Akashi Miyamoto

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.

KCNE5 (KCNE1L) Variants Are Novel Modulators of Brugada Syndrome and Idiopathic Ventricular Fibrillation

Background—Brugada syndrome (BrS) has a significantly higher incidence among the male sex. Among genes coding ion channels and their modulatory proteins, KCNE5 (KCNE1L) is located in the X chromosome and encodes an auxiliary &bgr;-subunit for K channels. KCNE5 has been shown to modify the transient outward current (Ito), which plays a key role in determining the repolarization process in the myocardium. This study investigated whether KCNE5 mutations could be responsible for BrS and other idiopathic ventricular fibrillation (IVF). Methods and Results—In 205 Japanese patients with BrS or IVF who tested negative for SCN5A mutation, we conducted a genetic screen for KCNE5 variants. We identified 2 novel KCNE5 variants: p.Y81H in 3 probands and p.[D92E;E93X] in 1 proband from 4 unrelated families. Y81H was identified in 1 man and 2 women; D92E;E93X was found in a 59-year-old man. All probands received implantable cardioverter-defibrillators. Functional consequences of the KCNE5 variants were determined through biophysical assay using cotransfection with KCND3 or KCNQ1. In the experiments with KCND3, which encodes Kv4.3, Ito was significantly increased for both KCNE5 variants compared to wild type. In contrast, there were no significant changes in current properties reconstructed by KCNQ1+ wild type KCNE5 and the 2 variants. With the simulation model, both variants demonstrated notch-and-dome or loss-of-dome patterns. Conclusions—KCNE5 modulates Ito, and its novel variants appeared to cause IVF, especially BrS, in male patients through gain-of-function effects on Ito. Screening for KCNE5 variants is relevant for BrS or IVF.

Phenotype Variability in Patients Carrying KCNJ2 Mutations

Background— Mutations of KCNJ2, the gene encoding the human inward rectifier potassium channel Kir2.1, cause Andersen-Tawil syndrome (ATS), a disease exhibiting ventricular arrhythmia, periodic paralysis, and dysmorphic features. However, some KCNJ2 mutation carriers lack the ATS triad and sometimes share the phenotype of catecholaminergic polymorphic ventricular tachycardia (CPVT). We investigated clinical and biophysical characteristics of KCNJ2 mutation carriers with “atypical ATS.” Methods and Results— Mutational analyses of KCNJ2 were performed in 57 unrelated probands showing typical (≥2 ATS features) and atypical (only 1 of the ATS features or CPVT) ATS. We identified 24 mutation carriers. Mutation-positive rates were 75% (15/20) in typical ATS, 71% (5/7) in cardiac phenotype alone, 100% (2/2) in periodic paralysis, and 7% (2/28) in CPVT. We divided all carriers (n=45, including family members) into 2 groups: typical ATS (A) (n=21, 47%) and atypical phenotype (B) (n=24, 53%). Patients in (A) had a longer QUc interval [(A): 695±52 versus (B): 643±35 ms] and higher U-wave amplitude (0.24±0.07 versus 0.18±0.08 mV). C-terminal mutations were more frequent in (A) (85% versus 38%, P<0.05). There were no significant differences in incidences of ventricular tachyarrhythmias. Functional analyses of 4 mutations found in (B) revealed that R82Q, R82W, and G144D exerted strong dominant negative suppression (current reduction by 95%, 97%, and 96%, respectively, versus WT at −50 mV) and T305S moderate suppression (reduction by 89%). Conclusions— KCNJ2 gene screening in atypical ATS phenotypes is of clinical importance because more than half of mutation carriers express atypical phenotypes, despite their arrhythmia severity.

P wave and the development of atrial fibrillation

BACKGROUND Terminal P-wave inversion in lead V(1) representing left atrial overload has been considered a precursor of atrial fibrillation (AF). OBJECTIVE The purpose of this study was to determine whether this P-wave morphologic characteristic can predict the development of AF. METHODS Digital analysis of 12-lead ECGs was performed to enroll patients with P terminal force > or =0.06 s x 2 mm in lead V(1) from among a database of 308,391 ECG recordings. The prognostic value of ECG characteristics for developing AF was determined. RESULTS A total of 78 patients (mean age 52 +/- 19 years) with left atrial overload were chosen from among 102,065 patients in the database. During mean follow-up of 43 months, 15 (19%) patients developed AF (AF group) versus 63 (81%) patients who did not (non-AF group). No significant difference was noted between the AF and non-AF groups with regard to the area, duration, and amplitude of the P-wave terminal portion in lead V(1). In contrast, the area, duration, and amplitude of the P-wave initial portion in the same lead were significantly greater in the AF group than in the non-AF group (114.6 +/- 73.0 microV x ms vs 73.1 +/- 59.3 microV x ms, 42.2 +/- 12.4 ms vs 35.7 +/- 10.1 ms, and 94.0 +/- 39.9 microV vs 68.8 +/- 49.4 microV, respectively; P <.05 for each). Multivariate analysis confirmed that the area of the P-wave initial portion was independently associated with the development of AF (hazard ratio 4.02, 95% confidence interval 1.25-17.8; P = .018). CONCLUSION P-wave initial portion in lead V(1) was an independent risk stratifier of AF development in patients with marked left atrial overload.

Gain-of-function KCNH2 mutations in patients with Brugada syndrome.

Brugada syndrome (BrS) is an inherited disease characterized by right precordial ST segment elevation on electrocardiograms (ECGs) that predisposes patients to sudden cardiac death as a result of polymorphic ventricular tachyarrhythmia or ventricular fibrillation (VF). In BrS patients, except for SCN5A, mutations in other responsible genes are poorly elucidated.

Clinical and electrocardiographic characteristics of patients with short QT interval in a large hospital-based population

BACKGROUND Short QT syndrome is one of the underlying disorders associated with ventricular fibrillation. However, the precise prognostic implication of a short QT interval remains unclear. OBJECTIVE The purpose of this study was to investigate the prevalence and long-term prognosis in patients with a shorter-than-normal QT interval in a large hospital-based population. METHODS We chose patients with a short Bazett QTc interval from a database consisting of 114,334 patients to determine the clinical characteristics and prognostic value of a short QT interval. RESULTS A total of 427 patients (mean age 43.4 ± 22.4 years) had a short QT interval with about a 1.2 times higher male predominance (234 men). The QTc interval was significantly longer in female than in male patients (363.8 ± 6.1 ms vs 357.1 ± 5.8 ms, P <.0001). The age-specific prevalence of patients with short QT interval was biphasic, peaking at young and old age. Atrial fibrillation and early repolarization were complicated with short QT interval in 39 (9.1%) and 26 (6.1%) patients, respectively. The prognosis of 327 patients (182 men; mean age, 46.4 ± 27.3 years) with a short QT interval could be assessed (mean follow-up period, 54.0 ± 62.0 months). During the follow-up, 2 patients, 1 of whom had early repolarization, developed life-threatening events, in contrast to 6 patients who died of noncardiac causes and did not have early repolarization. CONCLUSION The prevalence of a short QT interval showed a slight male preponderance and biphasic age-dependent distribution in both genders. The complication rate of atrial fibrillation was higher in those with a short QT interval than in general populations. The long-term outcome suggested that early repolarization in a short QT interval might be associated with potential risk of lethal arrhythmia.

Remission of Abnormal Conduction and Repolarization in the Right Ventricle After Chemotherapy in Patients With Anterior Mediastinal Tumor

A 22-year-old man with no significant past medical history presented with dry cough that lasted for a couple of months. The patient denied accompanying shortness of breath, palpitation, edema, high fever, or syncope. He had no family history of sudden death. On examination, he was afebrile with a blood pressure of 106/63 mm Hg, pulse rate of 88 beats/min, and normal oxygen saturation. His heart sound was normal without a pericardial rub. ECG (Fig. 1A) displayed a terminal r wave (arrow a) and ST-segment elevation (arrow b) followed by negative deflection of T wave (arrow c) in lead V1. Chest computed tomography (Fig. 1A) revealed the existence of demarcated tumor in the anterior mediastinal space that attached to the pericardium in front of the right atrium and ventricle. The tumor encompassed the right ventricular outflow tract (arrow) but did not show invasion into the intrapericardial space. The tumor was histologically diagnosed with the large B cell lymphoma from a specimen obtained by needle biopsy. He started to undergo chemotherapy including cyclophosphamide, vincristine, doxorubicin, rituximab, and prednisolone. Two months after the chemotheraphy, chest computed tomography confirmed that the lymphoma size

Prevalence and QT Interval of Early Repolarization in a Hospital-based Population

Background: Early repolarization, which was regarded as benign, has recently been associated with malignant arrhythmia. Despite the newly emerged importance of early repolarization, little is known about prevalence and QT interval of early repolarization. Methods: Early repolarization (defined as an elevation at the junction between QRS complex and ST segment ≥ 0.1 mV in at least 2 leads) was assessed in database containing 308,391 ECGs consisting of 102,065 patients (52,779 males and 49,286 females).

Flecainide reduces ventricular arrhythmias via a mechanism that differs from that of β-blockers in catecholaminergic polymorphic ventricular tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by episodic ventricular tachycardia induced by adrenergic stress. Although β‐blockers are used as first‐line therapy, their therapeutic effects are largely incomplete. Flecainide has recently been shown to modify the molecular defects in CPVT. The aim of this study was to investigate the effects of flecainide as an add‐on to conventional therapy on exercise‐induced ventricular arrhythmia and compare them with those of conventional therapy alone.

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.