NDLI: Sinus node dysfunction following targeted disruption of the murine cardiac sodium channel gene Scn5a

Content Provider	PubMed Central
Author	Lei, Ming Goddard, Catharine Liu, Jie Léoni, Anne-laure Royer, Anne Fung, Simon S-m Xiao, Guosheng Ma, Aiqun Zhang, Henggui Charpentier, Flavien Colledge, William H. Grace, Andrew A. Huang, Christopher L-h Vandenberg, Jamie I.
Copyright Year	2005
Abstract	We have examined sino-atrial node (SAN) function in hearts from adult mice with heterozygous targeted disruption of the Scn5a gene to clarify the role of Scn5a-encoded cardiac Na+ channels in normal SAN function and the mechanism(s) by which reduced Na+ channel function might cause sinus node dysfunction. Scn5a +/− mice showed depressed heart rates and occasional sino-atrial (SA) block. Their isolated peripheral SAN pacemaker cells showed a reduced Na+ channel expression and slowed intrinsic pacemaker rates. Wild-type (WT) and Scn5a+/− SAN preparations exhibited similar activation patterns but with significantly slower SA conduction and frequent sino-atrial conduction block in Scn5a+/− SAN preparations. Furthermore, isolated WT and Scn5a+/− SAN cells demonstrated differing correlations between cycle length, maximum upstroke velocity and action potential amplitude, and cell size. Small myocytes showed similar, but large myocytes reduced pacemaker rates, implicating the larger peripheral SAN cells in the reduced pacemaker rate that was observed in Scn5a+/− myocytes. These findings were successfully reproduced in a model that implicated i Na directly in action potential propagation through the SAN and from SAN to atria, and in modifying heart rate through a coupling of SAN and atrial cells. Functional alterations in the SAN following heterozygous-targeted disruption of Scn5a thus closely resemble those observed in clinical sinus node dysfunction. The findings accordingly provide a basis for understanding of the role of cardiac-type Na+ channels in normal SAN function and the pathophysiology of sinus node dysfunction and suggest new potential targets for its clinical management.
Related Links	http://dx.doi.org/10.1113/jphysiol.2005.083188
Ending Page	400
Page Count	14
Starting Page	387
File Format	PDF
ISSN	00223751
e-ISSN	14697793
Journal	The Journal of Physiology
Issue Number	Pt 2
Volume Number	567
Language	English
Publisher	Blackwell Science Inc
Publisher Date	2005-09-01
Access Restriction	Open
Rights Holder	Blackwell Science Inc
Subject Keyword	Physiology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Physiology Sports Science

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