Published online before print April 3, 2003, doi: 10.1161/01.RES.0000069689.09869.A8
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Submitted on April 12, 2002
Revised on March 21, 2003
Accepted on March 21, 2003
Contribution of Sodium Channel Mutations to Bradycardia and Sinus Node Dysfunction in LQT3 Families
Marieke W. Veldkamp *;
From the Experimental and Molecular Cardiology Group (M.W.V., A.B., C.R.B., A.A.M.W.) and the Departments of Physiology (R.W., J.G.Z.) and Clinical Genetics (C.R.B.), Academic Medical Center, University of Amsterdam, The Netherlands.
* To whom correspondence should be addressed. E-mail: m.w.veldkamp{at}amc.uva.nl.
One variant of the long-QT syndrome (LQT3) is caused by mutations in the human cardiac sodium channel gene. In addition to the characteristic QT prolongation, LQT3 carriers regularly present with bradycardia and sinus pauses. Therefore, we studied the effect of the 1795insD Na+ channel mutation on sinoatrial (SA) pacemaking. The 1795insD channel was previously characterized by the presence of a persistent inward current (Ipst) at -20 mV and a negative shift in voltage dependence of inactivation. In the present study, we first additionally characterized Ipst over the complete voltage range of the SA node action potential (AP) by measuring whole-cell Na+ currents (INa) in HEK-293 cells expressing either wild-type or 1795insD channels. Ipst for 1795insD channels varied between 0.8±0.2% and 1.9±0.8% of peak INa. Activity of 1795insD channels during SA node pacemaking was confirmed by AP clamp experiments. Next, Ipst and the negative shift were implemented into SA node AP models. The -10-mV shift decreased sinus rate by decreasing diastolic depolarization rate, whereas Ipst decreased sinus rate by AP prolongation, despite a concomitant increase in diastolic depolarization rate. In combination, moderate Ipst (1% to 2%) and the shift reduced sinus rate by 
10%. An additional increase in Ipst could result in plateau oscillations and failure to repolarize completely. Thus, Na+ channel mutations displaying an Ipst or a negative shift in inactivation may account for the bradycardia seen in LQT3 patients, whereas SA node pauses or arrest may result from failure of SA node cells to repolarize under conditions of extra net inward current.
Key words: long-QT syndrome • ion channels • sinoatrial node • electrophysiology • sudden death
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