Published online before print February 16, 2004, doi: 10.1161/01.CIR.0000117402.70689.75
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(Circulation. 2004;109:1048-1055.)
© 2004 American Heart Association, Inc.
Basic Science Reports |
Slow Conduction and Enhanced Anisotropy Increase the Propensity for Ventricular Tachyarrhythmias in Adult Mice With Induced Deletion of Connexin43
From the Department of Medical Physiology (H.V.M., H.J.J., J.M.T.d.B.), University Medical Center, Utrecht, the Netherlands; Institute of Genetics (D.E., J.D., M.T., T.O., K.W.), University of Bonn, Germany; and Interuniversity Cardiology Institute of the Netherlands (J.M.T.d.B.), Utrecht, the Netherlands. M.T. is presently at Howard Hughes Medical Institute, Center for Neurobiology and Behavior, Columbia University, New York, NY.
Correspondence to Harold V.M. van Rijen, PhD, Department of Medical Physiology, University Medical Center Utrecht, PO Box 80043, 3508TA Utrecht, The Netherlands. E-mail H.V.M.vanRijen{at}med.uu.nl
Received April 17, 2003; de novo received July 16, 2003; revision received October 23, 2003; accepted October 24, 2003.
Background— Connexin 43 (Cx43) is a major determinant of conduction in the ventricular working myocardium of mammals. We investigated the effect of decreased Cx43 expression on conduction velocity and arrhythmogenesis using adult mice with inducible deletion of Cx43.
Methods and Results— Cx43Cre-ER(T)/+ mice, in which 1 coding region of the Cx43 gene was replaced by Cre-ER(T), were mated to Cx43fl/fl mice, generating Cx43Cre-ER(T)/fl mice. Application of 4-hydroxytamoxifen (4-OHT) induced Cre-ER(T)–mediated deletion of the floxed Cx43 allele. Epicardial ventricular mapping using a 13x19 multiterminal electrode grid (300-µm spacing) was performed on Langendorff-perfused hearts from Cx43fl/fl plus carrier (n=10), Cx43fl/fl plus 4-OHT (n=10), Cx43 Cre-ER(T)/fl plus carrier (n=9), and Cx43Cre-ER(T)/fl plus 4-OHT (n=10). Cx43 protein amount in group 3 hearts was decreased by 
50% compared with group 1. 4-OHT did not affect cardiac protein amounts in group 2 but decreased Cx43 expression up to 95% in group 4 compared with group 3. Epicardial activation of both left ventricle (LV) and right ventricle (RV) during sinus rhythm was similar in all groups. Conduction velocity (CV) changed only in group 4 animals. For RV (LV), longitudinal CV decreased from 38 (35) to 31.6 (33.6) and transverse CV from 24.4 (16.8) to 10.1 (11.3) cm/s. Dispersion of conduction in RV (LV) was increased by 91% (38%). Programmed stimulation resulted in ventricular arrhythmias in group 4 (7 of 10 mice) but never in groups 1 through 3.
Conclusions— Heterozygous expression of Cx43 did not affect ventricular conduction velocity. Up to 95% decrease of Cx43 protein in 4-OHT–treated Cx43Cre-ER(T)/fl mice reduced conduction velocity and increased dispersion of conduction and propensity for ventricular arrhythmias.
Key Words: conduction • tachyarrhythmias • mapping
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