Advertisement

The Journal of Physiological Sciences

, Volume 68, Issue 4, pp 387–413 | Cite as

Transmural cellular heterogeneity in myocardial electromechanics

  • Anastasia KhokhlovaEmail author
  • Nathalie Balakina-Vikulova
  • Leonid Katsnelson
  • Gentaro Iribe
  • Olga Solovyova
Original Paper

Abstract

Myocardial heterogeneity is an attribute of the normal heart. We have developed integrative models of cardiomyocytes from the subendocardial (ENDO) and subepicardial (EPI) ventricular regions that take into account experimental data on specific regional features of intracellular electromechanical coupling in the guinea pig heart. The models adequately simulate experimental data on the differences in the action potential and contraction between the ENDO and EPI cells. The modeling results predict that heterogeneity in the parameters of calcium handling and myofilament mechanics in isolated ENDO and EPI cardiomyocytes are essential to produce the differences in Ca2+ transients and contraction profiles via cooperative mechanisms of mechano-calcium-electric feedback and may further slightly modulate transmural differences in the electrical properties between the cells. Simulation results predict that ENDO cells have greater sensitivity to changes in the mechanical load than EPI cells. These data are important for understanding the behavior of cardiomyocytes in the intact heart.

Keywords

Cardiac transmural heterogeneity Electromechanical coupling Mechano-calcium-electric feedback Cardiac modeling Cardiomyocyte 

Notes

Acknowledgments

This work was supported by RF Government Resolution #211 of March 16, 2013 and Program of the RAS Presidium #I.33П.

Author contributions

AK, NB-V: conception of the mathematical models, computational simulations, design, analysis and interpretation of the computational experiments. LK, OS: conception of the mathematical models, design, analysis and interpretation of the computational experiments. GI: analysis and interpretation of the computational experiments. The manuscript was written by AK and OS, with the assistance of NB-V, LK, GI. All authors approved the final version of the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest related to this study.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

References

  1. 1.
    Osadchii OE, Soltysinska E, Olesen SP (2011) Na+ channel distribution and electrophysiological heterogeneities in guinea pig ventricular wall. Am J Physiol Heart Circ Physiol 300(3):H989–H1002PubMedCrossRefGoogle Scholar
  2. 2.
    Nerbonne JM, Guo W (2002) Heterogeneous expression of voltage-gated potassium channels in the heart: roles in normal excitation and arrhythmias. J Cardiovasc Electrophysiol 13(4):406–409PubMedCrossRefGoogle Scholar
  3. 3.
    Wan X et al (2005) Molecular correlates of repolarization alternans in cardiac myocytes. J Mol Cell Cardiol 39(3):419–428PubMedCrossRefGoogle Scholar
  4. 4.
    Antzelevitch C, Fish J (2001) Electrical heterogeneity within the ventricular wall. Basic Res Cardiol 96(6):517–527PubMedCrossRefGoogle Scholar
  5. 5.
    Cazorla O et al (2000) Differential expression of cardiac titin isoforms and modulation of cellular stiffness. Circ Res 86(1):59–67PubMedCrossRefGoogle Scholar
  6. 6.
    Litten RZ et al (1985) Heterogeneity of myosin isozyme content of rabbit heart. Circ Res 57(3):406–414PubMedCrossRefGoogle Scholar
  7. 7.
    Stelzer JE et al (2008) Transmural variation in myosin heavy chain isoform expression modulates the timing of myocardial force generation in porcine left ventricle. J Physiol 586(Pt 21):5203–5214PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Ait Mou Y et al (2008) Differential contribution of cardiac sarcomeric proteins in the myofibrillar force response to stretch. Pflugers Arch 457(1):25–36PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Cazorla O et al (1997) Resting tension participates in the modulation of active tension in isolated guinea pig ventricular myocytes. J Mol Cell Cardiol 29(6):1629–1637PubMedCrossRefGoogle Scholar
  10. 10.
    Solovyova O et al (2003) Mechanical interaction of heterogeneous cardiac muscle segments in silico: effects on Ca2+ handling and action potential. Int J Bifurc Chaos 13(12):3757–3782CrossRefGoogle Scholar
  11. 11.
    Bryant SM et al (1998) Regional differences in the delayed rectifier current (IKr and IKs) contribute to the differences in action potential duration in basal left ventricular myocytes in guinea-pig. Cardiovasc Res 40(2):322–331PubMedCrossRefGoogle Scholar
  12. 12.
    Cordeiro JM et al (2004) Transmural heterogeneity of calcium activity and mechanical function in the canine left ventricle. Am J Physiol Heart Circ Physiol 286(4):H1471–H1479PubMedCrossRefGoogle Scholar
  13. 13.
    Lou Q et al (2011) Transmural heterogeneity and remodeling of ventricular excitation–contraction coupling in human heart failure. Circulation 123(17):1881–1890PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Derumeaux G et al (2000) Assessment of nonuniformity of transmural myocardial velocities by color-coded tissue Doppler imaging: characterization of normal, ischemic, and stunned myocardium. Circulation 101(12):1390–1395PubMedCrossRefGoogle Scholar
  15. 15.
    Ashikaga H et al (2007) Transmural dispersion of myofiber mechanics: implications for electrical heterogeneity in vivo. J Am Coll Cardiol 49(8):909–916PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Glukhov AV et al (2010) Transmural dispersion of repolarization in failing and nonfailing human ventricle. Circ Res 106(5):981–991PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Clark RB et al (1993) Heterogeneity of action potential waveforms and potassium currents in rat ventricle. Cardiovasc Res 27(10):1795–1799PubMedCrossRefGoogle Scholar
  18. 18.
    Dilly KW et al (2006) Mechanisms underlying variations in excitation-contraction coupling across the mouse left ventricular free wall. J Physiol 572(Pt 1):227–241PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Stankovicova T et al (2000) M cells and transmural heterogeneity of action potential configuration in myocytes from the left ventricular wall of the pig heart. Cardiovasc Res 45(4):952–960PubMedCrossRefGoogle Scholar
  20. 20.
    Antzelevitch C (2010) M cells in the human heart. Circ Res 106(5):815–817PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Quinn FR et al (2003) Myocardial infarction causes increased expression but decreased activity of the myocardial Na+–Ca2+ exchanger in the rabbit. J Physiol 553(Pt 1):229–242PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Bell SP et al (2000) Alterations in the determinants of diastolic suction during pacing tachycardia. Circ Res 87(3):235–240PubMedCrossRefGoogle Scholar
  23. 23.
    Wan X, Bryant SM, Hart G (2003) A topographical study of mechanical and electrical properties of single myocytes isolated from normal guinea-pig ventricular muscle. J Anat 202(6):525–536PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    ten Tusscher KH et al (2004) A model for human ventricular tissue. Am J Physiol Heart Circ Physiol 286(4):H1573–H1589PubMedCrossRefGoogle Scholar
  25. 25.
    Pandit SV et al (2001) A mathematical model of action potential heterogeneity in adult rat left ventricular myocytes. Biophys J 81(6):3029–3051PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Bondarenko VE, Rasmusson RL (2010) Transmural heterogeneity of repolarization and Ca2+ handling in a model of mouse ventricular tissue. Am J Physiol Heart Circ Physiol 299(2):H454–H469PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Benson AP et al (2008) The canine virtual ventricular wall: a platform for dissecting pharmacological effects on propagation and arrhythmogenesis. Prog Biophys Mol Biol 96(1–3):187–208PubMedCrossRefGoogle Scholar
  28. 28.
    Mullins PD, Bondarenko VE (2013) A mathematical model of the mouse ventricular myocyte contraction. PLoS One 8(5):e63141PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Campbell SG et al (2008) Mechanisms of transmurally varying myocyte electromechanics in an integrated computational model. Philos Trans Ser A Math Phys Eng Sci 366(1879):3361–3380. https://www.ncbi.nlm.nih.gov/labs/articles/18593662/ CrossRefGoogle Scholar
  30. 30.
    Kerckhoffs RC et al (2003) Homogeneity of cardiac contraction despite physiological asynchrony of depolarization: a model study. Ann Biomed Eng 31(5):536–547PubMedCrossRefGoogle Scholar
  31. 31.
    Nickerson D, Smith N, Hunter P (2005) New developments in a strongly coupled cardiac electromechanical model. Europace 7(Suppl 2):118–127PubMedCrossRefGoogle Scholar
  32. 32.
    Campbell SG et al (2009) Effect of transmurally heterogeneous myocyte excitation-contraction coupling on canine left ventricular electromechanics. Exp Physiol 94(5):541–552PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Gurev V et al (2010) Distribution of electromechanical delay in the heart: insights from a three-dimensional electromechanical model. Biophys J 99(3):745–754PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Vasilyeva AD, Solovyova OE (2012) Electromechanical coupling in cardiomyocytes from transmural layers of guinea pig left ventricle. Biophysics 57(5):661–667CrossRefGoogle Scholar
  35. 35.
    Vasilyeva A, Solovyova O (2012) Modeling of heterogeneity in electrical and mechanical properties of guinea pig ventricular myocytes. Comput Cardiol (CinC) 39:453–456Google Scholar
  36. 36.
    Gao J et al (2005) Transmural gradients in Na/K pump activity and [Na+]I in canine ventricle. Biophys J 89(3):1700–1709PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Bryant SM, Shipsey SJ, Hart G (1997) Regional differences in electrical and mechanical properties of myocytes from guinea-pig hearts with mild left ventricular hypertrophy. Cardiovasc Res 35(2):315–323PubMedCrossRefGoogle Scholar
  38. 38.
    Laurita KR et al (2003) Transmural heterogeneity of calcium handling in canine. Circ Res 92(6):668–675PubMedCrossRefGoogle Scholar
  39. 39.
    Sulman T et al (2008) Mathematical modeling of mechanically modulated rhythm disturbances in homogeneous and heterogeneous myocardium with attenuated activity of Na+–K+ pump. Bull Math Biol 70(3):910–949PubMedCrossRefGoogle Scholar
  40. 40.
    Noble D et al (1998) Improved guinea-pig ventricular cell model incorporating a diadic space, IKr and IKs, and length- and tension-dependent processes. Can J Cardiol 14(1):123–134PubMedGoogle Scholar
  41. 41.
    Izakov V et al (1991) Cooperative effects due to calcium binding by troponin and their consequences for contraction and relaxation of cardiac muscle under various conditions of mechanical loading. Circ Res 69(5):1171–1184PubMedCrossRefGoogle Scholar
  42. 42.
    Garny A et al (1895) Cellular open resource (COR): current status and future directions. Philos Trans Ser A Math Phys Eng Sci 2009(367):1885–1905Google Scholar
  43. 43.
    Zygmunt AC et al (2001) Larger late sodium conductance in M cells contributes to electrical heterogeneity in canine ventricle. Am J Physiol Heart Circ Physiol 281(2):H689–H697PubMedCrossRefGoogle Scholar
  44. 44.
    Zygmunt AC, Goodrow RJ, Antzelevitch C (2000) I(NaCa) contributes to electrical heterogeneity within the canine ventricle. Am J Physiol Heart Circ Physiol 278(5):H1671–H1678PubMedCrossRefGoogle Scholar
  45. 45.
    Banyasz T et al (2003) Endocardial versus epicardial differences in L-type calcium current in canine ventricular myocytes studied by action potential voltage clamp. Cardiovasc Res 58(1):66–75PubMedCrossRefGoogle Scholar
  46. 46.
    Khokhlova A, Iribe G, Solovyova O (2015) Load-dependency in mechanical properties of subepicardial and subendocardial cardiomyocytes. Comput Cardiol 42:965–968Google Scholar
  47. 47.
    McIntosh MA, Cobbe SM, Smith GL (2000) Heterogeneous changes in action potential and intracellular Ca2+ in left ventricular myocyte sub-types from rabbits with heart failure. Cardiovasc Res 45(2):397–409PubMedCrossRefGoogle Scholar
  48. 48.
    Cordeiro JM et al (2007) Cellular and subcellular alternans in the canine left ventricle. Am J Physiol Heart Circ Physiol 293(6):H3506–H3516PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Lab MJ, Allen DG, Orchard CH (1984) The effects of shortening on myoplasmic calcium concentration and on the action potential in mammalian ventricular muscle. Circ Res 55(6):825–829PubMedCrossRefGoogle Scholar
  50. 50.
    White E, Boyett MR, Orchard CH (1995) The effects of mechanical loading and changes of length on single guinea-pig ventricular myocytes. J Physiol 482(Pt 1):93–107PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Iribe G, Helmes M, Kohl P (2007) Force-length relations in isolated intact cardiomyocytes subjected to dynamic changes in mechanical load. Am J Physiol Heart Circ Physiol 292(3):H1487–H1497PubMedCrossRefGoogle Scholar
  52. 52.
    Katsnelson LB et al (2004) Influence of viscosity on myocardium mechanical activity: a mathematical model. J Theor Biol 230(3):385–405PubMedCrossRefGoogle Scholar
  53. 53.
    Markhasin VS et al (2003) Mechano-electric interactions in heterogeneous myocardium: development of fundamental experimental and theoretical models. Prog Biophys Mol Biol 82(1–3):207–220PubMedCrossRefGoogle Scholar
  54. 54.
    Katsnelson LB et al (2011) Contribution of mechanical factors to arrhythmogenesis in calcium overloaded cardiomyocytes: model predictions and experiments. Prog Biophys Mol Biol 107(1):81–89PubMedCrossRefGoogle Scholar
  55. 55.
    Markhasin VS et al (2012) Slow force response and auto-regulation of contractility in heterogeneous myocardium. Prog Biophys Mol Biol 110(2):305–318PubMedCrossRefGoogle Scholar
  56. 56.
    Ryder KO, Bryant SM, Hart G (1993) Membrane current changes in left ventricular myocytes isolated from guinea pigs after abdominal aortic coarctation. Cardiovasc Res 27(7):1278–1287PubMedCrossRefGoogle Scholar
  57. 57.
    Ashikaga H et al (2009) Transmural myocardial mechanics during isovolumic contraction. JACC Cardiovasc Imaging 2(2):202–211PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Bollensdorff C, Lookin O, Kohl P (2011) Assessment of contractility in intact ventricular cardiomyocytes using the dimensionless ‘Frank-Starling gain’ index. Pflugers Arch 462(1):39–48PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Katz AM, Katz PB (1989) Homogeneity out of heterogeneity. Circulation 79(3):712–717PubMedCrossRefGoogle Scholar
  60. 60.
    Kohl P et al (2001) Sudden cardiac death by commotio cordis: role of mechano-electric feedback. Cardiovasc Res 50(2):280–289PubMedCrossRefGoogle Scholar
  61. 61.
    Chung CS, Campbell KS (2013) Temperature and transmural region influence functional measurements in unloaded left ventricular cardiomyocytes. Physiol Rep 1(6):e00158PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Maltsev VA et al (2008) Molecular identity of the late sodium current in adult dog cardiomyocytes identified by Nav1. 5 antisense inhibition. Am J Physiol Heart Circ Physiol 64(2):H667CrossRefGoogle Scholar
  63. 63.
    Fujioka Y, Hiroe K, Matsuoka S (2000) Regulation kinetics of Na+–Ca2+ exchange current in guinea-pig ventricular myocytes. J Physiol 529(3):611–623PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© The Physiological Society of Japan and Springer Japan 2017

Authors and Affiliations

  1. 1.Ural Federal UniversityEkaterinburgRussia
  2. 2.Institute of Immunology and PhysiologyRussian Academy of SciencesEkaterinburgRussia
  3. 3.Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan

Personalised recommendations