Contribution of Sodium Channel Mutations to Bradycardia and Sinus Node Dysfunction in LQT3 Families

Abstract

Abstract-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 ϩ channel mutation on sinoatrial (SA) pacemaking. The 1795insD channel was previously characterized by the presence of a persistent inward current (I pst ) at Ϫ20 mV and a negative shift in voltage dependence of inactivation. In the present study, we first additionally characterized I pst over the complete voltage range of the SA node action potential (AP) by measuring whole-cell Na ϩ currents (I Na ) in HEK-293 cells expressing either wild-type or 1795insD channels. I pst for 1795insD channels varied between 0.8Ϯ0.2% and 1.9Ϯ0.8% of peak I Na . Activity of 1795insD channels during SA node pacemaking was confirmed by AP clamp experiments. Next, I pst and the negative shift were implemented into SA node AP models. The Ϫ10-mV shift decreased sinus rate by decreasing diastolic depolarization rate, whereas I pst decreased sinus rate by AP prolongation, despite a concomitant increase in diastolic depolarization rate. In combination, moderate I pst (1% to 2%) and the shift reduced sinus rate by Ϸ10%. An additional increase in I pst could result in plateau oscillations and failure to repolarize completely. Thus, Na ϩ channel mutations displaying an I pst 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 Ⅲ ion channels Ⅲ sinoatrial node Ⅲ electrophysiology Ⅲ sudden death T he inherited long-QT syndrome is a familial rhythm disorder typically characterized by prolongation of the QT-interval on the ECG and life-threatening cardiac arrhythmias. 1,2 One form of the familial long-QT syndrome (LQT3) is caused by mutations in the gene encoding the cardiac sodium channel (SCN5A). 3 To date, the biophysical properties of the mutant sodium channels have been assessed for at least 21 of the distinct genetic mutations in SCN5A that have been linked to LQT3 (see online Table 1, available in the online data supplement at http://www.circresaha.org). In most of these mutations, incomplete or slowed channel inactivation induces a small persistent sodium inward current (I pst ) during prolonged depolarization (see online Table 1). This small I pst at plateau potentials is sufficient to delay repolarization of the action potential and underlies the QT-prolongation on the ECG.Previous research has focused on the correlation between altered Na ϩ channel kinetics and ventricular action potential prolongation, because the latter renders the heart vulnerable to tachyarrhythmias, especially Torsade de Pointes. In addition to the characteristic QT-prolongation, however, bradycardia and sinus pauses have also been associated with the LQT3 phenotype, indicating a ro...

Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals

“…A group of SCN5A mutations that give rise to I NaP not only underlie QT-prolongation, but also result in sinus bradycardia and sinus pauses and have been postulated to be a direct cause of sudden death in some patients [44,45]. This group of mutations includes the LQT3 mutant, D1790G, which interrupts sodium channel α-β1 interactions [40].…”

Mechanism of Sinus Bradycardia in Carriers of the 1795insD Mutation in the SCN5A Gene

“…Also, the fully-activated I Na was reduced by 78% [10]. The QT prolonging effects could be explained by the persistent I Na of ≈1.5% (percent of peak I Na ) that was observed in patch clamp experiments on wild-type and mutant Na + channels expressed in HEK-293 cells [11].…”

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

“…In addition to the well-established role of voltage-gated sodium channels as major determinants of myocardial conduction velocity (17,18), recent data have also provided strong evidence of a critical role for cardiac sodium channels in sinus nodal pacemaker activity. Sodium channels are expressed in the SA node (and surrounding tissue), and sinus node dysfunction caused by the failure of impulse generation (sinus arrest) or conduction into the adjacent atrial myocardium (exit block) has been linked to sodium channel mutations (17)(18)(19)(20). 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).…”