Annals of Biomedical Engineering

, Volume 40, Issue 7, pp 1443–1454 | Cite as

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

  • S. H. Rambhia
  • X. Liang
  • M. Xenos
  • Y. Alemu
  • N. Maldonado
  • A. Kelly
  • S. Chakraborti
  • S. Weinbaum
  • L. Cardoso
  • S. Einav
  • Danny Bluestein
Article

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.

Keywords

Coronary vulnerable plaque Fluid–structure interaction Microcalcification Fibrous cap Micro-CT 

Supplementary material

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Supplementary material 1 (PPT 7656 kb)

References

  1. 1.
    ADINA. ADINA Manual, Theory and Modeling Guide: ARD 09-7, 2009.Google Scholar
  2. 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.PubMedGoogle Scholar
  3. 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.PubMedCrossRefGoogle Scholar
  4. 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.PubMedCrossRefGoogle Scholar
  5. 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.PubMedCrossRefGoogle Scholar
  6. 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.PubMedCrossRefGoogle Scholar
  7. 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.PubMedCrossRefGoogle Scholar
  8. 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.PubMedCrossRefGoogle Scholar
  9. 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.PubMedCrossRefGoogle Scholar
  10. 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.CrossRefGoogle Scholar
  11. 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. 12.
    Holzapfel, G. A. Nonlinear Solid Mechanics: A Continuum Approach for Engineering. New York: Wiley, 2000.Google Scholar
  13. 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.PubMedCrossRefGoogle Scholar
  14. 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.PubMedCrossRefGoogle Scholar
  15. 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.PubMedCrossRefGoogle Scholar
  16. 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.PubMedCrossRefGoogle Scholar
  17. 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.PubMedCrossRefGoogle Scholar
  18. 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.PubMedCrossRefGoogle Scholar
  19. 19.
    Libby, P. Molecular bases of the acute coronary syndromes. Circulation 91:2844–2850, 1995.PubMedCrossRefGoogle Scholar
  20. 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.PubMedGoogle Scholar
  21. 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.PubMedCrossRefGoogle Scholar
  22. 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.PubMedCrossRefGoogle Scholar
  23. 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.PubMedCrossRefGoogle Scholar
  24. 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.PubMedCrossRefGoogle Scholar
  25. 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.PubMedCrossRefGoogle Scholar
  26. 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.PubMedCrossRefGoogle Scholar
  27. 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.PubMedCrossRefGoogle Scholar
  28. 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.PubMedCrossRefGoogle Scholar
  29. 29.
    Sussman, T., and K. J. Bathe. A finite-element formulation for nonlinear incompressible elastic and inelastic analysis. Comput. Struct. 26:357–409, 1987.CrossRefGoogle Scholar
  30. 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.PubMedCrossRefGoogle Scholar
  31. 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.PubMedCrossRefGoogle Scholar
  32. 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.CrossRefGoogle Scholar
  33. 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.PubMedCrossRefGoogle Scholar
  34. 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.PubMedCrossRefGoogle Scholar
  35. 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.PubMedCrossRefGoogle Scholar
  36. 36.
    Thim, T., M. K. Hagensen, J. F. Bentzon, and E. Falk. From vulnerable plaque to atherothrombosis. J. Intern. Med. 263:506–516, 2008.PubMedCrossRefGoogle Scholar
  37. 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.PubMedGoogle Scholar
  38. 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.PubMedCrossRefGoogle Scholar
  39. 39.
    Virmani, R., A. P. Burke, A. Farb, and F. D. Kolodgie. Pathology of the unstable plaque. Prog. Cardiovasc. Dis. 44:349–356, 2002.PubMedCrossRefGoogle Scholar
  40. 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.PubMedCrossRefGoogle Scholar
  41. 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.PubMedCrossRefGoogle Scholar
  42. 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.PubMedCrossRefGoogle Scholar
  43. 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.PubMedCrossRefGoogle Scholar
  44. 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.PubMedCrossRefGoogle Scholar
  45. 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. 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.PubMedCrossRefGoogle Scholar

Copyright information

© Biomedical Engineering Society 2012

Authors and Affiliations

  • S. H. Rambhia
    • 1
    • 2
  • X. Liang
    • 1
  • M. Xenos
    • 1
  • Y. Alemu
    • 1
  • N. Maldonado
    • 3
  • A. Kelly
    • 3
  • S. Chakraborti
    • 3
  • S. Weinbaum
    • 3
  • L. Cardoso
    • 3
  • S. Einav
    • 1
    • 3
  • Danny Bluestein
    • 1
  1. 1.Department of Biomedical EngineeringStony Brook UniversityStony BrookUSA
  2. 2.School of Medicine, Stony Brook UniversityStony BrookUSA
  3. 3.Department of Biomedical EngineeringThe City College of the City University of New YorkNew YorkUSA

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