Cellular basis for electrocardiographic and arrhythmic manifestations of Andersen-Tawil syndrome (LQT7).
BACKGROUND
Andersen-Tawil syndrome, a skeletal muscle syndrome associated with periodic paralysis and long QT intervals on the ECG, has been linked to defects in KCNJ2, the gene encoding for the inward rectifier potassium channel (I(K1).)


OBJECTIVE
The purpose of this study was to examine the cellular mechanisms underlying the ECG and arrhythmic manifestations of Andersen-Tawil syndrome.


METHODS
To investigate the effects of KCNJ2 loss-of-function mutations responsible for Andersen-Tawil syndrome, we used barium chloride (BaCl(2)) to inhibit I(K1) in arterially perfused wedge preparation. Transmembrane action potentials (APs) were simultaneously recorded from endocardial, midmyocardial, and epicardial cells, together with a transmural ECG.


RESULTS
BaCl(2) (1 to 30 microM) produced a concentration-dependent prolongation of the QT interval, secondary to a homogeneous prolongation of AP duration of the three cell types. QT interval was prolonged without an increase in transmural dispersion of repolarization (TDR). Low extracellular potassium (2.0 mM), isoproterenol (20-50 nM), and an abrupt increase in temperature (36 degrees C-39 degrees C) in the presence of 10 microM BaCl(2) did not significantly increase TDR but increased ectopic extrasystolic activity. Early afterdepolarizations were not observed under any condition. Spontaneous torsades de pointes arrhythmias were never observed, nor could they be induced with programmed electrical stimulation under any of the conditions studied.


CONCLUSIONS
Our results provide an understanding of why QT prolongation associated with Andersen-Tawil syndrome is relatively benign in the clinic and provide further support for the hypothesis that the increase in TDR, rather than QT interval, is responsible for development of torsades de pointes.
Tsuboi
Masato
M
Masonic Medical Research Laboratory, 2150 Bleecker Street, Utica, NY 13501-1787, USA.
Antzelevitch
Charles
C
D000200:Action Potentials; D000704:Analysis of Variance; D050030:Andersen Syndrome / Q000235:genetics / Q000503:physiopathology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000503:physiopathology; D017609:Barium Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D002712:Chlorides / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D066298:In Vitro Techniques; D009154:Mutation; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors* / Q000235:genetics; D016171:Torsades de Pointes / Q000503:physiopathology
D017609:Barium Compounds; D002712:Chlorides; C489457:KCNJ2 protein, human; D024661:Potassium Channels, Inwardly Rectifying; C024986:barium chloride