Skip to main content
SpringerLink
Log in

Integrative Models for Understanding the Structural Basis of Regional Mechanical Dysfunction in Ischemic Myocardium

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

Abstract

Myocardial ischemia and many other cardiac pathologies are associated with regional ventricular dysfunction. Since the distributions of stress and material properties cannot be measured directly in intact myocardium, understanding how regional alterations in myocardial strain or segment function are related to underlying cellular dysfunction must be deduced from theoretical models. Here, we describe how anatomically detailed, three-dimensional computational models can be used in conjunction with experimental or clinical studies to elucidate the structural basis of regional dysfunction in acutely ischemic and ischemic-reperfused (“stunned”) myocardium in vivo. Integrative experimental and computational analysis shows that: (1) in acutely ischemic myocardium, the transition from abnormal systolic strain in the ischemic region to normal shortening in adjacent, normally perfused tissue is governed primarily by systolic blood pressure and regional fiber orientation rather than the geometry of the perfusion boundary; and (2) in stunned myocardium, the degree of reperfusion injury to the contractile apparatus may be uniform across the wall thickness despite observations that the extent of ischemia and the impairment of regional strain during reperfusion are both significantly greater in the subendocardium. © 2000 Biomedical Engineering Society.

PAC00: 8719Hh, 8719Uv, 8719Ff, 8719Rr, 8710+e

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. Allen, D. G., and C. H. Orchard. Myocardial contractile func-tion during ischemia and hypoxia. Circ.Res. 60:153–168, 1987.

    Google Scholar 

  2. Armour, A. J. Myocardial ischaemia and the cardiac nervous system. Cardiovasc.Res. 41:41–54, 1999.

    Google Scholar 

  3. Bogen, D. K., S. A. Rabinowitz, A. Needleman, T. A. Mc-Mahon, and W. H. Abelmann. An analysis of the mechanical disadvantage of myocardial infarction in the canine left ven-tricle. Circ.Res. 47:728–741, 1980.

    Google Scholar 

  4. Bolli, R. Mechanism of myocardial “stunning.” Circulation 82:723–738, 1990.

    Google Scholar 

  5. Bolli, R., B. S. Patel, C. J. Hartley, J. I. Thornby, M. O. Jeroudi, and R. Roberts. Nonuniform transmural recovery of contractile function in stunned myocardium. Am.J.Physiol. 257:H375–H385, 1989.

    Google Scholar 

  6. Bolli, R., W.-X. Zhu, J. I. Thornby, R. G. O'Neill, and R. Roberts. Time course and determinants of recovery function after reversible ischemia in conscious dogs. Am.J.Physiol. 254:H102–H114, 1988.

    Google Scholar 

  7. Bovendeerd, P. H. M., T. Arts, T. Delhaas, J. H. Huyghe, D. H. Van Campen, and R. S. Reneman. Regional wall mechan-ics in the ischemic left ventricle: Numerical modeling and dog experiments. Am.J.Physiol. 270:H398–H410, 1996.

    Google Scholar 

  8. Bradley, C. P., A. J. Pullan, and P. J. Hunter. Geometric modeling of the human torso using cubic Hermite elements. Ann.Biomed.Eng. 25:96–111, 1997.

    Google Scholar 

  9. Braunwald, E., and R. A. Kloner. The stunned myocardium: Prolonged, postischemic ventricular dysfunction. Circulation 66:1146–1149, 1982.

    Google Scholar 

  10. Canty, Jr., J. M.. Coronary pressure–function and steady-state pressure–flow relations during autoregulation in the unanesthetized dog. Circ.Res. 63:821–36, 1988.

    Google Scholar 

  11. Charnley, R. H., S. Takahashi, M. Zhao, E. H. Sonnenblick, and C. Eng. Collagen loss in the stunned mycardium. Circu-lation 85:1483–1490, 1992.

    Google Scholar 

  12. Costa, K. D., P. J. Hunter, J. M. Rogers, J.M. Guccione, L. K. Waldman, and A. D. McCulloch. A three-dimensional finite-element method for large elastic deformation of ven-tricular myocardium: II-prolate spheroidal coordinates. J.Biomech.Eng. 118:464–472, 1996.

    Google Scholar 

  13. Downey, J. M., H. F. Downey, and E. S. Kirk. Effects of myocardial strains on coronary blood flow. Circ.Res. 34:286–292, 1974.

    Google Scholar 

  14. Edwards, N. C., A. J. Sinusas, J. D. Bergin, D. D. Watson, M. Ruiz, and G. A. Beller. Influence of subendocardial is-chemia on transmural myocardial function. Am.J.Physiol. 262:H568–H576, 1992.

    Google Scholar 

  15. Ehring, T., J. D. Schipke, S. Rainer, and G. Heusch. Diastolic dysfunction of stunned myocardium. Am.J.Cardiovasc.Path. 4:358–366, 1993.

    Google Scholar 

  16. Elbeery, J. R., R. F. Williams, J. S. Rankin, D. D. Glower, D.C. Sabiston, Jr., and P. Van Trigt. Effects of arterial hyper-tension on myocardial recovery after ischemic injury. Am.J.Physiol. 263:H559–H564, 1992.

    Google Scholar 

  17. Emery, J. L., J. H. Omens, and A. D. McCulloch. Biaxial mechanics of the passively overstretched left ventricle. Am.J.Physiol. 272:H2299–H2305, 1997.

    Google Scholar 

  18. Gallagher, K. P., R. A. Gerren, M. Choy, M. C. Stirling, and R. C. Dysko. Subendocardial segment length shortening at lateral margin of ischemic myocardium in dogs. Am.J.Physiol. 253:H826–H837, 1987.

    Google Scholar 

  19. Gallagher, K. P., R. A. Gerren, M. C. Stirling, M. Choy, R. C. Dysko, S. P. McManimon, and W. R. Dunham. The dis-tribution of functional impairment across the lateral border of acutely ischemic myocardium. Circ.Res. 58:570–583, 1986.

    Google Scholar 

  20. Gallagher, K. P., T. Kumada, J. A. Koziol, M. D. McKown, W. S. Kemper, and J. J. Ross. Significance of regional wall thickening abnormalities relative to transmural myocardial perfusion in anesthetized dogs. Circulation 62:1266–1274, 1980.

    Google Scholar 

  21. Gallagher, K. P., M. Matsuzaki, J. A. Koziol, W. S. Kemper, and J. J. Ross. Regional myocardial perfusion and wall thick-ening during ischemia in conscious dogs. Am.J.Physiol. 16: H727–738, 1984.

    Google Scholar 

  22. Gallagher, K. P., T. B. McClanahan, M. J. Lynch, S. F. Bolling, and W. R. Dunham. Occlusion of the left anterior descending artery produces a larger functional border zone than circumflex occlusion. Circulation 60th Scientific Session: IV–373, 1987.

  23. Gallagher, K. P., X.-H. Ning, R. A. Gerren, D. H. Drake, and W. R. Dunham. Effects of aortic constriction on the func-tional border zone. Am.J.Physiol. 252:H826–H835, 1987.

    Google Scholar 

  24. Gao, W. D., D. Atar, P. H. Backx, and E. Marban. Relation-ship between intracellular calcium and contractile force in stunned myocardium. Circ.Res. 76:1036–1048, 1995.

    Google Scholar 

  25. Gao, W. D., D. Atar, Y. Liu, N. G. Perez, A. M. Murphy, and E. Marban. Role of troponin I proteolysis in the patho-genesis of stunned myocardium. Circ.Res. 80:393–399, 1997.

    Google Scholar 

  26. Gao, W. D., Y. Liu, and E. Marban. Selective effects of oxygen free radicals on excitation–contraction coupling in ventricular muscle. Circulation 94:2597–2604, 1996.

    Google Scholar 

  27. Gao, W. D., Y. Liu, R. Mellgren, and E. Marban. Intrinsic myofilament alterations underlying the decreased contractility of stunned myocardium. Circ.Res. 78:455–465, 1996.

    Google Scholar 

  28. Gotot, Y., H. Suga, O. Yamada, Y. Igarashi, M. Saito, and K. Hiramori. Left ventricular regional work from wall tension-area loop in canine heart. Am.J.Physiol. 250:H151–H158, 1986.

    Google Scholar 

  29. Grossman, W.. Cardiac hypertrophy: useful adaptation or pathologic process? Am.J.Med. 69: 576–583, 1980.

    Google Scholar 

  30. Guccione, J. M., K. D. Costa, and A. D. McCulloch. Finite-element stress analysis of left ventricular mechanics in the beating dog heart. J.Biomech. 28:1167–1177, 1995.

    Google Scholar 

  31. Guccione, J. M., A. D. McCulloch, and L. K. Waldman. Passive material properties of intact ventricular myocardium determined from a cylindrical model. J.Biomech.Eng. 113:42–55, 1991.

    Google Scholar 

  32. Guth, B. D., F. C. White, K. P. Gallagher, and C. M. Bloor. Passive material properties of intact ventricular myocardium determined from a cylindrical model. Am.Heart J. 107:458–464, 1984.

    Google Scholar 

  33. Hampton, T. G., I. Amende, K. E. Travers, and J. P. Morgan. Intracellular calcium dynamics in mouse model of myocar-dial stunning. Am.J.Physiol. 274:H1821–H1827, 1998.

    Google Scholar 

  34. Hashima, A. R., A. A. Young, A. D. McCulloch, and L. K. Waldman. Nonhomogeneous analysis of epicardial strain distributions during acute myocardial ischemia in the dog. J.Biomech. 26:19–35, 1993.

    Google Scholar 

  35. Hearse, D. J.. Reperfusion of the ischemic myocardium. J.Mol.Cell.Cardiol. 9:605–615, 1977.

    Google Scholar 

  36. Hearse, D. J., C. A. Muller, M. Fukanami, Y. Kudoh, L. H. Opie, and D. M. Yellon. Regional myocardial ischemia: char-acterization of temporal, transmural and lateral flow inter-faces in the porcine heart. Can.J.Cardiol. 2:48–61, 1986.

    Google Scholar 

  37. Heyndrickx, G. R., H. Baig, P. Nellens, I. Leusen, M. C. Fishbein, and S. F. Vatner. Depression of regional blood flow and wall thickening after brief coronary occlusion. Am.J.Physiol. 234:H653–H659, 1978.

    Google Scholar 

  38. Hoit, B. D., and W. Y. W. Lew. Functional consequences of acute anterior versus posterior wall ischemia in canine left ventricle. Am.J.Physiol. 254:H1065–H1073, 1988.

    Google Scholar 

  39. Huisman, R. M., G. Elzinga, N. Westerhof, and P. Sipkema. Measurement of left ventricular wall stress. Cardiovasc.Res. 14:142–153, 1980.

    Google Scholar 

  40. Hunter, P. J., A. D. McCulloch, and H. E. D. J. ter Keurs. Modeling the mechanical properties of cardiac muscle. Prog.Biophys.Mol.Biol. 69:289–331, 1998.

    Google Scholar 

  41. Kerber, R. E., M. L. Marcus, J. Ehrhardt, R. Wilson, and F.M. Abboud. Correlation between echocardiographically dem-onstrated segmental dyskinesis and regional myocardial per-fusion. Circulation 52:1097–1104, 1975.

    Google Scholar 

  42. Kloner, R. A., R. Bolli, E. Marban, L. Reinlib, and E. Braun-wald. Participants. Medical and cellular implication of stun-ning, hibernation, and preconditioning–An NHLBI workshop Circulation 97:1848–1867, 1998.

    Google Scholar 

  43. Kusuoka, H., Y. Koretsune, V. P. Chacko, M. L. Weisfeldt, and E. Marban. Excitation–contraction coupling in postischemic myocardium. Does failure of activator Ca2+ transients underlie stunning? Circ.Res. 66:1268–1276, 1990.

    Google Scholar 

  44. Kusuoka, H., and E. Marban. Cellular mechanisms of myocardial stunning. Annu.Rev.Physiol. 54:243–256, 1992.

    Google Scholar 

  45. Lew, W. Y. W., Z. Chen, B. Guth, and J. W. Covell. Mecha-nisms of augmented segment shortening in nonischemic area during acute ischemia of the canine left ventricle. Circ.Res. 56:351–358, 1985.

    Google Scholar 

  46. Lew, W. Y. W., and M. M. LeWinter. In: Acute Myocardial Infarction: Pathophysiology. Cardiology, Vol. 7, edited by W. W. Parmley and K. Chatterjee. (Philadelphia, PA: Lip-pincott; 1991), pp. 112–133.

    Google Scholar 

  47. Lima, J. A., L. C. Becker, J. A. Melin, S. Lima, C. A. Kallman, M. L. Weisfeldt, and J. L. Weiss. Impaired thick-ening of nonischemic myocardium during acute regional is-chemia in the dog. Circulation 71:1048–59, 1985.

    Google Scholar 

  48. Lin, D. H. S., and F. C. P. Yin. A multiaxial constitutive law for mammalian left ventricular myocardium in steady-state barium contracture or tetanus. J.Biomech.Eng. 120: 504–517, 1998.

    Google Scholar 

  49. Longhurst, J. C. Cardiac receptors: Their function in health and disease. Prog.Cardiovasc.Dis. 27:201–222, 1984.

    Google Scholar 

  50. MacKenna, D. A., J. H. Omens, A. D. McCulloch, and J. W. Covell. Contribution of collagen matrix to passive left ven-tricular mechanics in isolated rat hearts. Am.J.Physiol. 266:H1007–H1018, 1994.

    Google Scholar 

  51. Malliani, A., M. Pagani, P. Pizzinelli, R. Furlan, and S. Guzzetti. Cardiovascular reflexes mediated by sympathetic afferent fibers. J.Auton.Nerv.Syst. 7:295–301, 1983.

    Google Scholar 

  52. Mazhari, R. In: Regional flow–function relations during acute myocardial ischemia and reperfusion. PhD. Thesis. La Jolla, CA: UC San Diego, 1999.

    Google Scholar 

  53. Mazhari, R., and A. McCulloch. Three-dimensional mechan-ics of myocardial contraction: Mechanisms of transverse sys-tolic stress. Proc. of ASME 4th Summer Bioeng. Conf. BED, 1999, Vol. 4, pp. 43–44.

    Google Scholar 

  54. Mazhari, R., J. H. Omens, L. K. Waldman, and A. D. Mc-Culloch. Regional myocardial perfusion and mechanics: a model-based method of analysis. Ann.Biomed.Eng. 26:743–755, 1998.

    Google Scholar 

  55. McCulloch, A. D., D. Sung, J. M. Wilson, R. S. Pavelec, and J. H. Omens. Flow–function relations during graded coronary occlusions in the dog: effects of transmural location and segment orientation. Cardiovasc.Res. 37:636–645, 1998.

    Google Scholar 

  56. Murdock, Jr., R. H., D. M. Harlan, J. J. Morris, III, W. W. Pryor, Jr., and F. R. Cobb. Transitional blood flow zones between ischemic and nonischemic myocardium in the awake dog: Analysis based on distribution of the intramural vascu-lature. Circ.Res. 52:451–459, 1983.

    Google Scholar 

  57. Nielsen, P. M. F., I. J. LeGrice, B. H. Smaill, and P. J. Hunter. Mathematical model of geometry and fibrous struc-ture of the heart. Am.J.Physiol. 260:H1365–H1378, 1991.

    Google Scholar 

  58. Opie, L. H. The Heart. Physiology, from Cell to Circulation, 3rd ed. New York: Lippincott–Raven, 1997.

    Google Scholar 

  59. Parmley, W. W., L. Chuck, C. Kovowitz, J. M. Matloff, and J. C. Swan. In vitro length–tension relations of human ven-tricular aneurysms: Relation of stiffness to myocardial disad-vantage. Am.J.Cardiol. 32:889–894, 1973.

    Google Scholar 

  60. Pinzen, F. W., T. Arts, A. P. G. Hoeks, and R. S. Reneman. Discrepancies between myocardial blood flow and fiber shortening in the ischemic border zone as assessed with video mapping of epicardial deformation. Eur.J.Physiol. 415:220–229, 1989.

    Google Scholar 

  61. Prinzen, F. W., T. Arts, G. J. Van Der Vusse, and R. S. Reneman. Fiber shortening in the inner layers of the left venticular wall as assessed from epicardial deformation dur-ing normoxia and ischemia. J.Biomech. 17:801–812, 1984.

    Google Scholar 

  62. Przyklenk, K., and R. A. Kloner. What factors predict recov-ery of contractile function in the canine model of stunned myocardium? Am.J.Cardiol. 64:18F–26F, 1989.

    Google Scholar 

  63. Pzyklenk, K., B. Patel, and R. A. Kloner. Diastolic abnor-malities of postischemic “stunned” myocardium. Am.J.Cardiol. 60:1211–1213, 1987.

    Google Scholar 

  64. Ross, J. J. Myocardial perfusion-contraction matching. Cir-culation 83:1076–1083, 1991.

    Google Scholar 

  65. Rynning, S. E., E. Hexeberg, S. Birkeland, J. Westby, I. Hessevik, and K. Grong. Nonuniform recovery of perfor-mance in stunned myocardium evaluated by two-dimensional sonomicrometry. Acta Physiol.Scand. 149:441–449, 1993.

    Google Scholar 

  66. Sakai, K., K. Watanabe, and R. W. Millard. Defining the mechanical border zone: a study in the pig heart. Am.J.Physiol. 249:H88–H94, 1985.

    Google Scholar 

  67. Streeter, D. D. J., and W. T. Hanna. Engineering mechanics for successive states in canine left ventricular myocardium-II. Fiber angle and sarcomere length. Circ.Res. 33:656–664, 1973.

    Google Scholar 

  68. Stuyvers, B. D., M. Miura, and H. E. ter Keurs. Dynamics of viscoelastic properties of rat cardiac sarcomeres during the diastolic interval: Involvement of Ca2+. J.Physiol. 502:661–677, 1997.

    Google Scholar 

  69. Tennant, R., and C. J. Wiggers. The effect of coronary oc-clusion on myocardial contraction. Am.J.Physiol. 112:351–361, 1935.

    Google Scholar 

  70. Thames, M. D., M. E. Dibner-Dunlap, A. J. Minisi, and T. Kinugawa. Reflexes mediated by cardiac sympathetic affer-ents during myocardial ischaemia: role of adenosine. Clin.Exp.Pharm.Physiol. 23:709–714, 1996.

    Google Scholar 

  71. Torry, R. J., J. H. Myers, A. L. Adler, C. L. Liu, and K. P. Gallagher. Effects of nontransmural ischemia on inner and outer wall thickening in the canine left ventricle. Am.Heart J. 122:1292–1299, 1991.

    Google Scholar 

  72. Tyberg, J. V., J. S. Forrester, H. L. Wyatt, S. J. Goldner, W. W. Parmely, and H. J. C. Swan. An analysis of segmental ischemic dysfunction utilizing the pressure–length loop. Cir-culation 49:748–754, 1974.

    Google Scholar 

  73. Tyberg, J. V., W. W. Parmely, and E. H. Sonnenblick. In vitro studies of myocardial asynchrony and regional hypoxia. Circ.Res. 25:569–579, 1969.

    Google Scholar 

  74. Van Eyk, J. E., F. Powers, W. Law, C. Larue, R. S. Hodges, and R. J. Solaro. Breakdown of myofilament proteins during ischemia/reperfusion in rat hearts—Identification of degrada-tion products and effects on the pCa-force relation. Circ.Res. 82:261–271, 1998.

    Google Scholar 

  75. Van Leuven, S. L., L. K. Waldman, A. D. McCulloch, and J. W. Covell. Gradients of epicardial strain across the perfusion boundary during acute myocardial ischemia. Am.J.Physiol. 267:H2348–H2362, 1994.

    Google Scholar 

  76. Vatner, S. F. Correlation between acute reductions in myo-cardial blood flow and function in conscious dogs. Circ.Res. 47:201–7, 1980.

    Google Scholar 

  77. Villarreal, F. J., W. Y. Lew, L. K. Waldman, and J. W. Covell. Transmural myocardial deformation in the ischemic canine left ventricle. Circ.Res. 68:368–81, 1991.

    Google Scholar 

  78. Weintraub, W. S., S. Hattori, J. B. Agarwal, M. M. Beden-heimer, V. S. Banka, and R. H. Helfant. The relationship between myocardial blood flow and contraction by myocar-dial layer in the canine left ventricle during ischemia. Circ.Res. 48:430–438, 1981.

    Google Scholar 

  79. Weisman, H. F., and B. Healy. Myocardial infarct expansion, infarct extension, and reinfarction: pathophysiologic con-cepts. Prog.Cardiovasc.Dis. 30:73–110, 1987.

    Google Scholar 

  80. Westerhof, N., P. Sipkema, and M. A. Vis. How cardiac contraction affects the coronary vasculature. Adv.Exp.Med.Biol. 430:111–121, 1997.

    Google Scholar 

  81. Whittaker, P., D. R. Boughner, R. A. Kloner, and K. Przyklenk. Stunned myocardium and myocardial collagen damage: Differential effects of single and repeated occlu-sions. Am.Heart J. 121:434–441, 1991.

    Google Scholar 

  82. Weigner, A. W., G. J. Allen, and O. H. L. Bing. Weak and strong myocardium in series: implication for segmental dys-function. Am.J.Physiol. 4:H776–H783, 1978.

    Google Scholar 

  83. Wijns, W., P. W. Serruys, C. J. Slager, J. Grimm, H. P. Krayenbuehl, P. G. Hugenholtz, and O. M. Hess. Effect of coronary occlusion during percutaneous transluminal angio-plasty in humans on left ventricular chamber stiffness and regional diastolic pressure–radius relations. J.Am.Coll.Car-diol. 7:455–463, 1986.

  84. Wyatt, H. L., J. S. Forrester, P. L. da Luz, G. A. Diamond, R. Chagrasulis, and H. J. C. Swan. Functional abnormalities in nonoccluded regions of myocardium after experimental coronary occlusion. Am.J.Cardiol. 37:366–372, 1976.

    Google Scholar 

  85. Yellon, D. M., D. J. Hearse, R. Crome, J. Grannell, and R. K. Wyse. Characterization of the lateral interface between nor-mal and ischemic tissue in the canine heart during evolving myocardial infarction. Am.J.Cardiol. 47:1233–1239, 1981.

    Google Scholar 

  86. Yin, F. C. P. Ventricular wall stress. Circ.Res. 49:829–842, 1981.

    Google Scholar 

  87. Young, A. A., and L. Axel. Three-dimensional motion and deformation of heart wall: Estimation with spatial modulation of magnetization—a model-based approach. Radiology 185:241–247, 1992.

    Google Scholar 

  88. Zhao, M., H. Zhang, T. F. Robinson, S. M. Factor, E. H. Sonnenblick, and C. Eng. Profound structural alterations of the extracellular collagen matrix on postischemic dysfunc-tional (“stunned”) but viable myocardium. J.Am.Coll.Car-diol. 10:1322–1334, 1987.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Bioengineering, The Whitaker Institute for Biomedical Engineering, University of California, San Diego, La Jolla, CA

    Reza Mazhari & Andrew D. McCulloch

Authors
  1. Reza Mazhari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew D. McCulloch
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mazhari, R., McCulloch, A.D. Integrative Models for Understanding the Structural Basis of Regional Mechanical Dysfunction in Ischemic Myocardium. Annals of Biomedical Engineering 28, 979–990 (2000). https://doi.org/10.1114/1.1308502

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1114/1.1308502

Search

Navigation