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Cardiovascular Imaging pp 65–78Cite as

Molecular Imaging of Macrophages in Atherosclerosis

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Abstract

Activated macrophages play central roles in various stages of the pathogenesis of atherosclerosis. Particularly, the role macrophages play in the onset of acute thrombotic complications including myocardial infarction, a global health burden, has the large clinical impact. It is thus important to identify high-risk patients for these thrombotic complications to improve the prognosis by detecting macrophage-rich, subclinical lesions. In addition, macrophage imaging of vascular lesions in humans would facilitate understanding of the disease mechanisms and also help to monitor the effects of new therapies in the near future. These clinical needs have driven recent efforts on the development of molecular imaging modalities to visualize macrophages. Various imaging agents which are taken up by macrophages (e.g., superparamagnetic iron oxide for magnetic resonance imaging) or target a macrophage-specific biological process (e.g., proteinase activity for optical imaging) have become available. In the field of nuclear medicine, FDG-PET already has been in the stage of clinical trials. This chapter reviews current states and future perspectives of macrophage-targeted molecular imaging.

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References

  1. Libby P, Aikawa M. Stabilization of atherosclerotic plaques: new mechanisms and clinical targets. Nat Med. 2002;8(11):1257–62. doi:10.1038/nm1102-1257.

    Article  CAS  PubMed  Google Scholar 

  2. Deguchi J, Aikawa M, Tung CH, Aikawa E, Kim DE, Ntziachristos V, Weissleder R, Libby P. 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 

  3. Sukhova GK, Shi GP, Simon DI, Chapman HA, Libby P. Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells. J Clin Invest. 1998;102(3):576–83. doi:10.1172/JCI181.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Libby P. The molecular mechanisms of the thrombotic complications of atherosclerosis. J Intern Med. 2008;263(5):517–27. doi:10.1111/j.1365-2796.2008.01965.x.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Weissleder R, Nahrendorf M, Pittet MJ. Imaging macrophages with nanoparticles. Nat Mater. 2014;13(2):125–38. doi:10.1038/nmat3780.

    Article  CAS  PubMed  Google Scholar 

  6. Oikawa M, Ota H, Takaya N, Miller Z, Hatsukami TS, Yuan C. Carotid magnetic resonance imaging. A window to study atherosclerosis and identify high-risk plaques. Circ J Off J Jpn Circ Soc. 2009;73(10):1765–73.

    Google Scholar 

  7. Morishige K, Kacher DF, Libby P, Josephson L, Ganz P, Weissleder R, Aikawa M. 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  CAS  PubMed Central  PubMed  Google Scholar 

  8. Segers FM, den Adel B, Bot I, van der Graaf LM, van der Veer EP, Gonzalez W, Raynal I, de Winther M, Wodzig WK, Poelmann RE, van Berkel TJ, van der Weerd L, Biessen EA. Scavenger receptor-AI-targeted iron oxide nanoparticles for in vivo MRI detection of atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2013;33(8):1812–9. doi:10.1161/ATVBAHA.112.300707.

    Article  CAS  PubMed  Google Scholar 

  9. Wen S, Liu DF, Cui Y, Harris SS, Chen YC, Li KC, Ju SH, Teng GJ. In vivo MRI detection of carotid atherosclerotic lesions and kidney inflammation in ApoE-deficient mice by using LOX-1 targeted iron nanoparticles. Nanomed Nanotechnol Biol Med. 2013. doi:10.1016/j.nano.2013.09.009.

    Google Scholar 

  10. Trivedi RA, U-King-Im JM, Graves MJ, Kirkpatrick PJ, Gillard JH. Noninvasive imaging of carotid plaque inflammation. Neurology. 2004;63(1):187–8.

    Article  CAS  PubMed  Google Scholar 

  11. Patterson AJ, Tang TY, Graves MJ, Muller KH, Gillard JH. In vivo carotid plaque MRI using quantitative T2* measurements with ultrasmall superparamagnetic iron oxide particles: a dose-response study to statin therapy. NMR Biomed. 2011;24(1):89–95. doi:10.1002/nbm.1560.

    Article  PubMed  Google Scholar 

  12. Araki N, Johnson MT, Swanson JA. A role for phosphoinositide 3-kinase in the completion of macropinocytosis and phagocytosis by macrophages. J Cell Biol. 1996;135(5):1249–60.

    Article  CAS  PubMed  Google Scholar 

  13. Folco EJ, Sheikine Y, Rocha VZ, Christen T, Shvartz E, Sukhova GK, Di Carli MF, Libby P. Hypoxia but not inflammation augments glucose uptake in human macrophages: Implications for imaging atherosclerosis with 18fluorine-labeled 2-deoxy-D-glucose positron emission tomography. J Am Coll Cardiol. 2011;58(6):603–14. doi:10.1016/j.jacc.2011.03.044.

    Article  CAS  PubMed  Google Scholar 

  14. Figueroa AL, Subramanian SS, Cury RC, Truong QA, Gardecki JA, Tearney GJ, Hoffmann U, Brady TJ, Tawakol A. Distribution of inflammation within carotid atherosclerotic plaques with high-risk morphological features: a comparison between positron emission tomography activity, plaque morphology, and histopathology. Circ Cardiovasc Imaging. 2012;5(1):69–77. doi:10.1161/CIRCIMAGING.110.959478.

    Article  PubMed  Google Scholar 

  15. Rudd JH, Narula J, Strauss HW, Virmani R, Machac J, Klimas M, Tahara N, Fuster V, Warburton EA, Fayad ZA, Tawakol AA. Imaging atherosclerotic plaque inflammation by fluorodeoxyglucose with positron emission tomography: ready for prime time? J Am Coll Cardiol. 2010;55(23):2527–35. doi:10.1016/j.jacc.2009.12.061.

    Article  PubMed  Google Scholar 

  16. Tahara N, Kai H, Nakaura H, Mizoguchi M, Ishibashi M, Kaida H, Baba K, Hayabuchi N, Imaizumi T. The prevalence of inflammation in carotid atherosclerosis: analysis with fluorodeoxyglucose-positron emission tomography. Eur Heart J. 2007;28(18):2243–8. doi:10.1093/eurheartj/ehm245.

    Article  CAS  PubMed  Google Scholar 

  17. Tahara N, Kai H, Yamagishi S, Mizoguchi M, Nakaura H, Ishibashi M, Kaida H, Baba K, Hayabuchi N, Imaizumi T. Vascular inflammation evaluated by [18F]-fluorodeoxyglucose positron emission tomography is associated with the metabolic syndrome. J Am Coll Cardiol. 2007;49(14):1533–9. doi:10.1016/j.jacc.2006.11.046.

    Article  CAS  PubMed  Google Scholar 

  18. Tawakol A, Fayad ZA, Mogg R, Alon A, Klimas MT, Dansky H, Subramanian SS, Abdelbaky A, Rudd JH, Farkouh ME, Nunes IO, Beals CR, Shankar SS. 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.

    Article  CAS  PubMed  Google Scholar 

  19. Bucerius J, Mani V, Wong S, Moncrieff C, Izquierdo-Garcia D, Machac J, Fuster V, Farkouh ME, Rudd JH, Fayad ZA. Arterial and fat tissue inflammation are highly correlated : a prospective F-FDG PET/CT study. Eur J Nucl Med Mol Imaging. 2014. doi:10.1007/s00259-013-2653-y.

    Google Scholar 

  20. Mizoguchi M, Tahara N, Tahara A, Nitta Y, Kodama N, Oba T, Mawatari K, Yasukawa H, Kaida H, Ishibashi M, Hayabuchi N, Harada H, Ikeda H, Yamagishi S, Imaizumi T. Pioglitazone attenuates atherosclerotic plaque inflammation in patients with impaired glucose tolerance or diabetes a prospective, randomized, comparator-controlled study using serial FDG PET/CT imaging study of carotid artery and ascending aorta. JACC Cardiovasc Imaging. 2011;4(10):1110–8. doi:10.1016/j.jcmg.2011.08.007.

    Article  PubMed  Google Scholar 

  21. Nitta Y, Tahara N, Tahara A, Honda A, Kodama N, Mizoguchi M, Kaida H, Ishibashi M, Hayabuchi N, Ikeda H, Yamagishi S, Imaizumi T. Pioglitazone decreases coronary artery inflammation in impaired glucose tolerance and diabetes mellitus: evaluation by FDG-PET/CT imaging. JACC Cardiovasc Imaging. 2013;6(11):1172–82. doi:10.1016/j.jcmg.2013.09.004.

    Article  PubMed  Google Scholar 

  22. Bucerius J, Mani V, Moncrieff C, Machac J, Fuster V, Farkouh ME, Tawakol A, Rudd JH, Fayad ZA. Optimizing (18)F-FDG PET/CT imaging of vessel wall inflammation: the impact of (18)F-FDG circulation time, injected dose, uptake parameters, and fasting blood glucose levels. Eur J Nucl Med Mol Imaging. 2014;41(2):369–83. doi:10.1007/s00259-013-2569-6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Ishino S, Ogawa M, Mori I, Nishimura S, Ikeda S, Sugita T, Oikawa T, Horiguchi T, Magata Y. F-FDG PET and intravascular ultrasonography (IVUS) images compared with histology of atherosclerotic plaques: F-FDG accumulates in foamy macrophages. Eur J Nucl Med Mol Imaging. 2013. doi:10.1007/s00259-013-2635-0.

    PubMed  Google Scholar 

  24. Vucic E, Calcagno C, Dickson SD, Rudd JH, Hayashi K, Bucerius J, Moshier E, Mounessa JS, Roytman M, Moon MJ, Lin J, Ramachandran S, Tanimoto T, Brown K, Kotsuma M, Tsimikas S, Fisher EA, Nicolay K, Fuster V, Fayad ZA. Regression of inflammation in atherosclerosis by the LXR agonist R211945: a noninvasive assessment and comparison with atorvastatin. JACC Cardiovasc Imaging. 2012;5(8):819–28. doi:10.1016/j.jcmg.2011.11.025.

    Article  PubMed Central  PubMed  Google Scholar 

  25. Millon A, Dickson SD, Klink A, Izquierdo-Garcia D, Bini J, Lancelot E, Ballet S, Robert P, Mateo de Castro J, Corot C, Fayad ZA. Monitoring plaque inflammation in atherosclerotic rabbits with an iron oxide (P904) and (18)F-FDG using a combined PET/MR scanner. Atherosclerosis. 2013;228(2):339–45. doi:10.1016/j.atherosclerosis.2013.03.019.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Gaemperli O, Shalhoub J, Owen DRJ, Lamare F, Johansson S, Fouladi N, Davies AH, Rimoldi OE, Camici PG. Imaging intraplaque inflammation in carotid atherosclerosis with C-11-PK11195 positron emission tomography/computed tomography. Eur Heart J. 2012;33(15):1902–10. doi:10.1093/eurheartj/ehr367.

    Article  CAS  PubMed  Google Scholar 

  27. Tahara N, Mukherjee J, de Haas HJ, Petrov AD, Tawakol A, Haider N, Tahara A, Constantinescu CC, Zhou J, Boersma HH, Imaizumi T, Nakano M, Finn A, Fayad Z, Virmani R, Fuster V, Bosca L, Narula J. 2-deoxy-2-[F]fluoro-d-mannose positron emission tomography imaging in atherosclerosis. Nat Med. 2014. doi:10.1038/nm.3437.

    PubMed  Google Scholar 

  28. Beer AJ, Pelisek J, Heider P, Saraste A, Reeps C, Metz S, Seidl S, Kessler H, Wester HJ, Eckstein HH, Schwaiger M. PET/CT imaging of integrin alphavbeta3 expression in human carotid atherosclerosis. JACC Cardiovasc Imaging. 2014. doi:10.1016/j.jcmg.2013.12.003.

    PubMed  Google Scholar 

  29. Seo JW, Baek H, Mahakian LM, Kusunose J, Hamzah J, Ruoslahti E, Ferrara KW. Cu-labeled LyP-1-dendrimer for PET-CT imaging of atherosclerotic plaque. Bioconjug Chem. 2014. doi:10.1021/bc400347s.

    Google Scholar 

  30. Hatori A, Yui J, Xie L, Yamasaki T, Kumata K, Fujinaga M, Wakizaka H, Ogawa M, Nengaki N, Kawamura K, Zhang MR. Visualization of acute liver damage induced by cycloheximide in rats using PET with [(18)F]FEDAC, a radiotracer for translocator protein (18 kDa). PLoS One. 2014;9(1):e86625. doi:10.1371/journal.pone.0086625.

    Article  PubMed Central  PubMed  Google Scholar 

  31. Quillard T, Tesmenitsky Y, Croce K, Travers R, Shvartz E, Koskinas KC, Sukhova GK, Aikawa E, Aikawa M, Libby P. Selective inhibition of matrix metalloproteinase-13 increases collagen content of established mouse atherosclerosis. Arterioscler Thromb Vasc Biol. 2011;31(11):2464–72. doi:10.1161/ATVBAHA.111.231563.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. New SE, Aikawa E. Molecular imaging insights into early inflammatory stages of arterial and aortic valve calcification. Circ Res. 2011;108(11):1381–91. doi:10.1161/CIRCRESAHA.110.234146.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Aikawa E, Aikawa M, Libby P, Figueiredo JL, Rusanescu G, Iwamoto Y, Fukuda D, Kohler RH, Shi GP, Jaffer FA, Weissleder R. Arterial and aortic valve calcification abolished by elastolytic cathepsin S deficiency in chronic renal disease. Circulation. 2009;119(13):1785–94. doi:10.1161/CIRCULATIONAHA.108.827972.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Fukuda D, Aikawa E, Swirski FK, Novobrantseva TI, Kotelianski V, Gorgun CZ, Chudnovskiy A, Yamazaki H, Croce K, Weissleder R, Aster JC, Hotamisligil GS, Yagita H, Aikawa M. Notch ligand delta-like 4 blockade attenuates atherosclerosis and metabolic disorders. Proc Natl Acad Sci U S A. 2012;109(27):E1868–77. doi:10.1073/pnas.1116889109.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Yoo H, Kim JW, Shishkov M, Namati E, Morse T, Shubochkin R, McCarthy JR, Ntziachristos V, Bouma BE, Jaffer FA, Tearney GJ. Intra-arterial catheter for simultaneous microstructural and molecular imaging in vivo. Nat Med. 2011;17(12):1680–4. doi:10.1038/nm.2555.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Jaffer FA, Calfon MA, Rosenthal A, Mallas G, Razansky RN, Mauskapf A, Weissleder R, Libby P, Ntziachristos V. Two-dimensional intravascular near-infrared fluorescence molecular imaging of inflammation in atherosclerosis and stent-induced vascular injury. J Am Coll Cardiol. 2011;57(25):2516–26. doi:10.1016/j.jacc.2011.02.036.

    Article  PubMed Central  PubMed  Google Scholar 

  37. Zheng C, Morishige K, Aikawa M. Functional molecular imaging linking macrophages to reverse cholesterol transport. Circ J Off J Jpn Circ Soc. 2013;77(6):1403–6.

    CAS  Google Scholar 

  38. Cormode DP, Frias JC, Ma Y, Chen W, Skajaa T, Briley-Saebo K, Barazza A, Williams KJ, Mulder WJ, Fayad ZA, Fisher EA. HDL as a contrast agent for medical imaging. Clin Lipidol. 2009;4(4):493–500. doi:10.2217/clp.09.38.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Marrache S, Dhar S. Biodegradable synthetic high-density lipoprotein nanoparticles for atherosclerosis. Proc Natl Acad Sci U S A. 2013;110(23):9445–50. doi:10.1073/pnas.1301929110.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Miyama N, Dua MM, Schultz GM, Kosuge H, Terashima M, Pisani LJ, Dalman RL, McConnell MV. Bioluminescence and magnetic resonance imaging of macrophage homing to experimental abdominal aortic aneurysms. Mol Imaging. 2012;11(2):126–34.

    CAS  PubMed  Google Scholar 

  41. Richards JM, Semple SI, MacGillivray TJ, Gray C, Langrish JP, Williams M, Dweck M, Wallace W, McKillop G, Chalmers RT, Garden OJ, Newby DE. Abdominal aortic aneurysm growth predicted by uptake of ultrasmall superparamagnetic particles of iron oxide: a pilot study. Circ Cardiovasc Imaging. 2011;4(3):274–81. doi:10.1161/CIRCIMAGING.110.959866.

    Article  PubMed  Google Scholar 

  42. Pfefferkorn T, Saam T, Rominger A, Habs M, Gerdes LA, Schmidt C, Cyran C, Straube A, Linn J, Nikolaou K, Bartenstein P, Reiser M, Hacker M, Dichgans M. Vessel wall inflammation in spontaneous cervical artery dissection: a prospective, observational positron emission tomography, computed tomography, and magnetic resonance imaging study. Stroke J Cereb Circ. 2011;42(6):1563–8. doi:10.1161/STROKEAHA.110.599548.

    Article  Google Scholar 

  43. Reeps C, Pelisek J, Bundschuh RA, Gurdan M, Zimmermann A, Ockert S, Dobritz M, Eckstein HH, Essler M. Imaging of acute and chronic aortic dissection by 18F-FDG PET/CT. J Nucl Med Off Publ Soc Nucl Med. 2010;51(5):686–91. doi:10.2967/jnumed.109.072298.

    Google Scholar 

  44. Alam SR, Shah AS, Richards J, Lang NN, Barnes G, Joshi N, MacGillivray T, McKillop G, Mirsadraee S, Payne J, Fox KA, Henriksen P, Newby DE, Semple SI. Ultrasmall superparamagnetic particles of iron oxide in patients with acute myocardial infarction: early clinical experience. Circ Cardiovasc Imaging. 2012;5(5):559–65. doi:10.1161/CIRCIMAGING.112.974907.

    Article  PubMed  Google Scholar 

  45. Schroeter M, Dennin MA, Walberer M, Backes H, Neumaier B, Fink GR, Graf R. Neuroinflammation extends brain tissue at risk to vital peri-infarct tissue: a double tracer [11C]PK11195- and [18F]FDG-PET study. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 2009;29(6):1216–25. doi:10.1038/jcbfm.2009.36.

    Article  CAS  Google Scholar 

  46. Donath MY, Dalmas E, Sauter NS, Boni-Schnetzler M. Inflammation in obesity and diabetes: islet dysfunction and therapeutic opportunity. Cell Metab. 2013;17(6):860–72. doi:10.1016/j.cmet.2013.05.001.

    Article  CAS  PubMed  Google Scholar 

  47. Nishimura S, Manabe I, Nagasaki M, Seo K, Yamashita H, Hosoya Y, Ohsugi M, Tobe K, Kadowaki T, Nagai R, Sugiura S. In vivo imaging in mice reveals local cell dynamics and inflammation in obese adipose tissue. J Clin Invest. 2008;118(2):710–21. doi:10.1172/JCI33328.

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Jolesz FA. Intraoperative imaging in neurosurgery: where will the future take us? Acta Neurochir Suppl. 2011;109:21–5. doi:10.1007/978-3-211-99651-5_4.

    Article  PubMed Central  PubMed  Google Scholar 

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Authors and Affiliations

  1. The Center for Excellence in Vascular Biology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA, 02115, USA

    Jun-ichiro Koga MD, PhD & Masanori Aikawa MD, PhD

  2. The Center for Excellence in Vascular Biology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Masanori Aikawa MD, PhD

Authors
  1. Jun-ichiro Koga MD, PhD
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  2. Masanori Aikawa MD, PhD
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Correspondence to Masanori Aikawa MD, PhD .

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Editors and Affiliations

  1. Cardiovascular Medicine, Brigham and Women’s Hospital Harvard Medical School, Boston, Massachusetts, USA

    Elena Aikawa

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Koga, Ji., Aikawa, M. (2015). Molecular Imaging of Macrophages in Atherosclerosis. In: Aikawa, E. (eds) Cardiovascular Imaging. Springer, Cham. https://doi.org/10.1007/978-3-319-09268-3_3

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