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© 2001 American Heart Association, Inc.
Integrative Physiology |
Conduction Slowing and Sudden Arrhythmic Death in Mice With Cardiac-Restricted Inactivation of Connexin43
From the Section of Myocardial Biology, Cardiovascular Institute, Departments of Medicine (D.E.G., G.I.F.), Biochemistry and Molecular Biology (H.S., G.I.F.), and Physiology and Biophysics (G.I.F.), Mount Sinai School of Medicine, New York, NY; Department of Pharmacology (G.E.M., H.T., D.V.), SUNY Upstate Medical University, Syracuse, NY; Center for Cardiovascular Development (M.D.S.), Baylor College of Medicine, Houston, Tex; and UCSD-Salk NHLBI Program in Molecular Medicine (J.C., K.R.C.), Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, Calif. Present address for H.S. is Department of Vascular Biology, The Scripps Research Institute, La Jolla, Calif.
Correspondence to Dr Glenn I. Fishman, Mount Sinai School of Medicine, One Gustave L. Levy Pl, Box 1269, New York, NY 10029. E-mail fishmg01{at}doc.mssm.edu
Abstract—Cardiac arrhythmia is a common and often lethal manifestation of many forms of heart disease. Gap junction remodeling has been postulated to contribute to the increased propensity for arrhythmogenesis in diseased myocardium, although a causative role in vivo remains speculative. By generating mice with cardiac-restricted knockout of connexin43 (Cx43), we have circumvented the perinatal lethal developmental defect associated with germline inactivation of this gap junction channel gene and uncovered an essential role for Cx43 in the maintenance of electrical stability. Mice with cardiac-specific loss of Cx43 have normal heart structure and contractile function, and yet they uniformly (28 of 28 conditional Cx43 knockout mice observed) develop sudden cardiac death from spontaneous ventricular arrhythmias by 2 months of age. Optical mapping of the epicardial electrical activation pattern in Cx43 conditional knockout mice revealed that ventricular conduction velocity was significantly slowed by up to 55% in the transverse direction and 42% in the longitudinal direction, resulting in an increase in anisotropic ratio compared with control littermates (2.1±0.13 versus 1.66±0.06; P<0.01). This novel genetic murine model of primary sudden cardiac death defines gap junctional abnormalities as a key molecular feature of the arrhythmogenic substrate.
Key Words: gap junction • connexin43 • arrhythmia • conduction
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 B. G. Petrich, B. C. Eloff, D. L. Lerner, A. Kovacs, J. E. Saffitz, D. S. Rosenbaum, and Y. Wang Targeted Activation of c-Jun N-terminal Kinase in Vivo Induces Restrictive Cardiomyopathy and Conduction Defects J. Biol. Chem., April 9, 2004; 279(15): 15330 - 15338. [Abstract] [Full Text] [PDF]
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H. V.M. van Rijen, D. Eckardt, J. Degen, M. Theis, T. Ott, K. Willecke, H. J. Jongsma, T. Opthof, and J. M.T. de Bakker Slow Conduction and Enhanced Anisotropy Increase the Propensity for Ventricular Tachyarrhythmias in Adult Mice With Induced Deletion of Connexin43 Circulation, March 2, 2004; 109(8): 1048 - 1055. [Abstract] [Full Text] [PDF]
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S. Alcolea, T. Jarry-Guichard, J. de Bakker, D. Gonzalez, W. Lamers, S. Coppen, L. Barrio, H. Jongsma, D. Gros, and H. van Rijen Replacement of Connexin40 by Connexin45 in the Mouse: Impact on Cardiac Electrical Conduction Circ. Res., January 9, 2004; 94(1): 100 - 109. [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]
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J.-A. Yao, D. E. Gutstein, F. Liu, G. I. Fishman, and A. L. Wit Cell Coupling Between Ventricular Myocyte Pairs From Connexin43-Deficient Murine Hearts Circ. Res., October 17, 2003; 93(8): 736 - 743. [Abstract] [Full Text] [PDF]
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 J. C. SAEZ, V. M. BERTHOUD, M. C. BRANES, A. D. MARTINEZ, and E. C. BEYER Plasma Membrane Channels Formed by Connexins: Their Regulation and Functions Physiol Rev, October 1, 2003; 83(4): 1359 - 1400. [Abstract] [Full Text] [PDF]
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 T. N. Tulenko Regulating Cross-Talk Between Vascular Smooth Muscle Cells Arterioscler Thromb Vasc Biol, October 1, 2003; 23(10): 1707 - 1709. [Full Text] [PDF]
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X. Lin, M. Crye, and R. D. Veenstra Regulation of Connexin43 Gap Junctional Conductance by Ventricular Action Potentials Circ. Res., September 19, 2003; 93 (6): e63 - e73. [Abstract] [Full Text] [PDF]
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D. D. Spragg, C. Leclercq, M. Loghmani, O. P. Faris, R. S. Tunin, D. DiSilvestre, E. R. McVeigh, G. F. Tomaselli, and D. A. Kass Regional Alterations in Protein Expression in the Dyssynchronous Failing Heart Circulation, August 26, 2003; 108(8): 929 - 932. [Abstract] [Full Text] [PDF]
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D. E. Gutstein, S. B. Danik, J. B. Sereysky, G. E. Morley, and G. I. Fishman Subdiaphragmatic murine electrophysiological studies: sequential determination of ventricular refractoriness and arrhythmia induction Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H1091 - H1096. [Abstract] [Full Text] [PDF]
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S. P. Thomas, J. P. Kucera, L. Bircher-Lehmann, Y. Rudy, J. E. Saffitz, and A. G. Kleber Impulse Propagation in Synthetic Strands of Neonatal Cardiac Myocytes With Genetically Reduced Levels of Connexin43 Circ. Res., June 13, 2003; 92(11): 1209 - 1216. [Abstract] [Full Text] [PDF]
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P. Menasche Skeletal muscle satellite cell transplantation Cardiovasc Res, May 1, 2003; 58(2): 351 - 357. [Abstract] [Full Text] [PDF]
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T. Reffelmann and R. A. Kloner Cellular cardiomyoplasty--cardiomyocytes, skeletal myoblasts, or stem cells for regenerating myocardium and treatment of heart failure? Cardiovasc Res, May 1, 2003; 58(2): 358 - 368. [Full Text] [PDF]
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P. Menasche, A. A. Hagege, J.-T. Vilquin, M. Desnos, E. Abergel, B. Pouzet, A. Bel, S. Sarateanu, M. Scorsin, K. Schwartz, et al. Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction J. Am. Coll. Cardiol., April 2, 2003; 41(7): 1078 - 1083. [Abstract] [Full Text] [PDF]
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N. Al Attar, C. Carrion, S. Ghostine, I. Garcin, J.-T. Vilquin, A. A. Hagege, and P. Menasche Long-term (1 year) functional and histological results of autologous skeletal muscle cells transplantation in rat Cardiovasc Res, April 1, 2003; 58(1): 142 - 148. [Abstract] [Full Text] [PDF]
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D. E. Gutstein, F.-y. Liu, M. B. Meyers, A. Choo, and G. I. Fishman The organization of adherens junctions and desmosomes at the cardiac intercalated disc is independent of gap junctions J. Cell Sci., March 1, 2003; 116(5): 875 - 885. [Abstract] [Full Text] [PDF]
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B. R. Kwak, N. Veillard, G. Pelli, F. Mulhaupt, R. W. James, M. Chanson, and F. Mach Reduced Connexin43 Expression Inhibits Atherosclerotic Lesion Formation in Low-Density Lipoprotein Receptor-Deficient Mice Circulation, February 25, 2003; 107(7): 1033 - 1039. [Abstract] [Full Text] [PDF]
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H.-I. Yeh, Y.-J. Lai, Y.-N. Lee, Y.-J. Chen, Y.-C. Chen, C.-C. Chen, S.-A. Chen, C.-I. Lin, and C.-H. Tsai Differential Expression of Connexin43 Gap Junctions in Cardiomyocytes Isolated from Canine Thoracic Veins J. Histochem. Cytochem., February 1, 2003; 51(2): 259 - 266. [Abstract] [Full Text] [PDF]
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B. London, L. C. Baker, J. S. Lee, V. Shusterman, B.-R. Choi, T. Kubota, C. F. McTiernan, A. M. Feldman, and G. Salama Calcium-dependent arrhythmias in transgenic mice with heart failure Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H431 - H441. [Abstract] [Full Text] [PDF]
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K. A. Detillieux, F. Sheikh, E. Kardami, and P. A. Cattini Biological activities of fibroblast growth factor-2 in the adult myocardium Cardiovasc Res, January 1, 2003; 57(1): 8 - 19. [Abstract] [Full Text] [PDF]
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J. P. Kucera, S. Rohr, and Y. Rudy Localization of Sodium Channels in Intercalated Disks Modulates Cardiac Conduction Circ. Res., December 13, 2002; 91(12): 1176 - 1182. [Abstract] [Full Text] [PDF]
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R. J. Barker and R. G. Gourdie JNK Bond Regulation: Why Do Mammalian Hearts Invest in Connexin43? Circ. Res., October 4, 2002; 91(7): 556 - 558. [Full Text] [PDF]
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B. G. Petrich, X. Gong, D. L. Lerner, X. Wang, J. H. Brown, J. E. Saffitz, and Y. Wang c-Jun N-Terminal Kinase Activation Mediates Downregulation of Connexin43 in Cardiomyocytes Circ. Res., October 4, 2002; 91(7): 640 - 647. [Abstract] [Full Text] [PDF]
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