Journal
PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY
Volume 96, Issue 1-3, Pages 281-293Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pbiomolbio.2007.07.023
Keywords
sudden death; mutation; SCN5A; long QT syndrome; model
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In LQT3 patients, SCN5A mutations induce ultraslow inactivation of a small fraction of the hNav1.5 current, i.e. persistent Na+ current (I-pNa). We explored the time course of effects of such a change on the intracellular ionic homeostasis in a model of guinea-pig cardiac ventricular cell [Pasek, M., Simurda, J., Orchard, C.H., Christe, G., 2007b. A model of the guinea-pig ventricular cardiomyocyte incorporating a transverse-axial tubular system. Prog. Biophys. Mol. Biol., this issue]. Sudden addition of I-pNa prevented action potential (AP) repolarization when its conductance (g(pNa)) exceeded 0.12% of the maximal conductance of fast I-Na (g(Na)). With g(pNa) at 0.1% g(Na), the AP duration at 90% repolarization (APD(90)) was initially lengthened to 2.6-fold that in control. Under regular stimulation at 1 Hz it shortened progressively to 1.37-fold control APD(90), and intracellular [Na+](i) increased by 6% with a time constant of 106s. Further increasing g(pNa) to 0.2% g(Na) caused an immediate increase in APD(90) to 5.7-fold that in control, which decreased to 2.2-fold that in control in 30s stimulation at 1 Hz. At this time diastolic [Na+](i) and [Ca2+](i) were, respectively, 34% and 52% higher than in control and spontaneous erratic SR Ca release occurred. In the presence of I-pNa Causing 46% lengthening of APD(90), the model cell displayed arrhythmogenic behaviour when external [K+] was lowered to 5 mM from an initial value at 5.4 mM. By contrast, when K+ currents I-Kr and I-Ks were lowered in the model cell to produce the same lengthening of APD(90), no proarrhythmic behaviour was observed, even when external [K+] was lowered to 2.5 mM. (C) 2007 Elsevier Ltd. All rights reserved.
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