Imaging the subcellular structure of human coronary atherosclerosis using micro–optical coherence tomography

Abstract

Progress in understanding, diagnosis, and treatment of coronary artery disease (CAD) has been hindered by our inability to observe cells and extracellular components associated with human coronary atherosclerosis in situ. The current standards for microstructural investigation, histology and electron microscopy are destructive and prone to artifacts. The highest-resolution intracoronary imaging modality, optical coherence tomography (OCT), has a resolution of 10 μm, which is too coarse for visualizing most cells. Here we report a new form of OCT, termed micro–optical coherence tomography (μOCT), whose resolution is improved by an order of magnitude. We show that μOCT images of cadaver coronary arteries provide clear pictures of cellular and subcellular features associated with atherogenesis, thrombosis and responses to interventional therapy. These results suggest that μOCT can complement existing diagnostic techniques for investigating atherosclerotic specimens, and that μOCT may eventually become a useful tool for cellular and subcellular characterization of the human coronary wall in vivo.

Figure 1: μOCT images of a fibrocalcific human cadaver coronary plaque.
Figure 2: μOCT of superficial arterial morphology.
Figure 3: μOCT of plaque morphology in human cadaver specimens.
Figure 4: μOCT of stent and neointimal morphology in human cadaver specimens.

References

  1. 1

    Virmani, R., Kolodgie, F.D., Burke, A.P., Farb, A. & Schwartz, S.M. Lessons from sudden coronary death—a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler. Thromb. Vasc. Biol. 20, 1262–1275 (2000).

    CAS  Article  Google Scholar 

  2. 2

    Stary, H.C. et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis: a report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 92, 1355–1374 (1995).

    CAS  Article  Google Scholar 

  3. 3

    Grønholdt, M.L.M., Dalager-Pedersen, S. & Falk, E. Coronary atherosclerosis: determinants of plaque rupture. Eur. Heart J. 19, C24–C29 (1998).

    PubMed  Google Scholar 

  4. 4

    Davies, M.J. Acute coronary thrombosis—The role of plaque disruption and its initiation and prevention. Eur. Heart J. 16, 3–7 (1995).

    Article  Google Scholar 

  5. 5

    Pasternak, R.C., Baughman, K.L., Fallon, J.T. & Block, P.C. Scanning electron microscopy after coronary transluminal angioplasty of normal canine coronary arteries. Am. J. Cardiol. 45, 591–598 (1980).

    CAS  Article  Google Scholar 

  6. 6

    Bourassa, M.G., Cantin, M., Sandborn, E.B. & Pederson, E. Scanning electron microscopy of surface irregularities and thrombogenesis of polyurethane and polyethylene coronary catheters. Circulation 53, 992–996 (1976).

    CAS  Article  Google Scholar 

  7. 7

    Abela, G.S. & Aziz, K. Cholesterol crystals rupture biological membranes and human plaques during acute cardiovascular events–a novel insight into plaque rupture by scanning electron microscopy. Scanning 28, 1–10 (2006).

    CAS  Article  Google Scholar 

  8. 8

    Huang, D. et al. Optical coherence tomography. Science 254, 1178–1181 (1991).

    CAS  Article  Google Scholar 

  9. 9

    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 

  10. 10

    Yun, S.H. et al. Comprehensive volumetric optical microscopy in vivo. Nat. Med. 12, 1429–1433 (2006).

    CAS  Article  Google Scholar 

  11. 11

    Tearney, G.J. et al. Three-dimensional coronary artery microscopy by intracoronary optical frequency domain imaging. JACC Cardiovasc. Imaging 1, 752–761 (2008).

    Article  Google Scholar 

  12. 12

    Boppart, S.A. et al. In vivo cellular optical coherence tomography imaging. Nat. Med. 4, 861–865 (1998).

    CAS  Article  Google Scholar 

  13. 13

    Povazay, B. et al. Submicrometer axial resolution optical coherence tomography. Opt. Lett. 27, 1800–1802 (2002).

    CAS  Article  Google Scholar 

  14. 14

    Ralston, T.S., Marks, D.L., Carney, P.S. & Boppart, S.A. Interferometric synthetic aperture microscopy. Nat. Phys. 3, 129–134 (2007).

    CAS  Article  Google Scholar 

  15. 15

    Liu, L., Liu, C., Howe, W.C., Sheppard, C.J.R. & Chen, N.Q. Binary-phase spatial filter for real-time swept-source optical coherence microscopy. Opt. Lett. 32, 2375–2377 (2007).

    Article  Google Scholar 

  16. 16

    Ding, Z., Ren, H.W., Zhao, Y.H., Nelson, J.S. & Chen, Z.P. High-resolution optical coherence tomography over a large depth range with an axicon lens. Opt. Lett. 27, 243–245 (2002).

    Article  Google Scholar 

  17. 17

    Lee, K.S. & Rolland, L.P. Bessel beam spectral-domain high-resolution optical coherence tomography with micro-optic axicon providing extended focusing range. Opt. Lett. 33, 1696–1698 (2008).

    Article  Google Scholar 

  18. 18

    Leitgeb, R.A., Villiger, M., Bachmann, A.H., Steinmann, L. & Lasser, T. Extended focus depth for Fourier domain optical coherence microscopy. Opt. Lett. 31, 2450–2452 (2006).

    CAS  Article  Google Scholar 

  19. 19

    Vakhtin, A.B., Kane, D.J., Wood, W.R. & Peterson, K.A. Common-path interferometer for frequency-domain optical coherence tomography. Appl. Opt. 42, 6953–6958 (2003).

    Article  Google Scholar 

  20. 20

    Hausler, G. & Lindner, M.W. “Coherence radar” and “Spectral radar”—new tools for dermatological diagnosis. J. Biomed. Opt. 3, 21–31 (1998).

    CAS  Article  Google Scholar 

  21. 21

    Finn, A.V. et al. Pathological correlates of late drug-eluting stent thrombosis—strut coverage as a marker of endothelialization. Circulation 115, 2435–2441 (2007).

    Article  Google Scholar 

  22. 22

    Libby, P. Changing concepts of atherogenesis. J. Intern. Med. 247, 349–358 (2000).

    CAS  Article  Google Scholar 

  23. 23

    Lusis, A.J. Atherosclerosis. Nature 407, 233–241 (2000).

    CAS  Article  Google Scholar 

  24. 24

    Virmani, R., Burke, A.P., Farb, A. & Kolodgie, F.D. Pathology of the vulnerable plaque. J. Am. Coll. Cardiol. 47, C13–C18 (2006).

    CAS  Article  Google Scholar 

  25. 25

    Vengrenyuk, Y., Cardoso, L. & Weinbaum, S. μCT-based analysis of a new paradigm for vulnerable plaque rupture: cellular microcalcifications in fibrous caps. Mol. Cell. Biomech. 5, 37–47 (2008).

    PubMed  Google Scholar 

  26. 26

    Serruys, P.W. et al. A bioabsorbable everolimus-eluting coronary stent system (ABSORB): 2-year outcomes and results from multiple imaging methods. Lancet 373, 897–910 (2009).

    CAS  Article  Google Scholar 

  27. 27

    Rasband, W.S. ImageJ. (US National Institutes of Health, Bethesda, Maryland, 1997–2011).

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Acknowledgements

We wish to acknowledge contributions from D. Winsor-Hines of Boston Scientific for providing the stents that were used to create Supplementary Figure 4 , G. Veytsman of Capital Biosciences for providing explanted human hearts, and J. Zhao and the Wellman Center Photopathology Laboratory staff for expert histology processing. Swine arterial tissue was obtained from the Massachusetts General Hospital Knight Surgical Laboratory. Human tissue was provided by the National Disease Research Interchange and Capital Biosciences. Endothelial cells were supplied by the Schepens Eye Research Institute. This research was supported in part by the US National Institutes of Health (contracts R01HL076398 and R01HL093717) and the Cystic Fibrosis Foundation (contract TEARNE07XX0).

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Contributions

L.L. developed the μOCT system and participated in conducting the imaging studies and writing the manuscript. J.A.G. was responsible for procuring and preparing specimens, preparing the specimens for histopathology and organizing all digital histopathology data. S.K.N. and J.D.T. prepared the endothelial cell cultures. Y.Y. digitized the histopathology slides using her full-slide scanning systems. L.L. and G.J.T. analyzed and processed the data. B.E.B. contributed to the study design and participated in the analysis of the data. G.J.T. supervised the overall project and contributed to the design of experiments, interpretation of the μOCT image data and preparation of the manuscript. All authors read and edited the manuscript.

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Correspondence to Guillermo J Tearney.

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Competing interests

Massachusetts General Hospital has licensed OFDI technology to Terumo Corporation. B.E.B. and G.J.T. receive sponsored research relating to OFDI technology development from Terumo Corporation. B.E.B. and G.J.T. also have the right to receive royalty payments as part of this licensing arrangement.

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Supplementary Figures 1–4 and Supplementary Methods (PDF 1109 kb)

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Liu, L., Gardecki, J., Nadkarni, S. et al. Imaging the subcellular structure of human coronary atherosclerosis using micro–optical coherence tomography. Nat Med 17, 1010–1014 (2011). https://doi.org/10.1038/nm.2409

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