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Ultrasound Contrast Materials in Cardiovascular Medicine: from Perfusion Assessment to Molecular Imaging

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Abstract

Ultrasound imaging is widely used in cardiovascular diagnostics. Contrast agents expand the range of tasks that ultrasound can perform. In the clinic in the USA, endocardial border delineation and left ventricle opacification have been an approved indication for more than a decade. However, myocardial perfusion contrast ultrasound studies are still at the clinical trials stage. Blood pool contrast and perfusion in other tissues might be an easier indication to achieve: general blood pool ultrasound contrast is in wider use in Europe, Canada, Japan, and China. Targeted (molecular) contrast microbubbles will be the next generation of ultrasound imaging probes, capable of specific delineation of the areas of disease by adherence to molecular targets. The shell of targeted microbubbles (currently in the preclinical research and early stage clinical trials) is decorated with the ligands (antibodies, peptides or mimetics, hormones, and carbohydrates) that ensure firm binding to the molecular markers of disease.

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References

  1. Gramiak, R., & Shah, P. M. (1968). Echocardiography of the aortic root. Investigative Radiology, 3(5), 356–366.

    Article  PubMed  CAS  Google Scholar 

  2. Gramiak, R., & Shah, P. M. (1971). Detection of intracardiac blood flow by pulsed echo-ranging ultrasound. Radiology, 100(2), 415–418.

    PubMed  CAS  Google Scholar 

  3. Schurmann, R., & Schlief, R. (1994). Saccharide-based contrast agents. Characteristics and diagnostic potential. La Radiologia Medica, 87(5 Suppl 1), 15–23.

    PubMed  CAS  Google Scholar 

  4. Keller, M. W., Glasheen, W., & Kaul, S. (1989). Albunex: a safe and effective commercially produced agent for myocardial contrast echocardiography. Journal of the American Society of Echocardiography, 2(1), 48–52.

    PubMed  CAS  Google Scholar 

  5. Skyba, D. M., Camarano, G., Goodman, N. C., Price, R. J., Skalak, T. C., & Kaul, S. (1996). Hemodynamic characteristics, myocardial kinetics and microvascular rheology of FS-069, a second-generation echocardiographic contrast agent capable of producing myocardial opacification from a venous injection. Journal of the American College of Cardiology, 28(5), 1292–1300.

    Article  PubMed  CAS  Google Scholar 

  6. Schneider, M., Arditi, M., Barrau, M. B., Brochot, J., Broillet, A., Ventrone, R., et al. (1995). BR1: a new ultrasonographic contrast agent based on sulfur hexafluoride-filled microbubbles. Investigative Radiology, 30(8), 451–457.

    Article  PubMed  CAS  Google Scholar 

  7. Grauer, S. E., Pantely, G. A., Xu, J., Ge, S., Giraud, G. D., Shiota, T., et al. (1996). Myocardial imaging with a new transpulmonary lipid-fluorocarbon echo contrast agent: experimental studies in pigs. American Heart Journal, 132(5), 938–945.

    Article  PubMed  CAS  Google Scholar 

  8. Wijkstra H., Smeenge M., Rosette Jdl. , Pochon S., Tardy-Cantalupi I., Tranquart F. (2012) Targeted microbubble prostate cancer imagign with BR55. In: Cate Ft, Jong Nd, Leen E (eds) The 17th European Symposium on Ultrasound Contrast Imaging., Rotterdam, p 6.

  9. Leighton, T. G. (1994). The acoustic bubble. London: Academic Press.

    Google Scholar 

  10. de Jong, N., Emmer, M., van Wamel, A., & Versluis, M. (2009). Ultrasonic characterization of ultrasound contrast agents. Medical and Biological Engineering and Computing, 47(8), 861–873.

    Article  PubMed  Google Scholar 

  11. Bouakaz, A., Versluis, M., & de Jong, N. (2005). High-speed optical observations of contrast agent destruction. Ultrasound in Medicine and Biology, 31(3), 391–399.

    Article  PubMed  Google Scholar 

  12. Phillips, P., & Gardner, E. (2004). Contrast-agent detection and quantification. European Radiology, 14(Suppl 8), P4–P10.

    PubMed  Google Scholar 

  13. Klibanov, A. L., Rasche, P. T., Hughes, M. S., Wojdyla, J. K., Galen, K. P., Wible, J. H., Jr., et al. (2004). Detection of individual microbubbles of ultrasound contrast agents: imaging of free-floating and targeted bubbles. Investigative Radiology, 39(3), 187–195.

    Article  PubMed  Google Scholar 

  14. Senior, R., Lepper, W., Pasquet, A., Chung, G., Hoffman, R., Vanoverschelde, J. L., et al. (2004). Myocardial perfusion assessment in patients with medium probability of coronary artery disease and no prior myocardial infarction: comparison of myocardial contrast echocardiography with 99mTc single-photon emission computed tomography. American Heart Journal, 147(6), 1100–1105.

    Article  PubMed  Google Scholar 

  15. Dijkmans, P. A., Knaapen, P., Sieswerda, G. T., Aiazian, E., Visser, C. A., Lammertsma, A. A., et al. (2006). Quantification of myocardial perfusion using intravenous myocardial contrast echocardiography in healthy volunteers: comparison with positron emission tomography. Journal of the American Society of Echocardiography, 19(3), 285–293.

    Article  PubMed  Google Scholar 

  16. Wei, K., Jayaweera, A. R., Firoozan, S., Linka, A., Skyba, D. M., & Kaul, S. (1998). Quantification of myocardial blood flow with ultrasound-induced destruction of microbubbles administered as a constant venous infusion. Circulation, 97(5), 473–483.

    Article  PubMed  CAS  Google Scholar 

  17. Senior, R., Monaghan, M., Main, M. L., Zamorano, J. L., Tiemann, K., Agati, L., et al. (2009). Detection of coronary artery disease with perfusion stress echocardiography using a novel ultrasound imaging agent: two Phase 3 international trials in comparison with radionuclide perfusion imaging. European Journal of Echocardiography, 10(1), 26–35.

    Article  PubMed  Google Scholar 

  18. Wilson, S. R., Jang, H. J., Kim, T. K., Iijima, H., Kamiyama, N., & Burns, P. N. (2008). Real-time temporal maximum-intensity-projection imaging of hepatic lesions with contrast-enhanced sonography. AJR. American Journal of Roentgenology, 190(3), 691–695.

    Article  PubMed  Google Scholar 

  19. Kalantarinia, K., Belcik, J. T., Patrie, J. T., & Wei, K. (2009). Real-time measurement of renal blood flow in healthy subjects using contrast-enhanced ultrasound. American Journal of Physiology. Renal Physiology, 297(4), F1129–F1134.

    Article  PubMed  CAS  Google Scholar 

  20. Staub, D., Patel, M. B., Tibrewala, A., Ludden, D., Johnson, M., Espinosa, P., et al. (2011). Vasa vasorum and plaque neovascularization on contrast-enhanced carotid ultrasound imaging correlates with cardiovascular disease and past cardiovascular events. Stroke, 41(1), 41–47.

    Article  Google Scholar 

  21. Vavuranakis, M., Kakadiaris, I. A., O'Malley, S. M., Papaioannou, T. G., Sanidas, E. A., Naghavi, M., et al. (2008). A new method for assessment of plaque vulnerability based on vasa vasorum imaging, by using contrast-enhanced intravascular ultrasound and differential image analysis. International Journal of Cardiology, 130(1), 23–29.

    Article  PubMed  Google Scholar 

  22. Klibanov, A. L., Hughes, M. S., Marsh, J. N., Hall, C. S., Miller, J. G., Wible, J. H., et al. (1997). Targeting of ultrasound contrast material. An in vitro feasibility study. Acta Radiologica. Supplement, 412, 113–120.

    CAS  Google Scholar 

  23. Pochon, S., Tardy, I., Bussat, P., Bettinger, T., Brochot, J., von Wronski, M., et al. (2010). BR55: a lipopeptide-based VEGFR2-targeted ultrasound contrast agent for molecular imaging of angiogenesis. Investigative Radiology, 45(2), 89–95.

    Article  PubMed  CAS  Google Scholar 

  24. Pelura, T. J., & Pelura, T. J. (1998). Clinical experience with AF0150 (Imagent US), a new ultrasound contrast agent. Academic Radiology, 1(5 Suppl), S69–S71. discussion S72-64.

    Article  Google Scholar 

  25. Sugimoto, K., Moriyasu, F., Saito, K., Taira, J., Saguchi, T., Yoshimura, N., et al. (2012). Comparison of Kupffer-phase Sonazoid-enhanced sonography and hepatobiliary-phase gadoxetic acid-enhanced magnetic resonance imaging of hepatocellular carcinoma and correlation with histologic grading. Journal of Ultrasound in Medicine, 31(4), 529–538.

    PubMed  Google Scholar 

  26. Wible, J. H., Jr., Wojdyla, J. K., Bales, G. L., McMullen, W. N., Geiser, E. A., & Buss, D. D. (1996). Inhaled gases affect the ultrasound contrast produced by Albunex in anesthetized dogs. Journal of the American Society of Echocardiography, 9(4), 442–451.

    Article  PubMed  Google Scholar 

  27. Klibanov, A. L., Hughes, M. S., Villanueva, F. S., Jankowski, R. J., Wagner, W. R., Wojdyla, J. K., et al. (1999). Targeting and ultrasound imaging of microbubble-based contrast agents. Magma, 8(3), 177–184.

    PubMed  CAS  Google Scholar 

  28. Takalkar, A. M., Klibanov, A. L., Rychak, J. J., Lindner, J. R., & Ley, K. (2004). Binding and detachment dynamics of microbubbles targeted to P-selectin under controlled shear flow. Journal of Controlled Release, 96(3), 473–482.

    Article  PubMed  CAS  Google Scholar 

  29. Klibanov, A. L., Rychak, J. J., Yang, W. C., Alikhani, S., Li, B., Acton, S., et al. (2006). Targeted ultrasound contrast agent for molecular imaging of inflammation in high-shear flow. Contrast Media & Molecular Imaging, 1(6), 259–266.

    Article  CAS  Google Scholar 

  30. Guenther, F., von zur Muhlen, C., Ferrante, E. A., Grundmann, S., Bode, C., & Klibanov, A. L. (2010). An ultrasound contrast agent targeted to P-selectin detects activated platelets at supra-arterial shear flow conditions. Investigative Radiology, 45(10), 586–591.

    Article  PubMed  CAS  Google Scholar 

  31. Rychak, J. J., Li, B., Acton, S. T., Leppanen, A., Cummings, R. D., Ley, K., et al. (2006). Selectin ligands promote ultrasound contrast agent adhesion under shear flow. Molecular Pharmaceutics, 3(5), 516–524.

    Article  PubMed  CAS  Google Scholar 

  32. Kim, D. H., Klibanov, A. L., & Needham, D. (2000). The influence of tiered layers of surface-grafted poly(ethylene glycol) on receptor–ligand-mediated adhesion between phospholipid monolayer-stabilized microbubbles and coated glass beads. Langmuir, 16(6), 2808–2817.

    Article  CAS  Google Scholar 

  33. Ham, A. S., Klibanov, A. L., & Lawrence, M. B. (2009). Action at a distance: lengthening adhesion bonds with poly(ethylene glycol) spacers enhances mechanically stressed affinity for improved vascular targeting of microparticles. Langmuir, 25(17), 10038–10044.

    Article  PubMed  CAS  Google Scholar 

  34. Rychak, J. J., Lindner, J. R., Ley, K., & Klibanov, A. L. (2006). Deformable gas-filled microbubbles targeted to P-selectin. Journal of Controlled Release, 114(3), 288–299.

    Article  PubMed  CAS  Google Scholar 

  35. Ferrante, E. A., Pickard, J. E., Rychak, J., Klibanov, A., & Ley, K. (2009). Dual targeting improves microbubble contrast agent adhesion to VCAM-1 and P-selectin under flow. Journal of Controlled Release, 140(2), 100–107.

    Article  PubMed  CAS  Google Scholar 

  36. Maul, T. M., Dudgeon, D. D., Beste, M. T., Hammer, D. A., Lazo, J. S., Villanueva, F. S., et al. (2010). Optimization of ultrasound contrast agents with computational models to improve selection of ligands and binding strength. Biotechnology and Bioengineering, 107(5), 854–864.

    Article  PubMed  CAS  Google Scholar 

  37. Fadok, V. A., de Cathelineau, A., Daleke, D. L., Henson, P. M., & Bratton, D. L. (2001). Loss of phospholipid asymmetry and surface exposure of phosphatidylserine is required for phagocytosis of apoptotic cells by macrophages and fibroblasts. The Journal of Biological Chemistry, 276(2), 1071–1077.

    Article  PubMed  CAS  Google Scholar 

  38. Yanagisawa, K., Moriyasu, F., Miyahara, T., Yuki, M., & Iijima, H. (2007). Phagocytosis of ultrasound contrast agent microbubbles by Kupffer cells. Ultrasound in Medicine and Biology, 33(2), 318–325.

    Article  PubMed  Google Scholar 

  39. Lindner, J. R., Song, J., Xu, F., Klibanov, A. L., Singbartl, K., Ley, K., et al. (2000). Noninvasive ultrasound imaging of inflammation using microbubbles targeted to activated leukocytes. Circulation, 102(22), 2745–2750.

    Article  PubMed  CAS  Google Scholar 

  40. Christiansen, J. P., Leong-Poi, H., Klibanov, A. L., Kaul, S., & Lindner, J. R. (2002). Noninvasive imaging of myocardial reperfusion injury using leukocyte-targeted contrast echocardiography. Circulation, 105(15), 1764–1767.

    Article  PubMed  Google Scholar 

  41. Villanueva, F. S., Jankowski, R. J., Klibanov, S., Pina, M. L., Alber, S. M., Watkins, S. C., et al. (1998). Microbubbles targeted to intercellular adhesion molecule-1 bind to activated coronary artery endothelial cells. Circulation, 98(1), 1–5.

    Article  PubMed  CAS  Google Scholar 

  42. Kaufmann, B. A., Sanders, J. M., Davis, C., Xie, A., Aldred, P., Sarembock, I. J., et al. (2007). Molecular imaging of inflammation in atherosclerosis with targeted ultrasound detection of vascular cell adhesion molecule-1. Circulation, 116(3), 276–284.

    Article  PubMed  CAS  Google Scholar 

  43. Lindner, J. R., Song, J., Christiansen, J., Klibanov, A. L., Xu, F., & Ley, K. (2001). Ultrasound assessment of inflammation and renal tissue injury with microbubbles targeted to P-selectin. Circulation, 104(17), 2107–2112.

    Article  PubMed  CAS  Google Scholar 

  44. Davidson, B. P., Kaufmann, B. A., Belcik, J. T., Xie, A., Qi, Y., & Lindner, J. R. (2012). Detection of antecedent myocardial ischemia with multiselectin molecular imaging. Journal of the American College of Cardiology, 60(17), 1690–1697.

    Article  PubMed  CAS  Google Scholar 

  45. Myrset, A. H., Fjerdingstad, H. B., Bendiksen, R., Arbo, B. E., Bjerke, R. M., Johansen, J. H., et al. (2011). Design and characterization of targeted ultrasound microbubbles for diagnostic use. Ultrasound in Medicine and Biology, 37(1), 136–150.

    Article  PubMed  Google Scholar 

  46. Hust, M., Frenzel, A., Meyer, T., Schirrmann, T., & Dubel, S. (2012). Construction of human naive antibody gene libraries. Methods in Molecular Biology, 907, 85–107.

    PubMed  CAS  Google Scholar 

  47. Hernot, S., Unnikrishnan, S., Du, Z., Shevchenko, T., Cosyns, B., Broisat, A., et al. (2012). Nanobody-coupled microbubbles as novel molecular tracer. Journal of Controlled Release, 158(2), 346–353.

    Article  PubMed  CAS  Google Scholar 

  48. Feldwisch, J., & Tolmachev, V. (2012). Engineering of affibody molecules for therapy and diagnostics. Methods in Molecular Biology, 899, 103–126.

    Article  PubMed  CAS  Google Scholar 

  49. Hayat, S. A., & Senior, R. (2008). Myocardial contrast echocardiography in ST elevation myocardial infarction: ready for prime time? European Heart Journal, 29(3), 299–314.

    Article  PubMed  Google Scholar 

  50. Villanueva, F. S., Lu, E., Bowry, S., Kilic, S., Tom, E., Wang, J., et al. (2007). Myocardial ischemic memory imaging with molecular echocardiography. Circulation, 115(3), 345–352.

    Article  PubMed  Google Scholar 

  51. Weller, G. E., Lu, E., Csikari, M. M., Klibanov, A. L., Fischer, D., Wagner, W. R., et al. (2003). Ultrasound imaging of acute cardiac transplant rejection with microbubbles targeted to intercellular adhesion molecule-1. Circulation, 108(2), 218–224.

    Article  PubMed  Google Scholar 

  52. Wang, X., Hagemeyer, C. E., Hohmann, J. D., Leitner, E., Armstrong, P. C., Jia, F., et al. (2012). Novel single-chain antibody-targeted microbubbles for molecular ultrasound imaging of thrombosis: validation of a unique noninvasive method for rapid and sensitive detection of thrombi and monitoring of success or failure of thrombolysis in mice. Circulation, 125(25), 3117–3126.

    Article  PubMed  CAS  Google Scholar 

  53. Unger, E. C., McCreery, T. P., Sweitzer, R. H., Shen, D., & Wu, G. (1998). In vitro studies of a new thrombus-specific ultrasound contrast agent. The American Journal of Cardiology, 81(12A), 58G–61G.

    Article  PubMed  CAS  Google Scholar 

  54. Korosoglou, G., Behrens, S., Bekeredjian, R., Hardt, S., Hagenmueller, M., Dinjus, E., et al. (2006). The potential of a new stable ultrasound contrast agent for site-specific targeting. An in vitro experiment. Ultrasound Medicine Biology, 32(10), 1473–1478.

    Article  Google Scholar 

  55. Lindner, J. R. (2002). Detection of inflamed plaques with contrast ultrasound. The American Journal of Cardiology, 90(10C), 32L–35L.

    Article  PubMed  Google Scholar 

  56. Wu, J., Leong-Poi, H., Bin, J., Yang, L., Liao, Y., Liu, Y., et al. (2011). Efficacy of contrast-enhanced US and magnetic microbubbles targeted to vascular cell adhesion molecule-1 for molecular imaging of atherosclerosis. Radiology, 260(2), 463–471.

    Article  PubMed  Google Scholar 

  57. Anastasianides P., Mojica K., Matter M. L., Allen J. S. (http://www.acoustics.org/press/157th/anastasiadis.html) Targeted ultrasound contrast agents for the imaging of biofilm infections. Accessed 2013.05.26

  58. Dong, Y., Chen, S., Wang, Z., Peng, N., & Yu, J. (2013). Synergy of ultrasound microbubbles and vancomycin against Staphylococcus epidermidis biofilm. The Journal of Antimicrobial Chemotherapy, 68(4), 816–826.

    Article  PubMed  CAS  Google Scholar 

  59. Christiansen, J. P., French, B. A., Klibanov, A. L., Kaul, S., & Lindner, J. R. (2003). Targeted tissue transfection with ultrasound destruction of plasmid-bearing cationic microbubbles. Ultrasound in Medicine and Biology, 29(12), 1759–1767.

    Article  PubMed  Google Scholar 

  60. Leong-Poi, H., Kuliszewski, M. A., Lekas, M., Sibbald, M., Teichert-Kuliszewska, K., Klibanov, A. L., et al. (2007). Therapeutic arteriogenesis by ultrasound-mediated VEGF165 plasmid gene delivery to chronically ischemic skeletal muscle. Circulation Research, 101(3), 295–303.

    Article  PubMed  CAS  Google Scholar 

  61. Vannan, M., McCreery, T., Li, P., Han, Z., Unger, E., Kuersten, B., et al. (2002). Ultrasound-mediated transfection of canine myocardium by intravenous administration of cationic microbubble-linked plasmid DNA. Journal of the American Society of Echocardiography, 15(3), 214–218.

    Article  PubMed  Google Scholar 

  62. Carson, A. R., McTiernan, C. F., Lavery, L., Grata, M., Leng, X., Wang, J., et al. (2012). Ultrasound-targeted microbubble destruction to deliver siRNA cancer therapy. Cancer Research, 72(23), 6191–6199.

    Article  PubMed  CAS  Google Scholar 

  63. Wu, Y., Unger, E. C., McCreery, T. P., Sweitzer, R. H., Shen, D., Wu, G., et al. (1998). Binding and lysing of blood clots using MRX-408. Investigative Radiology, 33(12), 880–885.

    Article  PubMed  CAS  Google Scholar 

  64. Alexandrov, A. V. (2006). Ultrasound enhanced thrombolysis for stroke. International Journal of Stroke, 1(1), 26–29.

    Article  PubMed  Google Scholar 

  65. Hynynen, K., McDannold, N., Vykhodtseva, N., Raymond, S., Weissleder, R., Jolesz, F. A., et al. (2006). Focal disruption of the blood–brain barrier due to 260-kHz ultrasound bursts: a method for molecular imaging and targeted drug delivery. Journal of Neurosurgery, 105(3), 445–454.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

The author is grateful to numerous colleagues and collaborators, students, and fellows, at UVA and collaborating institutions, especially to Jonathan Lindner, Klaus Ley, and Joshua Rychak. Support by NIH (R21/33CA102880), earlier R01EB002185, SBIR subcontract via R43/44 EB007857, and a research grant from Philips Research are gratefully acknowledged.

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  1. Division of Cardiovascular Medicine and Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA

    Alexander L. Klibanov

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Associate Editor Angela Taylor oversaw the review of this article.

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Klibanov, A.L. Ultrasound Contrast Materials in Cardiovascular Medicine: from Perfusion Assessment to Molecular Imaging. J. of Cardiovasc. Trans. Res. 6, 729–739 (2013). https://doi.org/10.1007/s12265-013-9501-0

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