Skip to main content

Beneficial effect of anti-platelet therapies on atherosclerotic lesion formation assessed by phase-contrast X-ray CT imaging

The International Journal of Cardiovascular Imaging volume 28, pages 1181–1191 (2012)Cite this article

Abstract

We have applied an imaging system of phase-contrast X-ray CT to the detection of atherosclerotic plaque components by means of the differences of tissue mass densities. In this study, we investigated the effect of the anti-platelet therapies, widely used for secondly prevention of cardiovascular events, on plaque stability and examined whether this novel technique could detect the changes of plaque components under the therapy. Apolipoprotein E-deficient mice were fed on high-cholesterol diet alone and either with 0.1% cilostazol or clopidogrel for 10 weeks. We assessed atherosclerotic lesion volumes and components at brachiocephalic artery by the phase-contrast X-ray CT imaging and histochemistry. The phase-contrast X-ray CT imaging could reveal that cilostazol and clopidogrel significantly decreased atherosclerotic lesion volumes at brachiocephalic artery (31.2% reduction in cilostazol group and 37.4% reduction in clopidogrel group), compared with control group. In addition, the mass densities calculated by this method revealed the anti-platelet treatment increased stable plaque areas including high collagen content, but decreased unstable plaque areas including lipid and macrophage content. These findings were confirmed by histological analyses. Real-time PCR analyses indicated that anti-platelets inhibited gene expressions of cytokines and adhesion molecules, such as IFNγ and ICAM-1. Anti-platelet therapies had a beneficial effect on plaque stability maybe due to anti-inflammatory actions. Phase-contrast X-ray CT imaging could quantify the plaque volume and qualify the plaque components affected by anti-platelet therapies. This novel phase-contrast X-ray CT imaging system could be a plausible method to detect the unstable plaque non-invasively in the future.

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

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. Barrett NE, Holbrook L, Jones S, Kaiser WJ, Moraes LA, Rana R, Sage T, Stanley RG, Tucker KL, Wright B, Gibbins JM (2008) Future innovations in anti-platelet therapies. Br J Pharmacol 154:918–939

    PubMed  Article  CAS  Google Scholar 

  2. Meadows TA, Bhatt DL (2007) Clinical aspects of platelet inhibitors and thrombus formation. Circ Res 100:1261–1275

    PubMed  Article  CAS  Google Scholar 

  3. Hankey GJ, Norman PE, Eikelboom JW (2006) Medical treatment of peripheral arterial disease. JAMA 295:547–553

    PubMed  Article  CAS  Google Scholar 

  4. Fuster V, Moreno PR, Fayad ZA, Corti R, Badimon JJ (2005) Atherothrombosis and high-risk plaque: part I: evolving concepts. J Am Coll Cardiol 46:937–954

    PubMed  Article  Google Scholar 

  5. Libby P (2008) The molecular mechanisms of the thrombotic complications of atherosclerosis. J Intern Med 263:517–527

    PubMed  Article  CAS  Google Scholar 

  6. Uchiyama S, Demaerschalk BM, Goto S, Shinohara Y, Gotoh F, Stone WM, Money SR, Kwon SU (2009) Stroke prevention by cilostazol in patients with atherothrombosis: meta-analysis of placebo-controlled randomized trials. J Stroke Cerebrovasc Dis 18:482–490

    PubMed  Article  Google Scholar 

  7. CAPRIE Steering Committee (1996) A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events. (CAPRIE) Lancet 348:1329–1339

    Article  Google Scholar 

  8. Lee JH, Oh GT, Park SY, Choi JH, Park JG, Kim CD, Lee WS, Rhim BY, Shin YW, Hong KW (2005) Cilostazol reduces atherosclerosis by inhibition of superoxide and tumor necrosis factor-alpha formation in low-density lipoprotein receptor-null mice fed high cholesterol. J Pharmacol Exp Ther 313:502–509

    PubMed  Article  CAS  Google Scholar 

  9. Li M, Zhang Y, Ren H, Zhang Y, Zhu X (2007) Effect of clopidogrel on the inflammatory progression of early atherosclerosis in rabbits model. Atherosclerosis 194:348–356

    PubMed  Article  CAS  Google Scholar 

  10. Henneman MM, Schuijf JD, Pundziute G, van Werkhoven JM, van der Wall EE, Jukema JW, Bax JJ (2008) Noninvasive evaluation with multislice computed tomography in suspected acute coronary syndrome: plaque morphology on multislice computed tomography versus coronary calcium score. J Am Coll Cardiol 52:216–222

    PubMed  Article  Google Scholar 

  11. Raff GL, Goldstein JA (2007) Coronary angiography by computed tomography: coronary imaging evolves. J Am Coll Cardiol 49:1830–1833

    PubMed  Article  Google Scholar 

  12. Momose A (2005) Recent advances in X-ray phase imaging. Jpn J Appl Phys 44:6355–6367

    Article  CAS  Google Scholar 

  13. Shinohara M, Yamashita T, Tawa H, Takeda M, Sasaki N, Takaya T, Toh R, Takeuchi A, Ohigashi T, Shinohara K, Kawashima S, Yokoyama M, Hirata, Momose A (2008) Atherosclerotic plaque imaging using phase-contrast X-ray computed tomography. Am J Physiol Heart Circ Physiol 294:H1094–H1100

  14. Momose A (1995) Demonstration of phase-contrast X-ray computed tomography using an X-ray interferometer. Nucl Instrum Methods A 352:622–628

    Article  CAS  Google Scholar 

  15. Momose A, Takeda T, Itai Y, Hirano K (1996) Phase-contrast X-ray computed tomography for observing biological soft tissues. Nat Med 2:473–475

    PubMed  Article  CAS  Google Scholar 

  16. Takeda T, Momsoe A, Hirano K, Haraoka S, Watanabe T, Itai Y (2000) Human carcinoma: early experience with phase-contrast X-ray CT with synchrotron radiation—comparative specimen study with optical microscopy. Radiology 214:298–301

    PubMed  CAS  Google Scholar 

  17. Takeda T, Momose A, Wu J, Yu Q, Zeniya T, Lwin TT, Yoneyama A, Itai Y (2002) Vessel imaging by interferometric phase-contrast X-ray technique. Circulation 105:1708–1712

    Google Scholar 

  18. Wu J, Takeda T, Lwin TT, Momose A, Sunaguchi N, Fukami T, Yuasa T, Akatsuka T (2009) Imaging renal structures by X-ray phase-contrast microtomography. Kidney Int 75:945–951

    PubMed  Article  Google Scholar 

  19. Keul P, Tolle M, Lucke S, von Wnuck Lipinski K, Heusch G, Schuchardt M, van der Giet M, Levkau B (2007) The sphingosine-1-phosphate analogue FTY720 reduces atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 27:607–613

    PubMed  Article  CAS  Google Scholar 

  20. Takaya T, Kawashima S, Shinohara M, Yamashita T, Toh R, Sasaki N, Inoue N, Hirata K, Yokoyama M (2006) Angiotensin II type 1 receptor blocker telmisartan suppresses superoxide production and reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice. Atherosclerosis 186:402–410

    PubMed  Article  CAS  Google Scholar 

  21. Jawien J, Csanyi G, Gajda M, Mateuszuk L, Lomnicka M, Korbut R, Chlopicki S (2007) Ticlopidine attenuates progression of atherosclerosis in apolipoprotein E and low density lipoprotein receptor double knockout mice. Eur J Pharmacol 556:129–135

    PubMed  Article  CAS  Google Scholar 

  22. Schulz C, Konrad I, Sauer S, Orschiedt L, Koellnberger M, Lorenz R, Walter U, Massberg S (2008) Effect of chronic treatment with acetylsalicylic acid and clopidogrel on atheroprogression and atherothrombosis in ApoE-deficient mice in vivo. Thromb Haemost 99:190–195

    PubMed  CAS  Google Scholar 

  23. Park SY, Lee JH, Kim CD, Lee WS, Park WS, Han J, Kwak YG, Kim KY, Hong KW (2006) Cilostazol suppresses superoxide production and expression of adhesion molecules in human endothelial cells via mediation of cAMP-dependent protein kinase-mediated maxi-K channel activation. J Pharmacol Exp Ther 317:1238–1245

    PubMed  Article  CAS  Google Scholar 

  24. Takase H, Hashimoto A, Okutsu R, Hirose Y, Ito H, Imaizumi T, Miyakoda G, Mori T (2007) Anti-atherosclerotic effect of cilostazol in apolipoprotein-E knockout mice. Arzneimittelforschung 57:185–191

    PubMed  CAS  Google Scholar 

  25. Okutsu R, Yoshikawa T, Nagasawa M, Hirose Y, Takase H, Mitani K, Okada K, Miyakoda G, Yabuuchi Y (2009) Cilostazol inhibits modified low-density lipoprotein uptake and foam cell formation in mouse peritoneal macrophages. Atherosclerosis 204:405–411

    PubMed  Article  CAS  Google Scholar 

  26. Momose A, Fukuda J (1995) Phase-contrast radiographs of nonstained rat cerebellar specimen. Med Phys 22:375–379

    PubMed  Article  CAS  Google Scholar 

  27. Takeda T, Momose A, Itai Y, Wu J, Hirano K (1995) Phase-contrast imaging with synchrotoron X -rays for detecting caner lesions. Acad Radiol 2:799–803

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by Grant-in-aid for Scientific Research Japan Society for the Promotion of Science, and was carried out under the approval of the committee of SPring-8, Japan as the Medical-Biology Trial Use (Proposal No. 2008A1872).

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan

    Masafumi Takeda, Tomoya Yamashita, Masakazu Shinohara, Naoto Sasaki, Hideto Tawa, Kenji Nakajima & Ken-ichi Hirata

  2. Department of Advanced Materials Science, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan

    Atsushi Momose

Authors
  1. Masafumi Takeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tomoya Yamashita
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masakazu Shinohara
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Naoto Sasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hideto Tawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kenji Nakajima
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Atsushi Momose
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ken-ichi Hirata
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tomoya Yamashita.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Takeda, M., Yamashita, T., Shinohara, M. et al. Beneficial effect of anti-platelet therapies on atherosclerotic lesion formation assessed by phase-contrast X-ray CT imaging. Int J Cardiovasc Imaging 28, 1181–1191 (2012). https://doi.org/10.1007/s10554-011-9910-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10554-011-9910-6

Keywords

  • Anti-platelet therapy
  • Phase-contrast X-ray CT imaging
  • Plaque stability
  • Inflammation