Annals of Biomedical Engineering

, Volume 43, Issue 7, pp 1614–1625 | Cite as

Synergy Between Intercellular Communication and Intracellular Ca2+ Handling in Arrhythmogenesis

  • Etienne BoileauEmail author
  • Christopher H. George
  • Dimitris Parthimos
  • Alice N. Mitchell
  • Sabina Aziz
  • Perumal Nithiarasu


Calcium is the primary signalling component of excitation-contraction coupling, the process linking electrical excitability of cardiac muscle cells to coordinated contraction of the heart. Understanding \({\text{Ca}}^{2+}\) handling processes at the cellular level and the role of intercellular communication in the emergence of multicellular synchronization are key aspects in the study of arrhythmias. To probe these mechanisms, we have simulated cellular interactions on large scale arrays that mimic cardiac tissue, and where individual cells are represented by a mathematical model of intracellular \({\text{Ca}}^{2+}\) dynamics. Theoretical predictions successfully reproduced experimental findings and provide novel insights on the action of two pharmacological agents (ionomycin and verapamil) that modulate \({\text{Ca}}^{2+}\) signalling pathways via distinct mechanisms. Computational results have demonstrated how transitions between local synchronisation events and large scale wave formation are affected by these agents. Entrainment phenomena are shown to be linked to both intracellular \({\text{Ca}}^{2+}\) and coupling-specific dynamics in a synergistic manner. The intrinsic variability of the cellular matrix is also shown to affect emergent patterns of rhythmicity, providing insights into the origins of arrhythmogenic \({\text{Ca}}^{2+}\) perturbations in cardiac tissue in situ.


Membrane potential Intra cellular oscillator Coupling Synchronisation Complex dynamical system Emergence 



This work was partly supported by Grants from the British Heart Foundation (FS/09/028/27602, FS/06/082/21723), Heart Research UK (RG2559), Wellcome Trust (094219/Z/10/Z), and the Cardiff Partnership Fund. The authors also acknowledge the financial support provided by the Sêr Cymru National Research Network in Advanced Engineering and Materials.


  1. 1.
    Bers, D. M. Cardiac excitation-contraction coupling. Nature 415:198–205, 2002.PubMedCrossRefGoogle Scholar
  2. 2.
    Christ, G. J., D. C. Spray, M. El-Sabban, L. K. Moore, and P. R. Brink. Gap junctions in vascular tissues. Evaluating the role of intercellular communication in the modulation of vasomotor tone. Circ. Res. 79:631–646, 1996.PubMedCrossRefGoogle Scholar
  3. 3.
    Claycomb, W. C., N. A. Lanson, B. S. Stallworth, D. B. Egeland, J. B. Delcarpio, A. Bahinski, and N. J. Izzo Jr. HL-1 cells: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte. Proc. Natl Acad. Sci. U.S.A. 95:2979–2984, 1998.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Dehmelt, L., and P. I. H. Bastiaens. Spatial organization of intracellular communication: insights from imaging. Nat. Rev. Mol. Cell. Biol. 11:440–452, 2010.PubMedCrossRefGoogle Scholar
  5. 5.
    Dhillon, P. S., R. Gray, P. Kojodjojo, R. Jabr, R. Chowdhury, C. H. Fry, and N. S. Peters. Relationship between gap-junctional conductance and conduction velocity in mammalian myocardium. Circ. Arrhythm. Electrophysiol. 6:1208–1214, 2013.PubMedCrossRefGoogle Scholar
  6. 6.
    Drikakis, D., J. Lechuga, and S. Pal. Effects of shock waves on biological membranes: a molecular dynamics study. J. Comput. Theor. Nanos. 6:1437–1442, 2009.CrossRefGoogle Scholar
  7. 7.
    Falcke, M. Reading the patterns in living cells—the physics of Ca2+ signaling. Adv. Phys. 53:255–440, 2004.CrossRefGoogle Scholar
  8. 8.
    George, C. H., G. V. Higgs, and F. A. Lai. Ryanodine receptor mutations associated with stress-induced ventricular tachycardia mediate increased calcium release in stimulated cardiomyocytes. Circ. Res. 93:531–540, 2003.PubMedCrossRefGoogle Scholar
  9. 9.
    George, C. H., D. Parthimos, and N. C. Silvester. A network-oriented perspective on cardiac calcium signaling. Am. J. Physiol. Cell Physiol. 303:C897–C910, 2012.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Glass L. Synchronization and rhythmic processes in physiology. Nature 410:277–284, 2001.PubMedCrossRefGoogle Scholar
  11. 11.
    Guevara M. R., L. Glass, and A. Shrier. Phase locking, period doubling bifurcations and irregular dynamics in periodically stimulated cardiac cells. Science 214:1350–1353, 1981.PubMedCrossRefGoogle Scholar
  12. 12.
    Jacobsen, J. C., C. Aalkjaer, V. V. Matchkov, H. Nilsson, J. J. Freiberg, and N. H. Holstein-Rathlou. Heterogeneity and weak coupling may explain the synchronization characteristics of cells in the arterial wall. Philos. Trans. A. Math. Phys. Eng. Sci. 366:3483–3502, 2008.Google Scholar
  13. 13.
    Jordan, J. D., E. M. Landau, and R. Iyengar. Signaling networks: the origins of cellular multitasking. Cell 103:193–200, 2000.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Ter Keurs, H. E. D. J., and P. A. Boyden. Calcium and arrhythmogenesis. Physiol. Rev. 87:457–506, 2007.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Kholodenko, B., M. B. Yaffe, and W. Kolch. Computational approaches for analyzing information flow in biological networks. Sci. Signal. 5:re1, 2012.Google Scholar
  16. 16.
    Kim, J.-R., D. Shin, S. H. Jung, P. Heslop-Harrison, and K.-H. Cho. A design principle underlying the synchronization of oscillations in cellular systems. J. Cell Sci. 123:537–543, 2010.PubMedCrossRefGoogle Scholar
  17. 17.
    Kitano, H. Grand challenges in systems physiology. Front. Physiol. 1:3, 2010.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Koenigsberger, M., R. Sauser, and J.-J. Meister. Emergent properties of electrically coupled smooth muscle cells. Bull. Math. Biol. 67:1253–1272, 2005.PubMedCrossRefGoogle Scholar
  19. 19.
    Krikler, D. M. Verapamil in arrhythmia. Br. J. Clin. Pharmacol. 21(Suppl 2):1835:1895, 1986.Google Scholar
  20. 20.
    Kurz, F. T., M. A. Aon, B. O’Rourke, and A. A. Armoundas. Spatio-temporal oscillations of individual mitochondria in cardiac mycocytes reveal modulation of synchronized mitochondrial clusters. Proc. Natl Acad. Sci. U.S.A. 107:14315–14320, 2010.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Lakatta, E. G., V. A. Maltsev, K. Y. Bogdanov, M. D. Stern, and T. M. Vinogradova. Cyclic variation of intracellular calcium: a critical factor for cardiac pacemaker cell dominance. Circ. Res. 92:E45–E50, 2003.PubMedCrossRefGoogle Scholar
  22. 22.
    Lee, Y.-S., O. Z. Liu, and E. A. Sobie. Decoding myocardial Ca2+ signals across multiple spatial scales: a role for sensitivity analysis. J. Mol. Cell. Cardiol. 58:92–99, 2003.CrossRefGoogle Scholar
  23. 23.
    Li, X., and J. M. Simard. Multiple connexins form gap junction channels in rat basilar artery smooth muscle cells. Circ. Res. 84:1277–1284, 1999.PubMedCrossRefGoogle Scholar
  24. 24.
    Miura, M., P. A. Boyden, and H. E. ter Keurs. Calcium waves during triggered propagated contractions in intact trabeculae. Am. J. Physiol. 274:H266–H276, 1998.PubMedGoogle Scholar
  25. 25.
    Moreno, A. P., M. B. Rook, G. L. Fishman, and D. C. Spray. Gap junction channels: distinct voltage-sensitive and -insensitive conductance states. Biophys. J. 67:113–119, 1994.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Nakamura, N., T. Yamazawa, Y. Okubo, and M. Iino. Temporal switching and cell-to-cell variability in Ca2+ release activity in mammalian cells. Mol. Syst. Biol. 5:247, 2009.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Nivala, M., C. Y. Ko, M. Nivala, J. M. Weiss, and Z. Qu. Criticality in intracellular calcium signaling in cardiac myocytes. Biophys. J. 102:2433–2442, 2012.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Novak, B., and J. J. Tyson. Design principles of biochemical oscillators. Nat. Rev. Mol. Cell Biol. 9:981–991, 2008.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Parthimos, D., D. H. Edwards, and T. M. Griffith. Minimal model of arterial chaos generated by coupled intracellular and membrane Ca2+ oscillators. Am. J. Physiol. Heart Circ. Physiol. 46:H1119–H1144, 1999.Google Scholar
  30. 30.
    Parthimos, D., R. E. Haddock, C. E. Hill, and T. Griffith. Dynamics of a three-variable nonlinear model of vasomotion: comparison of theory and experiment. Biophys. J. 93:1534–1556, 2007.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Postma, A.V., I. Denjoy, T. M. Hoorntje, J. M. Lupoglazoff, A. Da Costa, P. Sebillon, M. M. A. M. Mannens, A. A. M. Wilde, and P. Guicheney. Absence of calsequestrin 2 causes severe forms of catecholaminergic polymorphic ventricular tachycardia. Circ. Res. 91:E21–E26, 2002.PubMedCrossRefGoogle Scholar
  32. 32.
    Roell, W., T. Lewalter, P. Sasse, Y. N. Tallini, B. R. Choi, M. Breithart, R. Doran, U. M. Becher, S. M. Hwang, T. Bostani, J. von Maltzahn, A. Hofmann, S. Reining, B. Eiberger, B. Gabris, A. Pfeifer, A. Welz, K. Willecke, G. Salama, J. W. Schrickel, M. I. Kotlikoff, and B. K. Fleischmann. Engraftment of connexin 43-expressing cells prevents post-infarct arrhythmia. Nature 450:819–826, 2007.PubMedCrossRefGoogle Scholar
  33. 33.
    Rudy, Y. Conductive bridges in cardiac tissue. A beneficial role or an arrhythmogenic substrate? Circ. Res. 94:709–711, 2004.PubMedCrossRefGoogle Scholar
  34. 34.
    Scoote, M., A. J. Williams. Myocardial calcium signalling and arrhythmia pathogenesis. Biochem. Biophys. Res. Commun. 322:1286–1309, 2004.PubMedCrossRefGoogle Scholar
  35. 35.
    Severs, N. J., S. R. Coppen, E. Dupont, H. I. Yeh, Y. S. Ko, and T. Matsushita. Gap junction alterations in human cardiac disease. Cardiovasc. Res. 62:368–377, 2004.PubMedCrossRefGoogle Scholar
  36. 36.
    Shaw, R. M., and Y. Rudy. Ionic mechanisms of propagation in cardiac tissue. Roles of the sodium and L-type calcium currents during reduced excitability and decreased gap junction coupling. Circ. Res. 81:727–741, 1997.PubMedCrossRefGoogle Scholar
  37. 37.
    Stern, M. D., L. A. Maltseva, M. Juhaszova, S. J. Sollott, E. G. Lakatta, and V. A. Maltsev. Hierarchical clustering of ryanodine receptors enables emergence of a calcium clock in sinoatrial node cells. J. Gen. Physiol. 143:577–604, 2014.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Tribulova, N., S. Seki, J. Radosinska, P. Kaplan, E. Babusikova, V. Knezl, and S. Mochizuki. Myocardial Ca2+ handling and cell-to-cell coupling, key factors in prevention of sudden cardiac death. Can. J. Physiol. Pharm. 87:1120–1129, 2009.CrossRefGoogle Scholar
  39. 39.
    Tyson, J. J., K. C. Chen, and B. Novak. Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signaling pathways in the cell. Curr. Opin. Cell Biol. 15:221–231, 2003.PubMedCrossRefGoogle Scholar
  40. 40.
    Weiss, J. N. How does falling out of phase of intracellular calcium and action potentials across the heart’s wall spell the beginning of chaos for the heart? Dialog. Cardiovasc. Med. 15:302–310, 2010.Google Scholar
  41. 41.
    Weiss, J. N., M. Nivala, A. Garfinkel, and Z. Qu. Alternans and arrrhythmias: from cell to heart. Circ. Res. 108:98–112, 2011.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Zhang, S., Z. Zhou, Q. Gong, J. C. Makielski, and C. T. January. Mechanisms of block and identification of the verapamil binding domain to HEGR potassium channels. Circ. Res. 84:989–998, 1999.PubMedCrossRefGoogle Scholar

Copyright information

© Biomedical Engineering Society 2015

Authors and Affiliations

  • Etienne Boileau
    • 1
    Email author
  • Christopher H. George
    • 2
  • Dimitris Parthimos
    • 2
  • Alice N. Mitchell
    • 2
  • Sabina Aziz
    • 2
  • Perumal Nithiarasu
    • 1
  1. 1.Biomedical Engineering and Rheology Group, Zienkiewicz Centre for Computational EngineeringSwansea UniversitySwanseaUK
  2. 2.Institute of Molecular and Experimental Medicine, Wales Heart Research InstituteCardiff University School of MedicineCardiffUK

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