Methods for non-invasive in vivo molecular imaging of cardiovascular disease have been developed, in large part, for their potential to improve patient care. These methods are already playing an important role in the research setting to discover potentially treatable pathobiology and to assess new therapies in clinical and pre- clinical studies. Our laboratory has pioneered novel contrast-enhanced ultrasound (CEU) molecular imaging techniques that rely on the detection of encapsulated microbubble (MB) contrast agents. This approach uniquely characterizes the endothelial-blood pool interface. In the prior funding period of this award, we used CEU molecular imaging to better understand how endothelial activation and platelet-endothelial interactions help to promote early atherogenesis and contribute to high-risk features in chronic late-stage atherosclerosis. We demonstrated that platelet adhesion occurs primarily because of excess endothelial-associated Von Willebrand factor (VWF) that happens in situations or regions of increased oxidative stress. The overall goal of this proposal is to leverage this knowledge in order to evaluate potentially treatable origins of acute cardiovascular complications that are attributable to the pro-inflammatory and pro-thrombotic effects of platelet adhesion to the endothelium, either in large vessels or the coronary microcirculation. We will also test novel therapies that prevent these events.
In Aim 1, molecular imaging of inflammatory activation, VWF, and platelet adhesion in atherosclerotic mice will be used to characterize global endothelial events that occur after a focal ischemic event (myocardial infarction [MI] or acute limb ischemia), and that we believe contribute to remote plaque activation in non-culprit arteries. We will also test whether platelet-endothelial interactions contribute to remote plaque inflammation; and will assess innovative treatment strategies that are based on their potential to reduce endothelial VWF and suppress platelet-endothelial interactions, including inhibitors of ROS and of Factor XI (FXI).
In Aim 2, we will integrate data from CEU molecular imaging and perfusion imaging in various gene-targeted murine strains undergoing MI in order to assess the contribution of VWF-mediated platelet adhesion to microvascular no-reflow, post-reperfusion inflammatory response, and infarct size. Again, we will test innovative pharmacologic interventions capable of rescuing the activity of the enzyme responsible for preventing excess endothelial VWF (ADAMTS13), including inhibitors of ROS and FXI, and recombinant ADAMTS13.
In Aim 3, myocardial ischemia-reperfusion injury will be performed in obese, atherosclerotic non- human primates (rhesus macaques on Western diet for >2 years). We will integrate data from molecular imaging, perfusion imaging, and morphologic imaging to evaluate the most promising therapies from Aim 1 and Aim 2 for preventing either: (a) impaired microvascular reflow; or (b) remote plaque activation in the carotid artery after MI. These studies are designed as a translational model to test efficacy, proof-of-mechanism, and safety of therapies that we can then apply in humans.

Public Health Relevance

The overall goal of this proposal is to apply many of the discoveries we have made in advanced diagnostic imaging of blood vessel health and apply it to better understand key processes involved in cardiovascular morbidity. Specifically, we believe we can improve healthcare by providing new diagnostic approaches for detecting and quantifying atherosclerotic disease, and create new therapies that prevent the progression of atherosclerotic plaques and injury following heart attack.

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; Weinkauf, Craig C; Davidson, Brian P et al. (2018) Ultrasound Molecular Imaging of Atherosclerosis Using Small-Peptide Targeting Ligands Against Endothelial Markers of Inflammation and Oxidative Stress. Ultrasound Med Biol 44:1155-1163
Tsimikas, Sotirios (2018) In search of a physiological function of lipoprotein(a): causality of elevated Lp(a) levels and reduced incidence of type 2 diabetes. J Lipid Res 59:741-744
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
Tsimikas, Sotirios; Fazio, Sergio; Ferdinand, Keith C et al. (2018) NHLBI Working Group Recommendations to Reduce Lipoprotein(a)-Mediated Risk of Cardiovascular Disease and Aortic Stenosis. J Am Coll Cardiol 71:177-192
Lindner, Jonathan R (2018) Microvascular Dysfunction and Clinical Outcomes. Circ Cardiovasc Imaging 11:e008381
Senders, Max L; Que, Xuchu; Cho, Young Seok et al. (2018) PET/MR Imaging of Malondialdehyde-Acetaldehyde Epitopes With a Human Antibody Detects Clinically Relevant Atherothrombosis. J Am Coll Cardiol 71:321-335

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