Impaired impulse propagation in Scn5a-knockout mice: combined contribution of excitability, connexin expression, and tissue architecture in relation to aging.
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.


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.
van Veen
Toon A B
TA
Heart Lung Center, Department of Medical Physiology, University Medical Center Utrecht, Utrecht, The Netherlands. A.A.B.vanVeen@med.uu.nl
Stein
Mera
M
Royer
Anne
A
Le Quang
Khaï
K
Charpentier
Flavien
F
Colledge
William H
WH
Huang
Christopher L-H
CL
Wilders
Ronald
R
Grace
Andrew A
AA
Escande
Denis
D
de Bakker
Jacques M T
JM
van Rijen
Harold V M
HV
D000375:Aging; D000818:Animals; D002036:Bundle of His / Q000378:metabolism; D018031:Connexin 43 / Q000378:metabolism; D017630:Connexins / Q000378:metabolism*; D004562:Electrocardiography; D005355:Fibrosis; D006325:Heart Atria; D006329:Heart Conduction System / Q000503:physiopathology*; D006352:Heart Ventricles; D006579:Heterozygote; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D015222:Sodium Channels / Q000172:deficiency*; D013997:Time Factors; D016276:Ventricular Function; D061566:Voltage-Gated Sodium Channels; D000097003:Gap Junction alpha-5 Protein
D018031:Connexin 43; D017630:Connexins; D015222:Sodium Channels; D061566:Voltage-Gated Sodium Channels; D000097003:Gap Junction alpha-5 Protein; C503483:Scn7a protein, mouse