Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Assessment of atherosclerotic plaque burden with an elastin-specific magnetic resonance contrast agent

Abstract

Atherosclerosis and its consequences remain the main cause of mortality in industrialized and developing nations. Plaque burden and progression have been shown to be independent predictors for future cardiac events by intravascular ultrasound. Routine prospective imaging is hampered by the invasive nature of intravascular ultrasound. A noninvasive technique would therefore be more suitable for screening of atherosclerosis in large populations. Here we introduce an elastin-specific magnetic resonance contrast agent (ESMA) for noninvasive quantification of plaque burden in a mouse model of atherosclerosis. The strong signal provided by ESMA allows for imaging with high spatial resolution, resulting in accurate assessment of plaque burden. Additionally, plaque characterization by quantifying intraplaque elastin content using signal intensity measurements is possible. Changes in elastin content and the high abundance of elastin during plaque development, in combination with the imaging properties of ESMA, provide potential for noninvasive assessment of plaque burden by molecular magnetic resonance imaging (MRI).

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Chemical structure of ESMA and binding characteristics determined by high-resolution DE-MRI.
Figure 2: In vivo MRI signal measurements and ex vivo quantification of contrast agent.
Figure 3: In vivo assessment of plaque burden by morphometric measurements.
Figure 4: In vivo assessment of plaque elastin composition using signal intensity measurements.
Figure 5: In and ex vivo characterization of binding of ESMA to elastin.

References

  1. Brown, B.G. et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N. Engl. J. Med. 345, 1583–1592 (2001).

    CAS  Article  Google Scholar 

  2. Mock, M.B. et al. Survival of medically treated patients in the coronary artery surgery study (CASS) registry. Circulation 66, 562–568 (1982).

    CAS  Article  Google Scholar 

  3. Ringqvist, I. et al. Prognostic value of angiographic indices of coronary artery disease from the Coronary Artery Surgery Study (CASS). J. Clin. Invest. 71, 1854–1866 (1983).

    CAS  Article  Google Scholar 

  4. Schoenhagen, P. et al. Extent and direction of arterial remodeling in stable versus unstable coronary syndromes: an intravascular ultrasound study. Circulation 101, 598–603 (2000).

    CAS  Article  Google Scholar 

  5. Jang, I.K. et al. Visualization of coronary atherosclerotic plaques in patients using optical coherence tomography: comparison with intravascular ultrasound. J. Am. Coll. Cardiol. 39, 604–609 (2002).

    Article  Google Scholar 

  6. Kawasaki, M. et al. Volumetric quantitative analysis of tissue characteristics of coronary plaques after statin therapy using three-dimensional integrated backscatter intravascular ultrasound. J. Am. Coll. Cardiol. 45, 1946–1953 (2005).

    CAS  Article  Google Scholar 

  7. Finn, A.V., Chandrashekhar, Y. & Narula, J. Seeking alternatives to Hard End Points: is imaging the best APPROACH? Circulation 121, 1165–1168 (2010).

    Article  Google Scholar 

  8. Brasselet, C. et al. Collagen and elastin cross-linking: a mechanism of constrictive remodeling after arterial injury. Am. J. Physiol. Heart Circ. Physiol. 289, H2228–H2233 (2005).

    CAS  Article  Google Scholar 

  9. Katsuda, S. & Kaji, T. Atherosclerosis and extracellular matrix. J. Atheroscler. Thromb. 10, 267–274 (2003).

    CAS  Article  Google Scholar 

  10. Isik, F.F., Clowes, A.W. & Gordon, D. Elastin expression in a model of acute arterial graft rejection. Transplantation 58, 1246–1251 (1994).

    CAS  PubMed  Google Scholar 

  11. Nikkari, S.T., Jarvelainen, H.T., Wight, T.N., Ferguson, M. & Clowes, A.W. Smooth muscle cell expression of extracellular matrix genes after arterial injury. Am. J. Pathol. 144, 1348–1356 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Masuda, H. et al. Adaptive remodeling of internal elastic lamina and endothelial lining during flow-induced arterial enlargement. Arterioscler. Thromb. Vasc. Biol. 19, 2298–2307 (1999).

    CAS  Article  Google Scholar 

  13. Nili, N., Zhang, M., Strauss, B.H. & Bendeck, M.P. Biochemical analysis of collagen and elastin synthesis in the balloon injured rat carotid artery. Cardiovasc. Pathol. 11, 272–276 (2002).

    CAS  Article  Google Scholar 

  14. Krettek, A., Sukhova, G.K. & Libby, P. Elastogenesis in human arterial disease: a role for macrophages in disordered elastin synthesis. Arterioscler. Thromb. Vasc. Biol. 23, 582–587 (2003).

    CAS  Article  Google Scholar 

  15. Senior, R.M., Griffin, G.L. & Mecham, R.P. Chemotactic activity of elastin-derived peptides. J. Clin. Invest. 66, 859–862 (1980).

    CAS  Article  Google Scholar 

  16. Karnik, S.K. A critical role for elastin signaling in vascular morphogenesis and disease. Development 130, 411–423 (2003).

    CAS  Article  Google Scholar 

  17. Brooke, B.S., Bayes-Genis, A. & Li, D.Y. New insights into elastin and vascular disease. Trends Cardiovasc. Med. 13, 176–181 (2003).

    CAS  Article  Google Scholar 

  18. Onthank, D. et al. Abstract 1914: BMS753951: A novel low molecular weight magnetic resonance contrast agent selective for arterial wall imaging. Circulation 116, II 411–II 412 (2007).

    Article  Google Scholar 

  19. Nakashima, Y., Plump, A.S., Raines, E.W., Breslow, J.L. & Ross, R. ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler. Thromb. 14, 133–140 (1994).

    CAS  Article  Google Scholar 

  20. Rosenfeld, M.E. et al. Advanced atherosclerotic lesions in the innominate artery of the ApoE knockout mouse. Arterioscler. Thromb. Vasc. Biol. 20, 2587–2592 (2000).

    CAS  Article  Google Scholar 

  21. Mintz, G.S. et al. American College of Cardiology Clinical Expert Consensus Document on Standards for Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies (IVUS). A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J. Am. Coll. Cardiol. 37, 1478–1492 (2001).

    CAS  Article  Google Scholar 

  22. Botnar, R.M. et al. In vivo magnetic resonance imaging of coronary thrombosis using a fibrin-binding molecular magnetic resonance contrast agent. Circulation 110, 1463–1466 (2004).

    Article  Google Scholar 

  23. Yeon, S.B. et al. Delayed-enhancement cardiovascular magnetic resonance coronary artery wall imaging: comparison with multislice computed tomography and quantitative coronary angiography. J. Am. Coll. Cardiol. 50, 441–447 (2007).

    Article  Google Scholar 

  24. Kim, W.Y. et al. Three-dimensional black-blood cardiac magnetic resonance coronary vessel wall imaging detects positive arterial remodeling in patients with nonsignificant coronary artery disease. Circulation 106, 296–299 (2002).

    Article  Google Scholar 

  25. Botnar, R.M. et al. Noninvasive coronary vessel wall and plaque imaging with magnetic resonance imaging. Circulation 102, 2582–2587 (2000).

    CAS  Article  Google Scholar 

  26. Fayad, Z.A. et al. Noninvasive in vivo human coronary artery lumen and wall imaging using black-blood magnetic resonance imaging. Circulation 102, 506–510 (2000).

    CAS  Article  Google Scholar 

  27. Wasserman, B.A. et al. Carotid artery atherosclerosis: in vivo morphologic characterization with gadolinium-enhanced double-oblique MR imaging initial results. Radiology 223, 566–573 (2002).

    Article  Google Scholar 

  28. Botnar, R.M. et al. 3D coronary vessel wall imaging utilizing a local inversion technique with spiral image acquisition. Magn. Reson. Med. 46, 848–854 (2001).

    CAS  Article  Google Scholar 

  29. Ibrahim, T. et al. Serial contrast-enhanced cardiac magnetic resonance imaging demonstrates regression of hyperenhancement within the coronary artery wall in patients after acute myocardial infarction. JACC Cardiovasc. Imaging 2, 580–588 (2009).

    Article  Google Scholar 

  30. Helm, P.A. et al. Postinfarction myocardial scarring in mice: molecular MR imaging with use of a collagen-targeting contrast agent. Radiology 247, 788–796 (2008).

    Article  Google Scholar 

  31. Nicholls, S.J. et al. Intravascular ultrasound–derived measures of coronary atherosclerotic plaque burden and clinical outcome. J. Am. Coll. Cardiol. 55, 2399–2407 (2010).

    Article  Google Scholar 

  32. Lorenz, M.W., Markus, H.S., Bots, M.L., Rosvall, M. & Sitzer, M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 115, 459–467 (2007).

    Article  Google Scholar 

  33. Mock, M.B. et al. Survival of medically treated patients in the coronary artery surgery study (CASS) registry. Circulation 66, 562–568 (1982).

    CAS  Article  Google Scholar 

  34. Hadamitzky, M. et al. Prognostic value of coronary computed tomographic angiography in diabetic patients without known coronary artery disease. Diabetes Care 33, 1358–1363 (2010).

    Article  Google Scholar 

  35. Libby, P. & Aikawa, M. Stabilization of atherosclerotic plaques: new mechanisms and clinical targets. Nat. Med. 8, 1257–1262 (2002).

    CAS  Article  Google Scholar 

  36. Kaufman, L., Kramer, D.M., Crooks, L.E. & Ortendahl, D.A. Measuring signal-to-noise ratios in MR imaging. Radiology 173, 265–267 (1989).

    CAS  Article  Google Scholar 

  37. Firbank, M.J., Harrison, R.M., Williams, E.D. & Coulthard, A. Quality assurance for MRI: practical experience. Br. J. Radiol. 73, 376–383 (2000).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This study was funded by a BHF project grant (PG/09/061) awarded to R.M.B. M.R.M. was partly funded by a BHF studentship awarded to R.M.B. ESMA (BMS753951) was provided by Lantheus Medical Imaging. Supporting data for the in vitro rabbit competition and in vivo mouse distribution studies were provided by P. Yalamanchili, M. Kavosi and P. Silva from Lantheus Medical Imaging.

Author information

Authors and Affiliations

Authors

Contributions

M.R.M. and R.M.B. are responsible for the overall study design and implemented and optimized the magnetic resonance imaging protocols. D.C.O., R.R.C. and S.P.R. designed and manufactured the contrast agent. U.B. and T.S. developed and implemented the T1 mapping sequence and analysis tools. M.R.M., R.M.B., A.J.W., A.S. and F.C. designed, conducted and analyzed the in vitro and in vivo experiments. A.W. performed the electron microscopy experiments. M.R.M., R.M.B., A.J.W., F.C., M.S.M., E.N., T.S., A.S., R.R. and C.H.P.J. contributed to the writing of the manuscript. All authors discussed and refined the manuscript.

Corresponding author

Correspondence to Marcus R Makowski.

Ethics declarations

Competing interests

The magnetic resonance imaging scanner is partly supported by Philips Healthcare. A.J.W.is an employee of Philips Healthcare. D.C.O., R.R.C. and S.P.R. are employees of Lantheus Medical Imaging. The study was funded by the British Heart Foundation (PG/09/061), and the contrast agent was provided by Lantheus Medical Imaging.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 and Supplementary Methods (PDF 2378 kb)

Supplementary Video 1

3D reconstruction (volume rendering) of elastin signal in the brachiocephalic artery of an Apoe−/− mouse. (MOV 257 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Makowski, M., Wiethoff, A., Blume, U. et al. Assessment of atherosclerotic plaque burden with an elastin-specific magnetic resonance contrast agent. Nat Med 17, 383–388 (2011). https://doi.org/10.1038/nm.2310

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2310

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing