on September 19, 2005
Published online before print September 19, 2005, doi: 10.1161/CIRCULATIONAHA.105.539072
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Submitted on February 2, 2005
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. * To whom correspondence should be addressed. E-mail: A.A.B.vanVeen{at}med.uu.nl.
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.
Revised on June 17, 2005
Accepted on June 24, 2005
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*,
Key words: fibrosis • gap junction • sodium channel • aging • conduction
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