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Cardiovascular Research Advance Access [Accepted Manuscript] published online on April 22, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp124
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Combined reduction of intercellular coupling and membrane excitability differentially affects transverse and longitudinal cardiac conduction

Mèra Stein1,2, Toon A.B. van Veen1, Carol Ann Remme4, Mohamed Boulaksil1,3, Maartje Noorman1, Leonie van Stuijvenberg1, Roel van der Nagel1, Connie R. Bezzina4, Richard N.W. Hauer2, Jacques M.T. de Bakker1,3,4 and Harold V.M. van Rijen1

1 Division of Heart & Lungs, Department of Medical Physiology, University Medical Center Utrecht, Utrecht, The Netherlands
2 Division of Heart & Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands
3 Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands
4 Heart Failure Research Center, Academic Medical Center, Amsterdam, The Netherlands

Corresponding Author: Harold V.M. van Rijen, Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Yalelaan 50, 3584CM Utrecht, The Netherlands. Phone: +31 30 2538900. Fax: +31 30 2539036 Email: h.v.m.vanrijen{at}umcutrecht.nl

Aims: Reduced excitability and gap junction expression are commonly found in electrically remodeled diseased hearts, but their contribution to slow conduction and arrhythmias is unclear. In this study, we have investigated the effect of isolated and combined reductions in membrane excitability and intercellular coupling on impulse propagation and arrhythmogeneity in genetically modified mice.

Methods: Cx43 and Scn5a1798insD/+ heterozygous (HZ) mice were crossbred to create a mixed offspring: wild-type (WT, n=15), Cx43 HZ (n=14), Scn5a1798insD/+ (Scn5a) HZ (n=17), and Cx43/ Scn5a1798insD/+ (Cx43/Scn5a) HZ (n=15) mice. After ECG recording, epicardial activation mapping (208 recording sites) was performed on Langendorff-perfused hearts. Arrhythmia inducibility was tested by 1-3 premature stimuli and burst pacing. Conduction velocity longitudinal (CVL) and transverse (CVT) to fiber orientation and dispersion of conduction were determined during S1-S1 pacing (150 ms). Connexin43 (Cx43) and sodium channel Nav1.5 protein expression and myocardial tissue collagen content were determined by immunohistology.

Results: Compared to WT animals, P, QRS and QTc intervals were prolonged in Scn5a HZ and Cx43/Scn5a HZ but not in Cx43 HZ animals. Scn5a HZ mice showed decreased CVL in right ventricle (RV) but not in left ventricle (LV) compared to WT. In RV of Cx43/Scn5a HZ, CVT was reduced, but CVL was not different from WT. Arrhythmia inducibility was low and not increased in either single- or double-mutant mice.

Conclusion: Reduction of both electrical coupling and excitability results in normal conduction velocity parallel to fiber orientation but in pronounced conduction slowing transverse to fiber orientation in RV only, although this does not affect arrhythmogeneity.

Time for primary review: 22 Days


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