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

Nature Medicine volume 17, pages 383–388 (2011)Cite this article

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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).

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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.

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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.

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Authors and Affiliations

  1. Division of Imaging Sciences and Biomedical Engineering, King's College London, London, UK

    Marcus R Makowski, Andrea J Wiethoff, Ulrike Blume, Christian H P Jansen, Eike Nagel, Reza Razavi, Tobias Schaeffter & René M Botnar

  2. British Heart Foundation (BHF) Centre of Excellence, King's College London, London, UK

    Marcus R Makowski, Friederike Cuello, Eike Nagel, Reza Razavi, Michael S Marber, Tobias Schaeffter & René M Botnar

  3. Department of Radiology, Charite, Berlin, Germany

    Marcus R Makowski

  4. Philips Healthcare, Guildford, UK

    Andrea J Wiethoff

  5. Cardiovascular Division, King's College London, London, UK

    Friederike Cuello, Michael S Marber & Alberto Smith

  6. Centre for Ultrastructural Imaging, King's College London, London, UK

    Alice Warley

  7. Wellcome Trust and Engineering and Physical Sciences Research Council Medical Engineering Center, King's College London, London, UK

    Eike Nagel, Reza Razavi, Tobias Schaeffter & René M Botnar

  8. National Institute of Health Research Biomedical Research Centre, King's College London, London, UK

    Eike Nagel, Reza Razavi, Michael S Marber, Tobias Schaeffter, Alberto Smith & René M Botnar

  9. Lantheus Medical Imaging, North Billerica, Massachusetts, USA

    David C Onthank, Richard R Cesati & Simon P Robinson

  10. Academic Surgery, King's College London, London, UK

    Alberto Smith

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  1. Marcus R Makowski
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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.

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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

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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)

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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

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