Skip to main content
Log in

Microcalcifications Increase Coronary Vulnerable Plaque Rupture Potential: A Patient-Based Micro-CT Fluid–Structure Interaction Study

  • Published:
Annals of Biomedical Engineering Aims and scope Submit manuscript

Abstract

Asymptomatic vulnerable plaques (VP) in coronary arteries accounts for significant level of morbidity. Their main risk is associated with their rupture which may prompt fatal heart attacks and strokes. The role of microcalcifications (micro-Ca), embedded in the VP fibrous cap, in the plaque rupture mechanics has been recently established. However, their diminutive size offers a major challenge for studying the VP rupture biomechanics on a patient specific basis. In this study, a highly detailed model was reconstructed from a post-mortem coronary specimen of a patient with observed VP, using high resolution micro-CT which captured the microcalcifications embedded in the fibrous cap. Fluid–structure interaction (FSI) simulations were conducted in the reconstructed model to examine the combined effects of micro-Ca, flow phase lag and plaque material properties on plaque burden and vulnerability. This dynamic fibrous cap stress mapping elucidates the contribution of micro-Ca and flow phase lag VP vulnerability independently. Micro-Ca embedded in the fibrous cap produced increased stresses predicted by previously published analytical model, and corroborated our previous studies. The ‘micro-CT to FSI’ methodology may offer better diagnostic tools for clinicians, while reducing morbidity and mortality rates for patients with vulnerable plaques and ameliorating the ensuing healthcare costs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

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

Instant access to the full article PDF.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. ADINA. ADINA Manual, Theory and Modeling Guide: ARD 09-7, 2009.

  2. Alsheikh-Ali, A. A., G. D. Kitsios, E. M. Balk, J. Lau, and S. Ip. The vulnerable atherosclerotic plaque: scope of the literature. Ann. Intern. Med. 153:387–395, 2010.

    PubMed  Google Scholar 

  3. Bluestein, D., Y. Alemu, I. Avrahami, M. Gharib, K. Dumont, J. J. Ricotta, and S. Einav. Influence of microcalcifications on vulnerable plaque mechanics using FSI modeling. J. Biomech. 41:1111–1118, 2008.

    Article  PubMed  Google Scholar 

  4. Bobryshev, Y. V., M. C. Killingsworth, R. S. Lord, and A. J. Grabs. Matrix vesicles in the fibrous cap of atherosclerotic plaque: possible contribution to plaque rupture. J. Cell Mol. Med. 12:2073–2082, 2008.

    Article  PubMed  CAS  Google Scholar 

  5. Burke, A. P., A. Farb, G. T. Malcom, Y. H. Liang, J. Smialek, and R. Virmani. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N. Engl. J. Med. 336:1276–1282, 1997.

    Article  PubMed  CAS  Google Scholar 

  6. Burke, A. P., A. Farb, G. T. Malcom, Y. Liang, J. Smialek, and R. Virmani. Effect of risk factors on the mechanism of acute thrombosis and sudden coronary death in women. Circulation 97:2110–2116, 1998.

    Article  PubMed  CAS  Google Scholar 

  7. Burke, A. P., D. K. Weber, F. D. Kolodgie, A. Farb, A. J. Taylor, and R. Virmani. Pathophysiology of calcium deposition in coronary arteries. Herz 26:239–244, 2001.

    Article  PubMed  CAS  Google Scholar 

  8. Cheng, G. C., H. M. Loree, R. D. Kamm, M. C. Fishbein, and R. T. Lee. Distribution of circumferential stress in ruptured and stable atherosclerotic lesions—a structural-analysis with histopathological correlation. Circulation 87:1179–1187, 1993.

    Article  PubMed  CAS  Google Scholar 

  9. Cheng, C., D. Tempel, R. van Haperen, A. van der Baan, F. Grosveld, M. J. Daemen, R. Krams, and R. de Crom. Atherosclerotic lesion size and vulnerability are determined by patterns of fluid shear stress. Circulation 113:2744–2753, 2006.

    Article  PubMed  Google Scholar 

  10. Gent, A. N., and B. Park. Failure processes in elastomers at or near a rigid spherical inclusion. J. Mater. Sci. 19:1947–1956, 1984.

    Article  CAS  Google Scholar 

  11. Hayashi, K., Y. Igarashi, and K. Takamizawa. Mechanical properties and hemodynamics in coronary arteries. In: New Approaches in Cardiac Mechanics, edited by K. Kitamura, H. Abe, and K. Sagawa. Tokyo: Gorden and Breach, 1986, pp. 285–294.

    Google Scholar 

  12. Holzapfel, G. A. Nonlinear Solid Mechanics: A Continuum Approach for Engineering. New York: Wiley, 2000.

    Google Scholar 

  13. Holzapfel, G. A., G. Sommer, C. T. Gasser, and P. Regitnig. Determination of layer-specific mechanical properties of human coronary arteries with nonatherosclerotic intimal thickening and related constitutive modeling. Am. J. Physiol. Heart Circ. Physiol. 289:H2048–H2058, 2005.

    Article  PubMed  CAS  Google Scholar 

  14. Holzapfel, G. A., G. Sommer, and P. Regitnig. Anisotropic mechanical properties of tissue components in human atherosclerotic plaques. J. Biomech. Eng. 126:657–665, 2004.

    Article  PubMed  Google Scholar 

  15. Holzapfel, G. A., M. Stadler, and C. A. Schulze-Bauer. A layer-specific three-dimensional model for the simulation of balloon angioplasty using magnetic resonance imaging and mechanical testing. Ann. Biomed. Eng. 30:753–767, 2002.

    Article  PubMed  Google Scholar 

  16. Huang, H., R. Virmani, H. Younis, A. P. Burke, R. D. Kamm, and R. T. Lee. The impact of calcification on the biomechanical stability of atherosclerotic plaques. Circulation 103:1051–1056, 2001.

    Article  PubMed  CAS  Google Scholar 

  17. Imoto, K., T. Hiro, T. Fujii, A. Murashige, Y. Fukumoto, G. Hashimoto, T. Okamura, J. Yamada, K. Mori, and M. Matsuzaki. Longitudinal structural determinants of atherosclerotic plaque vulnerability—a computational analysis of stress distribution using vessel models and three-dimensional intravascular ultrasound imaging. J. Am. Coll. Cardiol. 46:1507–1515, 2005.

    Article  PubMed  Google Scholar 

  18. Kajiya, F., K. Tsujioka, Y. Ogasawara, Y. Wada, S. Matsuoka, S. Kanazawa, O. Hiramatsu, S. Tadaoka, M. Goto, and T. Fujiwara. Analysis of flow characteristics in poststenotic regions of the human coronary artery during bypass graft surgery. Circulation 76:1092–1100, 1987.

    Article  PubMed  CAS  Google Scholar 

  19. Libby, P. Molecular bases of the acute coronary syndromes. Circulation 91:2844–2850, 1995.

    Article  PubMed  CAS  Google Scholar 

  20. Liu, B., and D. Tang. Influence of non-Newtonian properties of blood on the wall shear stress in human atherosclerotic right coronary arteries. Mol. Cell. Biomech. 8:73–90, 2011.

    PubMed  Google Scholar 

  21. Lloyd-Jones, D., R. J. Adams, T. M. Brown, M. Carnethon, S. Dai, G. De Simone, T. B. Ferguson, E. Ford, K. Furie, C. Gillespie, A. Go, K. Greenlund, N. Haase, S. Hailpern, P. M. Ho, V. Howard, B. Kissela, S. Kittner, D. Lackland, L. Lisabeth, A. Marelli, M. M. McDermott, J. Meigs, D. Mozaffarian, M. Mussolino, G. Nichol, V. L. Roger, W. Rosamond, R. Sacco, P. Sorlie, T. Thom, S. Wasserthiel-Smoller, N. D. Wong, and J. Wylie-Rosett. Heart disease and stroke statistics—2010 update: a report from the American Heart Association. Circulation 121:e46–e215, 2010.

    Article  PubMed  Google Scholar 

  22. Marques, K. M., H. J. Spruijt, C. Boer, N. Westerhof, C. A. Visser, and F. C. Visser. The diastolic flow-pressure gradient relation in coronary stenoses in humans. J. Am. Coll. Cardiol. 39:1630–1636, 2002.

    Article  PubMed  Google Scholar 

  23. Naghavi, M., P. Libby, E. Falk, S. W. Casscells, S. Litovsky, J. Rumberger, J. J. Badimon, C. Stefanadis, P. Moreno, G. Pasterkamp, Z. Fayad, P. H. Stone, S. Waxman, P. Raggi, M. Madjid, A. Zarrabi, A. Burke, C. Yuan, P. J. Fitzgerald, D. S. Siscovick, C. L. de Korte, M. Aikawa, K. E. Airaksinen, G. Assmann, C. R. Becker, J. H. Chesebro, A. Farb, Z. S. Galis, C. Jackson, I. K. Jang, W. Koenig, R. A. Lodder, K. March, J. Demirovic, M. Navab, S. G. Priori, M. D. Rekhter, R. Bahr, S. M. Grundy, R. Mehran, A. Colombo, E. Boerwinkle, C. Ballantyne, W. Insull, Jr., R. S. Schwartz, R. Vogel, P. W. Serruys, G. K. Hansson, D. P. Faxon, S. Kaul, H. Drexler, P. Greenland, J. E. Muller, R. Virmani, P. M. Ridker, D. P. Zipes, P. K. Shah, and J. T. Willerson. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part II. Circulation 108:1772–1778, 2003.

    Article  PubMed  Google Scholar 

  24. Naghavi, M., P. Libby, E. Falk, S. W. Casscells, S. Litovsky, J. Rumberger, J. J. Badimon, C. Stefanadis, P. Moreno, G. Pasterkamp, Z. Fayad, P. H. Stone, S. Waxman, P. Raggi, M. Madjid, A. Zarrabi, A. Burke, C. Yuan, P. J. Fitzgerald, D. S. Siscovick, C. L. de Korte, M. Aikawa, K. E. Juhani Airaksinen, G. Assmann, C. R. Becker, J. H. Chesebro, A. Farb, Z. S. Galis, C. Jackson, I. K. Jang, W. Koenig, R. A. Lodder, K. March, J. Demirovic, M. Navab, S. G. Priori, M. D. Rekhter, R. Bahr, S. M. Grundy, R. Mehran, A. Colombo, E. Boerwinkle, C. Ballantyne, W. Insull, Jr., R. S. Schwartz, R. Vogel, P. W. Serruys, G. K. Hansson, D. P. Faxon, S. Kaul, H. Drexler, P. Greenland, J. E. Muller, R. Virmani, P. M. Ridker, D. P. Zipes, P. K. Shah, and J. T. Willerson. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation 108:1664–1672, 2003.

    Article  PubMed  Google Scholar 

  25. Richardson, P. D., M. J. Davies, and G. V. R. Born. Influence of Plaque Configuration and Stress Distribution on Fissuring of Coronary Atherosclerotic Plaques. Lancet 2:941–944, 1989.

    Article  PubMed  CAS  Google Scholar 

  26. Rodriguez, J. F., C. Ruiz, M. Doblare, and G. A. Holzapfel. Mechanical stresses in abdominal aortic aneurysms: influence of diameter, asymmetry, and material anisotropy. J. Biomech. Eng. 130:021023, 2008.

    Article  PubMed  Google Scholar 

  27. Saba, L., F. Potters, A. van der Lugt, and G. Mallarini. Imaging of the fibrous cap in atherosclerotic carotid plaque. Cardiovasc. Intervent. Radiol. 33:681–689, 2010.

    Article  PubMed  Google Scholar 

  28. Samady, H., P. Eshtehardi, M. C. McDaniel, J. Suo, S. S. Dhawan, C. Maynard, L. H. Timmins, A. A. Quyyumi, and D. P. Giddens. Coronary artery wall shear stress is associated with progression and transformation of atherosclerotic plaque and arterial remodeling in patients with coronary artery disease. Circulation 124:779–788, 2011.

    Article  PubMed  CAS  Google Scholar 

  29. Sussman, T., and K. J. Bathe. A finite-element formulation for nonlinear incompressible elastic and inelastic analysis. Comput. Struct. 26:357–409, 1987.

    Article  Google Scholar 

  30. Tang, D., C. Yang, S. Kobayashi, and D. N. Ku. Effect of a lipid pool on stress/strain distributions in stenotic arteries: 3-D fluid–structure interactions (FSI) models. J. Biomech. Eng. 126:363–370, 2004.

    Article  PubMed  Google Scholar 

  31. Tang, D., C. Yang, S. Kobayashi, J. Zheng, P. K. Woodard, Z. Teng, K. Billiar, R. Bach, and D. N. Ku. 3D MRI-based anisotropic FSI models with cyclic bending for human coronary atherosclerotic plaque mechanical analysis. J. Biomech. Eng. 131:061010, 2009.

    Article  PubMed  Google Scholar 

  32. Tang, D., C. Yang, H. Walker, S. Kobayashi, and D. N. Ku. Simulating cyclic artery compression using a 3D unsteady model with fluid–structure interactions. Comput. Struct. 80:1651–1665, 2002.

    Article  Google Scholar 

  33. Tang, D., C. Yang, J. Zheng, P. K. Woodard, J. E. Saffitz, J. D. Petruccelli, G. A. Sicard, and C. Yuan. Local maximal stress hypothesis and computational plaque vulnerability index for atherosclerotic plaque assessment. Ann. Biomed. Eng. 33:1789–1801, 2005.

    Article  PubMed  Google Scholar 

  34. Tang, D., C. Yang, J. Zheng, P. K. Woodard, J. E. Saffitz, G. A. Sicard, T. K. Pilgram, and C. Yuan. Quantifying effects of plaque structure and material properties on stress distributions in human atherosclerotic plaques using 3D FSI models. J. Biomech. Eng. 127:1185–1194, 2005.

    Article  PubMed  Google Scholar 

  35. Tang, D., C. Yang, J. Zheng, P. K. Woodard, G. A. Sicard, J. E. Saffitz, and C. Yuan. 3D MRI-based multicomponent FSI models for atherosclerotic plaques. Ann. Biomed. Eng. 32:947–960, 2004.

    Article  PubMed  Google Scholar 

  36. Thim, T., M. K. Hagensen, J. F. Bentzon, and E. Falk. From vulnerable plaque to atherothrombosis. J. Intern. Med. 263:506–516, 2008.

    Article  PubMed  CAS  Google Scholar 

  37. Vengrenyuk, Y., L. Cardoso, and S. Weinbaum. Micro-CT 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 

  38. Vengrenyuk, Y., S. Carlier, S. Xanthos, L. Cardoso, P. Ganatos, R. Virmani, S. Einav, L. Gilchrist, and S. Weinbaum. A hypothesis for vulnerable plaque rupture due to stress-induced debonding around cellular microcalcifications in thin fibrous caps. Proc. Natl Acad. Sci. USA 103:14678–14683, 2006.

    Article  PubMed  CAS  Google Scholar 

  39. Virmani, R., A. P. Burke, A. Farb, and F. D. Kolodgie. Pathology of the unstable plaque. Prog. Cardiovasc. Dis. 44:349–356, 2002.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  41. Virmani, R., A. P. Burke, F. D. Kolodgie, and A. Farb. Pathology of the thin-cap fibroatheroma: a type of vulnerable plaque. J. Intervent. Cardiol. 16:267–272, 2003.

    Article  PubMed  Google Scholar 

  42. Wenk, J. F., P. Papadopoulos, and T. I. Zohdi. Numerical modeling of stress in stenotic arteries with microcalcifications: a micromechanical approximation. J. Biomech. Eng. 132:091011, 2010.

    Article  PubMed  Google Scholar 

  43. Xenos, M., Y. Alemu, D. Zamfir, S. Einav, J. J. Ricotta, N. Labropoulos, A. Tassiopoulos, and D. Bluestein. The effect of angulation in abdominal aortic aneurysms: fluid–structure interaction simulations of idealized geometries. Med. Biol. Eng. Comput. 48:1175–1190, 2010.

    Article  PubMed  Google Scholar 

  44. Xenos, M., S. H. Rambhia, Y. Alemu, S. Einav, N. Labropoulos, A. Tassiopoulos, J. J. Ricotta, and D. Bluestein. Patient-based abdominal aortic aneurysm rupture risk prediction with fluid structure interaction modeling. Ann. Biomed. Eng. 38:3323–3337, 2010.

    Article  PubMed  Google Scholar 

  45. Xenos, M., S. Rambhia, Y. Alemu, S. Einav, J. J. Ricotta, N. Labropoulos, A. Tassiopoulos, and D. Bluestein. Patient based abdominal aortic aneurysm rupture risk prediction combining clinical visualizing modalities with fluid structure interaction numerical simulations. Conf. Proc. IEEE Eng. Med. Biol. Soc. 1:5173–5176, 2010.

    Google Scholar 

  46. Yang, C., R. G. Bach, J. Zheng, I. E. Naqa, P. K. Woodard, Z. Teng, K. Billiar, and D. Tang. In vivo IVUS-based 3-D fluid–structure interaction models with cyclic bending and anisotropic vessel properties for human atherosclerotic coronary plaque mechanical analysis. IEEE Trans. Biomed. Eng. 56:2420–2428, 2009.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Danny Bluestein.

Additional information

Associate Editor Aleksander S. Popel oversaw the review of this article.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PPT 7656 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rambhia, S.H., Liang, X., Xenos, M. et al. Microcalcifications Increase Coronary Vulnerable Plaque Rupture Potential: A Patient-Based Micro-CT Fluid–Structure Interaction Study. Ann Biomed Eng 40, 1443–1454 (2012). https://doi.org/10.1007/s10439-012-0511-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10439-012-0511-x

Keywords

Navigation