A novel mechanism for LQT3 with 2:1 block: A pore-lining mutation in Nav1.5 significantly affects voltage-dependence of activation

作者：Horne Andrew J; Eldstrom Jodene; Sanatani Shubhayan; Fedida David^*

来源：Heart Rhythm, 2011, 8(5): 770-777.

DOI：10.1016/j.hrthm.2010.12.041

• Cardiac Sodium Channel
• LQT3
• V411M
• Flecainide
• Mexiletine
• Lidocaine

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 mu M 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.

• 出版日期2011-5