Coronary artery disease (CAD) is a worldwide leading cause of heart attacks, death and disability, and leads to billions of dollars of healthcar expenditures each year. Clinically, a widely effective interventional treatment for CAD is percutaneous coronary intervention (PCI) using coronary metal stents. Over 1 million coronary stents are placed annually in the US alone. Yet, two complications can limit the benefit of coronary stents: restenosis (scarring), and thrombosis (clotting). Prevention of plaque progression and stent complications would eliminate hundreds of thousands of invasive catheterizations, heart attacks, and deaths each year. Biologically, inflammation underlies all of these diseases: atherosclerosis, stent restenosis, and stent thrombosis. Yet the in vivo mechanisms by which inflammation drives plaques progression and the injury response to stenting remains poorly understood. The ability to quantitatively image inflammation in vivo, especially with translatable technology, could provide clinically relevant, vital new insights into these disorders. To address this unmet need, our laboratory is developing coronary artery-targeted intravascular near-infrared fluorescence (NIRF) molecular imaging approaches to image and quantify arterial inflammation and stent healing. Most recently we have developed an early-stage intravascular NIRF-optical frequency domain imaging (OFDI, Nature Medicine 2011; 17:1680-4) system to quantitatively image molecular signals in the context of arterial structure. The objective of this Proposal is to develop translatable intravascular NIRF-OFDI molecular-microstructural imaging approaches to better understand mechanisms of plaque progression and stent complications. This Proposal tests the central hypothesis that integrated NIRF-OFDI will comprehensively assess the role of in vivo inflammation in driving plaque progression, stent restenosis, and stent thrombosis. Our long-term goal is to assess inflammatory mechanisms in human coronary arteries and to ultimately reduce the immense burden of CAD and stent complications.
The Specific Aims of this proposal are:
Specific Aim 1. To engineer a next-generation intravascular NIRF-OFDI 2.9F catheter system.
Specific Aim 2. To determine how plaque inflammation modulates atheroma progression and stent restenosis.
Specific Aim 3. To determine how plaque inflammation modulates stent healing and risk of stent thrombosis. This research will transform the field of atherosclerosis and coronary stenting by (1) providing new, valuable pathobiological knowledge about the role of inflammation in regulating atheroma progression, restenosis, and stent malhealing; and (2) provide translatable strategies for inflammation-structural imaging, to ultimately improve the outcomes of patients with CAD and those undergoing coronary stenting.

Public Health Relevance

This proposal will develop new technology to image plaques and coronary stents that could cause heart attacks and death. We will image inflamed plaques and stents in living subjects that may progress, scar and clot. This information will help better guide current and new therapies to prevent heart attacks and death.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL122388-04
Application #
9397557
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Danthi, Narasimhan
Project Start
2014-11-14
Project End
2018-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
Hara, Tetsuya; Ughi, Giovanni J; McCarthy, Jason R et al. (2017) Intravascular fibrin molecular imaging improves the detection of unhealed stents assessed by optical coherence tomography in vivo. Eur Heart J 38:447-455
Osborn, Eric A; Kessinger, Chase W; Tawakol, Ahmed et al. (2017) Metabolic and Molecular Imaging of Atherosclerosis and Venous Thromboembolism. J Nucl Med 58:871-877
Stein-Merlob, Ashley F; Hara, Tetsuya; McCarthy, Jason R et al. (2017) Atheroma Susceptible to Thrombosis Exhibit Impaired Endothelial Permeability In Vivo as Assessed by Nanoparticle-Based Fluorescence Molecular Imaging. Circ Cardiovasc Imaging 10:
Calfon Press, Marcella A; Mallas, Georgios; Rosenthal, Amir et al. (2017) Everolimus-eluting stents stabilize plaque inflammation in vivo: assessment by intravascular fluorescence molecular imaging. Eur Heart J Cardiovasc Imaging 18:510-518
Bozhko, Dmitry; Osborn, Eric A; Rosenthal, Amir et al. (2017) Quantitative intravascular biological fluorescence-ultrasound imaging of coronary and peripheral arteries in vivo. Eur Heart J Cardiovasc Imaging 18:1253-1261
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
Ughi, Giovanni J; Wang, Hao; Gerbaud, Edouard et al. (2016) Clinical Characterization of Coronary Atherosclerosis With Dual-Modality OCT and Near-Infrared Autofluorescence Imaging. JACC Cardiovasc Imaging 9:1304-1314
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
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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