Extracorporeal membrane oxygenation for the anesthetic management of a patient with severe airway stenosis caused by thyroid carcinoma invasion.

The treatment of a thyroid carcinoma extending into the thoracic cavity with severe airway stenosis is difficult, since there is a risk of acute respiratory decompensation at every stage of anesthesia. Extracorporeal membrane oxygenation (ECMO) is a life support technique for maintaining both the cardiac and respiratory functions. It is used for the management of acute, severe, reversible respiratory or cardiac failure refractory to conventional management. We herein describe the use of ECMO for the anesthetic management of an elderly patient with severe airway stenosis caused by thyroid carcinoma invasion, which underwent total thyroidectomy with the resection of four tracheal rings and end-to-end anastomosis under a median sternotomy. Although the risks and benefits should be carefully weighed before a decision to use ECMO is made, the use of ECMO in the management of general anesthesia may be a rational and effective strategy for maintaining oxygenation.

A computational analysis of the effect of sevoflurane in a human ventricular cell model of long QT syndrome: Importance of repolarization reserve in the QT-prolonging effect of sevoflurane.

The slowly and rapidly activating delayed rectifier K+ channels (IKs and IKr, respectively) contribute to the repolarization of ventricular action potential in human heart and thereby determine QT interval on an electrocardiogram. Loss-of-function mutations in genes encoding IKs and IKr cause type 1 and type 2 long QT syndrome (LQT1 and LQT2, respectively), accompanied by a high risk of malignant ventricular arrhythmias and sudden cardiac death. This study was designed to investigate which cardiac electrophysiological conditions exaggerate QT-prolonging and arrhythmogenic effects of sevoflurane. We used the O'Hara-Rudy dynamic model to reconstruct human ventricular action potential and a pseudo-electrocardiogram, and simulated LQT1 and LQT2 phenotypes by decreasing conductances of IKs and IKr, respectively. Sevoflurane, but not propofol, prolonged ventricular action potential duration and QT interval in wild-type, LQT1 and LQT2 models. The QT-prolonging effect of sevoflurane was more profound in LQT2 than in wild-type and LQT1 models. The potent inhibitory effect of sevoflurane on IKs was primarily responsible for its QT-prolonging effect. In LQT2 model, IKs was considerably enhanced during excessive prolongation of ventricular action potential duration by reduction of IKr and relative contribution of IKs to ventricular repolarization was markedly elevated, which appears to underlie more pronounced QT-prolonging effect of sevoflurane in LQT2 model, compared with wild-type and LQT1 models. This simulation study clearly elucidates the electrophysiological basis underlying the difference in QT-prolonging effect of sevoflurane among wild-type, LQT1 and LQT2 models, and may provide important information for developing anesthetic strategies for patients with long QT syndrome in clinical settings.

Neonatal Wnt-dependent Lgr5 positive stem cells are essential for uterine gland development.

Wnt signaling is critical for directing epithelial gland development within the uterine lining to ensure successful gestation in adults. Wnt-dependent, Lgr5-expressing stem/progenitor cells are essential for the development of glandular epithelia in the intestine and stomach, but their existence in the developing reproductive tract has not been investigated. Here, we employ Lgr5-2A-EGFP/CreERT2/DTR mouse models to identify Lgr5-expressing cells in the developing uterus and to evaluate their stem cell identity and function. Lgr5 is broadly expressed in the uterine epithelium during embryogenesis, but becomes largely restricted to the tips of developing glands after birth. In-vivo lineage tracing/ablation/organoid culture assays identify these gland-resident Lgr5high cells as Wnt-dependent stem cells responsible for uterine gland development. Adjacent Lgr5neg epithelial cells within the neonatal glands function as essential niche components to support the function of Lgr5high stem cells ex-vivo. These findings constitute a major advance in our understanding of uterine development and lay the foundations for investigating potential contributions of Lgr5+ stem/progenitor cells to uterine disorders.

Microscopic heat pulses activate cardiac thin filaments.

During the excitation-contraction coupling of the heart, sarcomeres are activated via thin filament structural changes (i.e., from the "off" state to the "on" state) in response to a release of Ca2+ from the sarcoplasmic reticulum. This process involves chemical reactions that are highly dependent on ambient temperature; for example, catalytic activity of the actomyosin ATPase rises with increasing temperature. Here, we investigate the effects of rapid heating by focused infrared (IR) laser irradiation on the sliding of thin filaments reconstituted with human α-tropomyosin and bovine ventricular troponin in an in vitro motility assay. We perform high-precision analyses measuring temperature by the fluorescence intensity of rhodamine-phalloidin-labeled F-actin coupled with a fluorescent thermosensor sheet containing the temperature-sensitive dye Europium (III) thenoyltrifluoroacetonate trihydrate. This approach enables a shift in temperature from 25°C to ∼46°C within 0.2 s. We find that in the absence of Ca2+ and presence of ATP, IR laser irradiation elicits sliding movements of reconstituted thin filaments with a sliding velocity that increases as a function of temperature. The heating-induced acceleration of thin filament sliding likewise occurs in the presence of Ca2+ and ATP; however, the temperature dependence is more than twofold less pronounced. These findings could indicate that in the mammalian heart, the on-off equilibrium of the cardiac thin filament state is partially shifted toward the on state in diastole at physiological body temperature, enabling rapid and efficient myocardial dynamics in systole.

A hERG mutation E1039X produced a synergistic lesion on IKs together with KCNQ1-R174C mutation in a LQTS family with three compound mutations.

Congenital long QT syndrome (LQTS) caused by compound mutations is usually associated with more severe clinical phenotypes. We identified a LQTS family harboring three compound mutations in different genes (KCNQ1-R174C, hERG-E1039X and SCN5A-E428K). KCNQ1-R174C, hERG-E1039X and SCN5A-E428K mutations and/or relevant wild-type (WT) cDNAs were respectively expressed in mammalian cells. IKs-like, IKr-like, INa-like currents and the functional interaction between KCNQ1-R174C and hERG-E1039X channels were studied using patch-clamp and immunocytochemistry techniques. (1) Expression of KCNQ1-R174C alone showed no IKs. Co-expression of KCNQ1-WT + KCNQ1-R174C caused a loss-of-function in IKs and blunted the activation of IKs in response to isoproterenol. (2) Expression of hERG-E1039X alone and co-expression of hERG-WT + hERG-E1039X negatively shifted inactivation curves and decelerated the recovery time from inactivation. (3) Expression of SCN5A-E428K increased peak INa, but had no effect on late INa. (4) IKs and IKr interact, and hERG-E1039X caused a loss-of-function in IKs. (5) Immunocytochemical studies indicated that KCNQ1-R174C is trafficking defective and hERG-E1039X is defective in biosynthesis/degradation, but the abnormities were rescued by co-expression with WT. Thus, KCNQ1-R174C and hERG-E1039X disrupted IKs and IKr functions, respectively. The synergistic lesion, caused by KCNQ1-R174C and hERG-E1039X in IKs, is very likely why patients showed more severe phenotypes in the compound mutation case.

Population pharmacokinetics and pharmacogenomics of apixaban in Japanese adult patients with atrial fibrillation.

AIMS: This study aimed to analyse the effects of genetic polymorphisms in drug transporters and metabolizing enzymes, and clinical laboratory data on the pharmacokinetic parameters of apixaban. METHODS: Data were collected from 81 Japanese patients with atrial fibrillation. Pharmacogenomic data were stratified by ABCB1, ABCG2 and CYP3A5 polymorphisms. The pharmacokinetic profile of apixaban was described by a one-compartment model with first-order absorption. Population pharmacokinetic analysis was conducted using a nonlinear mixed effect modelling (NONMEM™) program. RESULTS: The nonlinear relationship between oral clearance (CL/F) of apixaban and creatinine clearance (Ccr) was observed. The population mean of CL/F for a typical patient (Ccr value of 70 ml min-1 ) with the CYP3A5*1/*1 and ABCG2 421C/C or C/A genotypes was estimated to be 3.06 l h-1 . When Ccr values were set to the typical value, the population mean of CL/F was 1.52 times higher in patients with the CYP3A5*1/*1 genotype compared with patients with the CYP3A5*1/*3 or *3/*3 genotype, while the population mean of CL/F was 1.49 times higher in patients with the ABCG2 421C/C or C/A genotype compared with patients with the ABCG2 421A/A genotype. However, no covariates affected the population mean of the apparent volume of distribution (Vd/F) of apixaban. The population mean of Vd/F was estimated to be 24.7 l. CONCLUSION: The present study suggests that the ABCG2 421A/A and CYP3A5*3 genotypes and renal function are intrinsic factors affecting apixaban pharmacokinetics. These findings may provide useful information for precision medicine using apixaban, to avoid the risk of adverse reactions.

Impact of ABCB1, ABCG2, and CYP3A5 polymorphisms on plasma trough concentrations of apixaban in Japanese patients with atrial fibrillation.

OBJECTIVES: During anticoagulant therapy, major bleeding is one of the most severe adverse effects. This study aimed to evaluate the relationships between ABCB1, ABCG2, and CYP3A5 polymorphisms and plasma trough concentrations of apixaban, a direct inhibitor of coagulation factor X. PATIENTS AND METHODS: A total of 70 plasma concentrations of apixaban from 44 Japanese patients with atrial fibrillation were analyzed. In these analyses, the plasma trough concentration/dose (C/D) ratio of apixaban was used as a pharmacokinetic index and all data were stratified according to the presence of ABCB1 (ABCB1 1236C>T, 2677G>T/A, and 3435C>T), ABCG2 (ABCG2 421C>A), and CYP3A5 (CYP3A5*3) polymorphisms. Influences of various clinical laboratory parameters (age, serum creatinine, estimated glomerular filtration rate, aspartate amino transferase, and alanine amino transferase) on the plasma trough C/D ratio of apixaban were included in analyses. RESULTS: Although no ABCB1 polymorphisms affected the plasma trough C/D ratio of apixaban, the plasma trough C/D ratio of apixaban was significantly higher in patients with the ABCG2 421A/A genotype than in patients with the ABCG2 421C/C genotype (P<0.01). The plasma trough C/D ratio of apixaban in patients with CYP3A5*1/*3 or *3/*3 genotypes was also significantly higher than that in patients with the CYP3A5*1/*1 genotype (P<0.05). Furthermore, the plasma trough C/D ratio of apixaban decreased with increased estimated glomerular filtration rate. CONCLUSION: These results indicate that ABCG2 421A/A and CYP3A5*3 genotypes and renal function are considered potential factors affecting trough concentrations of apixaban.

Drug-induced fatal arrhythmias: Acquired long QT and Brugada syndromes.

Since the early 1990s, the concept of primary "inherited" arrhythmia syndromes or ion channelopathies has evolved rapidly as a result of revolutionary progresses made in molecular genetics. Alterations in genes coding for membrane proteins such as ion channels or their associated proteins responsible for the generation of cardiac action potentials (AP) have been shown to cause specific malfunctions which eventually lead to cardiac arrhythmias. These arrhythmic disorders include congenital long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, short QT syndrome, progressive cardiac conduction disease, etc. Among these, long QT and Brugada syndromes are the most extensively studied, and drugs cause a phenocopy of these two diseases. To date, more than 10 different genes have been reported to be responsible for each syndrome. More recently, it was recognized that long QT syndrome can be latent, even in the presence of an unequivocally pathogenic mutation (silent mutation carrier). Co-existence of other pathological conditions in these silent mutation carriers may trigger a malignant form of ventricular arrhythmia, the so called torsade de pointes (TdP) that is most commonly brought about by drugs. In analogy to the drug-induced long QT syndrome, Brugada type 1 ECG can also be induced or unmasked by a wide variety of drugs and pathological conditions; so physicians may encounter patients with a latent form of Brugada syndrome. Of particular note, Brugada syndrome is frequently associated with atrial fibrillation whose therapeutic agents such as Vaughan Williams class IC drugs can unmask the dormant and asymptomatic Brugada syndrome. This review describes two types of drug-induced arrhythmias: the long QT and Brugada syndromes.

Patient-Specific Human Induced Pluripotent Stem Cell Model Assessed with Electrical Pacing Validates S107 as a Potential Therapeutic Agent for Catecholaminergic Polymorphic Ventricular Tachycardia.

INTRODUCTION: Human induced pluripotent stem cells (hiPSCs) offer a unique opportunity for disease modeling. However, it is not invariably successful to recapitulate the disease phenotype because of the immaturity of hiPSC-derived cardiomyocytes (hiPSC-CMs). The purpose of this study was to establish and analyze iPSC-based model of catecholaminergic polymorphic ventricular tachycardia (CPVT), which is characterized by adrenergically mediated lethal arrhythmias, more precisely using electrical pacing that could promote the development of new pharmacotherapies. METHOD AND RESULTS: We generated hiPSCs from a 37-year-old CPVT patient and differentiated them into cardiomyocytes. Under spontaneous beating conditions, no significant difference was found in the timing irregularity of spontaneous Ca2+ transients between control- and CPVT-hiPSC-CMs. Using Ca2+ imaging at 1 Hz electrical field stimulation, isoproterenol induced an abnormal diastolic Ca2+ increase more frequently in CPVT- than in control-hiPSC-CMs (control 12% vs. CPVT 43%, p<0.05). Action potential recordings of spontaneous beating hiPSC-CMs revealed no significant difference in the frequency of delayed afterdepolarizations (DADs) between control and CPVT cells. After isoproterenol application with pacing at 1 Hz, 87.5% of CPVT-hiPSC-CMs developed DADs, compared to 30% of control-hiPSC-CMs (p<0.05). Pre-incubation with 10 µM S107, which stabilizes the closed state of the ryanodine receptor 2, significantly decreased the percentage of CPVT-hiPSC-CMs presenting DADs to 25% (p<0.05). CONCLUSIONS: We recapitulated the electrophysiological features of CPVT-derived hiPSC-CMs using electrical pacing. The development of DADs in the presence of isoproterenol was significantly suppressed by S107. Our model provides a promising platform to study disease mechanisms and screen drugs.

Phenotypic Variability of ANK2 Mutations in Patients With Inherited Primary Arrhythmia Syndromes.

BACKGROUND: Mutations inANK2have been reported to cause various arrhythmia phenotypes. The prevalence ofANK2mutation carriers in inherited primary arrhythmia syndrome (IPAS), however, remains unknown in Japanese. Using a next-generation sequencer, we aimed to identifyANK2mutations in our cohort of IPAS patients, in whom conventional Sanger sequencing failed to identify pathogenic mutations in major causative genes, and to assess the clinical characteristics ofANK2mutation carriers.Methods and Results:We screened 535 probands with IPAS and analyzed 46 genes including wholeANK2exons using a bench-top NGS (MiSeq, Illumina) or performed whole-exome-sequencing using HiSeq2000 (Illumina). As a result, 12 of 535 probands (2.2%, aged 0-61 years, 5 males) were found to carry 7 different heterozygousANK2mutations.ANK2-W1535R was identified in 5 LQTS patients and 1 symptomatic BrS and was predicted as damaging by multiple prediction software. In total, as to phenotype, there were 8 LQTS, 2 BrS, 1 IVF, and 1 SSS/AF. Surprisingly, 4/8 LQTS patients had the acquired type of LQTS (aLQTS) and suffered torsades de pointes. A total of 7 of 12 patients had documented malignant ventricular tachyarrhythmias. CONCLUSIONS: VariousANK2mutations are associated with a wide range of phenotypes, including aLQTS, especially with ventricular fibrillation, representing "ankyrin-B" syndrome. (Circ J 2016; 80: 2435-2442).

Multigenerational Inheritance of Long QT Syndrome Type 2 in a Japanese Family.

Congenital long QT syndrome (LQTS) is an important cause of sudden cardiac death in young people without any other structural disease. Mutations in the genes encoding the cardiac ion channels or associated proteins have been shown to result in ion channel dysfunction and thereby causing LQTS. We investigated a Japanese family with LQTS for four generations, with the female family members showing severe symptoms. We performed genetic tests for LQTS-related genes and identified a heterozygous KCNH2 mutation (p.K638del). In the family, the KCNH2 mutation had a very high multigenerational inheritance, and female genotype positives showed more severe phenotypes.

Pediatric Cohort With Long QT Syndrome　- KCNH2 Mutation Carriers Present Late Onset But Severe Symptoms.

BACKGROUND: In children with long QT syndrome (LQTS), risk factors for cardiac events have been reported, but age-, gender- and genotype-related differences in prognosis remain unknown in Asian countries. METHODS AND RESULTS: The study examined clinical prognosis at age between 1 and 20 years in 496 LQTS patients who were genotyped as either of LQT1-3 (male, n=206). Heterozygous mutations were observed in 3 major responsible genes:KCNQ1in271,KCNH2in 192, andSCN5Ain 33 patients. LQTS-associated events were classified into 3 categories: (1) syncope (n=133); (2) repetitive torsade de pointes (TdP, n=3); and (3) cardiopulmonary arrest (CPA, n=4). The risk of cardiac events was significantly lower in LQT1 girls than boys≤12 years (HR, 0.55), whereas LQT2 female patients ≥13 years had the higher risk of cardiac events than male patients (HR, 4.60). Patients in the repetitive TdP or CPA group included 1 LQT1 female patient, 1 LQT2 male patient, and 5 LQT2 female patients. All LQT2 patients in these groups had TdP repeatedly immediately after the antecedent event. In addition, all 5 female LQT2 patients in these groups had the event after or near puberty. CONCLUSIONS: Female LQT2 children might have repeated TdP shortly after prior events, especially after puberty. (Circ J 2016; 80: 696-702).

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

BACKGROUND: 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. METHODS AND RESULTS: We identified 4 KCNH2 mutations, T152I, R164C, W927G, and R1135H, in 236 consecutive probands with BrS or Brugada-like ECG. Three of these mutation carriers showed QTc intervals shorter than 360 milliseconds and 1 experienced VF. We performed patch-clamp analyses on I(Kr) reconstituted with the KCNH2 mutations in Chinese hamster ovary cells and compared the phenotypes of the patients with different genotypes. Three mutations, R164C, W927G, and R1135H, increased I(Kr) densities. Three mutations, T152I, R164C, and W927G, caused a negative shift in voltage-dependent activation curves. Only the R1135H mutant channel prolonged the deactivation time constants. We also identified 20 SCN5A and 5 CACNA1C mutation carriers in our cohort. Comparison of probands' phenotypes with 3 different genotypes revealed that KCNH2 mutation carriers showed shorter QTc intervals and SCN5A mutation carriers had longer QRS durations. CONCLUSIONS: All KCNH2 mutations that we identified in probands with BrS exerted gain-of-function effects on I(Kr) channels, which may partially explain the ECG findings in our patients.

Cardiac channelopathies associated with infantile fatal ventricular arrhythmias: from the cradle to the bench.

BACKGROUND: Fatal ventricular arrhythmias in the early period of life have been associated with cardiac channelopathies for decades, and postmortem analyses in SIDS victims have provided evidence of this association. However, the prevalence and functional properties of cardiac ion channel mutations in infantile fatal arrhythmia cases are not clear. METHODS AND RESULTS: Seven infants with potentially lethal arrhythmias at age < 1 year (5 males, age of onset 44.1 ± 72.1 days) were genetically analyzed for KCNQ1, KCNH2, KCNE1-5, KCNJ2, SCN5A, GJA5, and CALM1 by using denaturing high-performance liquid chromatography and direct sequencing. Whole-cell currents of wildtype and mutant channels were recorded and analyzed in Chinese hamster ovary cells transfected with SCN5A and KCNH2 cDNA. In 5 of 7 patients, we identified 4 mutations (p.N1774D, p.T290fsX53, p.F1486del and p.N406K) in SCN5A, and 1 mutation (p.G628D) in KCNH2. N1774D, F1486del, and N406K in SCN5A displayed tetrodotoxin-sensitive persistent late Na(+) currents. By contrast, SCN5A-T290fsX53 was nonfunctional. KCNH2-G628D exhibited loss of channel function. CONCLUSION: Genetic screening of 7 patients was used to demonstrate the high prevalence of cardiac channelopathies. Functional assays revealed both gain and loss of channel function in SCN5A mutations, as well as loss of function associated with the KCNH2 mutation.

Trans-resectoscope stimulation predicts the need to block adductor response during bladder tumor resection.

BACKGROUND: Obturator nerve block is performed on patients who undergo transurethral resection of inferolateral bladder tumors to prevent thigh adductor muscle contraction. However, other than the tumor site, we have no criteria to judge whether this block is necessary in all patients. Moreover, it is difficult to predict the efficacy of obturator nerve block before resection. To solve these problems, we have devised a trans-resectoscope stimulation technique that involves delivering several single-twitch electrical stimuli to the inside wall of the bladder via a resectoscope to elicit contraction of the thigh adductor muscle. METHODS: Trans-resectoscope stimulation was performed in 51 cases on 45 patients for which urologists had requested obturator nerve block. If no thigh adductor muscle contraction was observed with trans-resectoscope stimulation (i.e., negative result), tumor resection was performed without further investigation. If the result was positive, we performed obturator nerve block or administered a muscle relaxant until the result turned negative. Positive or negative responses to the initial trans-resectoscope stimulation and thigh adductor muscle contraction during subsequent resection were recorded. RESULTS: The initial trans-resectoscope stimulation result was negative in 29 of the 51 cases (57%). In these cases, tumor resection was allowed to proceed, and no thigh adductor muscle contraction occurred (rate of incidence [95% confidence interval]: 0% [0%-5.7%]). In cases with a positive initial trans-resectoscope stimulation result (22/51 or 43%), we performed an obturator nerve block or administered a muscle relaxant after which we once again stimulated to verify the lack of adductor response before proceeding with the resection, and no thigh adductor muscle contraction was observed during resection. CONCLUSIONS: Trans-resectoscope stimulation is beneficial not only to predict the need to block the contraction of the thigh adductor during tumor resection but also to avoid unnecessary obturator nerve block.

Identification of a KCNQ1 polymorphism acting as a protective modifier against arrhythmic risk in long-QT syndrome.

BACKGROUND: Long-QT syndrome (LQTS) is characterized by such striking clinical heterogeneity that, even among family members carrying the same mutation, clinical outcome can range between sudden death and no symptoms. We investigated the role of genetic variants as modifiers of risk for cardiac events in patients with LQTS. METHODS AND RESULTS: In a matched case-control study including 112 patient duos with LQTS from France, Italy, and Japan, 25 polymorphisms were genotyped based on either their association with QTc duration in healthy populations or on their role in adrenergic responses. The duos were composed of 2 relatives harboring the same heterozygous KCNQ1 or KCNH2 mutation: 1 with cardiac events and 1 asymptomatic and untreated. The findings were then validated in 2 independent founder populations totaling 174 symptomatic and 162 asymptomatic patients with LQTS, and a meta-analysis was performed. The KCNQ1 rs2074238 T-allele was significantly associated with a decreased risk of symptoms 0.34 (0.19-0.61; P<0.0002) and with shorter QTc (P<0.0001) in the combined discovery and replication cohorts. CONCLUSIONS: We provide evidence that the KCNQ1 rs2074238 polymorphism is an independent risk modifier with the minor T-allele conferring protection against cardiac events in patients with LQTS. This finding is a step toward a novel approach for risk stratification in patients with LQTS.

Age-dependent clinical and genetic characteristics in Japanese patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a heart muscle disease caused by desmosomal gene mutations, and presents as ventricular tachycardia and sudden cardiac death. Although the mean age at onset or diagnosis of ARVC/D are reported to be around the 30-40s, the age-dependent clinical and genetic differences remain unknown. METHODS AND RESULTS: A total of 35 consecutive Japanese probands (23 male) who were clinically diagnosed with ARVC/D were enrolled in the present study, and genetic analysis of PKP2, DSP, DSG2, and DSC2 was done. The mean age at the first symptom and at diagnosis was 38.6±14.8 years and 40.5±17.7 years, respectively. Probands in whom the onset was cardiopulmonary arrest were significantly younger (22.3±15.3 years) than those with arrhythmia (41.1±13.2 years) or congestive heart failure (45.7±8.5 years). On genetic screening, 19 mutation carriers were identified. Although there was no age dependence for each gene mutation carrier, carriers with PKP2 premature stop codon developed the disease at a significantly younger age than other mutation carriers. CONCLUSIONS: The initial clinical manifestations in some young probands were very severe, and PKP2 mutations with a premature stop codon would be associated with disease onset at a younger age.

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.

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.