© 2000 American Heart Association, Inc.
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Gap Junctions in Cardiovascular Disease
From the Department of Medical Physiology, University Medical Center Utrecht, Utrecht, the Netherlands.
Correspondence to Habo J. Jongsma, Department of Medical Physiology, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, Netherlands. E-mail h.j.jongsma{at}med.uu.nl
Abstract—Connexins, the protein molecules forming gap junction channels, are reduced in number or redistributed from intercalated disks to lateral cell borders in a variety of cardiac diseases. This "gap junction remodeling" is considered to be arrhythmogenic. Using a simple model of human ventricular myocardium, we found that quantitative remodeling data extracted from the literature gave rise to only small to moderate changes in conduction velocity and the anisotropy ratio. Especially for longitudinal conduction, cytoplasmic resistivity (and thus cellular geometry) is much more important than commonly realized. None of the remodeling data gave rise to slow conduction on the order of a few centimeters per second.
Key Words: connexins • conduction velocity • arrhythmia • computer simulation
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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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|
|
|
|
 |
|
 S. A Jones, M. K Lancaster, and M. R Boyett Ageing-related changes of connexins and conduction within the sinoatrial node J. Physiol., October 15, 2004; 560(2): 429 - 437. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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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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|
|
|
|
|
|
K. H. W. J. ten Tusscher, D. Noble, P. J. Noble, and A. V. Panfilov A model for human ventricular tissue Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1573 - H1589. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
D. Garcia-Dorado, A. Rodriguez-Sinovas, and M. Ruiz-Meana Gap junction-mediated spread of cell injury and death during myocardial ischemia-reperfusion Cardiovasc Res, February 15, 2004; 61(3): 386 - 401. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
J. R. de Groot, T. Veenstra, A. O. Verkerk, R. Wilders, J. P.P. Smits, F. J.G. Wilms-Schopman, R. F. Wiegerinck, J. Bourier, C. N.W. Belterman, R. Coronel, et al. Conduction slowing by the gap junctional uncoupler carbenoxolone Cardiovasc Res, November 1, 2003; 60(2): 288 - 297. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R de Groot, C. A Schumacher, A. O Verkerk, A. Baartscheer, J. W.T Fiolet, and R. Coronel Intrinsic heterogeneity in repolarization is increased in isolated failing rabbit cardiomyocytes during simulated ischemia Cardiovasc Res, September 1, 2003; 59(3): 705 - 714. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
S. Kanno, A. Kovacs, K. A. Yamada, and J. E. Saffitz Connexin43 as a determinant of myocardial infarct size following coronary occlusion in mice J. Am. Coll. Cardiol., February 19, 2003; 41(4): 681 - 686. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Bursac, K.K. Parker, S. Iravanian, and L. Tung Cardiomyocyte Cultures With Controlled Macroscopic Anisotropy: A Model for Functional Electrophysiological Studies of Cardiac Muscle Circ. Res., December 13, 2002; 91 (12): e45 - e54. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. R Kwak, D. C Shah, and F. Mach A starting point for structure function relationships in the canine pulmonary veins Cardiovasc Res, September 1, 2002; 55(4): 703 - 705. [Full Text] [PDF]
|
|
|
|
|
|
D. Garcia-Dorado, M. Ruiz-Meana, F. Padilla, A. Rodriguez-Sinovas, and M. Mirabet Gap junction-mediated intercellular communication in ischemic preconditioning Cardiovasc Res, August 15, 2002; 55(3): 456 - 465. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
O. Bernus, R. Wilders, C. W. Zemlin, H. Verschelde, and A. V. Panfilov A computationally efficient electrophysiological model of human ventricular cells Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2296 - H2308. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. M. W. van der Velden, R. Wilders, and H. J. Jongsma Atrial fibrillation-induced gap junctional remodeling J. Am. Coll. Cardiol., May 15, 2002; 39(10): 1709 - 1709. [Full Text] [PDF]
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M. Allessie, J. Ausma, and U. Schotten Electrical, contractile and structural remodeling during atrial fibrillation Cardiovasc Res, May 1, 2002; 54(2): 230 - 246. [Abstract] [Full Text] [PDF]
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