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(Circulation. 2005;112:1927-1935.)
© 2005 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Impaired Impulse Propagation in Scn5a-Knockout Mice

Combined Contribution of Excitability, Connexin Expression, and Tissue Architecture in Relation to Aging

Toon A.B. van Veen, PhD^*; Mera Stein, MD^*; Anne Royer, PhD; Khaï Le Quang, MS; Flavien Charpentier, PhD; William H. Colledge, PhD; Christopher L.-H. Huang, MD, PhD; Ronald Wilders, PhD; Andrew A. Grace, PhD, FRCP; Denis Escande, MD, PhD; Jacques M.T. de Bakker, PhD; Harold V.M. van Rijen, PhD

From the Heart Lung Center Utrecht, Department of Medical Physiology (T.A.B.v.V., M.S., H.V.M.v.R.) and Department of Cardiology (M.S., J.M.T.d.B.), University Medical Center Utrecht, Utrecht, the Netherlands; INSERM U533 (A.R., K.L.Q., F.C., D.E.), l’Institut du Thorax, Faculté de Médecine, Nantes, France; Departments of Biochemistry and Physiology (W.H.C., C.L.-H.H., A.A.G.), University of Cambridge, Cambridge, United Kingdom; Department of Physiology (R.W.), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Interuniversity Cardiology Institute of the Netherlands (J.M.T.d.B.), Utrecht, the Netherlands; and the Experimental and Molecular Cardiology Group (J.M.T.d.B.), Cardiovascular Research Institute, Amsterdam, the Netherlands.

Correspondence to Toon A.B. Van Veen, PhD, Department of Medical Physiology, University Medical Center Utrecht, Yalelaan 50, 3584 CM Utrecht, The Netherlands. E-mail A.A.B.vanVeen{at}med.uu.nl

Received February 2, 2005; revision received June 17, 2005; accepted June 24, 2005.

Background— The SCN5A sodium channel is a major determinant for cardiac impulse propagation. We used epicardial mapping of the atria, ventricles, and septae to investigate conduction velocity (CV) in Scn5a heterozygous young and old mice.

Methods and Results— Mice were divided into 4 groups: (1) young (3 to 4 months) wild-type littermates (WT); (2) young heterozygous Scn5a-knockout mice (HZ); (3) old (12 to 17 months) WT; and (4) old HZ. In young HZ hearts, CV in the right but not the left ventricle was reduced in agreement with a rightward rotation in the QRS axes; fibrosis was virtually absent in both ventricles, and the pattern of connexin43 (Cx43) expression was similar to that of WT mice. In old WT animals, the right ventricle transversal CV was slightly reduced and was associated with interstitial fibrosis. In old HZ hearts, right and left ventricle CVs were severely reduced both in the transversal and longitudinal direction; multiple areas of severe reactive fibrosis invaded the myocardium, accompanied by markedly altered Cx43 expression. The right and left bundle-branch CVs were comparable to those of WT animals. The atria showed only mild fibrosis, with heterogeneously disturbed Cx40 and Cx43 expression.

Conclusions— A 50% reduction in Scn5a expression alone or age-related interstitial fibrosis only slightly affects conduction. In aged HZ mice, reduced Scn5a expression is accompanied by the presence of reactive fibrosis and disarrangement of gap junctions, which results in profound conduction impairment.

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