Approximately 1.1 million deaths each year are a result of emboli from carotid artery atherosclerosis. These deaths are highly preventable through lifestyle changes or drug therapy if the development of atherosclerosis is detected prior to plaque formation. Similarly, interventional treatment and therapy is available with good clinica efficacy at later stages of the disease if carotid plaques can be adequately characterized (i.e. vulnerable versus stable plaques). Ultrasound-based targeted molecular imaging represents an emerging technology with potential to provide both earlier detection of carotid atherosclerosis and more specific diagnosis and characterization of carotid plaques. However, current use of microbubble-based ultrasound imaging in the clinic is limited to a narrow set of indications (e.g. liver nodule diagnosis) and current clinical use of targeted microbubble imaging is non-existent largely due to technical challenges associated with imaging in large arteries. The overarching goal of this project is to break down the technological barriers currently preventing clinical utilty of ultrasound-based targeted molecular imaging for prevention of stroke. Successful achievement of this goal will involve in vivo demonstration of a novel targeted molecular imaging technology, called singular spectrum-based targeted molecular (SiSTM) imaging, with greater than 95% sensitivity and specificity for detection of early molecular markers for atherosclerosis in rabbit aorta arteries. Beam sequences specific to SiSTM imaging will be optimized for enhanced sensitivity and specificity including an adaptive blood velocity correction technique. Additionally, a dual frequency 1.5D molecular imaging probe will be designed, fabricated, and implemented on a research scanner. In vivo sensitivity and specificity of SiSTM imaging in large arteries will be assessed using Watanabe heritable hyperlipidemic strain (WHHL) rabbits exhibiting genetic predisposition for extreme hypercholesterolemia and advanced atherosclerosis. Immunohistochemistry results for disease markers will be correlated with SiSTM imaging data.

Public Health Relevance

Stroke is a leading cause of death in the world representing an estimated 7.2 million deaths annually. Ultrasound-based molecular imaging strategies are an emerging technology with potential for early detection and prevention of stroke by enabling early or prompt therapy of carotid atherosclerosis using simpler, lower risk, and lower cost approaches. This project will develop a new ultrasound-based molecular imaging technology, called singular spectrum-based targeted molecular (SiSTM) imaging, and validate the technique for detection of early markers for cardiovascular disease in in vivo rabbit studies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL111077-02
Application #
8528708
Study Section
Biomedical Imaging Technology Study Section (BMIT)
Program Officer
Kindzelski, Andrei L
Project Start
2012-08-15
Project End
2016-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$342,568
Indirect Cost
$104,568
Name
University of Virginia
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Wang, Shiying; Hossack, John A; Klibanov, Alexander L et al. (2014) Binding dynamics of targeted microbubbles in response to modulated acoustic radiation force. Phys Med Biol 59:465-84
Wang, Shiying; Mauldin, F William; Klibanov, Alexander L et al. (2013) Shear forces from flow are responsible for a distinct statistical signature of adherent microbubbles in large vessels. Mol Imaging 12:396-408