New imaging methods are urgently needed to identify and to guide treatment of high-risk atherosclerotic plaques before lead to their devastating complications of myocardial infarction and stroke. While imaging technologies have made progress in illuminating plaque volume and plaque structure, they do not routinely visualize aspects of plaque biology such as inflammation, a key determinant of plaque complications. Imaging of molecular and cellular detail in atherosclerosis offers a transformative approach to improve the biological diagnosis, risk stratification, and treatment of high-risk plaques. In addition, molecular imaging of atherosclerosis can identify new pharmacotherapies that favorably alter plaque biology (e.g. anti-inflammatory), with the potential to streamline drug development and to efficiently bring new therapies into the clinic. At present however, existing molecular imaging approaches are unable to routinely visualize high-risk plaques in human coronary arteries. The long-term objective of this grant proposal is to develop new human coronary artery-targeted intravascular near-infrared fluorescence (NIRF) molecular imaging strategies to identify atherosclerotic plaques responsible for myocardial infarction. Recently, a one-dimensional, manual pullback intravascular NIRF sensing catheter established the feasibility of imaging plaque inflammation through blood in coronary-sized vessels. The Proposal now aims to develop a next-generation intravascular NIRF catheter capable of true two- dimensional NIRF imaging in human coronary-sized arteries in vivo.
Specific Aim 1 will design, construct, and validate a rotational and automated pullback NIRF catheter to enable 360-degree and longitudinal 2D vessel wall imaging of atheroma inflammation in rabbit aortic vessels, an advance over existing limited-arc spectroscopic NIRF catheters.
Specific Aim 2 will utilize the validated NIRF rotational catheter to assess anti- inflammatory (statin) effects in experimental atherosclerosis, extending the in vivo imaging armamentarium to assess the efficacy of therapeutics for vascular disease.
Specific Aim 3 investigates the ability of indocyanine green, an FDA-approved diagnostic imaging agent, to serve as an inflammation-targeted intravascular NIRF imaging agent for atherosclerotic plaques.
Specific Aim 4 tests the NIRF catheter's ability to perform molecular imaging directly in experimental coronary arteries in vivo, with the goal of accelerating catheter translation into the clinical arena. The Proposal builds on established large animal catheter-based imaging efforts in the Investigator's laboratory and leverages established engineering, imaging, and biological expertise from a multidisciplinary team.

Public Health Relevance

New imaging methods are urgently needed to identify high-risk atherosclerotic plaques before they cause heart attacks. This research project is directed at developing new fluorescence catheters and approaches for imaging of high-risk plaques in human coronary-sized arteries. The results from this project could enable the development of clinical fluorescence imaging strategies to reduce heart attacks.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL108229-05
Application #
8663946
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Danthi, Narasimhan
Project Start
2010-07-15
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
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Verjans, Johan W; Osborn, Eric A; Ughi, Giovanni J et al. (2016) Targeted Near-Infrared Fluorescence Imaging of Atherosclerosis: Clinical and Intracoronary Evaluation of Indocyanine Green. JACC Cardiovasc Imaging 9:1087-1095
Stein-Merlob, Ashley F; Kessinger, Chase W; Erdem, S Sibel et al. (2015) Blood Accessibility to Fibrin in Venous Thrombosis is Thrombus Age-Dependent and Predicts Fibrinolytic Efficacy: An In Vivo Fibrin Molecular Imaging Study. Theranostics 5:1317-27
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Osborn, Eric A; Jaffer, Farouc A (2015) Imaging inflammation and neovascularization in atherosclerosis: clinical and translational molecular and structural imaging targets. Curr Opin Cardiol 30:671-80
Ughi, Giovanni J; Verjans, Johan; Fard, Ali M et al. (2015) Dual modality intravascular optical coherence tomography (OCT) and near-infrared fluorescence (NIRF) imaging: a fully automated algorithm for the distance-calibration of NIRF signal intensity for quantitative molecular imaging. Int J Cardiovasc Imaging 31:259-68
Sawada, Naoki; Jiang, Aihua; Takizawa, Fumihiko et al. (2014) Endothelial PGC-1? mediates vascular dysfunction in diabetes. Cell Metab 19:246-58
Hara, Tetsuya; Truelove, Jessica; Tawakol, Ahmed et al. (2014) 18F-fluorodeoxyglucose positron emission tomography/computed tomography enables the detection of recurrent same-site deep vein thrombosis by illuminating recently formed, neutrophil-rich thrombus. Circulation 130:1044-52

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