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Molecular Imaging of Atherosclerosis

  • Patrick KeeEmail author
  • Wouter Driessen
Chapter

Abstract

Atherosclerotic cardiovascular disease is an insidious condition that develops over an extended period of time. By the time the disease is apparent, the arterial wall has already undergone a substantial amount of remodeling. Current diagnostic tools are based on risk factor profiling, biomarker measurements, and lesion detection. Although relatively effective in large cohorts of subjects, risk factors and biomarkers are poor predictors of future risk in individual patients, because of the high occurrence of such factors. Conventional imaging modalities can detect only flow-limiting lesions. By the time advanced disease is diagnosed, mechanical and pharmacological interventions have only modest impact on disease progression. There is clearly a need to devise better imaging tools to measure plaque burden and disease activities within the arterial wall, to diagnose this disease at an earlier stage and to predict the short-term risks of developing complications. Given that molecular changes at a cellular level precede gross anatomic changes in the affected organ, application of techniques for detection of molecular changes in the arterial wall in living subjects might be feasible. Molecular imaging has the potential to (1) screen for early stages of atherosclerosis at which interventions are most effective, (2) follow the course of the disease and aid in the titration of therapy, and (3) detect the presence of vulnerable plaque that requires aggressive intervention. This review article, an overview of the current state of the art of molecular imaging, covers essential components that are vital to the success of the imaging strategy and highlights the potential challenges intrinsic to each component.

Keywords

Atherosclerosis Molecular imaging Biomarkers Contrast agents 

References

  1. 1.
    Abe Y, Sugisaki K, Dannenberg AM. (1996) Rabbit vascular endothelial adhesion ­molecules: ELAM-1 is most elevated in acute inflammation, whereas VCAM-1 and ICAM-1 predominate in chronic inflammation. J Leukoc Biol 60:692–703.PubMedGoogle Scholar
  2. 2.
    Aikawa M, Rabkin E, Okada Y et al. (1998) Lipid lowering by diet reduces matrix metalloproteinase activity and increases collagen content of rabbit atheroma: a potential mechanism of lesion stabilization. Circulation 97:2433–44.PubMedGoogle Scholar
  3. 3.
    Aikawa M, Voglic SJ, Sugiyama S et al. (1999) Dietary lipid lowering reduces tissue factor expression in rabbit atheroma. Circulation 100:1215–22.PubMedGoogle Scholar
  4. 4.
    Almutairi A, Rossin R, Shokeen M et al. (2009) Biodegradable dendritic positron-emitting nanoprobes for the noninvasive imaging of angiogenesis. Proc Natl Acad Sci USA 106:685–90.CrossRefPubMedGoogle Scholar
  5. 5.
    Amirbekian V, Lipinski MJ, Briley-Saebo KC et al. (2007) Detecting and assessing macrophages in vivo to evaluate atherosclerosis noninvasively using molecular MRI. Proc Natl Acad Sci USA 104:961–6.CrossRefPubMedGoogle Scholar
  6. 6.
    Arap W, Kolonin MG, Trepel M et al. (2002) Steps toward mapping the human vasculature by phage display. Nat Med 8:121–7.CrossRefPubMedGoogle Scholar
  7. 7.
    Babaev VR, Gleaves LA, Carter KJ et al. (2000) Reduced atherosclerotic lesions in mice deficient for total or macrophage-specific expression of scavenger receptor-A. Arterioscler Thromb 20:2593–9.Google Scholar
  8. 8.
    Behm C, Kaufmann B, Carr C et al. (2008) Molecular imaging of endothelial vascular cell adhesion molecule-1 expression and inflammatory cell recruitment during vasculogenesis and ischemia-mediated arteriogenesis. Circulation 117(22):2902–11.CrossRefPubMedGoogle Scholar
  9. 9.
    Botnar RM, Perez AS, Witte S et al. (2004) In vivo molecular imaging of acute and subacute thrombosis using a fibrin-binding magnetic resonance imaging contrast agent. Circulation 109:2023–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Briley-Saebo K, Shaw P, Mulder W et al. (2008) Targeted molecular probes for imaging atherosclerotic lesions with magnetic resonance using antibodies that recognize oxidation-specific epitopes. Circulation 117(25):3206–15.CrossRefPubMedGoogle Scholar
  11. 11.
    Broisat A, Riou LM, Ardisson V et al. (2007) Molecular imaging of vascular cell adhesion molecule-1 expression in experimental atherosclerotic plaques with radiolabelled B2702-p. Eur J Nucl Med Mol Imaging 34:830–40.CrossRefPubMedGoogle Scholar
  12. 12.
    Burtea C, Laurent S, Lancelot E et al. (2009) Peptidic targeting of phosphatidylserine for the MRI detection of apoptosis in atherosclerotic plaques. Mol Pharm 6:1903–19.CrossRefPubMedGoogle Scholar
  13. 13.
    Burtea C, Laurent S, Murariu O et al. (2008) Molecular imaging of alpha v beta3 integrin expression in atherosclerotic plaques with a mimetic of RGD peptide grafted to Gd-DTPA. Cardiovasc Res 78:148–57.CrossRefPubMedGoogle Scholar
  14. 14.
    Calara F, Silvestre M, Casanada F et al. (2001) Spontaneous plaque rupture and secondary thrombosis in apolipoprotein E-deficient and LDL receptor-deficient mice. J Pathol 195:257–63.CrossRefPubMedGoogle Scholar
  15. 15.
    Calcagno C, Cornily J, Hyafil F et al. (2008) Detection of neovessels in atherosclerotic plaques of rabbits using dynamic contrast enhanced MRI and 18F-FDG PET. Arterioscler Thromb Vasc Biol 28(7):1311–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Caravan P, Das B, Dumas S et al. (2007) Collagen-targeted MRI contrast agent for molecular imaging of fibrosis. Angew Chem Int Ed Engl 46:8171–3.CrossRefPubMedGoogle Scholar
  17. 17.
    Carrió I, Pieri PL, Narula J et al. (1998) Noninvasive localization of human atherosclerotic lesions with indium 111-labeled monoclonal Z2D3 antibody specific for proliferating smooth muscle cells. J Nucl Cardiol 5:551–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Chapman KB, Szostak JW. (1994) In vitro selection of catalytic RNAs. Curr Opin Struct Biol 4:618–22.CrossRefPubMedGoogle Scholar
  19. 19.
    Chen J, Tung CH, Mahmood U et al. (2002) In vivo imaging of proteolytic activity in ­atherosclerosis. Circulation 105:2766–71.CrossRefPubMedGoogle Scholar
  20. 20.
    Cheng C, Helderman F, Tempel D et al. (2007) Large variations in absolute wall shear stress levels within one species and between species. Atherosclerosis 195:225–35.CrossRefPubMedGoogle Scholar
  21. 21.
    Coli S, Magnoni M, Sangiorgi G et al. (2008) Contrast-enhanced ultrasound imaging of intraplaque neovascularization in carotid arteries: correlation with histology and plaque echogenicity. J Am Coll Cardiol 52:223–30.CrossRefPubMedGoogle Scholar
  22. 22.
    Deguchi J-o, Aikawa M, Tung C-H et al. (2006) Inflammation in atherosclerosis: visualizing matrix metalloproteinase action in macrophages in vivo. Circulation 114:55–62.CrossRefPubMedGoogle Scholar
  23. 23.
    Dias-Neto E, Nunes DN, Giordano RJ et al. (2009) Next-generation phage display: integrating and comparing available molecular tools to enable cost-effective high-throughput analysis. PLoS One 4:e8338.CrossRefPubMedGoogle Scholar
  24. 24.
    Driessen WH, Ozawa MG, Arap W et al. (2009) Ligand-directed cancer gene therapy to angiogenic vasculature. Adv Genet 67:103–21.CrossRefPubMedGoogle Scholar
  25. 25.
    Elitok S, Brodsky SV, Patschan D et al. (2006) Cyclic arginine-glycine-aspartic acid peptide inhibits macrophage infiltration of the kidney and carotid artery lesions in apo-E-deficient mice. Am J Physiol Renal Physiol 290(1):F159–66.CrossRefPubMedGoogle Scholar
  26. 26.
    Elmaleh DR, Fischman AJ, Tawakol A et al. (2006) Detection of inflamed atherosclerotic lesions with diadenosine-5′,5’’’-P1,P4-tetraphosphate (Ap4A) and positron-emission tomography. Proc Natl Acad Sci USA 103:15992–6.CrossRefPubMedGoogle Scholar
  27. 27.
    Ferrante EA, Pickard JE, Rychak J et al. (2009) Dual targeting improves microbubble contrast agent adhesion to VCAM-1 and P-selectin under flow. J Control Release 140:100–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Flacke S, Fischer S, Scott MJ et al. (2001) Novel MRI contrast agent for molecular imaging of fibrin: implications for detecting vulnerable plaques. Circulation 104:1280–5.CrossRefPubMedGoogle Scholar
  29. 29.
    Fujimoto S, Hartung D, Ohshima S et al. (2008) Molecular imaging of matrix metalloproteinase in atherosclerotic lesions: resolution with dietary modification and statin therapy. J Am Coll Cardiol 52:1847–57.CrossRefPubMedGoogle Scholar
  30. 30.
    Galis ZS, Sukhova GK, Lark MW et al. (1994) Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest 94:2493–503.CrossRefPubMedGoogle Scholar
  31. 31.
    Glagov S, Weisenberg E, Zarins CK et al. (1987) Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med 316:1371–5.CrossRefPubMedGoogle Scholar
  32. 32.
    Goertz D, Frijlink M, Tempel D et al. (2007) Subharmonic contrast intravascular ultrasound for vasa vasorum imaging. Ultrasound Med Biol 33(12):1859–72.CrossRefPubMedGoogle Scholar
  33. 33.
    Goertz DE, Frijlink ME, Tempel D et al. (2006) Contrast harmonic intravascular ultrasound: a feasibility study for vasa vasorum imaging. Invest Radiol 41:631–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Gold L, Polisky B, Uhlenbeck O et al. (1995) Diversity of oligonucleotide functions. Annu Rev Biochem 64:763–97.CrossRefPubMedGoogle Scholar
  35. 35.
    Gössl M, Versari D, Mannheim D et al. (2006) Increased spatial vasa vasorum density in the proximal LAD in hypercholesterolemia-implications for vulnerable plaque-development. Atherosclerosis 192(2):246–52.CrossRefPubMedGoogle Scholar
  36. 36.
    Graf K, Dietrich T, Tachezy M et al. (2008) Monitoring therapeutical intervention with ezetimibe using targeted near-infrared fluorescence imaging in experimental atherosclerosis. Mol Imaging 7:68–76.PubMedGoogle Scholar
  37. 37.
    Haider N, Hartung D, Fujimoto S et al. (2009) Dual molecular imaging for targeting metalloproteinase activity and apoptosis in atherosclerosis: molecular imaging facilitates understanding of pathogenesis. J Nucl Cardiol 16:753–62.CrossRefPubMedGoogle Scholar
  38. 38.
    Hamilton AJ, Huang S-L, Warnick D et al. (2004) Intravascular ultrasound molecular imaging of atheroma components in vivo. J Am Coll Cardiol 43:453–60.CrossRefPubMedGoogle Scholar
  39. 39.
    Herrmann J, Lerman LO, Rodriguez-Porcel M et al. (2001) Coronary vasa vasorum neovascularization precedes epicardial endothelial dysfunction in experimental hypercholesterolemia. Cardiovasc Res 51:762–6.CrossRefPubMedGoogle Scholar
  40. 40.
    Hong HY, Lee HY, Kwak W et al. (2007) Phage display selection of peptides that home to atherosclerotic plaques: IL-4 receptor as a candidate target in atherosclerosis. J Cell Mol Med 12(5B):2003–14.CrossRefGoogle Scholar
  41. 41.
    Hyafil F, Cornily JC, Feig JE et al. (2007) Noninvasive detection of macrophages using a nanoparticulate contrast agent for computed tomography. Nat Med 13:636–41.CrossRefPubMedGoogle Scholar
  42. 42.
    Iiyama K, Hajra L, Iiyama M et al. (1999) Patterns of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression in rabbit and mouse atherosclerotic lesions and at sites predisposed to lesion formation. Circ Res 85:199–207.PubMedGoogle Scholar
  43. 43.
    Jaffer FA, Kim DE, Quinti L et al. (2007) Optical visualization of cathepsin K activity in ather­osclerosis with a novel, protease-activatable fluorescence sensor. Circulation 115:2292–8.CrossRefPubMedGoogle Scholar
  44. 44.
    Johnson LL, Schofield L, Donahay T et al. (2005) 99mTc-annexin V imaging for in vivo detection of atherosclerotic lesions in porcine coronary arteries. J Nucl Med 46:1186–93.PubMedGoogle Scholar
  45. 45.
    Kaufmann BA, Carr CL, Belcik JT et al. (2010) Molecular imaging of the initial inflammatory response in atherosclerosis: implications for early detection of disease. Arterioscler Thromb Vasc Biol 30:54–9.CrossRefPubMedGoogle Scholar
  46. 46.
    Kaufmann BA, Sanders JM, Davis C et al. (2007) Molecular imaging of inflammation in atherosclerosis with targeted ultrasound detection of vascular cell adhesion molecule-1. Circulation 116:276–84.CrossRefPubMedGoogle Scholar
  47. 47.
    Kawamura A, Miura S, Murayama T et al. (2004) Increased expression of monocyte CD11a and intracellular adhesion molecule-1 in patients with initial atherosclerotic coronary stenosis. Circ J 68(1):6–10.CrossRefPubMedGoogle Scholar
  48. 48.
    Kelly KA, Allport JR, Tsourkas A et al. (2005) Detection of vascular adhesion molecule-1 expression using a novel multimodal nanoparticle. Circ Res 96:327–36.CrossRefPubMedGoogle Scholar
  49. 49.
    Kelly KA, Nahrendorf M, Yu AM et al. (2006) In vivo phage display selection yields atherosclerotic plaque targeted peptides for imaging. Mol Imaging Biol 8:201–7.CrossRefPubMedGoogle Scholar
  50. 50.
    Kietselaer BL, Reutelingsperger CP, Heidendal GA et al. (2004) Noninvasive detection of plaque instability with use of radiolabeled annexin A5 in patients with carotid-artery atherosclerosis. N Engl J Med 350:1472–3.CrossRefPubMedGoogle Scholar
  51. 51.
    Kircher M, Grimm J, Swirski F et al. (2008) Noninvasive in vivo imaging of monocyte trafficking to atherosclerotic lesions. Circulation 117(3):388–95.CrossRefPubMedGoogle Scholar
  52. 52.
    Klibanov AL, Maruyama K, Torchilin VP et al. (1990) Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes. FEBS Lett 268:235–7.CrossRefPubMedGoogle Scholar
  53. 53.
    Klibanov AL, Rychak JJ, Yang WC et al. (2006) Targeted ultrasound contrast agent for molecular imaging of inflammation in high-shear flow. Contrast Media Mol Imaging 1:259–66.CrossRefPubMedGoogle Scholar
  54. 54.
    Koivunen E, Arap W, Rajotte D et al. (1999) Identification of receptor ligands with phage display peptide libraries. J Nucl Med 40:883–8.PubMedGoogle Scholar
  55. 55.
    Kolonin MG, Sun J, Do KA et al. (2006) Synchronous selection of homing peptides for multiple tissues by in vivo phage display. FASEB J 20:979–81.CrossRefPubMedGoogle Scholar
  56. 56.
    Korosoglou G, Weiss RG, Kedziorek DA et al. (2008) Noninvasive detection of macrophage-rich atherosclerotic plaque in hyperlipidemic rabbits using “positive contrast” magnetic resonance imaging. J Am Coll Cardiol 52:483–91.CrossRefPubMedGoogle Scholar
  57. 57.
    Lancelot E, Amirbekian V, Brigger I et al. (2008) Evaluation of matrix metalloproteinases in atherosclerosis using a novel noninvasive imaging approach. Arterioscler Thromb Vasc Biol 28:425–32.CrossRefPubMedGoogle Scholar
  58. 58.
    Lanza GM, Wallace KD, Scott MJ et al. (1996) A novel site-targeted ultrasonic contrast agent with broad biomedical application. Circulation 94:3334–40.PubMedGoogle Scholar
  59. 59.
    Leong-Poi H, Christiansen J, Klibanov AL et al. (2003) Noninvasive assessment of angi­ogenesis by ultrasound and microbubbles targeted to alpha(v)-integrins. Circulation 107:455–60.CrossRefPubMedGoogle Scholar
  60. 60.
    Li H, Gray BD, Corbin I et al. (2004) MR and fluorescent imaging of low-density lipoprotein receptors. Acad Radiol 11:1251–9.CrossRefPubMedGoogle Scholar
  61. 61.
    Liu C, Bhattacharjee G, Boisvert W et al. (2003) In vivo interrogation of the molecular ­display of atherosclerotic lesion surfaces. Am J Pathol 163:1859–71.PubMedGoogle Scholar
  62. 62.
    Matter CM, Schuler PK, Alessi P et al. (2004) Molecular imaging of atherosclerotic plaques using a human antibody against the extra-domain B of fibronectin. Circ Res 95:1225–33.CrossRefPubMedGoogle Scholar
  63. 63.
    McAteer MA, Schneider JE, Ali ZA et al. (2008) Magnetic resonance imaging of endothelial adhesion molecules in mouse atherosclerosis using dual-targeted microparticles of iron oxide. Arterioscler Thromb Vasc Biol 28:77–83.CrossRefPubMedGoogle Scholar
  64. 64.
    Montecucco F, Steffens S, Burger F et al. (2008) Tumor necrosis factor-alpha (TNF-alpha) induces integrin CD11b/CD18 (Mac-1) up-regulation and migration to the CC chemokine CCL3 (MIP-1alpha) on human neutrophils through defined signalling pathways. Cell Signal 20(3):557–68.CrossRefPubMedGoogle Scholar
  65. 65.
    Nahrendorf M, Jaffer FA, Kelly KA et al. (2006) Noninvasive vascular cell adhesion molecule-1 imaging identifies inflammatory activation of cells in atherosclerosis. Circulation 114:1504–11.CrossRefPubMedGoogle Scholar
  66. 66.
    Nahrendorf M, Waterman P, Thurber G et al. (2009) Hybrid in vivo FMT-CT imaging of protease activity in atherosclerosis with customized nanosensors. Arterioscler Thromb Vasc Biol 29:1444–51.CrossRefPubMedGoogle Scholar
  67. 67.
    Nahrendorf M, Zhang H, Hembrador S et al. (2007) Nanoparticle PET-CT imaging of ­macrophages in inflammatory atherosclerosis. Circulation 117(3):379–87.CrossRefPubMedGoogle Scholar
  68. 68.
    Nakashima Y, Raines EW, Plump AS et al. (1998) Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in the ApoE-deficient mouse. Arterioscler Thromb Vasc Biol 18:842–51.PubMedGoogle Scholar
  69. 69.
    Ozawa MG, Zurita AJ, Dias-Neto E et al. (2008) Beyond receptor expression levels: the relevance of target accessibility in ligand-directed pharmacodelivery systems. Trends Cardiovasc Med 18:126–32.CrossRefPubMedGoogle Scholar
  70. 70.
    Pasqualini R. (1999) Vascular targeting with phage peptide libraries. Q J Nucl Med 43:159–62.PubMedGoogle Scholar
  71. 71.
    Pasqualini R, Ruoslahti E. (1996) Organ targeting in vivo using phage display peptide libra­ries. Nature 380:364–6.CrossRefPubMedGoogle Scholar
  72. 72.
    Rajotte D, Arap W, Hagedorn M et al. (1998) Molecular heterogeneity of the vascular endothelium revealed by in vivo phage display. J Clin Invest 102:430–7.CrossRefPubMedGoogle Scholar
  73. 73.
    Robert R, Jacobin-Valat M-J, Daret D et al. (2006) Identification of human scFvs targeting atherosclerotic lesions: selection by single round in vivo phage display. J Biol Chem 281:40135–43.CrossRefPubMedGoogle Scholar
  74. 74.
    Rychak JJ, Li B, Acton ST et al. (2006) Selectin ligands promote ultrasound contrast agent adhesion under shear flow. Mol Pharm 3:516–24.CrossRefPubMedGoogle Scholar
  75. 75.
    Samijo SK, Willigers JM, Barkhuysen R et al. (1998) Wall shear stress in the human ­common carotid artery as function of age and gender. Cardiovasc Res 39:515–22.CrossRefPubMedGoogle Scholar
  76. 76.
    Sarai M, Hartung D, Petrov A et al. (2007) Broad and specific caspase inhibitor-induced acute repression of apoptosis in atherosclerotic lesions evaluated by radiolabeled annexin A5 imaging. J Am Coll Cardiol 50:2305–12.CrossRefPubMedGoogle Scholar
  77. 77.
    Schumann PA, Christiansen JP, Quigley RM et al. (2002) Targeted-microbubble binding selectively to GPIIb IIIa receptors of platelet thrombi. Invest Radiol 37:587–93.CrossRefPubMedGoogle Scholar
  78. 78.
    Scott JK, Smith GP. (1990) Searching for peptide ligands with an epitope library. Science 249:386–90.CrossRefPubMedGoogle Scholar
  79. 79.
    Shaw PX, Horkko S, Tsimikas S et al. (2001) Human-derived anti-oxidized LDL autoantibody blocks uptake of oxidized LDL by macrophages and localizes to atherosclerotic lesions in vivo. Arterioscler Thromb Vasc Biol 21:1333–9.CrossRefPubMedGoogle Scholar
  80. 80.
    Sirol M, Fuster V, Badimon JJ et al. (2005) Chronic thrombus detection with in vivo magnetic resonance imaging and a fibrin-targeted contrast agent. Circulation 112:1594–600.CrossRefPubMedGoogle Scholar
  81. 81.
    Smith GP, Scott JK. (1993) Libraries of peptides and proteins displayed on filamentous phage. Methods Enzymol 217:228–57.CrossRefPubMedGoogle Scholar
  82. 82.
    Stieger SM, Dayton PA, Borden MA et al. (2008) Imaging of angiogenesis using Cadence contrast pulse sequencing and targeted contrast agents. Contrast Media Mol Imaging 3:9–18.CrossRefPubMedGoogle Scholar
  83. 83.
    Swirski FK, Pittet MJ, Kircher MF et al. (2006) Monocyte accumulation in mouse atherogenesis is progressive and proportional to extent of disease. Proc Natl Acad Sci USA 103:10340–5.CrossRefPubMedGoogle Scholar
  84. 84.
    Takalkar AM, Klibanov AL, Rychak JJ et al. (2004) Binding and detachment dynamics of microbubbles targeted to P-selectin under controlled shear flow. J Control Release 96:473–82.CrossRefPubMedGoogle Scholar
  85. 85.
    Thapa N, Hong H-Y, Sangeetha P et al. (2008) Identification of a peptide ligand recognizing dysfunctional endothelial cells for targeting atherosclerosis. J Control Release 131:27–33.CrossRefPubMedGoogle Scholar
  86. 86.
    Tiukinhoy-Laing SD, Buchanan K, Parikh D et al. (2007) Fibrin targeting of tissue plasminogen activator-loaded echogenic liposomes. J Drug Target 15:109–14.CrossRefPubMedGoogle Scholar
  87. 87.
    Tiukinhoy-Laing SD, Huang S, Klegerman M et al. (2007) Ultrasound-facilitated thrombolysis using tissue-plasminogen activator-loaded echogenic liposomes. Thromb Res 119:777–84.CrossRefPubMedGoogle Scholar
  88. 88.
    Torzewski M, Shaw PX, Han KR et al. (2004) Reduced in vivo aortic uptake of radiolabeled oxidation-specific antibodies reflects changes in plaque composition consistent with plaque stabilization. Arterioscler Thromb Vasc Biol 24:2307–12.CrossRefPubMedGoogle Scholar
  89. 89.
    Tsimikas S. (2002) Noninvasive imaging of oxidized low-density lipoprotein in atherosclerotic plaques with tagged oxidation-specific antibodies. Am J Cardiol 90:22L–7L.CrossRefPubMedGoogle Scholar
  90. 90.
    Tsimikas S, Palinski W, Halpern SE et al. (1999) Radiolabeled MDA2, an oxidation-specific, monoclonal antibody, identifies native atherosclerotic lesions in vivo. J Nucl Cardiol 6:41–53.CrossRefPubMedGoogle Scholar
  91. 91.
    Tsimikas S, Shortal BP, Witztum JL et al. (2000) In vivo uptake of radiolabeled MDA2, an oxidation-specific monoclonal antibody, provides an accurate measure of atherosclerotic lesions rich in oxidized LDL and is highly sensitive to their regression. Arterioscler Thromb Vasc Biol 20:689–97.PubMedGoogle Scholar
  92. 92.
    Unger EC, McCreery TP, Sweitzer RH et al. (1998) In vitro studies of a new thrombus-specific ultrasound contrast agent. Am J Cardiol 81:58G–61G.CrossRefPubMedGoogle Scholar
  93. 93.
    Vicenzini E, Giannoni MF, Puccinelli F et al. (2007) Detection of carotid adventitial vasa vasorum and plaque vascularization with ultrasound cadence contrast pulse sequencing ­technique and echo-contrast agent. Stroke 38:2841–3.CrossRefPubMedGoogle Scholar
  94. 94.
    Wagner S, Breyholz H-J, Faust A et al. (2006) Molecular imaging of matrix metalloprote­inases in vivo using small molecule inhibitors for SPECT and PET. Curr Med Chem 13:2819–38.CrossRefPubMedGoogle Scholar
  95. 95.
    Waldeck J, Häger F, Höltke C et al. (2008) Fluorescence reflectance imaging of macrophage-rich atherosclerotic plaques using an alphavbeta3 integrin-targeted fluorochrome. J Nucl Med 49:1845–51.CrossRefPubMedGoogle Scholar
  96. 96.
    Weissleder R, Kelly K, Sun EY et al. (2005) Cell-specific targeting of nanoparticles by multivalent attachment of small molecules. Nat Biotechnol 23:1418–23.CrossRefPubMedGoogle Scholar
  97. 97.
    Williams JK, Heistad DD. (1996) Structure and function of vasa vasorum. Trends Cardiovasc Med 6:53–7.CrossRefGoogle Scholar
  98. 98.
    Winter PM, Morawski AM, Caruthers SD et al. (2003) Molecular imaging of angiogenesis in early-stage atherosclerosis with alpha(v)beta3-integrin-targeted nanoparticles. Circulation 108:2270–4.CrossRefPubMedGoogle Scholar
  99. 99.
    Winter PM, Neubauer AM, Caruthers SD et al. (2006) Endothelial alpha(v)beta3 integrin-targeted fumagillin nanoparticles inhibit angiogenesis in atherosclerosis. Arterioscler Thromb 26:2103–9.CrossRefGoogle Scholar
  100. 100.
    Wu Y, Unger EC, McCreery TP et al. (1998) Binding and lysing of blood clots using ­MRX-408. Invest Radiol 33:880–5.CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Division of CardiologyUniversity of Texas Health SciencesHoustonUSA

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