Non-invasive anatomic and functional imaging of vascular inflammation and unstable plaque.

Over the last several decades, basic cardiovascular research has significantly enhanced our understanding of pathobiological processes leading to formation, progression, and complications of atherosclerotic plaques. By harnessing these advances in cardiovascular biology, imaging has advanced beyond its traditional anatomical domains to a tool that permits probing of particular molecular structures to image cellular behaviour and metabolic pathways involved in atherosclerosis. From the nascent atherosclerotic plaque to the death of inflammatory cells, several potential molecular and micro-anatomical targets for imaging with particular selective imaging probes and with a variety of imaging modalities have emerged from preclinical and animal investigations. Yet, substantive barriers stand between experimental use and wide clinical application of these novel imaging strategies. Each of the imaging modalities described herein faces hurdles-for example, sensitivity, resolution, radiation exposure, reproducibility, availability, standardization, or costs. This review summarizes the published literature reporting on functional imaging of vascular inflammation in atherosclerotic plaques emphasizing those techniques that have the greatest and/or most immediate potential for broad application in clinical practice. The prospective evaluation of these techniques and standardization of protocols by multinational networks could serve to determine their added value in clinical practice and guide their development and deployment.

[1]  F. Grosveld,et al.  Atherosclerotic Lesion Size and Vulnerability Are Determined by Patterns of Fluid Shear Stress , 2006, Circulation.

[2]  Jonathan R. Lindner,et al.  Imaging Tumor Angiogenesis With Contrast Ultrasound and Microbubbles Targeted to &agr;v&bgr;3 , 2003 .

[3]  Z. Fayad,et al.  Feasibility of in vivo identification of endogenous ferritin with positive contrast MRI in rabbit carotid crush injury using GRASP , 2006, Magnetic resonance in medicine.

[4]  V. Fuster,et al.  Relationships Among Regional Arterial Inflammation, Calcification, Risk Factors, and Biomarkers: A Prospective Fluorodeoxyglucose Positron-Emission Tomography/Computed Tomography Imaging Study , 2009, Circulation. Cardiovascular imaging.

[5]  Filippo Crea,et al.  Coronary microvascular dysfunction. , 2013, The New England journal of medicine.

[6]  Chun Yuan,et al.  In vivo accuracy of multispectral magnetic resonance imaging for identifying lipid-rich necrotic cores and intraplaque hemorrhage in advanced human carotid plaques. , 2002 .

[7]  T. Akasaka,et al.  Feasibility of noninvasive assessment of thin-cap fibroatheroma by multidetector computed tomography. , 2009, JACC. Cardiovascular imaging.

[8]  Hirofumi Anno,et al.  Multislice computed tomographic characteristics of coronary lesions in acute coronary syndromes. , 2007, Journal of the American College of Cardiology.

[9]  E. Edelman,et al.  Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior. , 2007, Journal of the American College of Cardiology.

[10]  J. Gillard,et al.  Identifying Inflamed Carotid Plaques Using In Vivo USPIO-Enhanced MR Imaging to Label Plaque Macrophages , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[11]  S. Achenbach,et al.  Noninvasive assessment of plaque morphology and composition in culprit and stable lesions in acute coronary syndrome and stable lesions in stable angina by multidetector computed tomography. , 2006, Journal of the American College of Cardiology.

[12]  J. Gillard,et al.  High-resolution magnetic resonance imaging-based biomechanical stress analysis of carotid atheroma: a comparison of single transient ischaemic attack, recurrent transient ischaemic attacks, non-disabling stroke and asymptomatic patient groups. , 2011, European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery.

[13]  Shuiyu Lu,et al.  Single-step high-yield radiosynthesis and evaluation of a sensitive 18F-labeled ligand for imaging brain peripheral benzodiazepine receptors with PET. , 2009, Journal of medicinal chemistry.

[14]  Ralph Weissleder,et al.  Noninvasive Vascular Cell Adhesion Molecule-1 Imaging Identifies Inflammatory Activation of Cells in Atherosclerosis , 2006, Circulation.

[15]  M J Davies,et al.  Plaque fissuring--the cause of acute myocardial infarction, sudden ischaemic death, and crescendo angina. , 1985, British heart journal.

[16]  E. Boerwinkle,et al.  From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. , 2003, Circulation.

[17]  E. Warburton,et al.  FDG–PET can distinguish inflamed from non-inflamed plaque in an animal model of atherosclerosis , 2009, The International Journal of Cardiovascular Imaging.

[18]  Ahmed Tawakol,et al.  In vivo 18F-fluorodeoxyglucose positron emission tomography imaging provides a noninvasive measure of carotid plaque inflammation in patients. , 2006, Journal of the American College of Cardiology.

[19]  René M. Botnar,et al.  Noninvasive Assessment of Atherosclerotic Plaque Progression in ApoE−/− Mice Using Susceptibility Gradient Mapping , 2011, Circulation. Cardiovascular imaging.

[20]  Chun Yuan,et al.  Quantitative Magnetic Resonance Imaging Analysis of Neovasculature Volume in Carotid Atherosclerotic Plaque , 2003, Circulation.

[21]  M. Rubens,et al.  Chronic inflammation and coronary microvascular dysfunction in patients without risk factors for coronary artery disease. , 2009, European heart journal.

[22]  Shelton D Caruthers,et al.  Molecular imaging of angiogenesis in early-stage atherosclerosis with alpha(v)beta3-integrin-targeted nanoparticles. , 2003, Circulation.

[23]  Richard D. White,et al.  Contrast enhancement of coronary atherosclerotic plaque: a high-resolution, multidetector-row computed tomography study of pressure-perfused, human ex-vivo coronary arteries , 2006, Coronary artery disease.

[24]  C. Caro Discovery of the Role of Wall Shear in Atherosclerosis , 2009, Arteriosclerosis, thrombosis, and vascular biology.

[25]  Chun Yuan,et al.  In Vivo Quantitative Measurement of Intact Fibrous Cap and Lipid-Rich Necrotic Core Size in Atherosclerotic Carotid Plaque: Comparison of High-Resolution, Contrast-Enhanced Magnetic Resonance Imaging and Histology , 2005, Circulation.

[26]  C. Yuan,et al.  MRI in the early identification and classification of high-risk atherosclerotic carotid plaques. , 2010, Imaging in medicine.

[27]  B. Weber,et al.  18F-Choline Images Murine Atherosclerotic Plaques Ex Vivo , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[28]  R. Virmani,et al.  Pathology of the Vulnerable Plaque , 2006 .

[29]  A. Sinusas,et al.  Atherosclerosis Plaque Heterogeneity and Response to Therapy Detected by In Vivo Molecular Imaging of Matrix Metalloproteinase Activation , 2011, The Journal of Nuclear Medicine.

[30]  Aad van der Lugt,et al.  Determinants of magnetic resonance imaging detected carotid plaque components: the Rotterdam Study. , 2012, European heart journal.

[31]  Masatoshi Ishibashi,et al.  Simvastatin attenuates plaque inflammation: evaluation by fluorodeoxyglucose positron emission tomography. , 2006, Journal of the American College of Cardiology.

[32]  Axel Thran,et al.  Note: This Copy Is for Your Personal, Non-commercial Use Only. to Order Presentation-ready Copies for Distribution to Your Colleagues or Clients, Contact Us at Www.rsna.org/rsnarights. Atherosclerotic Plaque Composition: Analysis with Multicolor Ct and Targeted Gold Nanoparticles 1 Materials and Met , 2022 .

[33]  C. Yuan,et al.  Discriminating Carotid Atherosclerotic Lesion Severity by Luminal Stenosis and Plaque Burden: A Comparison Utilizing High-Resolution Magnetic Resonance Imaging at 3.0 Tesla , 2011, Stroke.

[34]  P. Libby,et al.  Selective Inhibition of Matrix Metalloproteinase-13 Increases Collagen Content of Established Mouse Atherosclerosis , 2011, Arteriosclerosis, thrombosis, and vascular biology.

[35]  G. Moneta,et al.  Association Between Carotid Plaque Characteristics and Subsequent Ischemic Cerebrovascular Events: A Prospective Assessment With MRI—Initial Results , 2007 .

[36]  O. Rimoldi,et al.  Molecular imaging of vascular inflammation , 2010, European Journal of Nuclear Medicine and Molecular Imaging.

[37]  P. Libby,et al.  A novel fluorescent probe for the detection of myeloperoxidase activity in atherosclerosis-associated macrophages , 2009 .

[38]  W. Kerwin Noninvasive imaging of plaque inflammation: role of contrast-enhanced MRI. , 2010, JACC. Cardiovascular imaging.

[39]  P. Libby,et al.  Hypoxia but not inflammation augments glucose uptake in human macrophages: Implications for imaging atherosclerosis with 18fluorine-labeled 2-deoxy-D-glucose positron emission tomography. , 2011, Journal of the American College of Cardiology.

[40]  Hirofumi Anno,et al.  Computed tomographic angiography characteristics of atherosclerotic plaques subsequently resulting in acute coronary syndrome. , 2009, Journal of the American College of Cardiology.

[41]  Fabien Hyafil,et al.  Quantification of Inflammation Within Rabbit Atherosclerotic Plaques Using the Macrophage-Specific CT Contrast Agent N1177: A Comparison with 18F-FDG PET/CT and Histology , 2009, Journal of Nuclear Medicine.

[42]  R. Weissleder,et al.  Cellular Imaging of Inflammation in Atherosclerosis Using Magnetofluorescent Nanomaterials , 2006, Molecular imaging.

[43]  Timur Shtatland,et al.  Osteogenesis Associates With Inflammation in Early-Stage Atherosclerosis Evaluated by Molecular Imaging In Vivo , 2007, Circulation.

[44]  V. Fuster,et al.  The High-Risk Plaque Initiative: Primary Prevention of Atherothrombotic Events in the Asymptomatic Population , 2011, Current atherosclerosis reports.

[45]  Zahi A. Fayad,et al.  Imaging of atherosclerotic cardiovascular disease , 2008, Nature.

[46]  Ahmed Tawakol,et al.  Feasibility of FDG imaging of the coronary arteries: comparison between acute coronary syndrome and stable angina. , 2010, JACC. Cardiovascular imaging.

[47]  Martin J Graves,et al.  Assessment of Inflammatory Burden Contralateral to the Symptomatic Carotid Stenosis Using High-Resolution Ultrasmall, Superparamagnetic Iron Oxide–Enhanced MRI , 2006, Stroke.

[48]  S. P. S. Howarth,et al.  Temporal dependence of in vivo USPIO-enhanced MRI signal changes in human carotid atheromatous plaques , 2009, Neuroradiology.

[49]  Sungeun Kim,et al.  Vascular Inflammation in Patients With Impaired Glucose Tolerance and Type 2 Diabetes: Analysis With 18F-Fluorodeoxyglucose Positron Emission Tomography , 2010, Circulation. Cardiovascular imaging.

[50]  T. Imaizumi,et al.  Vascular inflammation evaluated by [18F]-fluorodeoxyglucose positron emission tomography is associated with the metabolic syndrome. , 2007, Journal of the American College of Cardiology.

[51]  B. Kaufmann Ultrasound Molecular Imaging of Cardiovascular Disease , 2010 .

[52]  P. Libby,et al.  Activatable Magnetic Resonance Imaging Agent Reports Myeloperoxidase Activity in Healing Infarcts and Noninvasively Detects the Antiinflammatory Effects of Atorvastatin on Ischemia-Reperfusion Injury , 2008, Circulation.

[53]  Vasilis Ntziachristos,et al.  Two-dimensional intravascular near-infrared fluorescence molecular imaging of inflammation in atherosclerosis and stent-induced vascular injury. , 2011, Journal of the American College of Cardiology.

[54]  V. Fuster,et al.  Targeted Molecular Probes for Imaging Atherosclerotic Lesions With Magnetic Resonance Using Antibodies That Recognize Oxidation-Specific Epitopes , 2008, Circulation.

[55]  Samuel A. Wickline,et al.  Molecular Imaging of Angiogenesis in Early-Stage Atherosclerosis With &agr;v&bgr;3-Integrin–Targeted Nanoparticles , 2003 .

[56]  Zahi A Fayad,et al.  Imaging atherosclerotic plaque inflammation , 2008, Nature Clinical Practice Cardiovascular Medicine.

[57]  R. Virmani,et al.  Targeting of Apoptotic Macrophages and Experimental Atheroma With Radiolabeled Annexin V: A Technique With Potential for Noninvasive Imaging of Vulnerable Plaque , 2003, Circulation.

[58]  Bernd J Pichler,et al.  Radionuclide imaging: a molecular key to the atherosclerotic plaque. , 2008, Journal of the American College of Cardiology.

[59]  A. Davies,et al.  Imaging of vascular inflammation with [11C]-PK11195 and positron emission tomography/computed tomography angiography. , 2010, Journal of the American College of Cardiology.

[60]  Ralph Weissleder,et al.  High-Resolution Magnetic Resonance Imaging Enhanced With Superparamagnetic Nanoparticles Measures Macrophage Burden in Atherosclerosis , 2010, Circulation.

[61]  V. Fuster,et al.  (18)Fluorodeoxyglucose positron emission tomography imaging of atherosclerotic plaque inflammation is highly reproducible: implications for atherosclerosis therapy trials. , 2007, Journal of the American College of Cardiology.

[62]  E. Warburton,et al.  Finite element analysis of vulnerable atherosclerotic plaques: a comparison of mechanical stresses within carotid plaques of acute and recently symptomatic patients with carotid artery disease , 2009, Journal of Neurology, Neurosurgery & Psychiatry.

[63]  A. Davies,et al.  Imaging intraplaque inflammation in carotid atherosclerosis with 11C-PK11195 positron emission tomography/computed tomography. , 2012, European heart journal.

[64]  Dalin Tang,et al.  Sites of Rupture in Human Atherosclerotic Carotid Plaques Are Associated With High Structural Stresses: An In Vivo MRI-Based 3D Fluid-Structure Interaction Study , 2009, Stroke.

[65]  Jonathan R. Lindner,et al.  Molecular imaging of cardiovascular disease with contrast-enhanced ultrasonography , 2009, Nature Reviews Cardiology.

[66]  F. Epstein,et al.  Multimodality cardiovascular molecular imaging, part I. , 2008, Circulation. Cardiovascular imaging.

[67]  Chun Yuan,et al.  Identification of Fibrous Cap Rupture With Magnetic Resonance Imaging Is Highly Associated With Recent Transient Ischemic Attack or Stroke , 2002, Circulation.

[68]  Jeroen J. Bax,et al.  Head-to-head comparison of coronary plaque evaluation between multislice computed tomography and intravascular ultrasound radiofrequency data analysis. , 2008, JACC. Cardiovascular interventions.

[69]  Roberto Chiesa,et al.  Contrast-enhanced ultrasound imaging of intraplaque neovascularization in carotid arteries: correlation with histology and plaque echogenicity. , 2008, Journal of the American College of Cardiology.

[70]  R. Boellaard,et al.  Noninvasive imaging of macrophages in rheumatoid synovitis using 11C-(R)-PK11195 and positron emission tomography. , 2008, Arthritis and rheumatism.

[71]  J. Lindner,et al.  Molecular Imaging of Inflammation in Atherosclerosis With Targeted Ultrasound Detection of Vascular Cell Adhesion Molecule-1 , 2007, Circulation.

[72]  Sameer Bansilal,et al.  Atherosclerosis Inflammation Imaging with 18F-FDG PET: Carotid, Iliac, and Femoral Uptake Reproducibility, Quantification Methods, and Recommendations , 2008, Journal of Nuclear Medicine.

[73]  J. Gladman,et al.  Plaque hemorrhage is a marker of thromboembolic activity in patients with symptomatic carotid disease. , 2011, Radiology.

[74]  C. Braestrup,et al.  Specific benzodiazepine receptors in rat brain characterized by high-affinity (3H)diazepam binding. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[75]  J. Wykrzykowska,et al.  Imaging of Inflamed and Vulnerable Plaque in Coronary Arteries with 18F-FDG PET/CT in Patients with Suppression of Myocardial Uptake Using a Low-Carbohydrate, High-Fat Preparation , 2009, Journal of Nuclear Medicine.

[76]  P. Joshi,et al.  Coronary atherosclerosis imaging by coronary CT angiography: current status, correlation with intravascular interrogation and meta-analysis. , 2011, JACC. Cardiovascular imaging.

[77]  M. Gavish,et al.  The peripheral-type benzodiazepine receptor and the cardiovascular system. Implications for drug development. , 2006, Pharmacology & therapeutics.

[78]  René M. Botnar,et al.  Selective coronary artery plaque visualization and differentiation by contrast-enhanced inversion prepared MRI. , 2006, European heart journal.

[79]  Zahi A Fayad,et al.  Noninvasive detection of macrophages using a nanoparticulate contrast agent for computed tomography , 2007, Nature Medicine.

[80]  Peter Libby,et al.  Atherosclerosis and proteinase activation. , 2006, Cardiovascular research.

[81]  G. Moneta Moderate Carotid Artery Stenosis: MR Imaging—depicted Intraplaque Hemorrhage Predicts Risk of Cerebrovascular Ischemic Events in Asymptomatic Men , 2010 .

[82]  C. Yuan,et al.  MR Carotid Plaque Imaging and Contrast-Enhanced MR Angiography Identifies Lesions Associated with Recent Ipsilateral Thromboembolic Symptoms: An In Vivo Study at 3T , 2010, American Journal of Neuroradiology.

[83]  Chun Yuan,et al.  In vivo accuracy of multisequence MR imaging for identifying unstable fibrous caps in advanced human carotid plaques , 2003, Journal of magnetic resonance imaging : JMRI.

[84]  Oliver Gaemperli,et al.  Detection and Quantification of Large-Vessel Inflammation with 11C-(R)-PK11195 PET/CT , 2011, The Journal of Nuclear Medicine.

[85]  V. Fuster,et al.  The BioImage Study: novel approaches to risk assessment in the primary prevention of atherosclerotic cardiovascular disease--study design and objectives. , 2010, American heart journal.

[86]  Mario J. Garcia,et al.  Report of the National Heart, Lung, and Blood Institute working group on the translation of cardiovascular molecular imaging. , 2011, Circulation.

[87]  W. Kerwin,et al.  The vulnerable, or high-risk, atherosclerotic plaque: noninvasive MR imaging for characterization and assessment. , 2007, Radiology.

[88]  Eun Jeong Lee,et al.  Reversal of Vascular 18F-FDG Uptake with Plasma High-Density Lipoprotein Elevation by Atherogenic Risk Reduction , 2008, Journal of Nuclear Medicine.

[89]  W. Kerwin,et al.  Carotid artery atherosclerosis: effect of intensive lipid therapy on the vasa vasorum--evaluation by using dynamic contrast-enhanced MR imaging. , 2011, Radiology.

[90]  Richard B. Banati,et al.  Positron emission tomography imaging of neuroinflammation , 2007, Neurotherapeutics.

[91]  M. Imaizumi,et al.  Increased peripheral benzodiazepine receptors in arterial plaque of patients with atherosclerosis: an autoradiographic study with [(3)H]PK 11195. , 2008, Atherosclerosis.

[92]  P. Casellas,et al.  Peripheral benzodiazepine receptor modulation with phagocyte differentiation. , 1993, Biochemical pharmacology.

[93]  Aloke V. Finn,et al.  Atherosclerotic Plaque Progression and Vulnerability to Rupture: Angiogenesis as a Source of Intraplaque Hemorrhage , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[94]  Anne L. Martel,et al.  Characterization of Complicated Carotid Plaque With Magnetic Resonance Direct Thrombus Imaging in Patients With Cerebral Ischemia , 2003, Circulation.

[95]  C. Yuan,et al.  Comparison of symptomatic and asymptomatic atherosclerotic carotid plaque features with in vivo MR imaging. , 2006, Radiology.

[96]  Chun Yuan,et al.  Presence of Intraplaque Hemorrhage Stimulates Progression of Carotid Atherosclerotic Plaques: A High-Resolution Magnetic Resonance Imaging Study , 2005, Circulation.

[97]  L. Badimón,et al.  Imaging of early inflammation in low-to-moderate carotid stenosis by 18-FDG-PET. , 2009, Frontiers in bioscience.

[98]  Diffusion-weighted magnetic resonance imaging for the detection of lipid-rich necrotic core in carotid atheroma in vivo , 2010, Neuroradiology.

[99]  R. Cury,et al.  Intra‐ and interreader reproducibility of magnetic resonance imaging for quantifying the lipid‐rich necrotic core is improved with gadolinium contrast enhancement , 2006, Journal of magnetic resonance imaging : JMRI.

[100]  Ahmed Tawakol,et al.  Noninvasive in vivo measurement of vascular inflammation with F-18 fluorodeoxyglucose positron emission tomography , 2005, Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology.

[101]  A. Alavi,et al.  FDG-PET is an effective imaging modality to detect and quantify age-related atherosclerosis in large arteries , 2008, European Journal of Nuclear Medicine and Molecular Imaging.

[102]  R. Cury,et al.  Vulnerable Plaque Detection by 3.0 Tesla Magnetic Resonance Imaging , 2006, Investigative radiology.

[103]  Martin J Graves,et al.  The ATHEROMA (Atorvastatin Therapy: Effects on Reduction of Macrophage Activity) Study. Evaluation using ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging in carotid disease. , 2009, Journal of the American College of Cardiology.

[104]  M. Reiser,et al.  18F-FDG PET/CT Identifies Patients at Risk for Future Vascular Events in an Otherwise Asymptomatic Cohort with Neoplastic Disease , 2009, Journal of Nuclear Medicine.

[105]  P. Libby,et al.  Improved characterization of atherosclerotic plaques by gadolinium contrast during intravascular magnetic resonance imaging of human arteries. , 2008, Atherosclerosis.

[106]  N. Wong,et al.  Molecular imaging of matrix metalloproteinase in atherosclerotic lesions: resolution with dietary modification and statin therapy. , 2008, Journal of the American College of Cardiology.

[107]  Chun Yuan,et al.  Inflammation in carotid atherosclerotic plaque: a dynamic contrast-enhanced MR imaging study. , 2006, Radiology.

[108]  P. Casellas,et al.  Distribution profile and properties of peripheral-type benzodiazepine receptors on human hemopoietic cells. , 1993, Life sciences.

[109]  Chun Yuan,et al.  Association Between Carotid Plaque Characteristics and Subsequent Ischemic Cerebrovascular Events: A Prospective Assessment With MRI—Initial Results , 2006, Stroke.

[110]  V. Fuster,et al.  Increased Neovascularization in Advanced Lipid-Rich Atherosclerotic Lesions Detected by Gadofluorine-M–Enhanced MRI: Implications for Plaque Vulnerability , 2009, Circulation. Cardiovascular imaging.

[111]  R Weissleder,et al.  Molecular imaging. , 2009, Radiology.

[112]  Ralph Weissleder,et al.  18F-4V for PET-CT imaging of VCAM-1 expression in atherosclerosis. , 2009, JACC. Cardiovascular imaging.

[113]  Fabien Hyafil,et al.  Inflammation Imaging in Atherosclerosis , 2009, Arteriosclerosis, thrombosis, and vascular biology.