(Circulation. 2000;102:584.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Arrhythmogenic Mechanism of an LQT-3 Mutation of the Human Heart Na+ Channel 
-Subunit
A Computational Analysis
From the Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY, and the Heiden Department of Cardiology, Bikur Cholim Hospital, Jerusalem, Israel (J.B.). Drs Wehrens, Abriel, and Cabo contributed equally to this work.
Correspondence to R.S. Kass, PhD, Department of Pharmacology, College of Physicians and Surgeons of Columbia University, 630 W 168th St, PH 7W 318, New York, NY 10032. E-mail rsk20{at}columbia.edu
Background—D1790G, a mutation of
SCN5A, the gene that encodes the human Na+
channel 
-subunit, is linked to 1 form of the congenital long-QT
syndrome (LQT-3). In contrast to other LQT-3–linked
SCN5A mutations, D1790G does not promote sustained
Na+ channel activity but instead alters the kinetics and
voltage-dependence of the inactivated state.
Methods and Results—We modeled the cardiac ventricular action potential (AP) using parameters and techniques described by Luo and Rudy as our control. On this background, we modified only the properties of the voltage-gated Na+ channel according to our patch-clamp analysis of D1790G channels. Our results indicate that D1790G-induced changes in Na+ channel activity prolong APs in a steeply heart rate–dependent manner not directly due to changes in Na+ entry through mutant channels but instead to alterations in the balance of net plateau currents by modulation of calcium-sensitive exchange and ion channel currents.
Conclusions—We conclude that the D1790G mutation of the
Na+ channel -subunit can prolong the cardiac
ventricular AP despite the absence of mutation-induced
sustained Na+ channel current. This prolongation is
calcium-dependent, is enhanced at slow heart rates, and at sufficiently
slow heart rate triggers arrhythmogenic early afterdepolarizations.
Key Words: sodium • calcium • arrhythmia • torsad de pointes • action potentials
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