Assessing the efficacy of saline flush in frequency-domain optical coherence tomography for intracoronary imaging.

BACKGROUND: The increased amount of contrast media in frequency-domain optical coherence tomography (FD-OCT) imaging during percutaneous coronary intervention (PCI) has raised potential concerns regarding impairment of renal function. OBJECTIVES: This study aimed to evaluate the effectiveness of heparinized saline flush in FD-OCT-guided PCI and identify clinical factors contributing to optimal image quality. METHODS: We retrospectively collected 100 lesions from 90 consecutive patients, and a total of 200 pullbacks were analyzed for the initial and final evaluation in which saline was used as the flushing medium. RESULTS: The study population had a mean age of 73, with 52% having chronic kidney disease (CKD). The median amount of contrast used was 28 ml, and no complications were observed associated with saline flush OCT. Imaging quality was then categorized as excellent, good, or unacceptable. Among the total runs, 87% demonstrated clinically acceptable image quality, with 66.5% classified as excellent images and 20.5% classified as good images. Independent predictors of excellent images included lumen area stenosis ≥ 70% (adjusted odds ratio [OR] 2.37, 95% confidence interval [CI] 1.02-5.47, P = 0.044), and the use of intensive flushing (adjusted OR 2.06, 95% CI 1.11-3.86, P = 0.023) defined as a deep engagement of guiding catheter (GC) or a selective insertion of guide extension catheter (GE). Intensive flushing was performed in 60% of the total pullbacks, and it was particularly effective in improving image quality in the left coronary artery (LCA). CONCLUSION: The use of saline flush during FD-OCT imaging was safe and feasible, which had a benefit in renal protection with adequate imaging quality.

Usefulness of serum biopterin as a predictive biomarker for childhood asthma control: A prospective cohort study.

BACKGROUND: Pteridines are metabolites of tetrahydrobiopterin, which serves as co-enzyme of nitric oxide synthase. We sought to investigate the usefulness of pteridines as biomarkers for childhood asthma control. METHODS: We conducted a single-center prospective cohort study involving 168 asthmatic children aged 4-17 years who visited the periodical asthma checkup program. Serum neopterin and biopterin levels were measured as pteridines at each visit along with measurement of FeNO, respiratory function tests, nasal eosinophil test, blood eosinophil count, and IgE level. We calculated coefficients for relation between pteridines and asthma control, which was assessed by questionnaires (JPAC: Japanese Pediatric Asthma Control Program). RESULTS: A total of 168 participants aged 10.3 ± 3.39 years (mean ± SD) with asthma were recruited. The participants in this study contained 58 patients (34.5%) of complete-controlled based on JPAC, 132 patients (76.0%) of well-controlled group based on GINA. FeNO and serum neopterin level did not correlate with following period's JPAC scores. In contrast, serum biopterin level significantly correlated with following period's JPAC total score (Coefficients 0.398; 95% CI 0.164 to 0.632; p value 0.001) and frequency of wheezing during exercise (Coefficients 0.272; 95% CI 0.217 to 0.328; p value < 0.001). CONCLUSIONS: We found serum biopterin effected the following period's control status of asthmatic children, thus monitoring biopterin level will be a useful for management of asthma to adjust treatment.

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.

Deteriorative Effect of a Combination of Hypertriglyceridemia and Low High-Density Lipoprotein Cholesterolemia on Target Lesion Revascularization after Everolimus-Eluting Stent Implantation.

AIM: This study aimed to investigate the association between a combination of elevated triglyceride (TG) and reduced high-density lipoprotein cholesterol (HDL-C) levels and target lesion revascularization (TLR) following everolimus-eluting stent (EES) implantation. The adverse impact of clinical, lesion, and procedural characteristics on TLR in patients with elevated TG and reduced HDL-C levels was also assessed. METHODS: We retrospectively collected data on 3,014 lesions from 2,022 consecutive patients, who underwent EES implantation at Koto Memorial Hospital. Atherogenic dyslipidemia (AD) is defined as a combination of non-fasting serum TG ≥ 175 mg/dL and HDL-C ＜40 mg/dL. RESULTS: AD was observed in 212 lesions in 139 (6.9%) patients. The cumulative incidence of clinically driven TLR was significantly higher in patients with AD than in those without AD (hazard ratio [HR] 2.31, 95% confidence interval [CI] 1.43-3.73, P=0.0006). Subgroup analysis showed that AD increased the risk of TLR with the implantation of small stents (≤ 2.75 mm). Multivariable Cox regression analysis showed that AD was an independent predictor of TLR in the small EES stratum (adjusted HR 3.00, 95% CI 1.53-5.93, P=0.004), whereas the incidence of TLR was similar in the non-small-EES stratum, irrespective of the presence or absence of AD. CONCLUSIONS: Patients with AD had a higher risk of TLR after EES implantation, and this risk was greater for lesions treated with small stents.

Seasonal and circadian distributions of cardiac events in genotyped patients with congenital long QT syndrome.

BACKGROUND: Although the incidence of ventricular tachyarrhythmias associated with structural heart disease is highest in winter and during the daytime, seasonal and circadian variations among cardiac events in patients with congenital long QT syndrome (LQTS) remain unknown. The present study aims to determine seasonal and circadian cardiac events in patients with a congenital LQTS genotype. METHODS AND RESULTS: The medical records of 196 consecutive patients with symptomatic LQTS (age, 32 ± 19 years; female, n=133; LQT1, n=86; LQT2, n=95; LQT3, n=15) who were genotyped between 1979 and 2006 at 2 major Japanese institutions were retrospectively analyzed. The patients with LQT1, LQT2, and LQT3 developed 223,550 and 59 cardiac events during a mean follow-up of 26, 33, and 25 years, respectively. The numbers of cardiac events significantly peaked during the summer among those with LQT1 (P<0.001) and from summer to fall in those with LQT2 (P<0.001), but reached the nadir in winter among those with LQT3 (P=0.003). Cardiac events significantly peaked in the afternoon (12:00-17:59) and morning (06:00-11:59) among those with LQT1 (P<0.001) and LQT2 (P<0.001). CONCLUSIONS: The frequency of cardiac events was specifically seasonal and circadian among patients with the 3 major genotypes of congenital LQTS.

Molecular characterization of phenylketonuria and tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Japan.

Phenylketonuria (PKU) is a heterogeneous metabolic disorder caused by a deficiency in hepatic phenylalanine hydroxylase (PAH). On the basis of phenotype/genotype correlations, determination of phenylketonuric genotype is important for classification of the clinical phenotype and treatment of PKU, including tetrahydrobiopterin therapy. We characterized the genotypes of 203 Japanese patients with PKU and hyperphenylalaninemia using the following systems: (1) denaturing high-performance liquid chromatography with a GC-clamped primer; (2) direct sequencing; and, (3) multiplex ligation-dependent probe amplification. Of 406 mutant alleles, 390 (96%) were genotyped; 65 mutations were identified, including 22 new mutations. R413P, R241C, IVS4-1g>a, R111X and R243Q were prevalent mutations. Mutations prevalent in the Japanese cohort are also common in Korean and Northern Chinese populations, suggesting same origin. The spectrum of prevalent mutations was not significantly different among six Japanese districts, indicating that Japan comprises a relatively homogeneous ethnic group. We classified the mutations by clinical phenotypes and in vivo PAH activity and estimated the mutations with potential tetrahydrobiopterin (BH(4)) responsiveness. The frequency of BH(4) responsiveness based on the genotype was 29.1% in Japanese PKU patients. A catalog of PKU genotypes would be useful for predicting clinical phenotype, deciding on the subsequent treatment of PKU including BH(4) therapy, and genetic counseling in East Asia.

Clinical and Genetic Characteristics of Patients with Mild Hyperphenylalaninemia Identified by Newborn Screening Program in Japan.

Phenylketonuria (PKU) and hyperphenylalaninemia (HPA), both identified in newborn screening, are attributable to variants in PAH. Reportedly, the p.R53H(c.158G>A) variant is common in patients with HPA in East Asia. Here, we aimed to define the association between p.R53H and HPA phenotype, and study the long-term outcome of patients with HPA carrying p.R53H. We retrospectively reviewed the genotype in 370 patients detected by newborn screening, and identified the phenotype in 280 (117, HPA; 163, PKU). p.R413P(c.1238G>C) was the most frequently found (n = 117, 31.6%) variant, followed by p.R53H (n = 89, 24.1%). The odds ratio for heterozygous p.R53H to cause HPA was 48.3 (95% CI 19.410-120.004). Furthermore, we assessed the non-linear association between the phenylalanine (Phe) value and elapsed time using the follow-up data of the blood Phe levels of 73 patients with HPA carrying p.R53H. The predicted levels peaked at 161.9 µmol (95% CI 152.088-172.343) at 50-60 months of age and did not exceed 360 µmol/L during the 210-month long observation period. The findings suggest that patients with HPA, carrying p.R53H, do not need frequent Phe monitoring as against those with PKU. Our study provides convincing evidence to determine clinical management of patients detected through newborn screening in Japan.

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 ß-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.

Atrioventricular block-induced Torsades de Pointes with clinical and molecular backgrounds similar to congenital long QT syndrome.

BACKGROUND: Atrioventricular block (AVB) sometimes complicates QT prolongation and torsades de pointes (TdP). METHODS AND RESULTS: The clinical and genetic background of 14 AVB patients (57±21 years, 13 females) who developed QT prolongation and TdP was analyzed. Electrophysiological characteristics of mutations were analyzed using heterologous expression in Chinese hamster ovary cells, together with computer simulation models. Every patient received a pacemaker or implantable cardioverter defibrillator; 3 patients had recurrence of TdP during follow-up because of pacing failure. Among the ECG parameters, QTc interval was prolonged to 561±76ms in the presence of AVB, but shortened to 495±42ms in the absence of AVB. Genetic screening for KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 revealed four heterozygous missense mutations of KCNQ1 or KCNH2 in 4 patients (28.6%). Functional analyses showed that all mutations had loss of functions and various gating dysfunctions of I(Ks) or I(Kr). Finally, action potential simulation based on the Luo-Rudy model demonstrated that most mutant channels induced bradycardia-related early afterdepolarizations. CONCLUSIONS: Incidental AVB, as a trigger of TdP, can manifest as clinical phenotypes of long QT syndrome (LQTS), and that some patients with AVB-induced TdP share a genetic background with those with congenital LQTS.

Effect of Glycemic Control During Follow-up on Late Target Lesion Revascularization After Implantation of New-Generation Drug-Eluting Stents in Patients With Diabetes　- A Single-Center Observational Study.

Background: Few studies have investigated the importance of glycemic control in patients with diabetes mellitus (DM) for reducing the incidence of late target lesion revascularization (TLR) after implantation of new-generation drug-eluting stents (DES). Methods and Results: We retrospectively identified 1,568 patients who underwent new-generation DES implantation. Patients were divided into 3 groups based on diabetic status and glycemic control 1 year after the procedure: those without DM (non-DM group; n=1,058) and those with DM at follow-up with either good (HbA1c <7%; n=328) or poor (HbA1c ≥7%; n=182) control. The cumulative 5-year incidence of clinically driven late TLR after the index procedure was significantly higher in DM with poor control at follow-up than in those with good control at follow-up or non-DM (14%, 4.8%, and 2.9%, respectively; P<0.0001). Multivariate analysis revealed that poor control at follow-up was significantly associated with a higher risk of clinically driven late TLR compared with the non-DM group (hazard ratio [HR] 4.58, 95% confidence interval [CI] 2.50-8.16, P<0.0001). However, good control at follow-up group was not associated with a higher risk of clinically driven late TLR compared with the non-DM group (HR 1.35, 95% CI 0.68-2.56, P=0.38). Conclusions: DM patients with poor glycemic control at follow-up had a significantly higher risk of clinically driven late TLR than non-DM patients.

A trafficking-deficient KCNQ1 mutation, T587M, causes a severe phenotype of long QT syndrome by interfering with intracellular hERG transport.

BACKGROUND: KCNQ1-T587M is a C-terminal mutation correlated with severe phenotypes of long QT syndrome (LQTS). However, functional analysis of KCNQ1 channels with the T587M mutation showed a mild genotype in the form of haploinsufficiency in a heterologous expression system. This study sought to explore the molecular mechanism underlying the phenotype-genotype dissociation of LQTS patients carrying the KCNQ1-T587M mutation. METHODS: cDNAs for wild-type (WT) and KCNQ1 mutations (R259C and T587M) were transiently transfected into HEK293 cells stably expressing hERG (hERG-HEK), and whole-cell patch-clamp technique was performed to examine the effect of KCNQ1 mutations on IKr-like currents. In addition, fluorescence resonance energy transfer (FRET) was conducted to demonstrate the molecular interaction between KCNQ1 and hERG when co-expressed in HEK293 cells. RESULTS: KCNQ1-T587M mutation produced a significant (p<0.01) decrease in IKr-like tail current densities without affecting the gating kinetics, while KCNQ1-R259C mutation had no significant effect on the IKr-like tail current densities. Consistent with this result, FRET experiments demonstrated that both KCNQ1-WT and -R259C interacted with hERG in the cytosol and on the plasma membrane; however, the interaction between KCNQ1-T587M and hERG was observed only in the cytosol, and hERG proteins were seldom transported to the cell membrane, suggesting that the KCNQ1-T587M mutation impaired the trafficking of hERG to the cell membrane. CONCLUSIONS: The disruption of hERG trafficking caused by the KCNQ1-T587M mutation is likely the reason why some patients exhibit severe LQTS phenotypes.

Successful Surgery of Right Common Iliac Artery Injury during Lumbar Discectomy with Endovascular Balloon Occlusion of the Aorta Performed by Cardiologists.

A 19-year-old woman developed hypotension and abdominal distension during lumbar discectomy. Computed tomography revealed a right common artery injury and a large retroperitoneal hematoma. She was transferred to our hospital and brought to an angiography room directly. Endovascular balloon occlusion of the aorta was performed by cardiologists while surgeons were preparing for surgery. With the hemodynamics stabilized, the injured artery was repaired. In such a case, closing the artery as soon as possible, whether by clamping or by balloon occlusion, is vital. The ability to respond with a "Heart Team" is essential for a small-manpower hospital to rescue a patient with a serious condition.

Post-intervention minimal stent area as a predictor of target lesion revascularization after everolimus-eluting stent implantation for in-stent restenosis: a single-center observational study.

BACKGROUND: Everolimus-eluting stent (EES) is effective for treating in-stent restenosis (ISR). However, the long-term incidence of target lesion revascularization (TLR) is unknown. Further, the role of post-intervention minimal stent area (MSA) measured by intravascular ultrasound (IVUS) in TLR is unknown in this setting. PATIENTS AND METHODS: Overall, 223 ISR lesions (192 patients) that were treated with EES between 2010 and 2016 were analyzed retrospectively. Lesions were divided into two groups according to the post-intervention MSA [ ≤ 5.3 mm: 72 lesions (67 patients), and > 5.3 mm: 151 lesions (138 patients)]. The cut-off point was determined on the basis of receiver operating characteristic curve analysis. RESULTS: The cumulative 5-year incidence of TLR was significantly higher in the group with MSA of 5.3 mm or less than in the group with MSA more than 5.3 mm (15.8 and 7.2%, P = 0.01). After adjusting for confounders, the excess risk of the group with MSA of 5.3 mm or less relative to the group with MSA more than 5.3 mm for TLR remained significant [hazard ratio: 3.07, 95% confidence interval (CI): 1.17-8.51, P = 0.02]. Using multivariate logistic regression analysis, we identified female sex (odds ratio: 2.39, 95% CI: 1.06-5.49, P = 0.04) and stent size of 3.0 mm or less (odds ratio: 13.43, 95% CI: 6.23-32.38, P < 0.0001) as independent predictors of MSA of 5.3 mm or less. CONCLUSION: EES implantation for ISR was associated with an acceptable rate of TLR through long-term follow-up. Postintervention MSA of 5.3 mm or less was associated independently with a higher risk for TLR.

Age- and genotype-specific triggers for life-threatening arrhythmia in the genotyped long QT syndrome.

INTRODUCTION: Patients with long QT syndrome (LQTS) become symptomatic in adolescence, but some become at age of >or=20 years. Since it remains unknown whether clinical features of symptomatic LQTS patients differ depending on the age of onset, we aimed to examine whether triggers for cardiac events are different depending on the age in genotyped and symptomatic LQTS patients. METHODS AND RESULTS: We identified 145 symptomatic LQTS patients, divided them into three groups according to the age of first onset of symptoms (young <20, intermediate 20-39, and older >or=40 years), and analyzed triggers of cardiac events (ventricular tachycardia, syncope, or cardiac arrest). The triggers were divided into three categories: (1) adrenergically mediated triggers: exercise, emotional stress, loud noise, and arousal; (2) vagally mediated triggers: rest/sleep; and (3) secondary triggers: drugs, hypokalemia, and atrioventricular (AV) block. In the young group, 78% of the cardiac events were initiated by adrenergically mediated triggers and 22% were vagally mediated, but none by secondary triggers. In contrast, the adrenergically mediated triggers were significantly lower in the intermediate group. The percentage of secondary triggers was significantly larger in the older group than in the other two groups (0% in young vs 23% in intermediate vs 72% in older; P < 0.0001). Concerning the subdivision of secondary triggers on the basis of genotype, hypokalemia was only observed in LQT1, drugs mainly in LQT2, and AV block only in LQT2. CONCLUSION: Arrhythmic triggers in LQTS differ depending on the age of the patients, stressing the importance of age-related therapy for genotyped LQTS patients.

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.

A novel KCNH2 mutation as a modifier for short QT interval.

In a 34-year-old man showing short QT interval (QTc 329 ms), we identified a novel C-terminal KCNH2 mutation, R1135H. Using a heterologous expression system with CHO cells, the mutant channels were found to display a significantly slow deactivation, which resulted in a gain-of-function for reconstituted 'I(Kr)' channels. This mutation could modify clinical phenotypes for this patient.

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.

Latent genetic backgrounds and molecular pathogenesis in drug-induced long-QT syndrome.

BACKGROUND: Drugs with I(Kr)-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 I(Kr)-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.

Hydroxyzine, a first generation H(1)-receptor antagonist, inhibits human ether-a-go-go-related gene (HERG) current and causes syncope in a patient with the HERG mutation.

QT prolongation, a risk factor for arrhythmias, can result from genetic variants in one (or more) of the genes governing cardiac repolarization as well as intake of drugs known to affect a cardiac K(+) channel encoded by human ether-a-go-go-related gene (HERG). In this paper, we will report a case of drug-induced long QT syndrome associated with an H(1)-receptor antagonist, hydroxyzine, in which a mutation was identified in the HERG gene. After taking 75 mg of hydroxyzine for several days, a 34-year-old female began to experience repetitive syncope. The deleterious effect of hydroxyzine was suspected because QTc interval shortened from 630 to 464 ms after cessation of the drug. Later on, the patient was found to harbor an A614V-HERG mutation. By using the patch-clamp technique in the heterologous expression system, we examined the functional outcome of the A614V mutation and confirmed a dominant-negative effect on HERG expression. Hydroxyzine concentration-dependently inhibited both wild-type (WT) and WT/A614V-HERG K(+) currents. Half-maximum block concentrations of WT and WT/A614V-HERG K(+) currents were 0.62 and 0.52 microM, respectively. Thus, accidental combination of genetic mutation and intake of hydroxyzine appeared to have led to a severe phenotype, probably, syncope due to torsade de pointes.

Mutation site dependent variability of cardiac events in Japanese LQT2 form of congenital long-QT syndrome.

BACKGROUND: In the LQT2 form of long QT syndrome (LQTS), mutation sites are reported to correlate with clinical phenotypes in Caucasians, but the relationship in Asian patients remains unknown. The present study was designed to determine whether the location of KCNH2 mutations would influence the arrhythmic risk in LQT2 patients. METHODS AND RESULTS: In 118 genetically-confirmed LQT2 patients (69 families, 62 KCNH2 mutations), the ECG parameters, Schwartz scores, and the incidence of cardiac events, defined as syncope, aborted cardiac arrest, and sudden cardiac death, were evaluated. To examine the effect of mutation sites, the participants were divided accordingly: pore (n=56) and non-pore (n=62) groups. The corrected QTend interval was significantly greater in the pore than in the non-pore group (QTc; 522+/-63 ms vs 490+/-49 ms, p=0.002). In this study, the clinical course of each of the probands did not differ according to the mutation sites, whereas non-probands carrying the pore site mutation experienced their first cardiac events at significantly younger age than those with the non-pore site mutation (log-rank, p=0.0005). CONCLUSIONS: In a Japanese LQT2 cohort, family members with the pore site mutation were at higher arrhythmic risk than those with the non-pore site mutation.