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

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.

Contribution of Nav1.1 to cellular synchronization and automaticity in spontaneous beating cultured neonatal rat ventricular cells

“…Previous studies have demonstrated that Na v 1.5 is involved in action potential propagation, but both Na v 1.1 and Na v 1.5 contribute to the pacemaking in SAN (Haufe et al 2005). However, knockout of Na v 1.5 mice caused bradycardia, which elucidates the possibility of Na v 1.5 contribution to the pacemaking (Lei et al 2005). Thus, the true nature of the spontaneous rhythm generation, synchronization and propagation of cells remains an open question with Na + channel isoforms participation.…”

Lithium-induced sinus node disease at therapeutic concentrations: Linking lithium-induced blockade of sodium channels to impaired pacemaker activity

“…Loss of function mutations in human cardiac sodium channels have been linked to atrial standstill (21), conduction system disease (22), sick sinus syndrome and bradyarrhythmia (19,20). Furthermore, a murine model with a partial loss of the pore-forming (alpha) subunits of the sodium channel essentially recapitulates the key features of sinus nodal dysfunction in humans (23).…”

Popeye proteins: muscle for the aging sinus node

“…An inward sodium current is also detectable in sinus node cells and is important for normal sinus node function (17,18). Furthermore, mice with a heterozygous mutation in Scn5a show sinus node dysfunction and age-dependent degeneration of sinus node tissue (19).…”