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(Circulation Research. 2001;88:1196.)
© 2001 American Heart Association, Inc.

Integrative Physiology

Null Mutation of Connexin43 Causes Slow Propagation of Ventricular Activation in the Late Stages of Mouse Embryonic Development

Dhananjay Vaidya, Houman S. Tamaddon, Cecilia W. Lo, Steven M. Taffet, Mario Delmar, Gregory E. Morley, José Jalife

From the Department of Pharmacology (D.V., H.S.T., M.D., G.E.M., J.J.) and Department of Microbiology and Immunology (S.M.T.), SUNY Upstate Medical University, Syracuse, NY, and Department of Biology (C.W.L.), University of Pennsylvania, Philadelphia, Pa.

Correspondence to José Jalife, MD, SUNY Upstate Medical University, 766 Irving Ave, Syracuse, NY 13210. E-mail jalifej{at}upstate.edu

Abstract

Abstract—Connexin43 (Cx43) is the principal connexin isoform in the mouse ventricle, where it is thought to provide electrical coupling between cells. Knocking out this gene results in anatomic malformations that nevertheless allow for survival through early neonatal life. We examined electrical wave propagation in the left (LV) and right (RV) ventricles of isolated Cx43 null mutated (Cx43^-/-), heterozygous (Cx43^+/-), and wild-type (WT) embryos using high-resolution mapping of voltage-sensitive dye fluorescence. Consistent with the compensating presence of the other connexins, no reduction in propagation velocity was seen in Cx43^-/- ventricles at postcoital day (dpc) 12.5 compared with WT or Cx43^+/- ventricles. A gross reduction in conduction velocity was seen in the RV at 15.5 dpc (in cm/second, mean [1 SE confidence interval], WT 9.9 [8.7 to 11.2], Cx43^+/- 9.9 [9.0 to 10.9], and Cx43^-/- 2.2 [1.8 to 2.7; P<0.005]) and in both ventricles at 17.5 dpc (in RV, WT 8.4 [7.6 to 9.3], Cx43^+/- 8.7 [8.1 to 9.3], and Cx43^-/- 1.1 [0.1 to 1.3; P<0.005]; in LV, WT 10.1 [9.4 to 10.7], Cx43^+/- 8.3 [7.8 to 8.9], and Cx43^-/- 1.7 [1.3 to 2.1; P<0.005]) corresponding with the downregulation of Cx40. Cx40 and Cx45 mRNAs were detectable in ventricular homogenates even at 17.5 dpc, probably accounting for the residual conduction function. Neonatal knockout hearts were arrhythmic in vivo as well as ex vivo. This study demonstrates the contribution of Cx43 to the electrical function of the developing mouse heart and the essential role of this gene in maintaining heart rhythm in postnatal life.

Key Words: connexin • development • arrhythmia • electrophysiology • knockout

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