Overlap syndrome of cardiac sodium channel disease in mice carrying the equivalent mutation of human SCN5A-1795insD.
BACKGROUND
Patients carrying the cardiac sodium channel (SCN5A) mutation 1795insD show sudden nocturnal death and signs of multiple arrhythmia syndromes including bradycardia, conduction delay, QT prolongation, and right precordial ST-elevation. We investigated the electrophysiological characteristics of a transgenic model of the murine equivalent mutation 1798insD.


RESULTS
On 24-hour continuous telemetry and surface ECG recordings, Scn5a(1798insD/+) heterozygous mice showed significantly lower heart rates, more bradycardic episodes (pauses > or = 500 ms), and increased PQ interval, QRS duration, and QTc interval compared with wild-type mice. The sodium channel blocker flecainide induced marked sinus bradycardia and/or sinus arrest in the majority of Scn5a(1798insD/+) mice, but not in wild-type mice. Epicardial mapping using a multielectrode grid on excised, Langendorff-perfused hearts showed preferential conduction slowing in the right ventricle of Scn5a(1798insD/+) hearts. On whole-cell patch-clamp analysis, ventricular myocytes isolated from Scn5a(1798insD/+) hearts displayed action potential prolongation, a 39% reduction in peak sodium current density and a similar reduction in action potential upstroke velocity. Scn5a(1798insD/+) myocytes displayed a slower time course of sodium current decay without significant differences in voltage-dependence of activation and steady-state inactivation, slow inactivation, or recovery from inactivation. Furthermore, Scn5a(1798insD/+) myocytes showed a larger tetrodotoxin-sensitive persistent inward current compared with wild-type myocytes.


CONCLUSIONS
Mice carrying the murine equivalent of the SCN5A-1795insD mutation display bradycardia, right ventricular conduction slowing, and QT prolongation, similar to the human phenotype. These results demonstrate that the presence of a single SCN5A mutation is indeed sufficient to cause an overlap syndrome of cardiac sodium channel disease.
Remme
Carol Ann
CA
Department of Cardiology, Academic Medical Center, Room K2-110, PO Box 22700, 1100 DE Amsterdam, The Netherlands. c.a.remme@amc.uva.nl
Verkerk
Arie O
AO
Nuyens
Dieter
D
van Ginneken
Antoni C G
AC
van Brunschot
Sandra
S
Belterman
Charly N W
CN
Wilders
Ronald
R
van Roon
Marian A
MA
Tan
Hanno L
HL
Wilde
Arthur A M
AA
Carmeliet
Peter
P
de Bakker
Jacques M T
JM
Veldkamp
Marieke W
MW
Bezzina
Connie R
CR
D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000235:genetics; D018780:Body Surface Potential Mapping; D001919:Bradycardia / Q000209:etiology / Q000235:genetics; D004562:Electrocardiography; D008133:Long QT Syndrome / Q000209:etiology / Q000235:genetics; D051379:Mice; D009154:Mutation; D032383:Myocytes, Cardiac / Q000502:physiology; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D015222:Sodium Channels / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D013577:Syndrome
D062554:NAV1.5 Voltage-Gated Sodium Channel; D012333:RNA, Messenger; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; D015222:Sodium Channels