Yuko Oka

A Novel SCN5A Gain-of-Function Mutation M1875T Associated With Familial Atrial Fibrillation

OBJECTIVES This study describes a novel heterozygous gain-of-function mutation in the cardiac sodium (Na+) channel gene, SCN5A, identified in a Japanese family with lone atrial fibrillation (AF). BACKGROUND SCN5A mutations have been associated with a variety of inherited arrhythmias, but the gain-of-function type modulation in SCN5A is associated with only 1 phenotype, long-QT syndrome type 3 (LQTS3). METHODS We studied a Japanese family with autosomal dominant hereditary AF, multiple members of which showed an onset of AF or frequent premature atrial contractions at a young age. RESULTS The 31-year-old proband received radiofrequency catheter ablation, during which time numerous ectopic firings and increased excitability throughout the right atrium were documented. Mutational analysis identified a novel missense mutation, M1875T, in SCN5A. Further investigations revealed the familial aggregation of this mutation in all of the affected individuals. Functional assays of the M1875T Na(+) channels using a whole-cell patch-clamp demonstrated a distinct gain-of-function type modulation; a pronounced depolarized shift (+16.4 mV) in V(1/2) of the voltage dependence of steady-state inactivation; and no persistent Na+ current, which is a defining mechanism of LQTS3. These biophysical features of the mutant channels are potentially associated with increased atrial excitability and normal QT interval in all of the affected individuals. CONCLUSIONS We identified a novel SCN5A mutation associated with familial AF. The mutant channels displayed a gain-of-function type modulation of cardiac Na+ channels, which is a novel mechanism predisposing to increased atrial excitability and familial AF. This is a new phenotype resulting from the SCN5A gain-of-function mutations and is distinct from LQTS3.

Latent Genetic Backgrounds and Molecular Pathogenesis in Drug-induced Long QT Syndrome

Background—Drugs with IKr-blocking action cause secondary long-QT syndrome. Several cases have been associated with mutations of genes coding cardiac ion channels, but their frequency among patients affected by drug-induced long-QT syndrome (dLQTS) and the resultant molecular effects remain unknown. Methods and Results—Genetic testing was carried out for long-QT syndrome–related genes in 20 subjects with dLQTS and 176 subjects with congenital long-QT syndrome (cLQTS); electrophysiological characteristics of dLQTS-associated mutations were analyzed using a heterologous expression system with Chinese hamster ovary cells together with a computer simulation model. The positive mutation rate in dLQTS was similar to cLQTS (dLQTS versus cLQTS, 8 of 20 [40%] versus 91 of 176 [52%] subjects, P=0.32). The incidence of mutations was higher in patients with torsades de pointes induced by nonantiarrhythmic drugs than by antiarrhythmic drugs (antiarrhythmic versus others, 3 of 14 [21%] versus 5 of 6 [83%] subjects, P<0.05). When reconstituted in Chinese hamster ovary cells, KCNQ1 and KCNH2 mutant channels showed complex gating defects without dominant negative effects or a relatively mild decreased current density. Drug sensitivity for mutant channels was similar to that of the wild-type channel. With the Luo-Rudy simulation model of action potentials, action potential durations of most mutant channels were between those of wild-type and cLQTS. Conclusions—dLQTS had a similar positive mutation rate compared with cLQTS, whereas the functional changes of these mutations identified in dLQTS were mild. When IKr-blocking agents produce excessive QT prolongation (dLQTS), the underlying genetic background of the dLQTS subject should also be taken into consideration, as would be the case with cLQTS; dLQTS can be regarded as a latent form of long-QT syndrome.

Cardioverter defibrillator implantation in a patient with double chambered right ventricle

Double-chambered right ventricle (DCRV) is a rare form of congenital heart disease in which the right ventricle is divided into a high-pressure inlet site and a low-pressure outlet site by anomalous muscle bands. We describe a patient with DCRV presenting with ventricular tachycardia.

Carvedilol, a Non-Selective β-with α1-Blocker is Effective in Long QT Syndrome Type 2

Background: β‐blockers offer the first line therapy in congenital long QT syndrome (LQTS), and are more effective to prevent the cardiac event in LQTS type 1 than in type 2 or 3. In contrast, left cardiac sympathetic denervation (LCS D) was shown to be highly effective in patients refractory to β‐blockers. Total sympathetic ablation by LCSD indicates the addititional involvement of α‐adr enoceptor‐mediated pathway. In genotyped LQT2 patients, we therefore hypothesized that blockade of α‐adrenoceptor in addition to α‐adrenoceptor by carvedilol could reduce cardiac events more efficiently than other types of β‐blockers.