic and anti-inflammatory effects of purinergic signaling. The overall aim of this renewal is to leverage knowledge from the first funding period in order to explore the therapeutic role of cavitation and non-cavitation US for acute and chronic ischemic syndromes.
In Aim 1 preclinical models will be used to determine whether limb flow-augmentation from MB cavitation using previously-optimized pulse schemes can: (a) prevent tissue necrosis in acute ischemia, with a particular focus on the effect of clinical variables (age, sex, hyperlipidemia, diabetes), and (b) improve wound healing and limb function in chronic disease. The functional role of purinergic vascular signaling will be evaluated by using inhibitor strategies or gene--modified models.
In Aim 2 we will determine whether MB cavitation directly augments myocardial perfusion in acute MI using murine models that allow us to manipulate purinergic pathways, and in primate models that more closely resemble human biology. We will also study how US-mediated ATP release has the potential to mitigate inflammation, and microvascular thrombosis upon reperfusion.
In Aim 3 we will test whether US energy from multi-element high-power intra- arterial catheters increases downstream perfusion through shear-mediated purinergic pathways.
This Aim i s based on evidence that therapeutic US catheters used in patients with pulmonary embolism can reduce pulmonary vascular resistance even without clot lysis. Our proposal represents the translational steps for development of non-invasive therapies for acute and chronic vascular diseases and will form the basis for the design of clinical trials that we plan to initiate as the key unsolved issues are addressed.

Public Health Relevance

The major objective of this project is to develop a new therapeutic approach for immediately increasing blood flow in patients who have severe atherosclerotic or thrombotic diseases that cause a critical lack of blood flow to the heart, legs or lung. The technique involves the application of ultrasound, with or without simultaneous administration of ultrasound contrast agents that cavitate or ?ring? in the ultrasound field. These ultrasound effects stimulate the release of substances that cause vasodilation and that reduce both inflammation and thrombosis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Danthi, Narasimhan
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Oregon Health and Science University
Internal Medicine/Medicine
Schools of Medicine
United States
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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

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