Skip to main content
Log in

Targeted Molecular Imaging to Detect Vascular Disease

  • Published:
Current Cardiovascular Risk Reports Aims and scope Submit manuscript

Abstract

Major challenges with vascular imaging are related to the deep-seated nature of blood vessels, small dimensions of the lumen, and poor access into the arterial wall. Current imaging techniques are limited to detecting structural abnormalities. To detect minute abnormalities in the vascular lumen or arterial wall, imaging techniques need to be modified to improve their spatial resolution and sensitivity as well as to develop unique homing mechanisms to target biomarkers expressed in the lumen or the wall of the blood vessels. Molecular imaging has the potential to detect pathologic biomarkers that would otherwise be difficult to be detected by current imaging techniques. This review provides an overview of the uses of molecular imaging to detect two major vascular conditions, thrombosis and atherosclerosis. Molecular imaging has the potential to screen for early stages of disease, follow the course of the disease, and detect the presence of vulnerable plaque or occult thromboses that require aggressive intervention.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Glagov S, Weisenberg E, Zarins CK, et al.: Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med 1987, 316:1371–1375.

    PubMed  CAS  Google Scholar 

  2. Takalkar AM, Klibanov AL, Rychak JJ, et al.: Binding and detachment dynamics of microbubbles targeted to P-selectin under controlled shear flow. J Control Release 2004, 96:473–482.

    Article  PubMed  CAS  Google Scholar 

  3. Rychak JJ, Li B, Acton ST, et al.: Selectin ligands promote ultrasound contrast agent adhesion under shear flow. Mol Pharm 2006, 3:516–524.

    Article  PubMed  CAS  Google Scholar 

  4. Klibanov AL, Rychak JJ, Yang WC, et al.: Targeted ultrasound contrast agent for molecular imaging of inflammation in high-shear flow. Contrast Media Mol Imaging 2006, 1:259–266.

    Article  PubMed  CAS  Google Scholar 

  5. Ferrante EA, Pickard JE, Rychak J, et al.: Dual targeting improves microbubble contrast agent adhesion to VCAM-1 and P-selectin under flow. J Control Release 2009, 140:100–107.

    Article  PubMed  CAS  Google Scholar 

  6. McAteer MA, Schneider JE, Ali ZA, et al.: 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.

    Article  PubMed  CAS  Google Scholar 

  7. •• Kaufmann BA, Carr CL, Belcik JT, et al.: Molecular imaging of the initial inflammatory response in atherosclerosis: implications for early detection of disease. Arterioscler Thromb Vasc Biol 2010, 30:54–59. This study demonstrated that dual targeting to P-selectin and VCAM-1 not only improved retention of targeted microbubbles to atheroma but also allowed staging of atherosclerosis in an age-dependent fashion.

    Article  PubMed  CAS  Google Scholar 

  8. • Ozawa MG, Zurita AJ, Dias-Neto E, et al.: Beyond receptor expression levels: the relevance of target accessibility in ligand-directed pharmacodelivery systems. Trends Cardiovasc Med 2008, 18:126–132. The accessibility of potential targets in atheroma and tumors to biopanning, contrast agents, and therapeutic agents depends on the integrity of the endothelium and other barriers. Knowledge of target accessibility will have important implications to receptor discovery, diagnosis, and treatment.

    Article  PubMed  CAS  Google Scholar 

  9. Kelly KA, Allport JR, Tsourkas A, et al.: Detection of vascular adhesion molecule-1 expression using a novel multimodal nanoparticle. Circ Res 2005, 96:327–336.

    Article  PubMed  CAS  Google Scholar 

  10. Nahrendorf M, Jaffer FA, Kelly KA, et al.: Noninvasive vascular cell adhesion molecule-1 imaging identifies inflammatory activation of cells in atherosclerosis. Circulation 2006, 114:1504–1511.

    Article  PubMed  CAS  Google Scholar 

  11. Chen J, Tung CH, Mahmood U, et al.: In vivo imaging of proteolytic activity in atherosclerosis. Circulation 2002, 105:2766–2771.

    Article  PubMed  Google Scholar 

  12. Deguchi J-O, Aikawa M, Tung C-H, et al.: Inflammation in atherosclerosis: visualizing matrix metalloproteinase action in macrophages in vivo. Circulation 2006, 114:55–62.

    Article  PubMed  Google Scholar 

  13. Jaffer FA, Kim DE, Quinti L, et al.: Optical visualization of cathepsin K activity in atherosclerosis with a novel, protease-activatable fluorescence sensor. Circulation 2007, 115:2292–2298.

    Article  PubMed  CAS  Google Scholar 

  14. Hamilton AJ, Huang SL, Warnick D, et al.: Intravascular ultrasound molecular imaging of atheroma components in vivo. J Am Coll Cardiol 2004, 43:453–460.

    Article  PubMed  Google Scholar 

  15. Vicenzini E, Giannoni MF, Puccinelli F, et al.: Detection of carotid adventitial vasa vasorum and plaque vascularization with ultrasound cadence contrast pulse sequencing technique and echo-contrast agent. Stroke 2007, 38:2841–2843.

    Article  PubMed  Google Scholar 

  16. • Coli S, Magnoni M, Sangiorgi G, et al.: Contrast-enhanced ultrasound imaging of intraplaque neovascularization in carotid arteries: correlation with histology and plaque echogenicity. J Am Coll Cardiol 2008, 52:223–230. This study demonstrated that contrast-enhancement of intraplaque neovascularization in carotid arteries can provide important information on plaque vulnerability and risk stratification.

    Article  PubMed  Google Scholar 

  17. • Stieger SM, Dayton PA, Borden MA, et al.: Imaging of angiogenesis using Cadence contrast pulse sequencing and targeted contrast agents. Contrast Media Mol Imaging 2008, 3:9–18. This study showed that contrast pulse sequencing can aid in selective visualization of targeted contrast agents independent of surrounding tissues and that echistatin-bearing microbubbles can specifically target angiogenesis.

    Article  PubMed  CAS  Google Scholar 

  18. Goertz D, Frijlink M, Tempel D, et al.: Subharmonic contrast intravascular ultrasound for vasa vasorum imaging. Ultrasound Med Biol 2007, 33:1859–1872.

    Article  PubMed  Google Scholar 

  19. Matter CM, Schuler PK, Alessi P, et al.: Molecular imaging of atherosclerotic plaques using a human antibody against the extra-domain B of fibronectin. Circ Res 2004, 95:1225–1233.

    Article  PubMed  CAS  Google Scholar 

  20. Carrió I, Pieri PL, Narula J, et al.: Noninvasive localization of human atherosclerotic lesions with indium 111-labeled monoclonal Z2D3 antibody specific for proliferating smooth muscle cells. J Nucl Cardiol 1998, 5:551–557.

    Article  PubMed  Google Scholar 

  21. Nahrendorf M, Zhang H, Hembrador S, et al.: Nanoparticle PET-CT imaging of macrophages in inflammatory atherosclerosis. Circulation 2008, 117:379–387.

    Article  PubMed  CAS  Google Scholar 

  22. Kircher M, Grimm J, Swirski F, et al.: Noninvasive in vivo imaging of monocyte trafficking to atherosclerotic lesions. Circulation 2008, 117(3):388–395.

    Article  PubMed  Google Scholar 

  23. Tsimikas S, Palinski W, Halpern SE, et al.: Radiolabeled MDA2, an oxidation-specific, monoclonal antibody, identifies native atherosclerotic lesions in vivo. J Nucl Cardiol 1999, 6:41–53.

    Article  PubMed  CAS  Google Scholar 

  24. Tsimikas S, Shortal BP, Witztum JL, et al.: 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 2000, 20:689–697.

    PubMed  CAS  Google Scholar 

  25. Torzewski M, Shaw PX, Han KR, et al.: Reduced in vivo aortic uptake of radiolabeled oxidation-specific antibodies reflects changes in plaque composition consistent with plaque stabilization. Arterioscler Thromb Vasc Biol 2004, 24:2307–2312.

    Article  PubMed  CAS  Google Scholar 

  26. Tsimikas S: Noninvasive imaging of oxidized low-density lipoprotein in atherosclerotic plaques with tagged oxidation-specific antibodies. Am J Cardiol 2002, 90:22L–27L.

    Article  PubMed  CAS  Google Scholar 

  27. Broisat A, Riou LM, Ardisson V, et al.: Molecular imaging of vascular cell adhesion molecule-1 expression in experimental atherosclerotic plaques with radiolabelled B2702-p. Eur J Nucl Med Mol Imaging 2007, 34:830–840.

    Article  PubMed  CAS  Google Scholar 

  28. Kietselaer BL, Reutelingsperger CP, Heidendal GA, et al.: Noninvasive detection of plaque instability with use of radiolabeled annexin A5 in patients with carotid-artery atherosclerosis. N Engl J Med 2004, 350:1472–1473.

    Article  PubMed  CAS  Google Scholar 

  29. Johnson LL, Schofield L, Donahay T, et al.: 99mTc-annexin V imaging for in vivo detection of atherosclerotic lesions in porcine coronary arteries. J Nucl Med 2005, 46:1186–1193.

    PubMed  Google Scholar 

  30. Sarai M, Hartung D, Petrov A, et al.: Broad and specific caspase inhibitor-induced acute repression of apoptosis in atherosclerotic lesions evaluated by radiolabeled annexin A5 imaging. J Am Coll Cardiol 2007, 50:2305–2312.

    Article  PubMed  CAS  Google Scholar 

  31. Haider N, Hartung D, Fujimoto S, et al.: Dual molecular imaging for targeting metalloproteinase activity and apoptosis in atherosclerosis: molecular imaging facilitates understanding of pathogenesis. J Nucl Cardiol 2009, 16:753–762.

    Article  PubMed  Google Scholar 

  32. Amirbekian V, Lipinski MJ, Briley-Saebo KC, et al.: Detecting and assessing macrophages in vivo to evaluate atherosclerosis noninvasively using molecular MRI. Proc Natl Acad Sci U S A 2007, 104:961–966.

    Article  PubMed  CAS  Google Scholar 

  33. Hyafil F, Cornily JC, Feig JE, et al.: Noninvasive detection of macrophages using a nanoparticulate contrast agent for computed tomography. Nat Med 2007, 13:636–641.

    Article  PubMed  CAS  Google Scholar 

  34. Calara F, Silvestre M, Casanada F, et al.: Spontaneous plaque rupture and secondary thrombosis in apolipoprotein E-deficient and LDL receptor-deficient mice. J Pathol 2001, 195:257–263.

    Article  PubMed  CAS  Google Scholar 

  35. Kelly KA, Nahrendorf M, Yu AM, et al.: In vivo phage display selection yields atherosclerotic plaque targeted peptides for imaging. Mol Imaging Biol 2006, 8:201–207.

    Article  PubMed  Google Scholar 

  36. Nakashima Y, Raines EW, Plump AS, et al.: Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in the ApoE-deficient mouse. Arterioscler Thromb Vasc Biol 1998, 18:842–851.

    PubMed  CAS  Google Scholar 

  37. Iiyama K, Hajra L, Iiyama M, et al.: 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 1999, 85:199–207.

    PubMed  CAS  Google Scholar 

  38. Kaufmann BA, Sanders JM, Davis C, et al.: Molecular imaging of inflammation in atherosclerosis with targeted ultrasound detection of vascular cell adhesion molecule-1. Circulation 2007, 116:276–284.

    Article  PubMed  CAS  Google Scholar 

  39. • Driessen WH, Danila DC, Conyer JL, et al.: Detection of VCAM-1 expression in inflamatory atherosclerosis using targeted ultrasound-based molecular imaging. Circulation 2009, 120:S326. This study showed that contrast pulse sequencing can selectively visualize targeted contrast agents independent of surrounding tissues, and VCAM-1 expression is present in advanced atherosclerosis in apoE -/- mice.

    Article  Google Scholar 

  40. Li H, Gray BD, Corbin I, et al.: MR and fluorescent imaging of low-density lipoprotein receptors. Acad Radiol 2004, 11:1251–1259.

    Article  PubMed  Google Scholar 

  41. Shaw PX, Horkko S, Tsimikas S, et al.: Human-derived anti-oxidized LDL autoantibody blocks uptake of oxidized LDL by macrophages and localizes to atherosclerotic lesions in vivo. Arterioscler Thromb Vasc Biol 2001, 21:1333–1339.

    Article  PubMed  CAS  Google Scholar 

  42. Briley-Saebo K, Shaw P, Mulder W, et al.: Targeted molecular probes for imaging atherosclerotic lesions with magnetic resonance using antibodies that recognize oxidation-specific epitopes. Circulation 2008, 117:3206–3215.

    Article  PubMed  CAS  Google Scholar 

  43. Swirski FK, Pittet MJ, Kircher MF, et al.: Monocyte accumulation in mouse atherogenesis is progressive and proportional to extent of disease. Proc Natl Acad Sci U S A 2006, 103:10340–10345.

    Article  PubMed  CAS  Google Scholar 

  44. Galis ZS, Sukhova GK, Lark MW, et al.: Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest 1994, 94:2493–2503.

    Article  PubMed  CAS  Google Scholar 

  45. • Lancelot E, Amirbekian V, Brigger I, et al.: Evaluation of matrix metalloproteinases in atherosclerosis using a novel noninvasive imaging approach. Arterioscler Thromb Vasc Biol 2008, 28:425–432. Direct detection of MMPs in atherosclerosis can be achieved with peptide-conjugated gadolinium-based MRI contrast agent.

    Article  PubMed  CAS  Google Scholar 

  46. • Fujimoto S, Hartung D, Ohshima S, et al.: Molecular imaging of matrix metalloproteinase in atherosclerotic lesions: resolution with dietary modification and statin therapy. J Am Coll Cardiol 2008, 52:1847–1857. This study demonstrates that the levels of expression of MMPs in atherosclerosis in response to dietary modification and statin therapy can be used in conjunction with molecular imaging techniques.

    Article  PubMed  CAS  Google Scholar 

  47. Herrmann J, Lerman LO, Rodriguez-Porcel M, et al.: Coronary vasa vasorum neovascularization precedes epicardial endothelial dysfunction in experimental hypercholesterolemia. Cardiovasc Res 2001, 51:762–766.

    Article  PubMed  CAS  Google Scholar 

  48. Gössl M, Versari D, Mannheim D, et al.: Increased spatial vasa vasorum density in the proximal LAD in hypercholesterolemia-Implications for vulnerable plaque-development. Atherosclerosis 2007, 192:246–252.

    Article  PubMed  CAS  Google Scholar 

  49. Burtea C, Laurent S, Murariu O, et al.: Molecular imaging of alpha v beta3 integrin expression in atherosclerotic plaques with a mimetic of RGD peptide grafted to Gd-DTPA. Cardiovasc Res 2008, 78:148–157.

    Article  PubMed  CAS  Google Scholar 

  50. Winter PM, Morawski AM, Caruthers SD, et al.: Molecular imaging of angiogenesis in early-stage atherosclerosis with alpha(v)beta3-integrin-targeted nanoparticles. Circulation 2003, 108:2270–2274.

    Article  PubMed  CAS  Google Scholar 

  51. • Winter PM, Neubauer AM, Caruthers SD, et al.: Endothelial alpha(v)beta3 integrin-targeted fumagillin nanoparticles inhibit angiogenesis in atherosclerosis. Arterioscler Thromb 2006, 26:2103–2109. This study demonstrated that drug-loaded nanoparticle targeting of atheroma can deliver therapeutics at high local concentrations with minimal systemic adverse effects and can also monitor the regression of disease.

    Article  CAS  Google Scholar 

  52. Flacke S, Fischer S, Scott MJ, et al.: Novel MRI contrast agent for molecular imaging of fibrin: implications for detecting vulnerable plaques. Circulation 2001, 104:1280–1285.

    Article  PubMed  CAS  Google Scholar 

  53. Botnar RM, Perez AS, Witte S, et al.: In vivo molecular imaging of acute and subacute thrombosis using a fibrin-binding magnetic resonance imaging contrast agent. Circulation 2004, 109:2023–2029.

    Article  PubMed  CAS  Google Scholar 

  54. Sirol M, Fuster V, Badimon JJ, et al.: Chronic thrombus detection with in vivo magnetic resonance imaging and a fibrin-targeted contrast agent. Circulation 2005, 112:1594–1600.

    Article  PubMed  Google Scholar 

  55. Vymzaal J, Spuentrup E, Cardenas G, et al.: The use of a fibrin-binding magnetic resonance imaging agent P-2104R to visualize thrombi in the venous and arterial vasculature. Presented at Radiological Society of North America Annual Meeting. Chicago, IL; 2006.

  56. Winter PM, Shukla HP, Caruthers SD, et al.: Molecular imaging of human thrombus with computed tomography. Acad Radiol 2005, 12(Suppl 1):S9–13.

    Article  PubMed  Google Scholar 

  57. Unger EC, McCreery TP, Sweitzer RH, et al.: In vitro studies of a new thrombus-specific ultrasound contrast agent. Am J Cardiol 1998, 81:58G–61G.

    Article  PubMed  CAS  Google Scholar 

  58. Wu Y, Unger EC, McCreery TP, et al.: Binding and lysing of blood clots using MRX-408. Invest Radiol 1998, 33:880–885.

    Article  PubMed  CAS  Google Scholar 

  59. Schumann PA, Christiansen JP, Quigley RM, et al.: Targeted-microbubble binding selectively to GPIIb IIIa receptors of platelet thrombi. Invest Radiol 2002, 37:587–593.

    Article  PubMed  CAS  Google Scholar 

  60. Tiukinhoy-Laing SD, Buchanan K, Parikh D, et al.: Fibrin targeting of tissue plasminogen activator-loaded echogenic liposomes. J Drug Target 2007, 15:109–114.

    Article  PubMed  CAS  Google Scholar 

  61. Tiukinhoy-Laing SD, Huang S, Klegerman M, et al.: Ultrasound-facilitated thrombolysis using tissue-plasminogen activator-loaded echogenic liposomes. Thromb Res 2007, 119:777–784.

    Article  PubMed  CAS  Google Scholar 

Download references

Disclosure

No potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Patrick H. Kee.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Driessen, W., Kee, P.H. Targeted Molecular Imaging to Detect Vascular Disease. Curr Cardio Risk Rep 4, 332–339 (2010). https://doi.org/10.1007/s12170-010-0116-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12170-010-0116-6

Keywords

Navigation