BACKGROUND: SCN5A mutations that cause a gain of function in the cardiac voltage-gated sodium channel (Nav1.5) lead to long QT syndrome and a higher risk for sudden cardiac death. OBJECTIVE: Here we functionally characterize the biophysical properties of the LQT3 variant, V411M, found in a newborn with a QT interval of 640 ms and 2:1 atrioventricular block. METHODS: Whole cell patch clamp was performed on wild-type and V411M Nav1.5 channels stably expressed in human embryonic kidney cells. RESULTS: V411M channels showed hyperpolarizing shifts in both the conductance-voltage (V(1/2) = -48.5 ± 2.2 mV vs. -40.4 ± 1.6 mV for wild-type) and inactivation-voltage (-95.6 ± 1.9 mV vs. -87.7 ± 1.7 mV) relationships, and a two-fold increase in late (sustained) sodium current during voltage ramp repolarizations. While neither mexiletine nor lidocaine exhibited potency differences between WT and V411M, or shortened the QTc in vivo, increased mutant block was observed with 10 μM flecainide (71.4 ± 3.0% vs. 60.3 ± 2.8%), in a voltage-dependent manner. Incorporation of V411M kinetics into atrial and ventricular action potential models reproduced prolonged action potential repolarization. CONCLUSIONS: Our data suggest a novel mechanism for LQT3, a result of a hyperpolarizing shift in the steady state activation relationship and re-activation of Nav1.5 towards a higher open probability during repolarization of the cardiac action potential. This results in an increased number of open-activated sodium channels, and so drugs that bind this state preferentially are expected to shorten the QTc more than those that favour the inactivated state.
BACKGROUND:SCN5A mutations that cause a gain of function in the cardiac voltage-gated sodium channel (Nav1.5) lead to long QT syndrome and a higher risk for sudden cardiac death. OBJECTIVE: Here we functionally characterize the biophysical properties of the LQT3 variant, V411M, found in a newborn with a QT interval of 640 ms and 2:1 atrioventricular block. METHODS: Whole cell patch clamp was performed on wild-type and V411MNav1.5 channels stably expressed in humanembryonic kidney cells. RESULTS:V411M channels showed hyperpolarizing shifts in both the conductance-voltage (V(1/2) = -48.5 ± 2.2 mV vs. -40.4 ± 1.6 mV for wild-type) and inactivation-voltage (-95.6 ± 1.9 mV vs. -87.7 ± 1.7 mV) relationships, and a two-fold increase in late (sustained) sodium current during voltage ramp repolarizations. While neither mexiletine nor lidocaine exhibited potency differences between WT and V411M, or shortened the QTc in vivo, increased mutant block was observed with 10 μM flecainide (71.4 ± 3.0% vs. 60.3 ± 2.8%), in a voltage-dependent manner. Incorporation of V411M kinetics into atrial and ventricular action potential models reproduced prolonged action potential repolarization. CONCLUSIONS: Our data suggest a novel mechanism for LQT3, a result of a hyperpolarizing shift in the steady state activation relationship and re-activation of Nav1.5 towards a higher open probability during repolarization of the cardiac action potential. This results in an increased number of open-activated sodium channels, and so drugs that bind this state preferentially are expected to shorten the QTc more than those that favour the inactivated state.
Authors: James R Priest; Scott R Ceresnak; Frederick E Dewey; Lindsey E Malloy-Walton; Kyla Dunn; Megan E Grove; Marco V Perez; Katsuhide Maeda; Anne M Dubin; Euan A Ashley Journal: Heart Rhythm Date: 2014-06-25 Impact factor: 6.343