Technical Report | Published:

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

Nature Medicine volume 17, pages 383388 (2011) | Download Citation

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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References

  1. 1.

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

  2. 2.

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

  3. 3.

    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).

  4. 4.

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

  5. 5.

    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).

  6. 6.

    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).

  7. 7.

    , & Seeking alternatives to Hard End Points: is imaging the best APPROACH? Circulation 121, 1165–1168 (2010).

  8. 8.

    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).

  9. 9.

    & Atherosclerosis and extracellular matrix. J. Atheroscler. Thromb. 10, 267–274 (2003).

  10. 10.

    , & Elastin expression in a model of acute arterial graft rejection. Transplantation 58, 1246–1251 (1994).

  11. 11.

    , , , & Smooth muscle cell expression of extracellular matrix genes after arterial injury. Am. J. Pathol. 144, 1348–1356 (1994).

  12. 12.

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

  13. 13.

    , , & Biochemical analysis of collagen and elastin synthesis in the balloon injured rat carotid artery. Cardiovasc. Pathol. 11, 272–276 (2002).

  14. 14.

    , & Elastogenesis in human arterial disease: a role for macrophages in disordered elastin synthesis. Arterioscler. Thromb. Vasc. Biol. 23, 582–587 (2003).

  15. 15.

    , & Chemotactic activity of elastin-derived peptides. J. Clin. Invest. 66, 859–862 (1980).

  16. 16.

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

  17. 17.

    , & New insights into elastin and vascular disease. Trends Cardiovasc. Med. 13, 176–181 (2003).

  18. 18.

    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).

  19. 19.

    , , , & ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler. Thromb. 14, 133–140 (1994).

  20. 20.

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

  21. 21.

    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).

  22. 22.

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

  23. 23.

    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).

  24. 24.

    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).

  25. 25.

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

  26. 26.

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

  27. 27.

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

  28. 28.

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

  29. 29.

    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).

  30. 30.

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

  31. 31.

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

  32. 32.

    , , , & Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 115, 459–467 (2007).

  33. 33.

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

  34. 34.

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

  35. 35.

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

  36. 36.

    , , & Measuring signal-to-noise ratios in MR imaging. Radiology 173, 265–267 (1989).

  37. 37.

    , , & Quality assurance for MRI: practical experience. Br. J. Radiol. 73, 376–383 (2000).

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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.

Author information

Affiliations

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

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.

Corresponding author

Correspondence to Marcus R Makowski.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–3 and Supplementary Methods

Videos

  1. 1.

    Supplementary Video 1

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

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DOI

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

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