Annals of Biomedical Engineering

, Volume 38, Issue 3, pp 738–747 | Cite as

Computational Stress Analysis of Atherosclerotic Plaques in ApoE Knockout Mice

  • Yuliya Vengrenyuk
  • Theodore J. Kaplan
  • Luis Cardoso
  • Gwendalyn J. Randolph
  • Sheldon Weinbaum


The aortic sinus lesions of apolipoprotein E knockout (ApoE KO) mice seldom show any signs of fibrous cap disruption, whereas cap ruptures have been recently reported in the proximal part of their brachiocephalic arteries (BCA). We use histology based finite element analysis to evaluate peak circumferential stresses in aortic and BCA lesions from six 42–56 week-old fat-fed ApoE KO mice. This analysis is able to both explain the greater stability of aortic lesions in mice and provide new insight into the BCA lesion as a model for the stability of human lesions with and without microcalcifications in their fibrous caps. The predicted average peak stress in fibrous caps of aortic lesions of 205.8 kPa is significantly lower than the average value of maximum stresses of 568.8 kPa in BCA caps. The aortic plaque stresses only slightly depend on the cap thickness, while BCA lesions demonstrate an exponential growth of peak cap stresses with decreasing cap thickness similar to human vulnerable plaques. Murine BCA ruptured lesions with mean cap thickness of 2 μm show stresses ≈1400 kPa, three times higher than human ruptured plaques with a mean cap thickness of 23 μm without microcalcifications in the cap, but nearly identical to the peak stress around an elongated microcalcification with aspect ratio 2 in a human thin cap ≈50 μm thick. We predict biomechanical stress patterns in mouse BCA close to human vulnerable plaques without microcalcification in the cap, while aortic lesions show stress tendency similar to stable lesions in human.


Atherosclerosis Plaque rupture Apolipoprotein E Mouse Stress Calcification 


  1. 1.
    Altenburg, M., J. Homeister, H. Doherty, and N. Maeda. Genetics of atherosclerosis in murine models. Curr. Drug Targets 8(11):1161–1171, 2007.CrossRefPubMedGoogle Scholar
  2. 2.
    Bennett, B. J., M. Scatena, E. A. Kirk, M. Rattazzi, R. M. Varon, M. Averill, S. M. Schwartz, C. M. Giachelli, and M. E. Rosenfeld. Osteoprotegerin inactivation accelerates advanced atherosclerotic lesion progression and calcification in older ApoE−/− mice. Arterioscler. Thromb. Vasc. Biol. 26(9):2117–2124, 2006.CrossRefPubMedGoogle Scholar
  3. 3.
    Breslow, J. L. Mouse models of atherosclerosis. Science 272(5262):685–688, 1996.CrossRefPubMedGoogle Scholar
  4. 4.
    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(18):1276–1282, 1997.CrossRefPubMedGoogle Scholar
  5. 5.
    Calara, F., M. Silvestre, F. Casanada, N. Yuan, C. Napoli, and W. Palinski. Spontaneous plaque rupture and secondary thrombosis in apolipoprotein E-deficient and LDL receptor-deficient mice. J. Pathol. 195(2):257–263, 2001.CrossRefPubMedGoogle Scholar
  6. 6.
    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(4):1179–1187, 1993.PubMedGoogle Scholar
  7. 7.
    Cheruvu, P. K., A. V. Finn, C. Gardner, J. Caplan, J. Goldstein, G. W. Stone, R. Virmani, and J. E. Muller. Frequency and distribution of thin-cap fibroatheroma and ruptured plaques in human coronary arteries: a pathologic study. J. Am. Coll. Cardiol. 50(10):940–949, 2007.CrossRefPubMedGoogle Scholar
  8. 8.
    Daugherty, A. Mouse models of atherosclerosis. Am. J. Med. Sci. 323(1):3–10, 2002.CrossRefPubMedGoogle Scholar
  9. 9.
    Finet, G., J. Ohayon, and G. Rioufol. Biomechanical interaction between cap thickness, lipid core composition and blood pressure in vulnerable coronary plaque: impact on stability or instability. Coron. Artery Dis. 15(1):13–20, 2004.CrossRefPubMedGoogle Scholar
  10. 10.
    Glagov, S., E. Weisenberg, C. K. Zarins, R. Stankunavicius, and G. J. Kolettis. Compensatory enlargement of human atherosclerotic coronary arteries. N. Engl. J. Med. 316(22):1371–1375, 1987.PubMedCrossRefGoogle Scholar
  11. 11.
    Glass, C. K., and J. L. Witztum. Atherosclerosis. The road ahead. Cell 104(4):503–516, 2001.CrossRefPubMedGoogle Scholar
  12. 12.
    Greve, J. M., A. S. Les, B. T. Tang, M. T. Draney Blomme, N. M. Wilson, R. L. Dalman, N. J. Pelc, and C. A. Taylor. Allometric scaling of wall shear stress from mice to humans: quantification using cine phase-contrast MRI and computational fluid dynamics. Am. J. Physiol. Heart Circ. Physiol. 291(4):H1700–H1708, 2006.CrossRefPubMedGoogle Scholar
  13. 13.
    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(8):1051–1056, 2001.PubMedGoogle Scholar
  14. 14.
    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(8):1507–1515, 2005.CrossRefPubMedGoogle Scholar
  15. 15.
    Jackson, C. L. Defining and defending murine models of plaque rupture. Arterioscler. Thromb. Vasc. Biol. 27(4):973–977, 2007.CrossRefPubMedGoogle Scholar
  16. 16.
    Jackson, C. L., M. R. Bennett, E. A. Biessen, J. L. Johnson, and R. Krams. Assessment of unstable atherosclerosis in mice. Arterioscler. Thromb. Vasc. Biol. 27(4):714–720, 2007.CrossRefPubMedGoogle Scholar
  17. 17.
    Jin, X., S. Iwasa, K. Okada, A. Ooi, K. Mitsui, and M. Mitsumata. Shear stress-induced collagen XII expression is associated with atherogenesis. Biochem. Biophys. Res. Commun. 308(1):152–158, 2003.CrossRefPubMedGoogle Scholar
  18. 18.
    Johnson, J., K. Carson, H. Williams, S. Karanam, A. Newby, G. Angelini, S. George, and C. Jackson. Plaque rupture after short periods of fat feeding in the apolipoprotein E-knockout mouse: model characterization and effects of pravastatin treatment. Circulation 111(11):1422–1430, 2005.CrossRefPubMedGoogle Scholar
  19. 19.
    Johnson, J. L., and C. L. Jackson. Atherosclerotic plaque rupture in the apolipoprotein E knockout mouse. Atherosclerosis 154(2):399–406, 2001.CrossRefPubMedGoogle Scholar
  20. 20.
    Kolodgie, F. D., A. P. Burke, A. Farb, H. K. Gold, J. Yuan, J. Narula, A. V. Finn, and R. Virmani. The thin-cap fibroatheroma: a type of vulnerable plaque: the major precursor lesion to acute coronary syndromes. Curr. Opin. Cardiol. 16(5):285–292, 2001.CrossRefPubMedGoogle Scholar
  21. 21.
    Loree, H. M., R. D. Kamm, R. G. Stringfellow, and R. T. Lee. Effects of fibrous cap thickness on peak circumferential stress in model atherosclerotic vessels. Circ. Res. 71(4):850–858, 1992.PubMedGoogle Scholar
  22. 22.
    Nakashima, Y., A. S. Plump, E. W. Raines, J. L. Breslow, and R. Ross. ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler. Thromb. 14(1):133–140, 1994.PubMedGoogle Scholar
  23. 23.
    Ohayon, J., G. Finet, A. M. Gharib, D. A. Herzka, P. Tracqui, J. Heroux, G. Rioufol, M. S. Kotys, A. Elagha, and R. I. Pettigrew. Necrotic core thickness and positive arterial remodeling index: emergent biomechanical factors for evaluating the risk of plaque rupture. Am. J. Physiol. Heart Circ. Physiol. 295(2):H717–H727, 2008.CrossRefPubMedGoogle Scholar
  24. 24.
    Plump, A. S., J. D. Smith, T. Hayek, K. Aalto-Setala, A. Walsh, J. G. Verstuyft, E. M. Rubin, and J. L. Breslow. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell 71(2):343–353, 1992.CrossRefPubMedGoogle Scholar
  25. 25.
    Rattazzi, M., B. J. Bennett, F. Bea, E. A. Kirk, J. L. Ricks, M. Speer, S. M. Schwartz, C. M. Giachelli, and M. E. Rosenfeld. Calcification of advanced atherosclerotic lesions in the innominate arteries of ApoE-deficient mice: potential role of chondrocyte-like cells. Arterioscler. Thromb. Vasc. Biol. 25(7):1420–1425, 2005.CrossRefPubMedGoogle Scholar
  26. 26.
    Reddick, R. L., S. H. Zhang, and N. Maeda. Atherosclerosis in mice lacking apo E. Evaluation of lesional development and progression. Arterioscler. Thromb. 14(1):141–147, 1994.PubMedGoogle Scholar
  27. 27.
    Richardson, P. D., M. J. Davies, and G. V. Born. Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques. Lancet 2(8669):941–944, 1989.CrossRefPubMedGoogle Scholar
  28. 28.
    Rosenfeld, M. E., P. Polinsky, R. Virmani, K. Kauser, G. Rubanyi, and S. M. Schwartz. Advanced atherosclerotic lesions in the innominate artery of the ApoE knockout mouse. Arterioscler. Thromb. Vasc. Biol. 20(12):2587–2592, 2000.PubMedGoogle Scholar
  29. 29.
    Schoenhagen, P., K. M. Ziada, S. R. Kapadia, T. D. Crowe, S. E. Nissen, and E. M. Tuzcu. Extent and direction of arterial remodeling in stable versus unstable coronary syndromes: an intravascular ultrasound study. Circulation 101(6):598–603, 2000.PubMedGoogle Scholar
  30. 30.
    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(12):1789–1801, 2005.CrossRefPubMedGoogle Scholar
  31. 31.
    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(7):947–960, 2004.CrossRefPubMedGoogle Scholar
  32. 32.
    Varnava, A. M., P. G. Mills, and M. J. Davies. Relationship between coronary artery remodeling and plaque vulnerability. Circulation 105(8):939–943, 2002.CrossRefPubMedGoogle Scholar
  33. 33.
    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(1):37–47, 2008.PubMedGoogle Scholar
  34. 34.
    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(40):14678–14683, 2006.CrossRefPubMedGoogle Scholar
  35. 35.
    Virmani, R., A. P. Burke, F. D. Kolodgie, and A. Farb. Pathology of the thin-cap fibroatheroma: a type of vulnerable plaque. J. Interv. Cardiol. 16(3):267–272, 2003.CrossRefPubMedGoogle Scholar
  36. 36.
    Virmani, R., F. D. Kolodgie, A. P. Burke, A. Farb, and S. M. Schwartz. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler. Thromb. Vasc. Biol. 20(5):1262–1275, 2000.PubMedGoogle Scholar
  37. 37.
    Williams, H., J. L. Johnson, K. G. Carson, and C. L. Jackson. Characteristics of intact and ruptured atherosclerotic plaques in brachiocephalic arteries of apolipoprotein E knockout mice. Arterioscler. Thromb. Vasc. Biol. 22(5):788–792, 2002.CrossRefPubMedGoogle Scholar
  38. 38.
    Zhang, S. H., R. L. Reddick, J. A. Piedrahita, and N. Maeda. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science 258(5081):468–471, 1992.CrossRefPubMedGoogle Scholar

Copyright information

© Biomedical Engineering Society 2010

Authors and Affiliations

  • Yuliya Vengrenyuk
    • 1
  • Theodore J. Kaplan
    • 2
  • Luis Cardoso
    • 1
  • Gwendalyn J. Randolph
    • 2
  • Sheldon Weinbaum
    • 1
    • 3
  1. 1.Department of Biomedical EngineeringThe City College of New York, CUNYNew YorkUSA
  2. 2.Department of Gene and Cell MedicineMount Sinai School of MedicineNew YorkUSA
  3. 3.Department of Mechanical EngineeringThe City College of New York, CUNYNew YorkUSA

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