Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Molecular imaging of cardiovascular disease with contrast-enhanced ultrasonography

Nature Reviews Cardiology volume 6, pages 475–481 (2009)Cite this article

Abstract

Techniques for noninvasive imaging of specific disease-related molecular changes are being developed to enhance diagnosis and therapeutic decision making in the clinical setting, and to facilitate research efforts. Molecular imaging with contrast-enhanced ultrasonography relies on the detection of the acoustic signal produced by microbubble or nanoparticle agents that are targeted to sites of disease. This Review describes the basis for ultrasound molecular imaging, the unique features of contrast agent behavior or detector performance in relation to clinical or research needs, and the progress that has been made to date in imaging key events in cardiovascular medicine, such as atherosclerosis, postischemic inflammation, angiogenesis, transplant rejection and thrombus formation.

Key Points

  • Targeted microbubble contrast agents are intravascular tracers and are, therefore, best suited to detection of disease states where molecular changes occur within the vascular space

  • Advantages of contrast-enhanced ultrasonography for molecular imaging include speed of imaging (10 min), ability to perform repetitive injections to image multiple targets, and sensitivity

  • Disadvantages of contrast-enhanced ultrasonography are that the contrast agent cannot access pathologic targets outside the vascular space and has a relatively short lifespan, which limits their ability to track cell migration or survival

  • Imaging of inflammation in ischemia, infarction, transplant rejection, and atherosclerosis has been achieved by targeting microbubbles to immune cells (including monocytes and neutrophils) or to endothelial cell adhesion molecules

  • Imaging of endothelial markers of angiogenesis or components of the immune response associated with angiogenesis can provide information on endogenous or growth-factor-stimulated vascular remodeling before flow changes occur

  • Thrombus targeting is possible by targeting ultrasound contrast agents to activated platelets or fibrin, although problems with ligand specificity have limited rapid progress of this strategy

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Targeted contrast-enhanced ultrasonography of leukocyte recruitment with phosphatidylserine-containing microbubbles.
Figure 2: Molecular imaging of endothelial activation in progressive atherosclerosis.
Figure 3: Contrast-enhanced ultrasound imaging data with microbubbles targeted to monocyte α5-integrin expression and control microbubbles at 2, 4, and 7 days after creation of hindlimb ischemia where flow does not fully recover until day 21.

Similar content being viewed by others

References

  1. DeJong, N. et al. Optical imaging of contrast agent microbubbles in an ultrasound field with a 100-MHz camera. Ultrasound Med. Biol. 26, 487–492 (2000).

    Article  CAS  Google Scholar 

  2. Dayton, P. A., Morgan, K. E., Klibanov, A. L., Brandenburger, G. H. & Ferrara, K. W. Optical and acoustical observations of the effects of ultrasound on contrast agents. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 46, 220–232 (1999).

    Article  CAS  Google Scholar 

  3. Kaufmann, B., Wei, K. & Lindner, J. R. Contrast Echocardiography. Curr. Prob. Cardiol. 32, 45–96 (2007).

    Article  Google Scholar 

  4. Epstein, P. S. & Plesset, M. S. On the stability of gas bubbles in liquid-gas solutions. J. Chem. Phys. 18, 1505–1509 (1950).

    Article  CAS  Google Scholar 

  5. Sarkar, K., Shi, W. T., Chatterjee, D. & Forsberg, F. Characterization of ultrsaound contrast microbubbles using in vitro experiments and viscous and viscoelastic interface models for encapsulation. J. Acoust. Soc. Am. 118, 539–550 (2005).

    Article  CAS  Google Scholar 

  6. Lindner, J. R. et al. Noninvasive imaging of inflammation by ultrasound detection of phagocytosed microbubbles. Circulation 102, 531–538 (2000).

    Article  CAS  Google Scholar 

  7. Dayton, P. A. et al. Optical and acoustical dynamics of microbubble contrast agents inside neutrophils. Biophys. J. 80, 1547–1556 (2000).

    Article  Google Scholar 

  8. Dayton, P. A. et al. Ultrasonic analysis of peptide- and antibody-targeted microbubble contrast agents for molecular imaging of αvβ3-expressing cells. Mol. Imag. 3, 125–134 (2004).

    Article  CAS  Google Scholar 

  9. Lankford, M. et al. Effect of microbubble attachment to cells on ultrasound signal enhancement: implications for targeted imaging. Invest. Radiol. 41, 721–728 (2006).

    Article  Google Scholar 

  10. Lindner, J. R. et al. Microbubble persistence in the microcirculation during ischemia-reperfusion and inflammation: integrin- and complement-mediated adherence to activated leukocytes. Circulation 101, 668–675 (2000).

    Article  CAS  Google Scholar 

  11. Lindner, J. R. et al. Noninvasive ultrasound imaging of inflammation using microbubbles targeted to activated leukocytes. Circulation 102, 2745–2750 (2000).

    Article  CAS  Google Scholar 

  12. Christiansen, J. P. et al. Non-invasive imaging of myocardial reperfusion injury using leukocyte-targeted contrast echocardiography. Circulation 105, 1764–1767 (2002).

    Article  Google Scholar 

  13. Kondo, I. et al. Leukocyte-targeted myocardial contrast echocardiography can assess the degree of acute allograft rejection in a rat cardiac transplantation model. Circulation 109, 1056–1061 (2004).

    Article  Google Scholar 

  14. Behm, C. Z. et al. Molecular imaging of VCAM-1 and inflammatory cell recruitment during arteriogenesis and vasculogenesis. Circulation 117, 2902–2911 (2008).

    Article  CAS  Google Scholar 

  15. Lindner, J. R., Song, J., Jayaweera, A. R., Sklenar, J. & Kaul, S. Microvascular rheology of Definity microbubbles after intra-arterial and intravenous administration. J. Am. Soc. Echocardiogr. 15, 396–403 (2002).

    Article  Google Scholar 

  16. Anderson, D. R., Tsutsui, J. M., Xie, F., Radio, S. J. & Porter, T. R. The role of complement in the adherence of microbubbles to dysfunctional arterial endothelium and atherosclerotic plaque. Cardiovasc. Res. 73, 597–606 (2007).

    Article  CAS  Google Scholar 

  17. Lindner, J. R. et al. Ultrasound assessment of inflammation and renal tissue injury with microbubbles targeted to P-selectin. Circulation 104, 2107–2112 (2001).

    Article  CAS  Google Scholar 

  18. Bevilacqua, M. & Nelson, R. M. Selectins. J. Clin. Invest. 91, 379–387 (1993).

    Article  CAS  Google Scholar 

  19. Chukwuemeka, A. O., Brown, A., Venn, G. E. & Chambers, D. J. Changes in P-selectin expression on cardiac microvessels in blood-perfused rat hearts subjected to ischemia reperfusion. Ann. Thorac. Surg. 79, 204–211 (2005).

    Article  Google Scholar 

  20. Kaufmann, B., Lewis, C., Xie, A., Mirza-Mohd, A. & Lindner, J. R. Detection of recent myocardial ischemia by molecular imaging of P-selectin with targeted contrast echocardiography. Eur. Heart J. 28, 2011–2017 (2007).

    Article  Google Scholar 

  21. Villanueva, F. S. et al. Myocardial ischemic memory imaging with molecular echocardiography. Circulation 115, 345–352 (2007).

    Article  Google Scholar 

  22. Weller, G. E. et al. Ultrasound imaging of acute cardiac transplant rejection with microbubbles targeted to intercellular adhesion molecule-1. Circulation 108, 218–224 (2003).

    Article  Google Scholar 

  23. Iiyama, K. 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. 85, 199–207 (1999).

    Article  CAS  Google Scholar 

  24. O'Brien, K. D., McDonald, T. O., Chait, A., Allen, M. D., Alpers, C. E. Neovascular expression of E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in human atherosclerosis and their relation to intimal leukocyte content. Circulation 93, 672–682 (1996).

    Article  CAS  Google Scholar 

  25. Kaufmann, B. et al. Molecular imaging of inflammation in atherosclerosis with targeted ultrasound detection of vascular cell adhesion molecule-I. Circulation 116, 276–284 (2007).

    Article  CAS  Google Scholar 

  26. Demos, S. M. et al. In vivo targeting of acoustically reflective liposomes for intravascular and transvascular ultrasonic enhancement. J. Am. Coll. Cardiol. 33, 867–875 (1999).

    Article  CAS  Google Scholar 

  27. Hamilton, A. J. et al. Intravascular ultrasound molecular imaging of atheroma components in vivo. J. Am. Coll. Cardiol. 43, 453–460 (2004).

    Article  Google Scholar 

  28. Kaufmann, B. A. et al. Molecular imaging of endothelial cell activation predicts future atherosclerotic plaque development [abstract 904-253]. J. Am. Coll. Cardiol. 51 (Suppl. A), A125 (2008).

    Google Scholar 

  29. Lee, S. et al. Contrast-enhanced ultrasound characterization of inflammation and vasa vasoral proliferation caused by mural hemorrhage and platelet deposition [abstract 1074]. Circulation 118 (Suppl. 2), S644 (2008).

    Google Scholar 

  30. Kolodgie, F. D. et al. Intraplaque hemorrhage and progression of coronary atheroma. N. Engl. J. Med. 349, 2316–2325 (2003).

    Article  CAS  Google Scholar 

  31. Moreno, P. R., Purushothaman, K. R., Sirol, M., Levy, A. P. & Fuster, V. Neovascularization in human atherosclerosis. Circulation 113, 2245–2252 (2006).

    Article  Google Scholar 

  32. Leong-Poi, H., Christiansen, J., Klibanov, A. L., Kaul, S. & Lindner, J. R. Non-invasive assessment of angiogenesis by ultrasound and microbubbles targeted to αv-integrins. Circulation 107, 455–460 (2003).

    Article  CAS  Google Scholar 

  33. Ellegala, D. B. et al. Imaging tumor angiogenesis with contrast ultrasound and microbubbles targeted to αvβ3 . Circulation 108, 336–341 (2003).

    Article  Google Scholar 

  34. Leong Poi, H. et al. Assessment of endogenous and therapeutic arteriogenesis by contrast ultrasound molecular imaging of integrin expression. Circulation 111, 3248–3254 (2005).

    Article  CAS  Google Scholar 

  35. Unger, E. C., McCreery, T. P., Sweitzer, R. H., Shen, D. & Wu, G. In vitro studies of a new thrombus-specific ultrasound contrast agent. Am. J. Cardiol. 81, 58G–61G (1998).

    Article  CAS  Google Scholar 

  36. Alonso, A. et al. Molecular imaging of human thrombus with novel abciximab immunobubbles and ultrasound. Stroke 38, 1508–1514 (2007).

    Article  CAS  Google Scholar 

  37. Takeuchi, M. et al. Enhanced visualization of intravascular and left atrial appendage thrombus with the use of a thrombus-targeting ultrasonographic contrast agent (mrx-408a1): In vivo experimental echocardiographic studies. J. Am. Soc. Echocardiogr. 12, 1015–1021 (1999).

    Article  CAS  Google Scholar 

  38. Lanza, G. M. et al. A novel site-targeted ultrasonic contrast agent with broad biomedical application. Circulation 9, 3334–3340 (1996).

    Article  Google Scholar 

  39. Molina, C. A. et al. Microbubble administration accelerates clot lysis during continuous 2-MHz ultrasound monitoring in stroke patients treated with intravenous tissue plasminogen activator. Stroke 37, 425–429 (2006).

    Article  CAS  Google Scholar 

  40. Xie, F. et al. Effectiveness of lipid microbubbles and ultrasound in declotting thrombosis. Ultrasound Med. Biol. 31, 979–985 (2005).

    Article  Google Scholar 

  41. Bekeredjian, R., Grayburn, P. A. & Shohet, R. V. Use of ultrasound contrast agents for gene or drug delivery in cardiovascular medicine. J. Am. Coll. Cardiol. 45, 329–335 (2005).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cardiovascular Medicine, Oregon Health & Science University, Portland, OR, USA

    Jonathan R. Lindner

Authors
  1. Jonathan R. Lindner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jonathan R. Lindner.

Ethics declarations

Competing interests

J. R. Lindner is a patent holder/applicant with the Oregon Health & Science University.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lindner, J. Molecular imaging of cardiovascular disease with contrast-enhanced ultrasonography. Nat Rev Cardiol 6, 475–481 (2009). https://doi.org/10.1038/nrcardio.2009.77

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrcardio.2009.77

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing