Circulation Research. 2003;93:421-428
Published online before print July 31, 2003, doi: 10.1161/01.RES.0000089258.40661.0C
Published online before print July 31, 2003, doi: 10.1161/01.RES.0000089258.40661.0C
© 2003 American Heart Association, Inc.
Cellular Biology |
Coupling of Cardiac Electrical Activity Over Extended Distances by Fibroblasts of Cardiac Origin
From the Department of Physiology (G.G., M.M., S.R.), University of Bern, Bern, Switzerland, and the Department of Cardiology (S.P.T), Westmead Hospital, Westmead, Australia.
Correspondence to Dr Stephan Rohr, Department of Physiology, University of Bern, Bühlplatz 5, CH-3012 Bern, Switzerland. E-mail rohr{at}pyl.unibe.ch
Roughly half of the cells of the heart consist of nonmyocardial cells, with fibroblasts representing the predominant cell type. It is well established that individual cardiomyocytes and fibroblasts in culture establish gap junctional communication at the single cell level (short-range interaction). However, it is not known whether such coupling permits activation of cardiac tissue over extended distances (long-range interaction). Long-range interactions may be responsible for electrical synchronization of donor and recipient tissue after heart transplantation and may play a role in arrhythmogenesis. This question was investigated using a novel heterocellular culture model with strands of cardiomyocytes interrupted by cardiac fibroblasts over defined distances. With use of optical recording techniques, it could be shown that impulse propagation along fibroblast inserts was successful over distances up to 300 µm and was characterized by length-dependent local propagation delays ranging from 11 to 68 ms (apparent local "conduction velocities" 4.6±1.8 mm/s, n=23). Involvement of mechanical stretch in this phenomenon was excluded by showing that inserts consisting of communication-deficient HeLa cells were incapable of supporting propagation. In contrast, HeLa cells expressing connexin43 permitted impulse conduction over distances as long as 600 µm. Immunocytochemistry showed that fibroblasts and cardiomyocytes expressed connexin43 and connexin45, whereas connexin40 was absent. These results illustrate that fibroblasts of cardiac origin are capable of synchronizing electrical activity of multicellular cardiac tissue over extended distances through electrotonic interactions. This synchronization is accompanied by extremely large local conduction delays, which might contribute to the generation of arrhythmias in fibrotic hearts.
Key Words: electrophysiology • cell culture • cardiac fibroblasts • fibrosis • gap junctions
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|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
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|
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|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
I. R. Efimov and C. M. Ripplinger Tornado in a dish: Revealing the mechanisms of ventricular arrhythmias in engineered cardiac tissues Cardiovasc Res, February 1, 2006; 69(2): 307 - 308. [Full Text] [PDF]
|
|
|
|
 |
|
 S. L.M.A. Beeres, D. E. Atsma, A. van der Laarse, D. A. Pijnappels, J. van Tuyn, W. E. Fibbe, A. A.F. de Vries, D. L. Ypey, E. E. van der Wall, and M. J. Schalij Human Adult Bone Marrow Mesenchymal Stem Cells Repair Experimental Conduction Block in Rat Cardiomyocyte Cultures J. Am. Coll. Cardiol., November 15, 2005; 46(10): 1943 - 1952. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Yue, T. R. Betts, P. R. Roberts, and J. M. Morgan Global Dynamic Coupling of Activation and Repolarization in the Human Ventricle Circulation, October 25, 2005; 112(17): 2592 - 2601. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
L. Chilton, S. Ohya, D. Freed, E. George, V. Drobic, Y. Shibukawa, K. A. MacCannell, Y. Imaizumi, R. B. Clark, I. M. C. Dixon, et al. K+ currents regulate the resting membrane potential, proliferation, and contractile responses in ventricular fibroblasts and myofibroblasts Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2931 - H2939. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Allessie, U. Schotten, S. Verheule, and E. Harks Gene Therapy for Repair of Cardiac Fibrosis: A Long Way to Tipperary Circulation, February 1, 2005; 111(4): 391 - 393. [Full Text] [PDF]
|
|
|
|
|
|
F. Rothenberg, V. P. Nikolski, M. Watanabe, and I. R. Efimov Electrophysiology and anatomy of embryonic rabbit hearts before and after septation Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H344 - H351. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Camelliti, T. K. Borg, and P. Kohl Structural and functional characterisation of cardiac fibroblasts Cardiovasc Res, January 1, 2005; 65(1): 40 - 51. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rubart Two-Photon Microscopy of Cells and Tissue Circ. Res., December 10, 2004; 95(12): 1154 - 1166. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Rohr Role of gap junctions in the propagation of the cardiac action potential Cardiovasc Res, May 1, 2004; 62(2): 309 - 322. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Rudy Conductive Bridges in Cardiac Tissue: A Beneficial Role or an Arrhythmogenic Substrate? Circ. Res., April 2, 2004; 94(6): 709 - 711. [Full Text] [PDF]
|
|
|
|
|
|
P. Camelliti, C. R. Green, I. LeGrice, and P. Kohl Fibroblast Network in Rabbit Sinoatrial Node: Structural and Functional Identification of Homogeneous and Heterogeneous Cell Coupling Circ. Res., April 2, 2004; 94(6): 828 - 835. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Gepstein, Y. Feld, and L. Yankelson Somatic gene and cell therapy strategies for the treatment of cardiac arrhythmias Am J Physiol Heart Circ Physiol, March 1, 2004; 286(3): H815 - H822. [Full Text] [PDF]
|
|
|
|
|
|
P. Kohl Heterogeneous Cell Coupling in the Heart: An Electrophysiological Role for Fibroblasts Circ. Res., September 5, 2003; 93(5): 381 - 383. [Full Text] [PDF]
|
|