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Pathobiology and Mechanisms of Atherosclerosis

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Cardiovascular Imaging

Abstract

Atherosclerosis is a disease of medium and large arteries in which atherosclerotic plaque narrowing of the arterial lumen causes obstruction of blood flow and tissue ischemia. Vascular inflammation is central to the pathobiology of atherosclerosis, and inflammatory processes play critical roles in early plaque formation, plaque progression, and atherothrombotic plaque complications. Advances in anatomic and molecular imaging techniques have enhanced the ability to quantify atherosclerotic plaque burden and to study the cellular and molecular processes that promote atherogenesis. This chapter provides an overview of the mechanisms of atherosclerosis and focuses on structural and physiological entities that can be evaluated by anatomic or molecular imaging techniques.

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Abbreviations

ALP:

Alkaline phosphatase

CT:

Computed tomography

CTA:

CT angiography

CVD:

Cardiovascular disease

EC:

Endothelial cell

ECM:

Extracellular matrix

FCH:

Fluorocholine

FDG:

Fluorine-labeled 2-deoxy-D-glucose

Gp IIb/IIIa:

Glycoprotein IIb/IIIa

HMGCOA:

3-hydroxy-3-methylglutaryl-coenzyme A

HSP:

Heat shock proteins

ICAM-1:

Intercellular adhesion molecule 1

IPH:

Intraplaque hemorrhage

IVUS:

Intravascular ultrasound

LDL:

Low-density lipoprotein

LOX-1:

Lectin-like oxidized LDL receptor

LSS:

Low shear stress

MCP-1:

Monocyte chemotactic protein 1

MDA:

Malondialdehyde-lysine

MGP:

Matrix Gla-protein

MI:

Myocardial infarction

MMP:

Matrix metalloproteinases

MPO:

Myeloperoxidase

MRA:

Magnetic resonance angiography

MRI:

Magnetic resonance imaging

NaF:

Sodium fluoride

NIR:

Near infrared

NO:

Nitric oxide

OCT:

Optical coherence tomography

OFDI:

Optical frequency domain imaging

PET:

Positron emission tomography

PPARγ:

Peroxisome proliferator-activated receptor γ

PS:

Phosphatidylserine

RBC:

Red blood cells

RGD:

Arg-Gly-Asp

ROS:

Reactive oxygen species

SMC:

Smooth muscle cell

SPECT:

Single-photon emission computed tomography

SPIO:

Superparamagnetic iron oxide probes

SR:

Scavenger receptors

SR-A:

Scavenger receptor-A

TF:

Tissue factor

TGF-β:

Transforming growth factor-β

TLR:

Toll-like receptor

TNF-α:

Tumor necrosis factor-α

t-PA:

Plasminogen activator

u-PA:

Urokinase plasminogen activator

USPIO:

Ultrasmall superparamagnetic iron oxide

VCAM-1:

Vascular cell adhesion molecule 1

VH-IVUS:

Virtual histology IVUS

References

  1. Pober JS, Sessa WC. Evolving functions of endothelial cells in inflammation. Nat Rev Immunol. 2007;7:803–15.

    CAS  PubMed  Google Scholar 

  2. Guerci B, Bohme P, Kearney-Schwartz A, Zannad F, Drouin P. Endothelial dysfunction and type 2 diabetes. Part 2: altered endothelial function and the effects of treatments in type 2 diabetes mellitus. Diabetes Metab. 2001;27:436–47.

    CAS  PubMed  Google Scholar 

  3. Feron O, Dessy C, Moniotte S, Desager JP, Balligand JL. Hypercholesterolemia decreases nitric oxide production by promoting the interaction of caveolin and endothelial nitric oxide synthase. J Clin Invest. 1999;103:897–905.

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Labreuche J, Deplanque D, Touboul PJ, Bruckert E, Amarenco P. Association between change in plasma triglyceride levels and risk of stroke and carotid atherosclerosis: systematic review and meta-regression analysis. Atherosclerosis. 2010;212:9–15.

    CAS  PubMed  Google Scholar 

  5. Barua RS, Ambrose JA, Eales-Reynolds LJ, DeVoe MC, Zervas JG, Saha DC. Dysfunctional endothelial nitric oxide biosynthesis in healthy smokers with impaired endothelium-dependent vasodilatation. Circulation. 2001;104:1905–10.

    CAS  PubMed  Google Scholar 

  6. Barua RS, Ambrose JA, Srivastava S, DeVoe MC, Eales-Reynolds LJ. Reactive oxygen species are involved in smoking-induced dysfunction of nitric oxide biosynthesis and upregulation of endothelial nitric oxide synthase: an in vitro demonstration in human coronary artery endothelial cells. Circulation. 2003;107:2342–7.

    CAS  PubMed  Google Scholar 

  7. Ota Y, Kugiyama K, Sugiyama S, Ohgushi M, Matsumura T, Doi H, Ogata N, Oka H, Yasue H. Impairment of endothelium-dependent relaxation of rabbit aortas by cigarette smoke extract – role of free radicals and attenuation by captopril. Atherosclerosis. 1997;131:195–202.

    CAS  PubMed  Google Scholar 

  8. Zhang S, Day I, Ye S. Nicotine induced changes in gene expression by human coronary artery endothelial cells. Atherosclerosis. 2001;154:277–83.

    CAS  PubMed  Google Scholar 

  9. Chiu JJ, Chien S. Effects of disturbed flow on vascular endothelium: pathophysiological basis and clinical perspectives. Physiol Rev. 2011;91:327–87.

    PubMed  Google Scholar 

  10. Hsieh HJ, Liu CA, Huang B, Tseng AH, Wang DL. Shear-induced endothelial mechanotransduction: the interplay between reactive oxygen species (ROS) and nitric oxide (NO) and the pathophysiological implications. J Biomed Sci. 2014;21:3.

    PubMed Central  PubMed  Google Scholar 

  11. Miyazaki T, Taketomi Y, Takimoto M, Lei XF, Arita S, Kim-Kaneyama JR, Arata S, Ohata H, Ota H, Murakami M, Miyazaki A. m-calpain induction in vascular endothelial cells on human and mouse atheromas and its roles in VE-cadherin disorganization and atherosclerosis. Circulation. 2011;124:2522–32.

    CAS  PubMed  Google Scholar 

  12. Ley K, Laudanna C, Cybulsky MI, Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol. 2007;7:678–89.

    CAS  PubMed  Google Scholar 

  13. Robbins CS, Chudnovskiy A, Rauch PJ, Figueiredo JL, Iwamoto Y, Gorbatov R, Etzrodt M, Weber GF, Ueno T, van Rooijen N, Mulligan-Kehoe MJ, Libby P, Nahrendorf M, Pittet MJ, Weissleder R, Swirski FK. Extramedullary hematopoiesis generates Ly-6C(high) monocytes that infiltrate atherosclerotic lesions. Circulation. 2012;125:364–74.

    PubMed Central  PubMed  Google Scholar 

  14. Swirski FK, Pittet MJ, Kircher MF, Aikawa E, Jaffer FA, Libby P, Weissleder R. Monocyte accumulation in mouse atherogenesis is progressive and proportional to extent of disease. Proc Natl Acad Sci U S A. 2006;103:10340–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Swirski FK, Libby P, Aikawa E, Alcaide P, Luscinskas FW, Weissleder R, Pittet MJ. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest. 2007;117:195–205.

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, Figueiredo JL, Kohler RH, Chudnovskiy A, Waterman P, Aikawa E, Mempel TR, Libby P, Weissleder R, Pittet MJ. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science. 2009;325:612–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  17. Tacke F, Alvarez D, Kaplan TJ, Jakubzick C, Spanbroek R, Llodra J, Garin A, Liu J, Mack M, van Rooijen N, Lira SA, Habenicht AJ, Randolph GJ. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J Clin Invest. 2007;117:185–94.

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Johnson JL, Newby AC. Macrophage heterogeneity in atherosclerotic plaques. Curr Opin Lipidol. 2009;20:370–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Stoger JL, Gijbels MJ, van der Velden S, Manca M, van der Loos CM, Biessen EA, Daemen MJ, Lutgens E, de Winther MP. Distribution of macrophage polarization markers in human atherosclerosis. Atherosclerosis. 2012;225:461–8.

    PubMed  Google Scholar 

  20. Kruth HS. The fate of lipoprotein cholesterol entering the arterial wall. Curr Opin Lipidol. 1997;8:246–52.

    CAS  PubMed  Google Scholar 

  21. Kruth HS. Sequestration of aggregated low-density lipoproteins by macrophages. Curr Opin Lipidol. 2002;13:483–8.

    CAS  PubMed  Google Scholar 

  22. Newby AC, George SJ, Ismail Y, Johnson JL, Sala-Newby GB, Thomas AC. Vulnerable atherosclerotic plaque metalloproteinases and foam cell phenotypes. Thromb Haemost. 2009;101:1006–11.

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Mach F, Schonbeck U, Bonnefoy JY, Pober JS, Libby P. Activation of monocyte/macrophage functions related to acute atheroma complication by ligation of cd40: induction of collagenase, stromelysin, and tissue factor. Circulation. 1997;96:396–9.

    CAS  PubMed  Google Scholar 

  24. Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell. 2011;145:341–55.

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Toutouzas K, Synetos A, Nikolaou C, Tsiamis E, Tousoulis D, Stefanadis C. Matrix metalloproteinases and vulnerable atheromatous plaque. Curr Top Med Chem. 2012;12:1166–80.

    CAS  PubMed  Google Scholar 

  26. Rademakers T, Douma K, Hackeng TM, Post MJ, Sluimer JC, Daemen MJ, Biessen EA, Heeneman S, van Zandvoort MA. Plaque-associated vasa vasorum in aged apolipoprotein e-deficient mice exhibit proatherogenic functional features in vivo. Arterioscler Thromb Vasc Biol. 2013;33:249–56.

    CAS  PubMed  Google Scholar 

  27. Galis ZS, Khatri JJ. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res. 2002;90:251–62.

    CAS  PubMed  Google Scholar 

  28. Lutgens SP, Cleutjens KB, Daemen MJ, Heeneman S. Cathepsin cysteine proteases in cardiovascular disease. FASEB J. 2007;21:3029–41.

    CAS  PubMed  Google Scholar 

  29. Ambrose JA, Tannenbaum MA, Alexopoulos D, Hjemdahl-Monsen CE, Leavy J, Weiss M, Borrico S, Gorlin R, Fuster V. Angiographic progression of coronary artery disease and the development of myocardial infarction. J Am Coll Cardiol. 1988;12:56–62.

    CAS  PubMed  Google Scholar 

  30. Mann J, Davies MJ. Mechanisms of progression in native coronary artery disease: role of healed plaque disruption. Heart. 1999;82:265–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  31. Richardson PD, Davies MJ, Born GV. Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques. Lancet. 1989;2:941–4.

    CAS  PubMed  Google Scholar 

  32. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2000;20:1262–75.

    CAS  PubMed  Google Scholar 

  33. Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest. 1994;94:2493–503.

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Nikkari ST, O’Brien KD, Ferguson M, Hatsukami T, Welgus HG, Alpers CE, Clowes AW. Interstitial collagenase (MMP-1) expression in human carotid atherosclerosis. Circulation. 1995;92:1393–8.

    CAS  PubMed  Google Scholar 

  35. Herman MP, Sukhova GK, Libby P, Gerdes N, Tang N, Horton DB, Kilbride M, Breitbart RE, Chun M, Schonbeck U. Expression of neutrophil collagenase (matrix metalloproteinase-8) in human atheroma: a novel collagenolytic pathway suggested by transcriptional profiling. Circulation. 2001;104:1899–904.

    CAS  PubMed  Google Scholar 

  36. Sukhova GK, Schonbeck U, Rabkin E, Schoen FJ, Poole AR, Billinghurst RC, Libby P. Evidence for increased collagenolysis by interstitial collagenases-1 and -3 in vulnerable human atheromatous plaques. Circulation. 1999;99:2503–9.

    CAS  PubMed  Google Scholar 

  37. Shah PK, Falk E, Badimon JJ, Fernandez-Ortiz A, Mailhac A, Villareal-Levy G, Fallon JT, Regnstrom J, Fuster V. Human monocyte-derived macrophages induce collagen breakdown in fibrous caps of atherosclerotic plaques. Potential role of matrix-degrading metalloproteinases and implications for plaque rupture. Circulation. 1995;92:1565–9.

    CAS  PubMed  Google Scholar 

  38. Aikawa E, Aikawa M, Libby P, Figueiredo JL, Rusanescu G, Iwamoto Y, Fukuda D, Kohler RH, Shi GP, Jaffer FA, Weissleder R. Arterial and aortic valve calcification abolished by elastolytic cathepsin s deficiency in chronic renal disease. Circulation. 2009;119:1785–94.

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Lutgens E, van Suylen RJ, Faber BC, Gijbels MJ, Eurlings PM, Bijnens AP, Cleutjens KB, Heeneman S, Daemen MJ. Atherosclerotic plaque rupture: local or systemic process? Arterioscler Thromb Vasc Biol. 2003;23:2123–30.

    CAS  PubMed  Google Scholar 

  40. Alexopoulos N, Raggi P. Calcification in atherosclerosis. Nat Rev Cardiol. 2009;6:681–8.

    CAS  PubMed  Google Scholar 

  41. O’Donnell CJ, Kavousi M, Smith AV, Kardia SL, Feitosa MF, Hwang SJ, Sun YV, Province MA, Aspelund T, Dehghan A, Hoffmann U, Bielak LF, Zhang Q, Eiriksdottir G, van Duijn CM, Fox CS, de Andrade M, Kraja AT, Sigurdsson S, Elias-Smale SE, Murabito JM, Launer LJ, van der Lugt A, Kathiresan S, Krestin GP, Herrington DM, Howard TD, Liu Y, Post W, Mitchell BD, O’Connell JR, Shen H, Shuldiner AR, Altshuler D, Elosua R, Salomaa V, Schwartz SM, Siscovick DS, Voight BF, Bis JC, Glazer NL, Psaty BM, Boerwinkle E, Heiss G, Blankenberg S, Zeller T, Wild PS, Schnabel RB, Schillert A, Ziegler A, Munzel TF, White CC, Rotter JI, Nalls M, Oudkerk M, Johnson AD, Newman AB, Uitterlinden AG, Massaro JM, Cunningham J, Harris TB, Hofman A, Peyser PA, Borecki IB, Cupples LA, Gudnason V, Witteman JC. Genome-wide association study for coronary artery calcification with follow-up in myocardial infarction. Circulation. 2011;124:2855–64.

    PubMed Central  PubMed  Google Scholar 

  42. Folsom AR, Kronmal RA, Detrano RC, O’Leary DH, Bild DE, Bluemke DA, Budoff MJ, Liu K, Shea S, Szklo M, Tracy RP, Watson KE, Burke GL. Coronary artery calcification compared with carotid intima-media thickness in the prediction of cardiovascular disease incidence: the multi-ethnic study of atherosclerosis (mesa). Arch Intern Med. 2008;168:1333–9.

    PubMed Central  PubMed  Google Scholar 

  43. Arbab-Zadeh A, Nakano M, Virmani R, Fuster V. Acute coronary events. Circulation. 2012;125:1147–56.

    PubMed Central  PubMed  Google Scholar 

  44. Falk E, Nakano M, Bentzon JF, Finn AV, Virmani R. Update on acute coronary syndromes: the pathologists’ view. Eur Heart J. 2013;34:719–28.

    CAS  PubMed  Google Scholar 

  45. Sugiyama S, Kugiyama K, Aikawa M, Nakamura S, Ogawa H, Libby P. Hypochlorous acid, a macrophage product, induces endothelial apoptosis and tissue factor expression: involvement of myeloperoxidase-mediated oxidant in plaque erosion and thrombogenesis. Arterioscler Thromb Vasc Biol. 2004;24:1309–14.

    CAS  PubMed  Google Scholar 

  46. van den Berg JJ, Op den Kamp JA, Lubin BH, Roelofsen B, Kuypers FA. Kinetics and site specificity of hydroperoxide-induced oxidative damage in red blood cells. Free Radic Biol Med. 1992;12:487–98.

    PubMed  Google Scholar 

  47. Nagy E, Eaton JW, Jeney V, Soares MP, Varga Z, Galajda Z, Szentmiklosi J, Mehes G, Csonka T, Smith A, Vercellotti GM, Balla G, Balla J. Red cells, hemoglobin, heme, iron, and atherogenesis. Arterioscler Thromb Vasc Biol. 2010;30:1347–53.

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Abraham NG, Lavrovsky Y, Schwartzman ML, Stoltz RA, Levere RD, Gerritsen ME, Shibahara S, Kappas A. Transfection of the human heme oxygenase gene into rabbit coronary microvessel endothelial cells: protective effect against heme and hemoglobin toxicity. Proc Natl Acad Sci U S A. 1995;92:6798–802.

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Balla G, Jacob HS, Eaton JW, Belcher JD, Vercellotti GM. Hemin: a possible physiological mediator of low density lipoprotein oxidation and endothelial injury. Arterioscler Thromb. 1991;11:1700–11.

    CAS  PubMed  Google Scholar 

  50. Tavora F, Cresswell N, Li L, Ripple M, Burke A. Immunolocalisation of fibrin in coronary atherosclerosis: implications for necrotic core development. Pathology. 2010;42:15–22.

    CAS  PubMed  Google Scholar 

  51. Ionita MG, van den Borne P, Catanzariti LM, Moll FL, de Vries JP, Pasterkamp G, Vink A, de Kleijn DP. High neutrophil numbers in human carotid atherosclerotic plaques are associated with characteristics of rupture-prone lesions. Arterioscler Thromb Vasc Biol. 2010;30:1842–8.

    CAS  PubMed  Google Scholar 

  52. Martin-Ventura JL, Leclercq A, Blanco-Colio LM, Egido J, Rossignol P, Meilhac O, Michel JB. Low plasma levels of HSP70 in patients with carotid atherosclerosis are associated with increased levels of proteolytic markers of neutrophil activation. Atherosclerosis. 2007;194:334–41.

    CAS  PubMed  Google Scholar 

  53. Martin-Ventura JL, Nicolas V, Houard X, Blanco-Colio LM, Leclercq A, Egido J, Vranckx R, Michel JB, Meilhac O. Biological significance of decreased HSP27 in human atherosclerosis. Arterioscler Thromb Vasc Biol. 2006;26:1337–43.

    CAS  PubMed  Google Scholar 

  54. Leuschner F, Nahrendorf M. Molecular imaging of coronary atherosclerosis and myocardial infarction: considerations for the bench and perspectives for the clinic. Circ Res. 2011;108:593–606.

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Gorenoi V, Schonermark MP, Hagen A. Ct coronary angiography vs. Invasive coronary angiography in chd. GMS Health Technol Assess. 2012;8:Doc02.

    PubMed Central  PubMed  Google Scholar 

  56. Kelle S, Hays AG, Hirsch GA, Gerstenblith G, Miller JM, Steinberg AM, Schar M, Texter JH, Wellnhofer E, Weiss RG, Stuber M. Coronary artery distensibility assessed by 3.0 tesla coronary magnetic resonance imaging in subjects with and without coronary artery disease. Am J Cardiol. 2011;108:491–7.

    PubMed Central  PubMed  Google Scholar 

  57. Zhao X, Underhill HR, Zhao Q, Cai J, Li F, Oikawa M, Dong L, Ota H, Hatsukami TS, Chu B, Yuan C. Discriminating carotid atherosclerotic lesion severity by luminal stenosis and plaque burden: a comparison utilizing high-resolution magnetic resonance imaging at 3.0 tesla. Stroke. 2011;42:347–53.

    PubMed  Google Scholar 

  58. Maroules CD, McColl R, Khera A, Peshock RM. Assessment and reproducibility of aortic atherosclerosis magnetic resonance imaging: impact of 3-tesla field strength and parallel imaging. Invest Radiol. 2008;43:656–62.

    PubMed  Google Scholar 

  59. Larose E, Yeghiazarians Y, Libby P, Yucel EK, Aikawa M, Kacher DF, Aikawa E, Kinlay S, Schoen FJ, Selwyn AP, Ganz P. Characterization of human atherosclerotic plaques by intravascular magnetic resonance imaging. Circulation. 2005;112:2324–31.

    PubMed  Google Scholar 

  60. Claessen BE, Maehara A, Fahy M, Xu K, Stone GW, Mintz GS. Plaque composition by intravascular ultrasound and distal embolization after percutaneous coronary intervention. JACC Cardiovasc Imaging. 2012;5:S111–8.

    PubMed  Google Scholar 

  61. Kubo T, Ino Y, Tanimoto T, Kitabata H, Tanaka A, Akasaka T. Optical coherence tomography imaging in acute coronary syndromes. Cardiol Res Pract. 2011;2011:312978.

    PubMed Central  PubMed  Google Scholar 

  62. Bouki KP, Katsafados MG, Chatzopoulos DN, Psychari SN, Toutouzas KP, Charalampopoulos AF, Sakkali EN, Koudouri AA, Liakos GK, Apostolou TS. Inflammatory markers and plaque morphology: an optical coherence tomography study. Int J Cardiol. 2012;154:287–92.

    PubMed  Google Scholar 

  63. Cilingiroglu M, Oh JH, Sugunan B, Kemp NJ, Kim J, Lee S, Zaatari HN, Escobedo D, Thomsen S, Milner TE, Feldman MD. Detection of vulnerable plaque in a murine model of atherosclerosis with optical coherence tomography. Catheter Cardiovasc Interv. 2006;67:915–23.

    PubMed  Google Scholar 

  64. Gardner CM, Tan H, Hull EL, Lisauskas JB, Sum ST, Meese TM, Jiang C, Madden SP, Caplan JD, Burke AP, Virmani R, Goldstein J, Muller JE. Detection of lipid core coronary plaques in autopsy specimens with a novel catheter-based near-infrared spectroscopy system. JACC Cardiovasc Imaging. 2008;1:638–48.

    PubMed  Google Scholar 

  65. McAteer MA, Schneider JE, Ali ZA, Warrick N, Bursill CA, von zur Muhlen C, Greaves DR, Neubauer S, Channon KM, Choudhury RP. Magnetic resonance imaging of endothelial adhesion molecules in mouse atherosclerosis using dual-targeted microparticles of iron oxide. Arterioscler Thromb Vasc Biol. 2008;28:77–83.

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Broisat A, Riou LM, Ardisson V, Boturyn D, Dumy P, Fagret D, Ghezzi C. Molecular imaging of vascular cell adhesion molecule-1 expression in experimental atherosclerotic plaques with radiolabelled B2702-p. Eur J Nucl Med Mol Imaging. 2007;34:830–40.

    CAS  PubMed  Google Scholar 

  67. Ferrante EA, Pickard JE, Rychak J, Klibanov A, Ley K. Dual targeting improves microbubble contrast agent adhesion to VCAM-1 and P-selectin under flow. J Control Release. 2009;140:100–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Kaufmann BA, Sanders JM, Davis C, Xie A, Aldred P, Sarembock IJ, Lindner JR. Molecular imaging of inflammation in atherosclerosis with targeted ultrasound detection of vascular cell adhesion molecule-1. Circulation. 2007;116:276–84.

    CAS  PubMed  Google Scholar 

  69. Kelly KA, Nahrendorf M, Yu AM, Reynolds F, Weissleder R. In vivo phage display selection yields atherosclerotic plaque targeted peptides for imaging. Mol Imaging Biol. 2006;8:201–7.

    PubMed  Google Scholar 

  70. Southworth R, Kaneda M, Chen J, Zhang L, Zhang H, Yang X, Razavi R, Lanza G, Wickline SA. Renal vascular inflammation induced by western diet in ApoE-null mice quantified by (19)F NMR of VCAM-1 targeted nanobeacons. Nanomedicine. 2009;5:359–67.

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Liu Y, Davidson BP, Yue Q, Belcik T, Xie A, Inaba Y, McCarty OJ, Tormoen GW, Zhao Y, Ruggeri ZM, Kaufmann BA, Lindner JR. Molecular imaging of inflammation and platelet adhesion in advanced atherosclerosis effects of antioxidant therapy with NADPH oxidase inhibition. Circ Cardiovasc Imaging. 2013;6:74–82.

    PubMed Central  PubMed  Google Scholar 

  72. Nahrendorf M, Jaffer FA, Kelly KA, Sosnovik DE, Aikawa E, Libby P, Weissleder R. Noninvasive vascular cell adhesion molecule-1 imaging identifies inflammatory activation of cells in atherosclerosis. Circulation. 2006;114:1504–11.

    CAS  PubMed  Google Scholar 

  73. Nahrendorf M, Keliher E, Panizzi P, Zhang H, Hembrador S, Figueiredo JL, Aikawa E, Kelly K, Libby P, Weissleder R. 18F-4V for PET-CT imaging of VCAM-1 expression in atherosclerosis. JACC Cardiovasc Imaging. 2009;2:1213–22.

    PubMed Central  PubMed  Google Scholar 

  74. Kaufmann BA, Carr CL, Belcik JT, Xie A, Yue Q, Chadderdon S, Caplan ES, Khangura J, Bullens S, Bunting S, Lindner JR. Molecular imaging of the initial inflammatory response in atherosclerosis: implications for early detection of disease. Arterioscler Thromb Vasc Biol. 2010;30:54–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  75. McAteer MA, Akhtar AM, von Zur Muhlen C, Choudhury RP. An approach to molecular imaging of atherosclerosis, thrombosis, and vascular inflammation using microparticles of iron oxide. Atherosclerosis. 2010;209:18–27.

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Khanicheh E, Qi Y, Xie A, Mitterhuber M, Xu L, Mochizuki M, Daali Y, Jaquet V, Krause KH, Ruggeri ZM, Kuster GM, Lindner JR, Kaufmann BA. Molecular imaging reveals rapid reduction of endothelial activation in early atherosclerosis with apocynin independent of antioxidative properties. Arterioscler Thromb Vasc Biol. 2013;33:2187–92.

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Villanueva FS, Jankowski RJ, Klibanov S, Pina ML, Alber SM, Watkins SC, Brandenburger GH, Wagner WR. Microbubbles targeted to intercellular adhesion molecule-1 bind to activated coronary artery endothelial cells. Circulation. 1998;98:1–5.

    CAS  PubMed  Google Scholar 

  78. Demos SM, Alkan-Onyuksel H, Kane BJ, Ramani K, Nagaraj A, Greene R, Klegerman M, McPherson DD. In vivo targeting of acoustically reflective liposomes for intravascular and transvascular ultrasonic enhancement. J Am Coll Cardiol. 1999;33:867–75.

    CAS  PubMed  Google Scholar 

  79. Kang HW, Torres D, Wald L, Weissleder R, Bogdanov Jr AA. Targeted imaging of human endothelial-specific marker in a model of adoptive cell transfer. Lab Invest. 2006;86:599–609.

    CAS  PubMed  Google Scholar 

  80. Nakamura I, Hasegawa K, Wada Y, Hirase T, Node K, Watanabe Y. Detection of early stage atherosclerotic plaques using pet and ct fusion imaging targeting p-selectin in low density lipoprotein receptor-deficient mice. Biochem Biophys Res Commun. 2013;433:47–51.

    CAS  PubMed  Google Scholar 

  81. Rouzet F, Bachelet-Violette L, Alsac JM, Suzuki M, Meulemans A, Louedec L, Petiet A, Jandrot-Perrus M, Chaubet F, Michel JB, Le Guludec D, Letourneur D. Radiolabeled fucoidan as a p-selectin targeting agent for in vivo imaging of platelet-rich thrombus and endothelial activation. J Nucl Med. 2011;52:1433–40.

    CAS  PubMed  Google Scholar 

  82. Kim H, Kee PH, Rim Y, Moody MR, Klegerman ME, Vela D, Huang SL, McPherson DD, Laing ST. Nitric oxide improves molecular imaging of inflammatory atheroma using targeted echogenic immunoliposomes. Atherosclerosis. 2013;231:252–60.

    CAS  PubMed  Google Scholar 

  83. Jefferson A, Wijesurendra RS, McAteer MA, Digby JE, Douglas G, Bannister T, Perez-Balderas F, Bagi Z, Lindsay AC, Choudhury RP. Molecular imaging with optical coherence tomography using ligand-conjugated microparticles that detect activated endothelial cells: rational design through target quantification. Atherosclerosis. 2011;219:579–87.

    CAS  PubMed Central  PubMed  Google Scholar 

  84. McAteer MA, Mankia K, Ruparelia N, Jefferson A, Nugent HB, Stork LA, Channon KM, Schneider JE, Choudhury RP. A leukocyte-mimetic magnetic resonance imaging contrast agent homes rapidly to activated endothelium and tracks with atherosclerotic lesion macrophage content. Arterioscler Thromb Vasc Biol. 2012;32:1427–35.

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Maiseyeu A, Badgeley MA, Kampfrath T, Mihai G, Deiuliis JA, Liu C, Sun Q, Parthasarathy S, Simon DI, Croce K, Rajagopalan S. In vivo targeting of inflammation-associated myeloid-related protein 8/14 via gadolinium immunonanoparticles. Arterioscler Thromb Vasc Biol. 2012;32:962–70.

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Boyle JJ. Macrophage activation in atherosclerosis: pathogenesis and pharmacology of plaque rupture. Curr Vasc Pharmacol. 2005;3:63–8.

    CAS  PubMed  Google Scholar 

  87. Tsuchiya K, Nitta N, Sonoda A, Nitta-Seko A, Ohta S, Takahashi M, Murata K, Mukaisho K, Shiomi M, Tabata Y, Nohara S. Evaluation of atherosclerotic lesions using dextran- and mannan-dextran-coated USPIO: Mri analysis and pathological findings. Int J Nanomedicine. 2012;7:2271–80.

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Tsuchiya K, Nitta N, Sonoda A, Otani H, Takahashi M, Murata K, Shiomi M, Tabata Y, Nohara S. Atherosclerotic imaging using 4 types of superparamagnetic iron oxides: new possibilities for mannan-coated particles. Eur J Radiol. 2013;82:1919–25.

    PubMed  Google Scholar 

  89. Korosoglou G, Weiss RG, Kedziorek DA, Walczak P, Gilson WD, Schar M, Sosnovik DE, Kraitchman DL, Boston RC, Bulte JW, Weissleder R, Stuber M. Noninvasive detection of macrophage-rich atherosclerotic plaque in hyperlipidemic rabbits using “positive contrast” magnetic resonance imaging. J Am Coll Cardiol. 2008;52:483–91.

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Morishige K, Kacher DF, Libby P, Josephson L, Ganz P, Weissleder R, Aikawa M. High-resolution magnetic resonance imaging enhanced with superparamagnetic nanoparticles measures macrophage burden in atherosclerosis. Circulation. 2010;122:1707–15.

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Ruehm SG, Corot C, Vogt P, Kolb S, Debatin JF. Magnetic resonance imaging of atherosclerotic plaque with ultrasmall superparamagnetic particles of iron oxide in hyperlipidemic rabbits. Circulation. 2001;103:415–22.

    CAS  PubMed  Google Scholar 

  92. Tang TY, Howarth SP, Miller SR, Graves MJ, Patterson AJ, UK-I JM, Li ZY, Walsh SR, Brown AP, Kirkpatrick PJ, Warburton EA, Hayes PD, Varty K, Boyle JR, Gaunt ME, Zalewski A, Gillard JH. The atheroma (atorvastatin therapy: effects on reduction of macrophage activity) study. Evaluation using ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging in carotid disease. J Am Coll Cardiol. 2009;53:2039–50.

    CAS  PubMed  Google Scholar 

  93. Jung C, Kaul MG, Bruns OT, Ducic T, Freund B, Heine M, Reimer R, Meents A, Salmen SC, Weller H, Nielsen P, Adam G, Heeren J, Ittrich H. Intraperitoneal injection improves the uptake of nanoparticle labeled HDL to atherosclerotic plaques compared to intravenous injection: a multimodal imaging study in ApoE−/− mice. Circ Cardiovasc Imaging. 2014;7(2):303–11.

    Google Scholar 

  94. Ogawa M, Umeda IO, Kosugi M, Kawai A, Hamaya Y, Takashima M, Yin H, Kudoh T, Seno M, Magata Y. Development of 111In-labeled liposomes for vulnerable atherosclerotic plaque imaging. J Nucl Med. 2014;55:115–20.

    CAS  PubMed  Google Scholar 

  95. Nahrendorf M, Zhang H, Hembrador S, Panizzi P, Sosnovik DE, Aikawa E, Libby P, Swirski FK, Weissleder R. Nanoparticle pet-ct imaging of macrophages in inflammatory atherosclerosis. Circulation. 2008;117:379–87.

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Tassa C, Shaw SY, Weissleder R. Dextran-coated iron oxide nanoparticles: a versatile platform for targeted molecular imaging, molecular diagnostics, and therapy. Acc Chem Res. 2011;44:842–52.

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Hyafil F, Cornily JC, Feig JE, Gordon R, Vucic E, Amirbekian V, Fisher EA, Fuster V, Feldman LJ, Fayad ZA. Noninvasive detection of macrophages using a nanoparticulate contrast agent for computed tomography. Nat Med. 2007;13:636–41.

    CAS  PubMed  Google Scholar 

  98. van der Wal AC, Becker AE. Atherosclerotic plaque rupture–pathologic basis of plaque stability and instability. Cardiovasc Res. 1999;41:334–44.

    PubMed  Google Scholar 

  99. Lees AM, Lees RS, Schoen FJ, Isaacsohn JL, Fischman AJ, McKusick KA, Strauss HW. Imaging human atherosclerosis with 99MTC-labeled low density lipoproteins. Arteriosclerosis. 1988;8:461–70.

    CAS  PubMed  Google Scholar 

  100. Frias JC, Lipinski MJ, Lipinski SE, Albelda MT. Modified lipoproteins as contrast agents for imaging of atherosclerosis. Contrast Media Mol Imaging. 2007;2:16–23.

    CAS  PubMed  Google Scholar 

  101. Ishino S, Mukai T, Kuge Y, Kume N, Ogawa M, Takai N, Kamihashi J, Shiomi M, Minami M, Kita T, Saji H. Targeting of lectinlike oxidized low-density lipoprotein receptor 1 (LOX-1) with 99m TC-labeled anti-LOX-1 antibody: potential agent for imaging of vulnerable plaque. J Nucl Med. 2008;49:1677–85.

    CAS  PubMed  Google Scholar 

  102. Wen S, Liu DF, Cui Y, Harris SS, Chen YC, Li KC, Ju SH, Teng GJ. In vivo MRI detection of carotid atherosclerotic lesions and kidney inflammation in ApoE-deficient mice by using LOX-1 targeted iron nanoparticles. Nanomedicine. 2014;10:639–49.

    CAS  PubMed  Google Scholar 

  103. Li D, Patel AR, Klibanov AL, Kramer CM, Ruiz M, Kang BY, Mehta JL, Beller GA, Glover DK, Meyer CH. Molecular imaging of atherosclerotic plaques targeted to oxidized LDL receptor LOX-1 by SPECT/CT and magnetic resonance. Circ Cardiovasc Imaging. 2010;3:464–72.

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Lu T, Wen S, Cui Y, Ju SH, Li KC, Teng GJ. Near-infrared fluorescence imaging of murine atherosclerosis using an oxidized low density lipoprotein-targeted fluorochrome. Int J Cardiovasc Imaging. 2014;30:221–31.

    PubMed  Google Scholar 

  105. Hanssen NM, Wouters K, Huijberts MS, Gijbels MJ, Sluimer JC, Scheijen JL, Heeneman S, Biessen EA, Daemen MJ, Brownlee M, de Kleijn DP, Stehouwer CD, Pasterkamp G, Schalkwijk CG. Higher levels of advanced glycation endproducts in human carotid atherosclerotic plaques are associated with a rupture-prone phenotype. Eur Heart J. 2014;35:1137–46.

    CAS  PubMed  Google Scholar 

  106. Tavakoli S, Zamora D, Ullevig S, Asmis R. Bioenergetic profiles diverge during macrophage polarization: implications for the interpretation of 18F-FDG PET imaging of atherosclerosis. J Nucl Med. 2013;54:1661–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Tawakol A, Migrino RQ, Hoffmann U, Abbara S, Houser S, Gewirtz H, Muller JE, Brady TJ, Fischman AJ. Noninvasive in vivo measurement of vascular inflammation with F-18 fluorodeoxyglucose positron emission tomography. J Nucl Cardiol. 2005;12:294–301.

    PubMed  Google Scholar 

  108. Pedersen SF, Graebe M, Fisker Hag AM, Hojgaard L, Sillesen H, Kjaer A. Gene expression and 18FDG uptake in atherosclerotic carotid plaques. Nucl Med Commun. 2010;31:423–9.

    CAS  PubMed  Google Scholar 

  109. Dweck MR, Jones C, Joshi NV, Fletcher AM, Richardson H, White A, Marsden M, Pessotto R, Clark JC, Wallace WA, Salter DM, McKillop G, van Beek EJ, Boon NA, Rudd JH, Newby DE. Assessment of valvular calcification and inflammation by positron emission tomography in patients with aortic stenosis. Circulation. 2012;125:76–86.

    CAS  PubMed  Google Scholar 

  110. Hag AM, Pedersen SF, Christoffersen C, Binderup T, Jensen MM, Jorgensen JT, Skovgaard D, Ripa RS, Kjaer A. (18)F-FDG PET imaging of murine atherosclerosis: association with gene expression of key molecular markers. PLoS One. 2012;7:e50908.

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Myers KS, Rudd JH, Hailman EP, Bolognese JA, Burke J, Pinto CA, Klimas M, Hargreaves R, Dansky HM, Fayad ZA. Correlation between arterial FDG uptake and biomarkers in peripheral artery disease. JACC Cardiovasc Imaging. 2012;5:38–45.

    PubMed Central  PubMed  Google Scholar 

  112. Ogawa M, Nakamura S, Saito Y, Kosugi M, Magata Y. What can be seen by 18F-FDG PET in atherosclerosis imaging? The effect of foam cell formation on 18F-FDG uptake to macrophages in vitro. J Nucl Med. 2012;53:55–8.

    CAS  PubMed  Google Scholar 

  113. Calcagno C, Ramachandran S, Izquierdo-Garcia D, Mani V, Millon A, Rosenbaum D, Tawakol A, Woodward M, Bucerius J, Moshier E, Godbold J, Kallend D, Farkouh ME, Fuster V, Rudd JH, Fayad ZA. The complementary roles of dynamic contrast-enhanced MRI and 18F-fluorodeoxyglucose PET/CT for imaging of carotid atherosclerosis. Eur J Nucl Med Mol Imaging. 2013;40:1884–93.

    CAS  PubMed  Google Scholar 

  114. Duivenvoorden R, Mani V, Woodward M, Kallend D, Suchankova G, Fuster V, Rudd JH, Tawakol A, Farkouh ME, Fayad ZA. Relationship of serum inflammatory biomarkers with plaque inflammation assessed by FDG PET/CT: the dal-plaque study. JACC Cardiovasc Imaging. 2013;6:1087–94.

    PubMed  Google Scholar 

  115. Millon A, Dickson SD, Klink A, Izquierdo-Garcia D, Bini J, Lancelot E, Ballet S, Robert P, Mateo de Castro J, Corot C, Fayad ZA. Monitoring plaque inflammation in atherosclerotic rabbits with an iron oxide (P904) and (18)F-FDG using a combined PET/MR scanner. Atherosclerosis. 2013;228:339–45.

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Zhao QM, Zhao X, Feng TT, Zhang MD, Zhuang XC, Zhao XC, Li LQ, Li DP, Liu Y. Detection of vulnerable atherosclerotic plaque and prediction of thrombosis events in a rabbit model using 18F-FDG -PET/CT. PLoS One. 2013;8:e61140.

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Fayad ZA, Mani V, Woodward M, Kallend D, Abt M, Burgess T, Fuster V, Ballantyne CM, Stein EA, Tardif JC, Rudd JH, Farkouh ME, Tawakol A. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial. Lancet. 2011;378:1547–59.

    CAS  PubMed Central  PubMed  Google Scholar 

  118. Tahara N, Kai H, Ishibashi M, Nakaura H, Kaida H, Baba K, Hayabuchi N, Imaizumi T. Simvastatin attenuates plaque inflammation: evaluation by fluorodeoxyglucose positron emission tomography. J Am Coll Cardiol. 2006;48:1825–31.

    CAS  PubMed  Google Scholar 

  119. Lee SJ, On YK, Lee EJ, Choi JY, Kim BT, Lee KH. Reversal of vascular 18F-FDG uptake with plasma high-density lipoprotein elevation by atherogenic risk reduction. J Nucl Med. 2008;49:1277–82.

    CAS  PubMed  Google Scholar 

  120. Hacker M. Monitoring anti-inflammatory therapies in patients with atherosclerosis: FDG PET emerges as the method of choice. Eur J Nucl Med Mol Imaging. 2012;39:396–8.

    CAS  PubMed  Google Scholar 

  121. Lobatto ME, Calcagno C, Metselaar JM, Storm G, Stroes ES, Fayad ZA, Mulder WJ. Imaging the efficacy of anti-inflammatory liposomes in a rabbit model of atherosclerosis by non-invasive imaging. Methods Enzymol. 2012;508:211–28.

    CAS  PubMed Central  PubMed  Google Scholar 

  122. Vucic E, Calcagno C, Dickson SD, Rudd JH, Hayashi K, Bucerius J, Moshier E, Mounessa JS, Roytman M, Moon MJ, Lin J, Ramachandran S, Tanimoto T, Brown K, Kotsuma M, Tsimikas S, Fisher EA, Nicolay K, Fuster V, Fayad ZA. Regression of inflammation in atherosclerosis by the LXR agonist R211945: a noninvasive assessment and comparison with atorvastatin. JACC Cardiovasc Imaging. 2012;5:819–28.

    PubMed Central  PubMed  Google Scholar 

  123. Nitta Y, Tahara N, Tahara A, Honda A, Kodama N, Mizoguchi M, Kaida H, Ishibashi M, Hayabuchi N, Ikeda H, Yamagishi S, Imaizumi T. Pioglitazone decreases coronary artery inflammation in impaired glucose tolerance and diabetes mellitus: evaluation by FDG-PET/CT imaging. JACC Cardiovasc Imaging. 2013;6:1172–82.

    PubMed  Google Scholar 

  124. Tawakol A, Fayad ZA, Mogg R, Alon A, Klimas MT, Dansky H, Subramanian SS, Abdelbaky A, Rudd JH, Farkouh ME, Nunes IO, Beals CR, Shankar SS. Intensification of statin therapy results in a rapid reduction in atherosclerotic inflammation: results of a multicenter fluorodeoxyglucose-positron emission tomography/computed tomography feasibility study. J Am Coll Cardiol. 2013;62:909–17.

    CAS  PubMed  Google Scholar 

  125. Tawakol A, Singh P, Rudd JH, Soffer J, Cai G, Vucic E, Brannan SP, Tarka EA, Shaddinger BC, Sarov-Blat L, Matthews P, Subramanian S, Farkouh M, Fayad ZA. Effect of treatment for 12 weeks with rilapladib, a lipoprotein-associated phospholipase A2 inhibitor, on arterial inflammation as assessed with 18F-fluorodeoxyglucose-pet imaging. J Am Coll Cardiol. 2014;63:86–8.

    CAS  PubMed  Google Scholar 

  126. Matter CM, Wyss MT, Meier P, Spath N, von Lukowicz T, Lohmann C, Weber B, Ramirez de Molina A, Lacal JC, Ametamey SM, von Schulthess GK, Luscher TF, Kaufmann PA, Buck A. 18F-choline images murine atherosclerotic plaques ex vivo. Arterioscler Thromb Vasc Biol. 2006;26:584–9.

    CAS  PubMed  Google Scholar 

  127. Takumi T, Lee S, Hamasaki S, Toyonaga K, Kanda D, Kusumoto K, Toda H, Takenaka T, Miyata M, Anan R, Otsuji Y, Tei C. Limitation of angiography to identify the culprit plaque in acute myocardial infarction with coronary total occlusion utility of coronary plaque temperature measurement to identify the culprit plaque. J Am Coll Cardiol. 2007;50:2197–203.

    PubMed  Google Scholar 

  128. Geng YJ, Wu Q, Muszynski M, Hansson GK, Libby P. Apoptosis of vascular smooth muscle cells induced by in vitro stimulation with interferon-gamma, tumor necrosis factor-alpha, and interleukin-1 beta. Arterioscler Thromb Vasc Biol. 1996;16:19–27.

    CAS  PubMed  Google Scholar 

  129. Sosnovik DE, Garanger E, Aikawa E, Nahrendorf M, Figuiredo JL, Dai G, Reynolds F, Rosenzweig A, Weissleder R, Josephson L. Molecular MRI of cardiomyocyte apoptosis with simultaneous delayed-enhancement MRI distinguishes apoptotic and necrotic myocytes in vivo: potential for midmyocardial salvage in acute ischemia. Circ Cardiovasc Imaging. 2009;2:460–7.

    PubMed Central  PubMed  Google Scholar 

  130. van Tilborg GA, Mulder WJ, Deckers N, Storm G, Reutelingsperger CP, Strijkers GJ, Nicolay K. Annexin a5-functionalized bimodal lipid-based contrast agents for the detection of apoptosis. Bioconjug Chem. 2006;17:741–9.

    PubMed  Google Scholar 

  131. Johnson LL, Schofield L, Donahay T, Narula N, Narula J. 99mtc-annexin v imaging for in vivo detection of atherosclerotic lesions in porcine coronary arteries. J Nucl Med. 2005;46:1186–93.

    PubMed  Google Scholar 

  132. Ishino S, Kuge Y, Takai N, Tamaki N, Strauss HW, Blankenberg FG, Shiomi M, Saji H. 99mtc-annexin a5 for noninvasive characterization of atherosclerotic lesions: Imaging and histological studies in myocardial infarction-prone watanabe heritable hyperlipidemic rabbits. Eur J Nucl Med Mol Imaging. 2007;34:889–99.

    PubMed  Google Scholar 

  133. Laufer EM, Winkens HM, Corsten MF, Reutelingsperger CP, Narula J, Hofstra L. Pet and spect imaging of apoptosis in vulnerable atherosclerotic plaques with radiolabeled annexin a5. Q J Nucl Med Mol Imaging. 2009;53:26–34.

    CAS  PubMed  Google Scholar 

  134. Hofstra L, Liem IH, Dumont EA, Boersma HH, van Heerde WL, Doevendans PA, De Muinck E, Wellens HJ, Kemerink GJ, Reutelingsperger CP, Heidendal GA. Visualisation of cell death in vivo in patients with acute myocardial infarction. Lancet. 2000;356:209–12.

    CAS  PubMed  Google Scholar 

  135. Zhao Y, Zhao S, Kuge Y, Strauss HW, Blankenberg FG, Tamaki N. Attenuation of apoptosis by telmisartan in atherosclerotic plaques of apolipoprotein e−/− mice: evaluation using technetium 99m-annexin a5. Mol Imaging. 2013;12:300–9.

    CAS  PubMed  Google Scholar 

  136. De Saint-Hubert M, Bauwens M, Deckers N, Drummen M, Douma K, Granton P, Hendrikx G, Kusters D, Bucerius J, Reutelingsperger CP, Mottaghy FM. In vivo molecular imaging of apoptosis and necrosis in atherosclerotic plaques using microSPECT-CT and microPET-CT imaging. Mol Imaging Biol. 2014;16:246–54.

    PubMed  Google Scholar 

  137. Jiang B, Wang J, Ni Y, Chen F. Necrosis avidity: a newly discovered feature of hypericin and its preclinical applications in necrosis imaging. Theranostics. 2013;3:667–76.

    PubMed Central  PubMed  Google Scholar 

  138. Chen K, Keaney Jr JF. Evolving concepts of oxidative stress and reactive oxygen species in cardiovascular disease. Curr Atheroscler Rep. 2012;14:476–83.

    CAS  PubMed  Google Scholar 

  139. Briley-Saebo KC, Cho YS, Tsimikas S. Imaging of oxidation-specific epitopes in atherosclerosis and macrophage-rich vulnerable plaques. Curr Cardiovasc Imaging Rep. 2011;4:4–16.

    PubMed Central  PubMed  Google Scholar 

  140. Torzewski M, Shaw PX, Han KR, Shortal B, Lackner KJ, Witztum JL, Palinski W, Tsimikas S. Reduced in vivo aortic uptake of radiolabeled oxidation-specific antibodies reflects changes in plaque composition consistent with plaque stabilization. Arterioscler Thromb Vasc Biol. 2004;24:2307–12.

    CAS  PubMed  Google Scholar 

  141. Nahrendorf M, Sosnovik D, Chen JW, Panizzi P, Figueiredo JL, Aikawa E, Libby P, Swirski FK, Weissleder R. Activatable magnetic resonance imaging agent reports myeloperoxidase activity in healing infarcts and noninvasively detects the antiinflammatory effects of atorvastatin on ischemia-reperfusion injury. Circulation. 2008;117:1153–60.

    CAS  PubMed Central  PubMed  Google Scholar 

  142. Panizzi P, Nahrendorf M, Wildgruber M, Waterman P, Figueiredo JL, Aikawa E, McCarthy J, Weissleder R, Hilderbrand SA. Oxazine conjugated nanoparticle detects in vivo hypochlorous acid and peroxynitrite generation. J Am Chem Soc. 2009;131:15739–44.

    CAS  PubMed Central  PubMed  Google Scholar 

  143. Lal H, Verma SK, Foster DM, Golden HB, Reneau JC, Watson LE, Singh H, Dostal DE. Integrins and proximal signaling mechanisms in cardiovascular disease. Front Biosci. 2009;14:2307–34.

    CAS  Google Scholar 

  144. Winter PM, Morawski AM, Caruthers SD, Fuhrhop RW, Zhang H, Williams TA, Allen JS, Lacy EK, Robertson JD, Lanza GM, Wickline SA. Molecular imaging of angiogenesis in early-stage atherosclerosis with alpha(v)beta3-integrin-targeted nanoparticles. Circulation. 2003;108:2270–4.

    CAS  PubMed  Google Scholar 

  145. Burtea C, Laurent S, Murariu O, Rattat D, Toubeau G, Verbruggen A, Vansthertem D, Vander Elst L, Muller RN. Molecular imaging of alpha v beta3 integrin expression in atherosclerotic plaques with a mimetic of rgd peptide grafted to gd-dtpa. Cardiovasc Res. 2008;78:148–57.

    CAS  PubMed  Google Scholar 

  146. Winter PM, Caruthers SD, Zhang H, Williams TA, Wickline SA, Lanza GM. Antiangiogenic synergism of integrin-targeted fumagillin nanoparticles and atorvastatin in atherosclerosis. JACC Cardiovasc Imaging. 2008;1:624–34.

    PubMed Central  PubMed  Google Scholar 

  147. Winter PM, Neubauer AM, Caruthers SD, Harris TD, Robertson JD, Williams TA, Schmieder AH, Hu G, Allen JS, Lacy EK, Zhang H, Wickline SA, Lanza GM. Endothelial alpha(v)beta3 integrin-targeted fumagillin nanoparticles inhibit angiogenesis in atherosclerosis. Arterioscler Thromb Vasc Biol. 2006;26:2103–9.

    CAS  PubMed  Google Scholar 

  148. Laitinen I, Saraste A, Weidl E, Poethko T, Weber AW, Nekolla SG, Leppanen P, Yla-Herttuala S, Holzlwimmer G, Walch A, Esposito I, Wester HJ, Knuuti J, Schwaiger M. Evaluation of alphavbeta3 integrin-targeted positron emission tomography tracer 18F-galacto-RGD for imaging of vascular inflammation in atherosclerotic mice. Circ Cardiovasc Imaging. 2009;2:331–8.

    PubMed  Google Scholar 

  149. Partovi S, Loebe M, Aschwanden M, Baldi T, Jager KA, Feinstein SB, Staub D. Contrast-enhanced ultrasound for assessing carotid atherosclerotic plaque lesions. AJR Am J Roentgenol. 2012;198:W13–9.

    PubMed  Google Scholar 

  150. Heroux J, Gharib AM, Danthi NS, Cecchini S, Ohayon J, Pettigrew RI. High-affinity alphavbeta3 integrin targeted optical probe as a new imaging biomarker for early atherosclerosis: initial studies in watanabe rabbits. Mol Imaging Biol. 2010;12:2–8.

    PubMed  Google Scholar 

  151. de Vries BM W, Hillebrands JL, van Dam GM, Tio RA, de Jong JS, Slart RH, Zeebregts CJ. Images in cardiovascular medicine. Multispectral near-infrared fluorescence molecular imaging of matrix metalloproteinases in a human carotid plaque using a matrix-degrading metalloproteinase-sensitive activatable fluorescent probe. Circulation. 2009;119:e534–6.

    Google Scholar 

  152. Razansky D, Harlaar NJ, Hillebrands JL, Taruttis A, Herzog E, Zeebregts CJ, van Dam GM, Ntziachristos V. Multispectral optoacoustic tomography of matrix metalloproteinase activity in vulnerable human carotid plaques. Mol Imaging Biol. 2012;14:277–85.

    PubMed Central  PubMed  Google Scholar 

  153. Quillard T, Tesmenitsky Y, Croce K, Travers R, Shvartz E, Koskinas KC, Sukhova GK, Aikawa E, Aikawa M, Libby P. Selective inhibition of matrix metalloproteinase-13 increases collagen content of established mouse atherosclerosis. Arterioscler Thromb Vasc Biol. 2011;31:2464–72.

    CAS  PubMed Central  PubMed  Google Scholar 

  154. Chang K, Francis SA, Aikawa E, Figueiredo JL, Kohler RH, McCarthy JR, Weissleder R, Plutzky J, Jaffer FA. Pioglitazone suppresses inflammation in vivo in murine carotid atherosclerosis: novel detection by dual-target fluorescence molecular imaging. Arterioscler Thromb Vasc Biol. 2010;30:1933–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  155. Deguchi JO, Aikawa M, Tung CH, Aikawa E, Kim DE, Ntziachristos V, Weissleder R, Libby P. Inflammation in atherosclerosis: visualizing matrix metalloproteinase action in macrophages in vivo. Circulation. 2006;114:55–62.

    PubMed  Google Scholar 

  156. Lin SA, Patel M, Suresch D, Connolly B, Bao B, Groves K, Rajopadhye M, Peterson JD, Klimas M, Sur C, Bednar B. Quantitative longitudinal imaging of vascular inflammation and treatment by ezetimibe in apoe mice by fmt using new optical imaging biomarkers of cathepsin activity and alpha(v)beta(3) integrin. Int J Mol Imaging. 2012;2012:189254.

    PubMed Central  PubMed  Google Scholar 

  157. Jaffer FA, Kim DE, Quinti L, Tung CH, Aikawa E, Pande AN, Kohler RH, Shi GP, Libby P, Weissleder R. Optical visualization of cathepsin k activity in atherosclerosis with a novel, protease-activatable fluorescence sensor. Circulation. 2007;115:2292–8.

    CAS  PubMed  Google Scholar 

  158. Kim DE, Kim JY, Schellingerhout D, Shon SM, Jeong SW, Kim EJ, Kim WK. Molecular imaging of cathepsin b proteolytic enzyme activity reflects the inflammatory component of atherosclerotic pathology and can quantitatively demonstrate the antiatherosclerotic therapeutic effects of atorvastatin and glucosamine. Mol Imaging. 2009;8:291–301.

    CAS  PubMed  Google Scholar 

  159. Jaffer FA, Vinegoni C, John MC, Aikawa E, Gold HK, Finn AV, Ntziachristos V, Libby P, Weissleder R. Real-time catheter molecular sensing of inflammation in proteolytically active atherosclerosis. Circulation. 2008;118:1802–9.

    PubMed Central  PubMed  Google Scholar 

  160. Myochin T, Hanaoka K, Komatsu T, Terai T, Nagano T. Design strategy for a near-infrared fluorescence probe for matrix metalloproteinase utilizing highly cell permeable boron dipyrromethene. J Am Chem Soc. 2012;134:13730–7.

    CAS  PubMed  Google Scholar 

  161. Olson ES, Whitney MA, Friedman B, Aguilera TA, Crisp JL, Baik FM, Jiang T, Baird SM, Tsimikas S, Tsien RY, Nguyen QT. In vivo fluorescence imaging of atherosclerotic plaques with activatable cell-penetrating peptides targeting thrombin activity. Integr Biol (Camb). 2012;4:595–605.

    CAS  PubMed Central  Google Scholar 

  162. Haider N, Hartung D, Fujimoto S, Petrov A, Kolodgie FD, Virmani R, Ohshima S, Liu H, Zhou J, Fujimoto A, Tahara A, Hofstra L, Narula N, Reutelingsperger C, Narula J. Dual molecular imaging for targeting metalloproteinase activity and apoptosis in atherosclerosis: molecular imaging facilitates understanding of pathogenesis. J Nucl Cardiol. 2009;16:753–62.

    PubMed Central  PubMed  Google Scholar 

  163. Razavian M, Tavakoli S, Zhang J, Nie L, Dobrucki LW, Sinusas AJ, Azure M, Robinson S, Sadeghi MM. Atherosclerosis plaque heterogeneity and response to therapy detected by in vivo molecular imaging of matrix metalloproteinase activation. J Nucl Med. 2011;52:1795–802.

    CAS  PubMed Central  PubMed  Google Scholar 

  164. Amirbekian V, Aguinaldo JG, Amirbekian S, Hyafil F, Vucic E, Sirol M, Weinreb DB, Le Greneur S, Lancelot E, Corot C, Fisher EA, Galis ZS, Fayad ZA. Atherosclerosis and matrix metalloproteinases: experimental molecular mr imaging in vivo. Radiology. 2009;251:429–38.

    PubMed Central  PubMed  Google Scholar 

  165. Olson ES, Jiang T, Aguilera TA, Nguyen QT, Ellies LG, Scadeng M, Tsien RY. Activatable cell penetrating peptides linked to nanoparticles as dual probes for in vivo fluorescence and mr imaging of proteases. Proc Natl Acad Sci U S A. 2010;107:4311–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  166. Liu CH, You Z, Liu CM, Kim YR, Whalen MJ, Rosen BR, Liu PK. Diffusion-weighted magnetic resonance imaging reversal by gene knockdown of matrix metalloproteinase-9 activities in live animal brains. J Neurosci. 2009;29:3508–17.

    CAS  PubMed Central  PubMed  Google Scholar 

  167. Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. 2003;92:827–39.

    CAS  PubMed  Google Scholar 

  168. Jacobin-Valat MJ, Deramchia K, Mornet S, Hagemeyer CE, Bonetto S, Robert R, Biran M, Massot P, Miraux S, Sanchez S, Bouzier-Sore AK, Franconi JM, Duguet E, Clofent-Sanchez G. Mri of inducible p-selectin expression in human activated platelets involved in the early stages of atherosclerosis. NMR Biomed. 2011;24:413–24.

    CAS  PubMed  Google Scholar 

  169. Duerschmied D, Meiner M, Peter K, Neudorfer I, Roming F, Zirlik A, Bode C, von Elverfeldt D, von Zur MC. Molecular magnetic resonance imaging allows the detection of activated platelets in a new mouse model of coronary artery thrombosis. Invest Radiol. 2011;46:618–23.

    PubMed  Google Scholar 

  170. von zur Muhlen C, Peter K, Ali ZA, Schneider JE, McAteer MA, Neubauer S, Channon KM, Bode C, Choudhury RP. Visualization of activated platelets by targeted magnetic resonance imaging utilizing conformation-specific antibodies against glycoprotein iib/iiia. J Vasc Res. 2009;46:6–14.

    Google Scholar 

  171. von Elverfeldt D, Meissner M, Peter K, Paul D, Meixner F, Neudorfer I, Merkle A, Harloff A, Zirlik A, Schollhorn J, Markl M, Hennig J, Bode C, von zur Muhlen C. An approach towards molecular imaging of activated platelets allows imaging of symptomatic human carotid plaques in a new model of a tissue flow chamber. Contrast Media Mol Imaging. 2012;7:204–13.

    Google Scholar 

  172. Uppal R, Catana C, Ay I, Benner T, Sorensen AG, Caravan P. Bimodal thrombus imaging: simultaneous pet/mr imaging with a fibrin-targeted dual pet/mr probe–feasibility study in rat model. Radiology. 2011;258:812–20.

    PubMed Central  PubMed  Google Scholar 

  173. Vymazal J, Spuentrup E, Cardenas-Molina G, Wiethoff AJ, Hartmann MG, Caravan P, Parsons Jr EC. Thrombus imaging with fibrin-specific gadolinium-based mr contrast agent ep-2104r: results of a phase ii clinical study of feasibility. Invest Radiol. 2009;44:697–704.

    CAS  PubMed  Google Scholar 

  174. Wu X, Balu N, Li W, Chen Y, Shi X, Kummitha CM, Yu X, Yuan C, Lu ZR. Molecular MRI of atherosclerotic plaque progression in an apoe(−/−) mouse model with a clt1 peptide targeted macrocyclic gd(iii) chelate. Am J Nucl Med Mol Imaging. 2013;3:446–55.

    CAS  PubMed Central  PubMed  Google Scholar 

  175. Starmans LW, van Duijnhoven SM, Rossin R, Berben M, Aime S, Daemen MJ, Nicolay K, Grull H. Evaluation of 111In-labeled EPep and FibPep as tracers for fibrin SPECT imaging. Mol Pharm. 2013;10(11):4309–21.

    CAS  PubMed  Google Scholar 

  176. Makowski MR, Forbes SC, Blume U, Warley A, Jansen CH, Schuster A, Wiethoff AJ, Botnar RM. In vivo assessment of intraplaque and endothelial fibrin in apoe(−/−) mice by molecular MRI. Atherosclerosis. 2012;222:43–9.

    CAS  PubMed  Google Scholar 

  177. McCarthy JR, Patel P, Botnaru I, Haghayeghi P, Weissleder R, Jaffer FA. Multimodal nanoagents for the detection of intravascular thrombi. Bioconjug Chem. 2009;20:1251–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  178. Jaffer FA, Tung CH, Wykrzykowska JJ, Ho NH, Houng AK, Reed GL, Weissleder R. Molecular imaging of factor xiiia activity in thrombosis using a novel, near-infrared fluorescent contrast agent that covalently links to thrombi. Circulation. 2004;110:170–6.

    CAS  PubMed  Google Scholar 

  179. Tei L, Mazooz G, Shellef Y, Avni R, Vandoorne K, Barge A, Kalchenko V, Dewhirst MW, Chaabane L, Miragoli L, Longo D, Neeman M, Aime S. Novel MRI and fluorescent probes responsive to the factor XIII transglutaminase activity. Contrast Media Mol Imaging. 2010;5:213–22.

    CAS  PubMed  Google Scholar 

  180. Miserus RJ, Herias MV, Prinzen L, Lobbes MB, Van Suylen RJ, Dirksen A, Hackeng TM, Heemskerk JW, van Engelshoven JM, Daemen MJ, van Zandvoort MA, Heeneman S, Kooi ME. Molecular MRI of early thrombus formation using a bimodal alpha2-antiplasmin-based contrast agent. JACC Cardiovasc Imaging. 2009;2:987–96.

    PubMed  Google Scholar 

  181. Majmudar MD, Keliher EJ, Heidt T, Leuschner F, Truelove J, Sena BF, Gorbatov R, Iwamoto Y, Dutta P, Wojtkiewicz G, Courties G, Sebas M, Borodovsky A, Fitzgerald K, Nolte MW, Dickneite G, Chen JW, Anderson DG, Swirski FK, Weissleder R, Nahrendorf M. Monocyte-directed rnai targeting ccr2 improves infarct healing in atherosclerosis-prone mice. Circulation. 2013;127:2038–46.

    CAS  PubMed Central  PubMed  Google Scholar 

  182. Beheshti M, Saboury B, Mehta NN, Torigian DA, Werner T, Mohler E, Wilensky R, Newberg AB, Basu S, Langsteger W, Alavi A. Detection and global quantification of cardiovascular molecular calcification by fluoro18-fluoride positron emission tomography/computed tomography–a novel concept. Hell J Nucl Med. 2011;14:114–20.

    PubMed  Google Scholar 

  183. Zaheer A, Murshed M, De Grand AM, Morgan TG, Karsenty G, Frangioni JV. Optical imaging of hydroxyapatite in the calcified vasculature of transgenic animals. Arterioscler Thromb Vasc Biol. 2006;26:1132–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  184. Lee JS, Morrisett JD, Tung CH. Detection of hydroxyapatite in calcified cardiovascular tissues. Atherosclerosis. 2012;224:340–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  185. Aikawa E, Nahrendorf M, Figueiredo JL, Swirski FK, Shtatland T, Kohler RH, Jaffer FA, Aikawa M, Weissleder R. Osteogenesis associates with inflammation in early-stage atherosclerosis evaluated by molecular imaging in vivo. Circulation. 2007;116:2841–50.

    CAS  PubMed  Google Scholar 

  186. Aikawa E, Nahrendorf M, Sosnovik D, Lok VM, Jaffer FA, Aikawa M, Weissleder R. Multimodality molecular imaging identifies proteolytic and osteogenic activities in early aortic valve disease. Circulation. 2007;115:377–86.

    CAS  PubMed  Google Scholar 

  187. White CJ, Ramee SR, Collins TJ, Murgo JP. Coronary angioscopy. Tex Heart Inst J. 1995;22(1):20–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  188. Donnelly P, et al. Multimodality imaging atlas of coronary atherosclerosis. JACC Cardiovasc Imaging. 2010;3:876–80.

    PubMed  Google Scholar 

  189. Majmudar MD, et al. Cardiovascular molecular imaging: the road ahead. J Nucl Med. 2012;53(5):673–6.

    Google Scholar 

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Authors and Affiliations

  1. INSERM, UMR957, LPRO, Nantes, F-44035, France

    Thibaut Quillard PhD

  2. Cardiovascular Division, Interventional Cardiology, Brigham and Women’s Hospital, Harvard Medical School, 77 Ave Louis Pasteur, NRB 742, Boston, MA, 02115, USA

    Kevin J. Croce MD, PhD

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  1. Thibaut Quillard PhD
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Correspondence to Kevin J. Croce MD, PhD .

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  1. Cardiovascular Medicine, Brigham and Women’s Hospital Harvard Medical School, Boston, Massachusetts, USA

    Elena Aikawa

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Quillard, T., Croce, K.J. (2015). Pathobiology and Mechanisms of Atherosclerosis. In: Aikawa, E. (eds) Cardiovascular Imaging. Springer, Cham. https://doi.org/10.1007/978-3-319-09268-3_1

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