Skip to main content
SpringerLink
Log in

Vulnerable Plaque: Molecular Imaging

  • Intravascular Imaging (I.-K. Jang, Section Editor)
  • Published:
Current Cardiovascular Imaging Reports Aims and scope Submit manuscript

Abstract

Despite the remarkable advances in cardiovascular imaging over the last decade, it is still challenging to identify high-risk atherosclerotic plaques prior to onset of major cardiovascular complications. Accumulating knowledge regarding the pathophysiological properties of vulnerable plaque (VP) has driven the development of molecular imaging technologies that target biologic process to characterize vulnerable plaques. Given the importance of VP detection in vivo, molecular imaging has emerged as an attractive diagnostic tool to more accurately estimate the risk of plaque rupture.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

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

  1. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, et al. Executive summary: heart disease and stroke statistics–2013 update: a report from the American Heart Association. Circulation. 2013;127(1):143–52. doi:10.1161/CIR.0b013e318282ab8f.

    Article  PubMed  Google Scholar 

  2. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352(16):1685–95. doi:10.1056/NEJMra043430.

    Article  CAS  PubMed  Google Scholar 

  3. Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature. 2011;473(7347):317–25.

    Article  CAS  PubMed  Google Scholar 

  4. Sanz J, Fayad ZA. Imaging of atherosclerotic cardiovascular disease. Nature. 2008;451(7181):953–7. doi:10.1038/nature06803.

    Article  CAS  PubMed  Google Scholar 

  5. Kusters DH, Tegtmeier J, Schurgers LJ, Reutelingsperger CP. Molecular imaging to identify the vulnerable plaque—from basic research to clinical practice. Mol Imaging Biol. 2012;14(5):523–33. doi:10.1007/s11307-012-0586-7.

    Article  PubMed  Google Scholar 

  6. Silvestre-Roig C, de Winther MP, Weber C, Daemen MJ, Lutgens E, Soehnlein O. Atherosclerotic plaque destabilization: mechanisms, models, and therapeutic strategies. Circ Res. 2014;114(1):214–26. doi:10.1161/CIRCRESAHA.114.302355.

    Article  CAS  PubMed  Google Scholar 

  7. Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J, et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation. 2003;108(14):1664–72. doi:10.1161/01.cir.0000087480.94275.97.

    Article  PubMed  Google Scholar 

  8. Libby P. Mechanisms of acute coronary syndromes and their implications for therapy. The New England journal of medicine. 2013;368(21):2004–13. doi:10.1056/NEJMra1216063

  9. Narula J, Nakano M, Virmani R, Kolodgie FD, Petersen R, Newcomb R, et al. Histopathologic characteristics of atherosclerotic coronary disease and implications of the findings for the invasive and noninvasive detection of vulnerable plaques. J Am Coll Cardiol. 2013;61(10):1041–51. doi:10.1016/j.jacc.2012.10.054.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Derksen WJ, Peeters W, van Lammeren GW, Tersteeg C, de Vries JP, de Kleijn DP, et al. Different stages of intraplaque hemorrhage are associated with different plaque phenotypes: a large histopathological study in 794 carotid and 276 femoral endarterectomy specimens. Atherosclerosis. 2011;218(2):369–77. doi:10.1016/j.atherosclerosis.2011.07.104.

    Article  CAS  PubMed  Google Scholar 

  11. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989;320(14):915–24. doi:10.1056/nejm198904063201407.

    Article  CAS  PubMed  Google Scholar 

  12. Kaufmann BA, Sanders JM, Davis C, Xie A, Aldred P, Sarembock IJ, et al. Molecular imaging of inflammation in atherosclerosis with targeted ultrasound detection of vascular cell adhesion molecule-1. Circulation. 2007;116(3):276–84. doi:10.1161/CIRCULATIONAHA.106.684738.

    Article  CAS  PubMed  Google Scholar 

  13. Nahrendorf M, Keliher E, Panizzi P, Zhang H, Hembrador S, Figueiredo JL, et al. 18 F-4V for PET-CT imaging of VCAM-1 expression in atherosclerosis. J Am Coll Cardiol Img. 2009;2(10):1213–22. doi:10.1016/j.jcmg.2009.04.016.

  14. McAteer MA, Schneider JE, Ali ZA, Warrick N, Bursill CA, von Zur Muhlen C, 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(1):77–83. doi:10.1161/ATVBAHA.107.145466.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Mulder WJ, Jaffer FA, Fayad ZA, Nahrendorf M. Imaging and nanomedicine in inflammatory atherosclerosis. Sci Transl Med. 2014;6(239):239sr1. doi:10.1126/scitranslmed.3005101.

    Article  PubMed Central  PubMed  Google Scholar 

  16. Tawakol A, Migrino RQ, Bashian GG, Bedri S, Vermylen D, Cury RC, et al. In vivo 18 F-fluorodeoxyglucose positron emission tomography imaging provides a noninvasive measure of carotid plaque inflammation in patients. J Am Coll Cardiol. 2006;48(9):1818–24. doi:10.1016/j.jacc.2006.05.076.

  17. Tawakol A, Fayad ZA, Mogg R, Alon A, Klimas MT, Dansky H, et al. 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(10):909–17. doi:10.1016/j.jacc.2013.04.066. This article demonstrates the feasibility of therapeutic monitoring for individual patients by using a noninvasive PET/CT imaging with FDG probe.

    Article  CAS  PubMed  Google Scholar 

  18. Rogers IS, Nasir K, Figueroa AL, Cury RC, Hoffmann U, Vermylen DA, et al. Feasibility of FDG imaging of the coronary arteries: comparison between acute coronary syndrome and stable angina. J Am Coll Cardiol Img. 2010;3(4):388–97. doi:10.1016/j.jcmg.2010.01.004.

    Article  Google Scholar 

  19. Kooi ME, Cappendijk VC, Cleutjens KB, Kessels AG, Kitslaar PJ, Borgers M, et al. Accumulation of ultrasmall superparamagnetic particles of iron oxide in human atherosclerotic plaques can be detected by in vivo magnetic resonance imaging. Circulation. 2003;107(19):2453–8. doi:10.1161/01.cir.0000068315.98705.cc.

    Article  CAS  PubMed  Google Scholar 

  20. Tang TY, Howarth SP, Miller SR, Graves MJ, Patterson AJ, UK-I JM, et al. 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(22):2039–50. doi:10.1016/j.jacc.2009.03.018.

    Article  CAS  PubMed  Google Scholar 

  21. Morishige K, Kacher DF, Libby P, Josephson L, Ganz P, Weissleder R, et al. High-resolution magnetic resonance imaging enhanced with superparamagnetic nanoparticles measures macrophage burden in atherosclerosis. Circulation. 2010;122(17):1707–15. doi:10.1161/CIRCULATIONAHA.109.891804.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Lancelot E, Amirbekian V, Brigger I, Raynaud JS, Ballet S, David C, et al. Evaluation of matrix metalloproteinases in atherosclerosis using a novel noninvasive imaging approach. Arterioscler Thromb Vasc Biol. 2008;28(3):425–32. doi:10.1161/ATVBAHA.107.149666.

    Article  CAS  PubMed  Google Scholar 

  23. Hyafil F, Vucic E, Cornily JC, Sharma R, Amirbekian V, Blackwell F, et al. Monitoring of arterial wall remodelling in atherosclerotic rabbits with a magnetic resonance imaging contrast agent binding to matrix metalloproteinases. Eur Heart J. 2011;32(12):1561–71. doi:10.1093/eurheartj/ehq413.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Deguchi JO, Aikawa M, Tung CH, Aikawa E, Kim DE, Ntziachristos V, et al. Inflammation in atherosclerosis: visualizing matrix metalloproteinase action in macrophages in vivo. Circulation. 2006;114(1):55–62. doi:10.1161/CIRCULATIONAHA.106.619056.

    Article  PubMed  Google Scholar 

  25. Razavian M, Tavakoli S, Zhang J, Nie L, Dobrucki LW, Sinusas AJ, et al. Atherosclerosis plaque heterogeneity and response to therapy detected by in vivo molecular imaging of matrix metalloproteinase activation. J Nucl Med. 2011;52(11):1795–802. doi:10.2967/jnumed.111.092379.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Chen J, Tung CH, Allport JR, Chen S, Weissleder R, Huang PL. Near-infrared fluorescent imaging of matrix metalloproteinase activity after myocardial infarction. Circulation. 2005;111(14):1800–5. doi:10.1161/01.cir.0000160936.91849.9f.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Jaffer FA, Kim DE, Quinti L, Tung CH, Aikawa E, Pande AN, et al. Optical visualization of cathepsin K activity in atherosclerosis with a novel, protease-activatable fluorescence sensor. Circulation. 2007;115(17):2292–8. doi:10.1161/circulationaha.106.660340.

    Article  CAS  PubMed  Google Scholar 

  28. Jaffer FA, Vinegoni C, John MC, Aikawa E, Gold HK, Finn AV, et al. Real-time catheter molecular sensing of inflammation in proteolytically active atherosclerosis. Circulation. 2008;118(18):1802–9. doi:10.1161/circulationaha.108.785881.

    Article  PubMed Central  PubMed  Google Scholar 

  29. Yoo H, Kim JW, Shishkov M, Namati E, Morse T, Shubochkin R, et al. Intra-arterial catheter for simultaneous microstructural and molecular imaging in vivo. Nat Med. 2011;17(12):1680–4. doi:10.1038/nm.2555. This is the first study of catheter-based, dual-modality intravascular OFDI/NIRF imaging in vivo to identify high-risk plaques.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Lee S, Lee MW, Cho HS, Song JW, Nam HS, Oh DJ, et al. Fully integrated high-speed intravascular optical coherence tomography/near-infrared fluorescence structural/molecular imaging in vivo using a clinically available near-infrared fluorescence-emitting indocyanine green to detect inflamed lipid-rich atheromata in coronary-sized vessels. Circ Cardiovasc Interv. 2014;7(4):560–9. doi:10.1161/circinterventions.114.001498. This study demonstrates important progress in intravascular structural/molecular imaging of high-risk atheroma in coronary-sized vessels in vivo using a clinically available NIRF-emiiting ICG by utilizing an advanced OCT-NIRF system.

    Article  CAS  PubMed  Google Scholar 

  31. Werner SG, Langer HE, Schott P, Bahner M, Schwenke C, Lind-Albrecht G, et al. Indocyanine green-enhanced fluorescence optical imaging in patients with early and very early arthritis: a comparative study with magnetic resonance imaging. Arthritis Rheum. 2013;65(12):3036–44. doi:10.1002/art.38175.

    Article  CAS  PubMed  Google Scholar 

  32. Vinegoni C, Botnaru I, Aikawa E, Calfon MA, Iwamoto Y, Folco EJ, et al. Indocyanine green enables near-infrared fluorescence imaging of lipid-rich, inflamed atherosclerotic plaques. Sci Transl Med. 2011;3(84):84ra45. doi:10.1126/scitranslmed.3001577.

    Article  PubMed Central  PubMed  Google Scholar 

  33. Kim S, Lee MW, Cho HS, Song JW, Lee S, Oh DJ, et al. Abstract 17216: Intracoronary Dual-modal OCT/NIRF Structural-Molecular Imaging with a Clinical Dose of Indocyanine Green (ICG) for Detection of High-risk Coronary Plaques in Diabetic Swine Model. Circulation. 2014;130 Suppl 2:A17216.

    Google Scholar 

  34. Tabas I. Macrophage death and defective inflammation resolution in atherosclerosis. Nat Rev Immunol. 2010;10(1):36–46. doi:10.1038/nri2675.

    PubMed Central  CAS  PubMed  Google Scholar 

  35. Wang JC, Bennett M. Aging and atherosclerosis: mechanisms, functional consequences, and potential therapeutics for cellular senescence. Circ Res. 2012;111(2):245–59. doi:10.1161/circresaha.111.261388.

    Article  CAS  PubMed  Google Scholar 

  36. Kietselaer BL, Reutelingsperger CP, Heidendal GA, Daemen MJ, Mess WH, Hofstra L, 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(14):1472–3. doi:10.1056/nejm200404013501425.

    Article  CAS  PubMed  Google Scholar 

  37. Laufer EM, Winkens MH, Narula J, Hofstra L. Molecular imaging of macrophage cell death for the assessment of plaque vulnerability. Arterioscler Thromb Vasc Biol. 2009;29(7):1031–8. doi:10.1161/ATVBAHA.108.165522.

    Article  CAS  PubMed  Google Scholar 

  38. Ramstrom S, O’Neill S, Dunne E, Kenny D. Annexin V binding to platelets is agonist, time and temperature dependent. Platelets. 2010;21(4):289–96. doi:10.3109/09537101003660564.

    Article  CAS  PubMed  Google Scholar 

  39. Edgington LE, Berger AB, Blum G, Albrow VE, Paulick MG, Lineberry N, et al. Noninvasive optical imaging of apoptosis by caspase-targeted activity-based probes. Nat Med. 2009;15(8):967–73. doi:10.1038/nm.1938.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Hight MR, Cheung YY, Nickels ML, Dawson ES, Zhao P, Saleh S, et al. A peptide-based positron emission tomography probe for in vivo detection of caspase activity in apoptotic cells. Clin Cancer Res. 2014;20(8):2126–35. doi:10.1158/1078-0432.CCR-13-2444.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Virmani R, Kolodgie FD, Burke AP, Finn AV, Gold HK, Tulenko TN, et al. Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol. 2005;25(10):2054–61. doi:10.1161/01.ATV.0000178991.71605.18.

    Article  CAS  PubMed  Google Scholar 

  42. Su H, Gorodny N, Gomez LF, Gangadharmath UB, Mu F, Chen G, et al. Atherosclerotic plaque uptake of a novel integrin tracer (1)(8)F-Flotegatide in a mouse model of atherosclerosis. J Nucl Cardiol. 2014;21(3):553–62. doi:10.1007/s12350-014-9879-3.

    Article  PubMed Central  PubMed  Google Scholar 

  43. Winter PM, Morawski AM, Caruthers SD, Fuhrhop RW, Zhang H, Williams TA, et al. Molecular imaging of angiogenesis in early-stage atherosclerosis with alpha(v)beta3-integrin-targeted nanoparticles. Circulation. 2003;108(18):2270–4. doi:10.1161/01.cir.0000093185.16083.95.

    Article  CAS  PubMed  Google Scholar 

  44. Beer AJ, Pelisek J, Heider P, Saraste A, Reeps C, Metz S, et al. PET/CT imaging of integrin alphavbeta3 expression in human carotid atherosclerosis. J Am Coll Cardiol Img. 2014;7(2):178–87. doi:10.1016/j.jcmg.2013.12.003.

    Article  Google Scholar 

  45. Otsuka F, Sakakura K, Yahagi K, Joner M, Virmani R. Has our understanding of calcification in human coronary atherosclerosis progressed? Arterioscler Thromb Vasc Biol. 2014;34(4):724–36. doi:10.1161/atvbaha.113.302642.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Aikawa E, Nahrendorf M, Figueiredo JL, Swirski FK, Shtatland T, Kohler RH, et al. Osteogenesis associates with inflammation in early-stage atherosclerosis evaluated by molecular imaging in vivo. Circulation. 2007;116(24):2841–50. doi:10.1161/circulationaha.107.732867.

    Article  CAS  PubMed  Google Scholar 

  47. Dweck MR, Chow MW, Joshi NV, Williams MC, Jones C, Fletcher AM, et al. Coronary arterial 18 F-sodium fluoride uptake: a novel marker of plaque biology. J Am Coll Cardiol. 2012;59(17):1539–48. doi:10.1016/j.jacc.2011.12.037.

  48. Joshi NV, Vesey AT, Williams MC, Shah ASV, Calvert PA, Craighead FHM, et al. 18F-fluoride positron emission tomography for identification of ruptured and high-risk coronary atherosclerotic plaques: a prospective clinical trial. Lancet. 2014;383(9918):705–13. doi:10.1016/s0140-6736(13)61754-7. This is the first noninvasive molecular imaging method using 18F-NaF PET/CT for detecting high-risk plaques and localizing ruptured plaques as well.

    Article  PubMed  Google Scholar 

  49. Caplan JD, Waxman S, Nesto RW, Muller JE. Near-infrared spectroscopy for the detection of vulnerable coronary artery plaques. J Am Coll Cardiol. 2006;47(8 Suppl):C92–6. doi:10.1016/j.jacc.2005.12.045.

    Article  PubMed  Google Scholar 

  50. Jang IK. Near infrared spectroscopy: another toy or indispensible diagnostic tool? Circ Cardiovasc Interv. 2012;5(1):10–1. doi:10.1161/circinterventions.111.967935.

    Article  PubMed  Google Scholar 

  51. Madder RD, Goldstein JA, Madden SP, Puri R, Wolski K, Hendricks M, et al. Detection by near-infrared spectroscopy of large lipid core plaques at culprit sites in patients with acute ST-segment elevation myocardial infarction. JACC Cardiovasc Interv. 2013;6(8):838–46. doi:10.1016/j.jcin.2013.04.012.

    Article  PubMed  Google Scholar 

  52. Oemrawsingh RM, Cheng JM, Garcia-Garcia HM, van Geuns RJ, de Boer SP, Simsek C, et al. Near-infrared spectroscopy predicts cardiovascular outcome in patients with coronary artery disease. J Am Coll Cardiol. 2014;64(23):2510–8. doi:10.1016/j.jacc.2014.07.998. First prospective study assess the long-term prognostic value of intracoronary NIRS in coronary disease patients.

    Article  PubMed  Google Scholar 

  53. Ay I, Blasi F, Rietz TA, Rotile NJ, Kura S, Brownell AL, et al. In vivo molecular imaging of thrombosis and thrombolysis using a fibrin-binding positron emission tomographic probe. Circ Cardiovasc Imaging. 2014;7(4):697–705. doi:10.1161/circimaging.113.001806.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported in part by a grant through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (No. 2012R1A2A2A04046108 to Dr Kim).

Compliance with Ethics Guidelines

ᅟ

Conflict of Interest

S Lee and JW Kim both declare no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Multimodal Imaging and Theranostic Lab, Cardiovascular Center, Korea University Guro Hospital, Seoul, South Korea

    Sunki Lee & Jin Won Kim

  2. Cardiovascular Center, Korea University Guro Hospital, 80, Guro-dong, Guro-gu, Seoul, 152-703, Republic of Korea

    Sunki Lee & Jin Won Kim

Authors
  1. Sunki Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jin Won Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jin Won Kim.

Additional information

This article is part of Topical Collection on Intravascular Imaging

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, S., Kim, J.W. Vulnerable Plaque: Molecular Imaging. Curr Cardiovasc Imaging Rep 8, 19 (2015). https://doi.org/10.1007/s12410-015-9338-9

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s12410-015-9338-9

Keywords

Search

Navigation