Skip to main content
SpringerLink
Log in

Multi-slice computed tomography with N1177 identifies ruptured atherosclerotic plaques in rabbits

  • Original Contribution
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

Rupture-prone and ruptured plaques are characterized by the presence of large numbers of macrophages. N1177 is a contrast agent consisting of iodinated nanoparticles that are selectively phagocytosed by macrophages. The aim of this study was to investigate the effect of N1177 on the CT attenuation of rupture-prone and ruptured plaques in rabbits. In addition, we examined in vitro whether uptake of N1177 occurred without cytotoxic or pro-inflammatory effects on macrophages. In vitro, the viability of J774 macrophages was not affected by treatment with N1177. Moreover, N1177 had no effect on the phagocytic capacity or cytokine production of macrophages. For the in vivo experiments, 6 New Zealand White rabbits were fed a cholesterol-supplemented diet for 12–15 months, resulting in the development of large atherosclerotic plaques that resembled rupture-prone plaques in humans. In three rabbits, mechanical plaque rupture was induced by retrograde pullback of an embolic protection device. N1177 had no effect on the median density of rupture-prone plaques [35 HU (range 3–85) before injection vs. 32 HU (range 1–93) 2 h after injection of N1177; P > 0.05]. However, after induction of mechanical plaque rupture, the median density of the atherosclerotic plaques increased from 40 HU (range 6–86) before injection to 74 HU (range 14–111) 2 h after injection of N1177 (P < 0.001). Using time-of-flight static secondary ion mass spectrometry, the presence of N1177 nanoparticles was demonstrated in macrophage-rich areas of ruptured plaques, but not of non-ruptured plaques. In conclusion, our results show that N1177 is a contrast agent that can identify ruptured atherosclerotic plaques.

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

Similar content being viewed by others

References

  1. Barger AC, Beeuwkes R 3rd, Lainey LL, Silverman KJ (1984) Hypothesis: vasa vasorum and neovascularization of human coronary arteries. A possible role in the pathophysiology of atherosclerosis. N Engl J Med 310:175–177

    CAS  PubMed  Google Scholar 

  2. Barreto M, Schoenhagen P, Nair A, Amatangelo S, Milite M, Obuchowski NA, Lieber ML, Halliburton SS (2008) Potential of dual-energy computed tomography to characterize atherosclerotic plaque: ex vivo assessment of human coronary arteries in comparison to histology. J Cardiovasc Comput Tomogr 2:234–242

    Article  PubMed  Google Scholar 

  3. Becker CR, Nikolaou K, Muders M, Babaryka G, Crispin A, Schoepf UJ, Loehrs U, Reiser MF (2003) Ex vivo coronary atherosclerotic plaque characterization with multi-detector-row CT. Eur Radiol 13:2094–2098

    Article  PubMed  Google Scholar 

  4. Budoff MJ, Achenbach S, Blumenthal RS, Carr JJ, Goldin JG, Greenland P, Guerci AD, Lima JA, Rader DJ, Rubin GD, Shaw LJ, Wiegers SE (2006) Assessment of coronary artery disease by cardiac computed tomography: a scientific statement from the American Heart Association Committee on Cardiovascular Imaging and Intervention, Council on Cardiovascular Radiology and Intervention, and Committee on Cardiac Imaging, Council on Clinical Cardiology. Circulation 114:1761–1791

    Article  PubMed  Google Scholar 

  5. Bult H, De Meyer GRY, Herman AG (1995) Influence of chronic treatment with a nitric oxide donor on fatty streak development and reactivity of the rabbit aorta. Br J Pharmacol 114:1371–1382

    CAS  PubMed  Google Scholar 

  6. Carrascosa PM, Capunay CM, Garcia-Merletti P, Carrascosa J, Garcia MF (2006) Characterization of coronary atherosclerotic plaques by multidetector computed tomography. Am J Cardiol 97:598–602

    Article  PubMed  Google Scholar 

  7. Caussin C, Ohanessian A, Ghostine S, Jacq L, Lancelin B, Dambrin G, Sigal-Cinqualbre A, Angel CY, Paul JF (2004) Characterization of vulnerable nonstenotic plaque with 16-slice computed tomography compared with intravascular ultrasound. Am J Cardiol 94:99–104

    Article  PubMed  Google Scholar 

  8. De Meyer GRY, Hoylaerts MF, Kockx MM, Yamamoto H, Herman AG, Bult H (1999) Intimal deposition of functional von Willebrand factor in atherogenesis. Arterioscler Thromb Vasc Biol 19:2524–2534

    PubMed  Google Scholar 

  9. Flohr TG, Ohnesorge BM (2008) Imaging of the heart with computed tomography. Basic Res Cardiol 103:161–173

    Article  PubMed  Google Scholar 

  10. Funada R, Oikawa Y, Yajima J, Kirigaya H, Nagashima K, Ogasawara K, Matsuno S, Inaba T, Nakagawa Y, Nakamura M, Kurabayashi M, Aizawa T (2009) The potential of RF backscattered IVUS data and multidetector-row computed tomography images for tissue characterization of human coronary atherosclerotic plaques. Int J Cardiovasc Imaging 25:471–478

    Article  PubMed  Google Scholar 

  11. Goldstein JA, Gallagher MJ, O’Neill WW, Ross MA, O’Neil BJ, Raff GL (2007) A randomized controlled trial of multi-slice coronary computed tomography for evaluation of acute chest pain. J Am Coll Cardiol 49:863–871

    Article  PubMed  Google Scholar 

  12. Graf K, Grafe M, Fleck E (2008) Cardiovascular diseases as target for imaging. Basic Res Cardiol 103:82–86

    Article  PubMed  Google Scholar 

  13. Hoffmann U, Moselewski F, Nieman K, Jang IK, Ferencik M, Rahman AM, Cury RC, Abbara S, Joneidi-Jafari H, Achenbach S, Brady TJ (2006) Noninvasive assessment of plaque morphology and composition in culprit and stable lesions in acute coronary syndrome and stable lesions in stable angina by multidetector computed tomography. J Am Coll Cardiol 47:1655–1662

    Article  PubMed  Google Scholar 

  14. Husmann L, Valenta I, Gaemperli O, Adda O, Treyer V, Wyss CA, Veit-Haibach P, Tatsugami F, von Schulthess GK, Kaufmann PA (2008) Feasibility of low-dose coronary CT angiography: first experience with prospective ECG-gating. Eur Heart J 29:191–197

    Article  PubMed  Google Scholar 

  15. Hyafil F, Cornily J-C, Feig JE, Gordon R, Vucic E, Amirbekian V, Fisher EA, Fuster V, Feldman LJ, Fayad ZA (2007) Noninvasive detection of macrophages using a nanoparticulate contrast agent for computed tomography. Nat Med 13:636–641

    Article  CAS  PubMed  Google Scholar 

  16. Kitagawa T, Yamamoto H, Horiguchi J, Ohhashi N, Tadehara F, Shokawa T, Dohi Y, Kunita E, Utsunomiya H, Kohno N, Kihara Y (2009) Characterization of noncalcified coronary plaques and identification of culprit lesions in patients with acute coronary syndrome by 64-slice computed tomography. J Am Coll Cardiol Imaging 2:153–160

    Google Scholar 

  17. Knollmann F, Ducke F, Krist L, Kertesz T, Meyer R, Guski H, Felix R (2008) Quantification of atherosclerotic coronary plaque components by submillimeter computed tomography. Int J Cardiovasc Imaging 24:301–310

    Article  PubMed  Google Scholar 

  18. Kockx MM, Cromheeke KM, Knaapen MWM, Bosmans JM, De Meyer GRY, Herman AG, Bult H (2003) Phagocytosis and macrophage activation associated with hemorrhagic microvessels in human atherosclerosis. Arterioscler Thromb Vasc Biol 23:440–446

    Article  CAS  PubMed  Google Scholar 

  19. Kooi ME, Cappendijk VC, Cleutjens KBJM, Kessels AGH, Kitslaar PJEHM, Borgers M, Frederik PM, Daemen MJAP, van Engelshoven JMA (2003) Accumulation of ultrasmall superparamagnetic particles of iron oxide in human atherosclerotic plaques can be detected by in vivo magnetic resonance imaging. Circulation 107:2453–2458

    Article  CAS  PubMed  Google Scholar 

  20. Korosoglou G, Weiss RG, Kedziorek DA, Walczak P, Gilson WD, Schar M, Sosnovik DE, Kraitchman DL, Boston RC, Bulte JW, Weissleder R, Stuber M (2008) Noninvasive detection of macrophage-rich atherosclerotic plaque in hyperlipidemic rabbits using “positive contrast” magnetic resonance imaging. J Am Coll Cardiol 52:483–491

    Article  CAS  PubMed  Google Scholar 

  21. Leber AW, Becker A, Knez A, von Ziegler F, Sirol M, Nikolaou K, Ohnesorge B, Fayad ZA, Becker CR, Reiser M, Steinbeck G, Boekstegers P (2006) Accuracy of 64-slice computed tomography to classify and quantify plaque volumes in the proximal coronary system: a comparative study using intravascular ultrasound. J Am Coll Cardiol 47:672–677

    Article  PubMed  Google Scholar 

  22. Leber AW, Knez A, von Ziegler F, Becker A, Nikolaou K, Paul S, Wintersperger B, Reiser M, Becker CR, Steinbeck G, Boekstegers P (2005) Quantification of obstructive and nonobstructive coronary lesions by 64-slice computed tomography: a comparative study with quantitative coronary angiography and intravascular ultrasound. J Am Coll Cardiol 46:147–154

    Article  PubMed  Google Scholar 

  23. Levkau B (2008) Opportunities, challenges, and caveats of successful molecular imaging of cardiovascular diseases. Basic Res Cardiol 103:79–81

    Article  PubMed  Google Scholar 

  24. Libby P (2006) Atherosclerosis: disease biology affecting the coronary vasculature. Am J Cardiol 98:3Q–9Q

    Article  CAS  PubMed  Google Scholar 

  25. Lowik CW, Alblas MJ, van de Ruit M, Papapoulos SE, van der Pluijm G (1993) Quantification of adherent and nonadherent cells cultured in 96-well plates using the supravital stain neutral red. Anal Biochem 213:426–433

    Article  CAS  PubMed  Google Scholar 

  26. Martinet W, Schrijvers DM, Timmermans JP, Herman AG, De Meyer GR (2009) Phagocytosis of bacteria is enhanced in macrophages undergoing nutrient deprivation. FEBS J 276:2227–2240

    Article  CAS  PubMed  Google Scholar 

  27. Meijboom WB, Meijs MFL, Schuijf JD, Cramer MJ, Mollet NR, van Mieghem CAG, Nieman K, van Werkhoven JM, Pundziute G, Weustink AC, de Vos AM, Pugliese F, Rensing B, Jukema JW, Bax JJ, Prokop M, Doevendans PA, Hunink MGM, Krestin GP, de Feyter PJ (2008) Diagnostic accuracy of 64-slice computed tomography coronary angiography: a prospective, multicenter, multivendor study. J Am Coll Cardiol 52:2135–2144

    Article  PubMed  Google Scholar 

  28. Mintz GS, Painter JA, Pichard AD, Kent KM, Satler LF, Popma JJ, Chuang YC, Bucher TA, Sokolowicz LE, Leon MB (1995) Atherosclerosis in angiographically “normal” coronary artery reference segments: an intravascular ultrasound study with clinical correlations. J Am Coll Cardiol 25:1479–1485

    Article  CAS  PubMed  Google Scholar 

  29. Moreno PR, Falk E, Palacios IF, Newell JB, Fuster V, Fallon JT (1994) Macrophage infiltration in acute coronary syndromes. Implications for plaque rupture. Circulation 90:775–778

    CAS  PubMed  Google Scholar 

  30. Motoyama S, Kondo T, Sarai M, Sugiura A, Harigaya H, Sato T, Inoue K, Okumura M, Ishii J, Anno H, Virmani R, Ozaki Y, Hishida H, Narula J (2007) Multislice computed tomographic characteristics of coronary lesions in acute coronary syndromes. J Am Coll Cardiol 50:319–326

    Article  PubMed  Google Scholar 

  31. Nahrendorf M, Sosnovik DE, Weissleder R (2008) MR-optical imaging of cardiovascular molecular targets. Basic Res Cardiol 103:87–94

    Article  CAS  PubMed  Google Scholar 

  32. Petranovic M, Soni A, Bezzera H, Loureiro R, Sarwar A, Raffel C, Pomerantsev E, Jang IK, Brady TJ, Achenbach S, Cury RC (2009) Assessment of nonstenotic coronary lesions by 64-slice multidetector computed tomography in comparison to intravascular ultrasound: evaluation of nonculprit coronary lesions. J Cardiovasc Comput Tomogr 3:24–31

    Article  PubMed  Google Scholar 

  33. Pohle K, Achenbach S, Macneill B, Ropers D, Ferencik M, Moselewski F, Hoffmann U, Brady TJ, Jang IK, Daniel WG (2007) Characterization of non-calcified coronary atherosclerotic plaque by multi-detector row CT: comparison to IVUS. Atherosclerosis 190:174–180

    Article  CAS  PubMed  Google Scholar 

  34. Pouleur A-C, de Waroux J-B, Kefer J, Pasquet A, Vanoverschelde J-L, Gerber BL (2008) Direct comparison of whole-heart navigator-gated magnetic resonance coronary angiography and 40- and 64-slice multidetector row computed tomography to detect the coronary artery stenosis in patients scheduled for conventional coronary angiography. Circ Cardiovasc Imaging 1:114–121

    Article  PubMed  Google Scholar 

  35. Saitoh S, Saito T, Ohwada T, Ohtake A, Onogi F, Aikawa K, Maehara K, Maruyama Y (1998) Morphological and functional changes in coronary vessel evoked by repeated endothelial injury in pigs. Cardiovasc Res 38:772–781

    Article  CAS  PubMed  Google Scholar 

  36. Schafers M (2008) The future of molecular imaging in the clinic needs a clear strategy and a multidisciplinary effort. Basic Res Cardiol 103:200–202

    Article  CAS  PubMed  Google Scholar 

  37. Schrijvers DM, De Meyer GR, Herman AG, Martinet W (2007) Phagocytosis in atherosclerosis: molecular mechanisms and implications for plaque progression and stability. Cardiovasc Res 73:470–480

    Article  CAS  PubMed  Google Scholar 

  38. Schuijf JD, Beck T, Burgstahler C, Jukema JW, Dirksen MS, de Roos A, van der Wall EE, Schroeder S, Wijns W, Bax JJ (2007) Differences in plaque composition and distribution in stable coronary artery disease versus acute coronary syndromes: non-invasive evaluation with multi-slice computed tomography. Acute Card Care 9:48–53

    Article  CAS  PubMed  Google Scholar 

  39. Schwartz SM, Stemerman MB, Benditt EP (1975) The aortic intima. II. Repair of the aortic lining after mechanical denudation. Am J Pathol 81:15–42

    CAS  PubMed  Google Scholar 

  40. Shah PK, Falk E, Badimon JJ, Fernandez-Ortiz A, Mailhac A, Villareal-Levy G, Fallon JT, Regnstrom J, Fuster V (1995) Human monocyte-derived macrophages induce collagen breakdown in fibrous caps of atherosclerotic plaques. Potential role of matrix-degrading metalloproteinases and implications for plaque rupture. Circulation 92:1565–1569

    CAS  PubMed  Google Scholar 

  41. Sosnovik DE, Nahrendorf M, Weissleder R (2008) Magnetic nanoparticles for MR imaging: agents, techniques and cardiovascular applications. Basic Res Cardiol 103:122–130

    Article  CAS  PubMed  Google Scholar 

  42. Sun J, Zhang Z, Lu B, Yu W, Yang Y, Zhou Y, Wang Y, Fan Z (2008) Identification and quantification of coronary atherosclerotic plaques: a comparison of 64-MDCT and intravascular ultrasound. AJR Am J Roentgenol 190:748–754

    Article  PubMed  Google Scholar 

  43. Trivedi RA, U-King-Im J-M, Graves MJ, Cross JJ, Horsley J, Goddard MJ, Skepper JN, Quartey G, Warburton E, Joubert I, Wang L, Kirkpatrick PJ, Brown J, Gillard JH (2004) In vivo detection of macrophages in human carotid atheroma: temporal dependence of ultrasmall superparamagnetic particles of iron oxide-enhanced MRI. Stroke 35:1631–1635

    Article  PubMed  Google Scholar 

  44. van der Wal AC, Becker AE, van der Loos CM, Das PK (1994) Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 89:36–44

    PubMed  Google Scholar 

  45. Van Vaeck L, Adriaens A, Gijbels R (1999) Static secondary ion mass spectrometry (S-SIMS) Part 1: methodology and structural interpretation. Mass Spectrom Rev 18:1–47

    Article  Google Scholar 

  46. Verbeuren TJ, Jordaens FH, Zonnekeyn LL, Van Hove CE, Coene MC, Herman AG (1986) Effect of hypercholesterolemia on vascular reactivity in the rabbit. I. Endothelium-dependent and endothelium-independent contractions and relaxations in isolated arteries of control and hypercholesterolemic rabbits. Circ Res 58:552–564

    CAS  PubMed  Google Scholar 

  47. Verheye S, Martinet W, Kockx MM, Knaapen MWM, Salu K, Timmermans J-P, Ellis JT, Kilpatrick DL, De Meyer GRY (2007) Selective clearance of macrophages in atherosclerotic plaques by autophagy. J Am Coll Cardiol 49:706–715

    Article  CAS  PubMed  Google Scholar 

  48. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM (2000) Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 20:1262–1275

    CAS  PubMed  Google Scholar 

  49. Virmani R, Narula J, Farb A (1998) When neoangiogenesis ricochets. Am Heart J 136:937–939

    Article  CAS  PubMed  Google Scholar 

  50. Webster WS, Bishop SP, Geer JC (1974) Experimental aortic intimal thickening. II. Endothelialization and permeability. Am J Pathol 76:265–284

    CAS  PubMed  Google Scholar 

  51. Weidinger FF, McLenachan JM, Cybulsky MI, Gordon JB, Rennke HG, Hollenberg NK, Fallon JT, Ganz P, Cooke JP (1990) Persistent dysfunction of regenerated endothelium after balloon angioplasty of rabbit iliac artery. Circulation 81:1667–1679

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Peter Soete, Rita Van den Bossche and Cor Van Hove for their excellent technical assistance. This work was financially supported by the Fund for Scientific Research (FWO)-Flanders (projects G.0112.08 and G.0113.06), the Bekales Foundation and the University of Antwerp (NOI-BOF). Jozef Van Herck is a research assistant of the FWO-Flanders. Wim Martinet is a postdoctoral fellow of the FWO-Flanders.

Conflict of interest statement

None.

Author information

Authors and Affiliations

  1. Division of Cardiology, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium

    Jozef Leo Van Herck, Bharati Shivalkar & Christiaan J. Vrints

  2. Division of Pharmacology, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium

    Guido R. Y. De Meyer, Wim Martinet, Hidde Bult & Arnold G. Herman

  3. Division of Radiology, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium

    Rodrigo A. Salgado

  4. Division of Chemistry, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium

    Roel De Mondt & Luc Van Vaeck

  5. Division of Pharmaceutical Technology, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium

    Helene Van De Ven & Annick Ludwig

  6. Division of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium

    Pieter Van Der Veken

Authors
  1. Jozef Leo Van Herck
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guido R. Y. De Meyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wim Martinet
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rodrigo A. Salgado
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bharati Shivalkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Roel De Mondt
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Helene Van De Ven
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Annick Ludwig
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Pieter Van Der Veken
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Luc Van Vaeck
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hidde Bult
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Arnold G. Herman
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Christiaan J. Vrints
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jozef Leo Van Herck.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Van Herck, J.L., De Meyer, G.R.Y., Martinet, W. et al. Multi-slice computed tomography with N1177 identifies ruptured atherosclerotic plaques in rabbits. Basic Res Cardiol 105, 51–59 (2010). https://doi.org/10.1007/s00395-009-0052-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00395-009-0052-0

Keywords

Search

Navigation