Background— Subclinical mutations in genes associated with the congenital long-QT syndromes (LQTS) have been suggested as a risk factor for drug-induced LQTS and accompanying life-threatening arrhythmias. Recent studies have identified genetic variants of the cardiac K + channel genes predisposing affected individuals to acquired LQTS. We have identified a novel Na + channel mutation in an individual who exhibited drug-induced LQTS. Methods and Results— An elderly Japanese woman with documented QT prolongation and torsade de pointes during treatment with the prokinetic drug cisapride underwent mutational analysis of LQTS-related genes. A novel missense mutation (L1825P) was identified within the C-terminus region of the cardiac Na + channel ( SCN5A ). The L1825P channel heterologously expressed in tsA-201 cells showed Na + current with slow decay and a prominent tetrodotoxin-sensitive noninactivating component, similar to the gain-of-function phenotype most commonly observed for SCN5A -associated congenital LQTS (LQT3). In addition, L1825P exhibited loss of function Na + channel features characteristic of Brugada syndrome. Peak Na + current density observed in cells expressing L1825P was significantly diminished, and the voltage dependence of activation and inactivation was shifted toward more positive and negative potentials, respectively. Conclusions— This study demonstrates that subclinical mutations in the LQTS-related gene SCN5A may predispose certain individuals to drug-induced cardiac arrhythmias.

These functional abnormalities may be responsible for the overlapping clinical phenotypes associated with Brugada syndrome and the cardiac conduction defect, a novel cardiac Na(+) channelopathy.

OBJECTIVES:The purpose of the study was to determine the clinical and biophysical characteristics of a novel SCN5A mutation identified in a family with atrial standstill. BACKGROUND:Congenital atrial standstill has been linked to SCN5A. Incomplete

Background-Mutations in the gene encoding the human cardiac Na ϩ channel ␣-subunit (hH1) are responsible for chromosome 3-linked congenital long-QT syndrome (LQT3) and idiopathic ventricular fibrillation (IVF). An auxiliary ␤ 1 -subunit, widely expressed in excitable tissues, shifts the voltage dependence of steady-state inactivation toward more negative potentials and restores normal gating kinetics of brain and skeletal muscle Na ϩ channels expressed in Xenopus oocytes but has little if any functional effect on the cardiac isoform. Here, we characterize the altered effects of a human ␤ 1 -subunit (h␤ 1 ) on the heterologously expressed hH1 mutation (T1620M) previously associated with IVF. Methods and Results-When expressed alone in Xenopus oocytes, T1620M exhibited no persistent currents, in contrast to the LQT3 mutant channels, but the midpoint of steady-state inactivation (V 1/2 ) was significantly shifted toward more positive potentials than for wild-type hH1. Coexpression of h␤ 1 did not significantly alter current decay or recovery from inactivation of wild-type hH1; however, it further shifted the V 1/2 and accelerated the recovery from inactivation of T1620M. Oocyte macropatch analysis revealed that the activation kinetics of T1620M were normal. Conclusions-It is suggested that coexpression of h␤ 1 exposes a more severe functional defect that results in a greater overlap in the relationship between channel inactivation and activation (window current) in T1620M, which is proposed to be a potential pathophysiological mechanism of IVF in vivo. One possible explanation for our finding is an altered ␣-/␤ 1 -subunit association in the mutant. (Circulation. 2000;101:54-60.)

Gating properties of Na ϩ channels are the critical determinants for the state-dependent block by class I antiarrhythmic drugs; however, recent site-directed mutagenesis studies have shown that the Na ϩ channel selectivity filter region controls drug access to and dissociation from the binding site. To validate these observations, we have exploited a naturally occurring cardiac Na ϩ channel mutation, S1710L, located next to the putative selectivity filter residue of domain 4, and evaluated the pharmacological properties to mexiletine using whole-cell, patchclamp recordings. Consistent with the large negative shift of steady-state inactivation and the enhanced slow inactivation, the S1710L channel showed greater mexiletine tonic block than wild-type (WT) channel. In contradiction, S1710L showed attenuated use-dependent block by mexiletine and accelerated recovery from block, suggesting that the drug escape though the external access path is facilitated. Extracellularly applied QX-314, a membrane-impermeant derivative of lidocaine, elicited significantly enhanced tonic block in S1710L similar to mexiletine. However, recovery from internally applied QX-314 was accelerated by 4.4-fold in S1710L compared with WT. These results suggest that the drug access to and dissociation from the binding site through the hydrophilic path are substantially altered. Moreover, K ϩ permeability was 1.9-fold increased in S1710L, verifying that the mutated residue is located in the ion-conducting pore. We propose that the Na ϩ channel selectivity filter region is a structural determinant for the antiarrhythmic drug sensitivity in addition to gating properties of the indigenous Na ϩ channels that govern the state-dependent drug block.

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We examined the dose distributions generated by Pinnacle3 (Philips Radiation Oncology Systems, Milpitas, CA) for intensity‐modulated radiotherapy (IMRT) plans using a cubic‐block‐piled compensator as the intensity modulator for 4‐MV and 10‐MV photon beams. The Pinnacle treatment planning system (TPS) uses an algorithm in which only the physical density of the absorber is required for calculating the characteristics of the modulator. The intensity modulator consists of cubic blocks (attenuator) of a tungsten alloy, plus cubic blocks of polyethylene resin foam that fill the spaces between the attenuator blocks and polymethyl methacrylate (PMMA) boards that act as the platform for the modulator. By measuring the transmission for various thicknesses of attenuator and by deriving values for the total physical density of the modulator, we determined the optimal effective density by comparing the curves fitted for the actual transmission data with the transmission calculated by the TPS. Using these effective densities, we examined the accuracy of Pinnacle3 for dose profiles of specific geometric patterns. The levels of consistency between the measurements and the calculations were within a tolerance of 3% of the dose difference and had a 3‐mm distance to agreement for the ladder‐, stairstep‐, and pyramid‐shaped test patterns, except in the high dose gradient region. In this modulator assembly, leakage occurred from the slits between the cubic blocks. This leakage was about 1.6% at maximum, and its influence on dose distribution was not crucial. In the TPS, in which physical density was the only user‐controllable parameter, we used the effective density of the absorber deduced from the effective mass attenuation coefficient. We conclude that the intensity modulation compensator system, together with a piled cubic attenuator, is clinically applicable, with an acceptable tolerance level. For the intensity map of the IMRT plan, measurements in treatment fields met 3% and 3‐mm criteria, excluding some regions of high gradient, which had a discrepancy of less than 5% and 4 mm.PACS numbers: 87.53.Mr, 87.53.Tf