Tomoko Sakaguchi

D85N, a KCNE1 Polymorphism, Is a Disease-Causing Gene Variant in Long QT Syndrome

OBJECTIVES This study aims to address whether D85N, a KCNE1 polymorphism, is a gene variant that causes long QT syndrome (LQTS) phenotype. BACKGROUND KCNE1 encodes the beta-subunit of cardiac voltage-gated K(+) channels and causes LQTS, which is characterized by the prolongation of the QT interval and torsades de pointes, a lethal arrhythmia. D85N, a KCNE1 polymorphism, is known to be a functional variant associated with drug-induced LQTS. METHODS In order to elucidate the prevalence and clinical significance of this polymorphism, we performed genetic screening in 317 LQTS probands. For comparison, we examined its presence in 496 healthy control subjects. We also conducted biophysical assays for the D85N variant in mammalian cells. RESULTS The allele frequency for D85N carriers was 0.81% in healthy people. In contrast, among LQTS probands, there were 1 homozygous and 23 heterozygous carriers (allele frequency 3.9%). Seven of 23 heterozygous carriers had additional mutations in LQTS-related genes, and 3 female subjects had documented factors predisposing to the symptom. After excluding these probands, the D85N prevalence was significantly higher compared with control subjects (allele frequency 2.1%, p < 0.05). In a heterologous expression study with Chinese hamster ovarian cells, KCNE1-D85N was found to exert significant loss-of-function effects on both KCNQ1- and KCNH2-encoded channel currents. CONCLUSIONS The KCNE1-D85N polymorphism was significantly more frequent in our LQTS probands. The functional variant is a disease-causing gene variant of LQTS phenotype that functions by interacting with KCNH2 and KCNQ1. Since its allele frequency was approximately 1% among control individuals, KCNE1-D85N may be a clinically important genetic variant.

Long QT syndrome with compound mutations is associated with a more severe phenotype: A Japanese multicenter study

BACKGROUND Long QT syndrome (LQTS) can be caused by mutations in the cardiac ion channels. Compound mutations occur at a frequency of 4% to 11% among genotyped LQTS cases. OBJECTIVE The purpose of this study was to determine the clinical characteristics and manner of onset of cardiac events in Japanese patients with LQTS and compound mutations. METHODS Six hundred three genotyped LQTS patients (310 probands and 293 family members) were divided into two groups: those with a single mutation (n = 568) and those with two mutations (n = 35). Clinical phenotypes were compared between the two groups. RESULTS Of 310 genotyped probands, 26 (8.4%) had two mutations in the same or different LQTS-related genes (compound mutations). Among the 603 LQTS patients, compound mutation carriers had significantly longer QTc interval (510 ± 56 ms vs 478± 53 ms, P = .001) and younger age at onset of cardiac events (10 ± 8 years vs 18 ± 16 years, P = .043) than did single mutation carriers. The incidence rate of cardiac events before age 40 years and use of beta-blocker therapy among compound mutation carriers also were different than in single mutation carriers. Subgroup analysis showed more cardiac events in LQTS type 1 (LQT1) and type 2 (LQT2) compound mutations compared to single LQT1 and LQT2 mutations. CONCLUSION Compound mutation carriers are associated with a more severe phenotype than single mutation carriers.

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.

Effect of an angiotensin II type 1 receptor blocker, valsartan, on neurohumoral factors in patients with hypertension: comparison with a long-acting calcium channel antagonist, amlodipine.

Summary: This study compared the effects of amlodipine and valsartan on the sympathetic nervous system, the renin‐angiotensin‐ aldosterone system, and brain natriuretic peptide, which are considered important parameters of the long‐term prognosis. Seventythree elderly patients, who had received antihypertensive treatment for more than 6 months with amlodipine, participated in this study. They were randomized to the V group (n = 36) and switched to valsartan from amlodipine, or to the A group (n = 37), which continued treatment with amlodipine. The dose of valsartan was set as that which controlled the blood pressure to the same extent as before switching. Blood samples were measured before and after 6 months of therapy. Data were analyzed by two‐way analysis of variance with the Newman‐Keuls test. In the V group, norepinephrine (from 597.0 ± 52.9 to 475 ± 43.8 pg/ml, p < 0.05) and aldosterone (from 74.5 ± 7.0 to 53.9 ± 5.3 pg/ml, p < 0.001) were decreased significantly after 6 months, although norepinephrine and aldosterone levels were unchanged in the A group. However, brain natriuretic peptide did not show a difference between the two groups. These findings suggested that valsartan is probably superior to amlodipine with respect to less activation of the sympathetic nervous system and preventing upregulation of the renin‐angiotensin‐aldosterone system.

Heart rate-dependent variability of cardiac events in type 2 congenital long-QT syndrome

AIMS We aimed to examine the validity of heart rate (HR) at rest before β-blocker therapy as a risk factor influencing cardiac events (ventricular fibrillation, torsades de pointes, or syncope) in long QT type 2 (LQT2) patients. METHODS AND RESULTS In 110 genetically confirmed LQT2 patients (45 probands), we examined the significance of variables [HR at rest, corrected QT (QTc), female gender, age of the first cardiac event, mutation site] as a risk factor for cardiac events. We also evaluated frequency of cardiac events in four groups classified by the combination of basal HR and QTc with cutoff values of 60 b.p.m. and 500 ms to estimate if these two electrocardiographic parameters in combination could be a good predictor of outcome (mean follow-up period: 50 ± 39 months). Logistic regression analysis revealed three predictors: HR < 60 b.p.m., QTc ≥ 500 ms, and female gender. When the study population was divided into four groups using the cutoff values of 60 b.p.m. for HR and 500 ms for QTc, the cumulative event-free survival by the Kaplan-Meier method was significantly higher in the group with HR ≥ 60 b.p.m. and QTc < 500 ms than in the group with HR < 60 b.p.m. and QTc < 500 ms or that with HR < 60 b.p.m. and QTc ≥ 500 m (P < 0.05). Irrespective of QTc interval, LQT2 patients with basal HR < 60 b.p.m. were at significantly higher risk. CONCLUSION The basal HR of < 60 b.p.m. is a notable risk factor for the prediction of life-threatening arrhythmias in LQT2 patients.

Different responses to exercise between Andersen–Tawil syndrome and catecholaminergic polymorphic ventricular tachycardia

Aims Andersen-Tawil Syndrome (ATS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) are both inherited arrhythmic disorders characterized by bidirectional ventricular tachycardia (VT). The aim of this study was to evaluate the diagnostic value of exercise stress tests for differentiating between ATS and CPVT. Methods and results We included 26 ATS patients with KCNJ2 mutations from 22 families and 25 CPVT patients with RyR2 mutations from 22 families. We compared the clinical and electrocardiographic (ECG) characteristics, responses of ventricular arrhythmias (VAs) to exercise testing, and the morphology of VAs between ATS and CPVT patients. Ventricular arrhythmias were more frequently observed at baseline in ATS patients compared with CPVT patients [the ratio of ventricular premature beats (VPBs)/sinus: 0.83 ± 1.87 vs. 0.06 ± 0.30, P = 0.01]. At peak exercise, VAs were suppressed in ATS patients, whereas they were increased in CPVT patients (0.14 ± 0.40 vs. 1.94 ± 2.71, P < 0.001). Twelve-lead ECG showed that all 25 VPBs and 15 (94%) of 16 bidirectional VTs were right bundle branch block (RBBB) morphology in ATS patients, whereas 19 (86%) of 22 VPBs had left bundle branch block (LBBB), and 12 (71%) of 17 bidirectional VT had LBBB and RBBB morphologies in CPVT patients. Conclusion In patients with ATS, VAs with RBBB morphology were frequently observed at baseline and suppressed at peak exercise. In contrast, exercise provoked VAs with mainly LBBB morphology in patients with CPVT. In adjunct to clinical and baseline ECG assessments, exercise testing might be useful for making the diagnosis of ATS vs. CPVT, both characterized by bidirectional VT.