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In cardiac myocytes, the slow component of the delayed rectifier K+ current (IKs) ensures repolarization of action potential during beta-adrenergic activation or when other repolarizing K+ currents fail. As a key factor of cardiac repolarization, IKs should be present in model species used for cardiovascular drug screening, preferably with pharmacological characteristics similar to those of the human IKs. To this end, we investigated the effects of inhibitors and activators of the IKs on KCNQ1 and KCNQ1 + KCNE1 channels of the zebrafish, an important model species, in Chinese hamster ovary cells. Inhibitors of IKs, chromanol 293B and HMR-1556, inhibited zebrafish IKs channels with approximately similar potency as that of mammalian IKs. Chromanol 293B concentration for half-maximal inhibition (IC50) of zebrafish IKs was at 13.1 ± 5.8 and 13.4 ± 2.8 µM for KCNQ1 and KCNQ1+KCNE1 channels, respectively. HMR-1556 was a more potent inhibitor of zebrafish IKs channels with IC50 = 0.1 ± 0.1 µM and 1.5 ± 0.8 µM for KCNQ1 and KCNQ1 + KCNE1 channels, respectively. R-L3 and mefenamic acid, generally identified as IKs activators, both inhibited zebrafish IKs. R-L3 almost completely inhibited the current generated by KCNQ1 and KCNQ1 + KCNE1 channels with similar potency (IC50 1.1 ± 0.4 and 1.0 ± 0.4 µM, respectively). Mefenamic acid partially blocked zebrafish KCNQ1 (IC50 = 9.5 ± 4.8 µM) and completely blocked KCNQ1 + KCNE1 channels (IC50 = 3.3 ± 1.8 µM). Although zebrafish IKs channels respond to IKs inhibitors in the same way as mammalian IKs channels, their response to activators is atypical, probably because of the differences in the binding domain of KCNE1 to KCNQ1. Therefore, care must be taken when translating the results from zebrafish to humans.

INTRODUCTION Subjective tinnitus, a perception of phantom sound, is a common otological condition that affects almost 15% of the general population. It is known that noise-induced hearing loss (NIHL) and tinnitus exhibit a high level of comorbidity in individuals exposed to intense noise and music. However, the influence of genetic variants associated with NIHL on tinnitus remains elusive. We hypothesized that young musicians carrying genetic variants associated with NIHL would exhibit a higher prevalence of tinnitus than their counterparts. METHODS To test this hypothesis, we analyzed the database by Bhatt et al. (2020) (originally developed by Phillips et al., 2015) that investigated the genetic links to NIHL in young college-aged musicians. The present study identified 186 participants (average age = 20.3 yrs, range = 18-25 yrs) with normal tympanometry and otoscopic findings and with no missing data. We included 19 single nucleotide polymorphisms in 13 cochlear genes that were previously associated with NIHL. The candidate genes include: KCNE1, KCNQ1, CDH23, GJB2, GJB4, KCNJ10, CAT, HSP70, PCDH70, MYH14, GRM7, PON2, and ESRRB. RESULTS We find that individuals with at least one minor allele of rs163171 (C > T) in KCNQ1 exhibit significantly higher odds of reporting tinnitus compared to individuals carrying the major allele of rs163171. KCNE1 rs2070358 revealed a suggestive association (p = 0.049) with tinnitus, but the FDR corrected p-value did not achieve statistical significance (p

Background Diagnosis of congenital long‐QT syndrome (LQTS) is complicated by phenotypic ambiguity, with a frequent normal‐to‐borderline resting QT interval. A 3‐step algorithm based on exercise response of the corrected QT interval (QTc) was previously developed to diagnose patients with LQTS and predict subtype. This study evaluated the 3‐step algorithm in a population that is more representative of the general population with LQTS with milder phenotypes and establishes sex‐specific cutoffs beyond the resting QTc. Methods and Results We identified 208 LQTS likely pathogenic or pathogenic KCNQ1 or KCNH2 variant carriers in the Canadian NLQTS (National Long‐QT Syndrome) Registry and 215 unaffected controls from the HiRO (Hearts in Rhythm Organization) Registry. Exercise treadmill tests were analyzed across the 5 stages of the Bruce protocol. The predictive value of exercise ECG characteristics was analyzed using receiver operating characteristic curve analysis to identify optimal cutoff values. A total of 78% of male carriers and 74% of female carriers had a resting QTc value in the normal‐to‐borderline range. The 4‐minute recovery QTc demonstrated the best predictive value for carrier status in both sexes, with better LQTS ascertainment in female patients (area under the curve, 0.90 versus 0.82), with greater sensitivity and specificity. The optimal cutoff value for the 4‐minute recovery period was 440 milliseconds for male patients and 450 milliseconds for female patients. The 1‐minute recovery QTc had the best predictive value in female patients for differentiating LQTS1 versus LQTS2 (area under the curve, 0.82), and the peak exercise QTc had a marginally better predictive value in male patients for subtype with (area under the curve, 0.71). The optimal cutoff value for the 1‐minute recovery period was 435 milliseconds for male patients and 455 milliseconds for femal patients. Conclusions The 3‐step QT exercise algorithm is a valid tool for the diagnosis of LQTS in a general population with more frequent ambiguity in phenotype. The algorithm is a simple and reliable method for the identification and prediction of the 2 major genotypes of LQTS.

Purpose of review Our purpose is to provide an update on the new clinical and genetic aspects of long QT syndrome (LQTS). LQTS is the most common channelopathy and a cause of syncope and sudden death in the young. Although there are 17 types of LQTS, most patients have types 1 or 2 which are due to mutations in KCNQ1 and KCNH2 (encoding for the cardiac potassium channels), and type 3 which is due to a mutation in SCN5A (encoding for the sodium channel). LQTS is characterized by incomplete penetrance and variable expressivity. Significant data exist concerning the common types of LQTS and include mutational location, biophysical function, gene-specific triggers, and disease modifiers that are known and help characterize the disease. Recent findings Recent studies support the use of β-blockers in LQTS. Nadolol and propranolol are superior likely because of their sodium channel blocking effects. There are recent data supporting the use of β-blockers in LQTS type 3 in which their use was once discouraged. There are increasing data that left cardiac sympathetic denervation is effective in LQTS and should be considered before an implantable cardioverter defibrillator is implanted. Summary LQTS is a model for effective collaboration between clinicians and basic scientists and between cardiologists and geneticists. Recent advances in the derivation of induced pluripotent stem cells from LQTS patients and creation of genetically engineered human models using clusters of regularly interspaced palindromic repeats (CRISPR/Cas9) will advance translational arrhythmia research and move us toward the goal of personalized medicine.

Background: Long QT syndrome (LQTS) is caused by the abnormal function of ion channels, which may also affect atrial electrophysiology and be associated with the risk of atrial fibrillation (AF). However, large-scale studies of AF risk among patients with LQTS and its relation to LQTS manifestations are lacking. We aimed to assess the risk of AF and its relationship to the LQTS genotype and the long-term prognosis in patients with LQTS. Methods: Genotype-positive patients with LQTS (784 LQT1, 746 LQT2, and 233 LQT3) were compared with 2043 genotype-negative family members. Information on the occurrence of AF was based on physician-reported ECG-verified events. Multivariate Cox proportional hazards regression analyses were performed for ages 0 to 60 and after 60 years (reflecting an early and late-onset of AF) to assess the risk of incident AF by genotype and the relationship of AF to the risk of cardiac events defined as syncope, documented torsades de pointes, and aborted cardiac arrest or sudden cardiac death. Results: In patients followed from birth to 60 years of age, patients with LQT3 had an increased risk of AF compared with genotype-negative family members (hazard ratio=6.62; 95% CI, 2.04–21.49; P P =0.011). AF was a significant predictor of cardiac events in patients with LQT3 through the age of 60 (hazard ratio=5.38; 95% CI, 1.17–24.82; P =0.031). Conclusions: Our data demonstrate an increased risk of early age AF in patients with LQT3 and also indicate a protective effect of the LQT2 genotype in it’s association with a decreased risk of AF after the age of 60.

Rationale: Long QT syndrome (LQTS) is an inheritable disease characterized by prolonged QT interval on the electrocardiogram. The pathogenesis of LQTS is related to mutations in LQTS-susceptible genes encoding cardiac ion channel proteins or subunits. Patient concerns: Here, we reported a 37-year-old female Uygur patient with palpitation and loss of consciousness. Diagnoses: At the time of admission, a 12-lead electrocardiogram showed a QTc interval of 514 ms. Genetic analysis revealed KCNQ1 G219E and TRPM4 T160M mutations. Interventions: Although beta-blockers remain the mainstay in treating LQTS, the patient underwent implantation of an automatic cardioverter defibrillator due to life-threatening arrhythmias. Outcomes: To explore the effect of the calcium ion antagonist verapamil on ion channels, we generated human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) from the peripheral blood mononuclear cells of the patient. The changes of action potential duration in response to verapamil were observed. Lessons: Our results showed that patient-derived hiPSC-CMs could recapitulate the electrophysiological features of LQTS and display pharmaceutical responses to verapamil.

Introduction: Long QT syndrome (LQTS) is a congenital disorder characterized by a prolongation of the QT interval on electrocardiograms (ECGs) and a propensity to ventricular tachyarrhythmias, which may lead to syncope, cardiac arrest, or sudden death. T-wave alternans (TWA) refers to the periodic beat-to-beat alternation of T-wave shape, polarity and amplitude on surface ECG during regular heart rhythm. In this report, a case of long QT syndrome with KCNQ1 gene mutation induced TWA in the head-up tilt test (HUTT), which has not been reported yet. Patient concerns: A 6-year-old boy presented with loss of consciousness twice, 5 months in duration. The boy's ECG showed prolonged QT interval (QTc = 600 ms, QTc = QT/RR1/2). During HUTT test, QT interval was significantly prolonged (QTc = 716 ms) based on macroscopic TWA. Diagnosis: The patient was diagnosed with 1. Long QT syndrome type 1(LQT1); 2. Vasovagal syncope (VVS) Interventions: Metoprolol 12.5 mg was given orally twice a day. The child was told avoid standing for a long time and strenuous exercises. Outcomes: There was no syncope or arrhythmia occurred during hospitalization and follow-up for 1 year. Conclusions: VVS may exist in patients with long QT syndrome. Increased sympathetic tone during the early stage of HUTT may induce macroscopic TWA in long QT syndrome with KCNQ1 gene mutation.

Background— An emerging standard-of-care for long-QT syndrome uses clinical genetic testing to identify genetic variants of the KCNQ1 potassium channel. However, interpreting results from genetic testing is confounded by the presence of variants of unknown significance for which there is inadequate evidence of pathogenicity. Methods and Results— In this study, we curated from the literature a high-quality set of 107 functionally characterized KCNQ1 variants. Based on this data set, we completed a detailed quantitative analysis on the sequence conservation patterns of subdomains of KCNQ1 and the distribution of pathogenic variants therein. We found that conserved subdomains generally are critical for channel function and are enriched with dysfunctional variants. Using this experimentally validated data set, we trained a neural network, designated Q1VarPred, specifically for predicting the functional impact of KCNQ1 variants of unknown significance. The estimated predictive performance of Q1VarPred in terms of Matthew’s correlation coefficient and area under the receiver operating characteristic curve were 0.581 and 0.884, respectively, superior to the performance of 8 previous methods tested in parallel. Q1VarPred is publicly available as a web server at http://meilerlab.org/q1varpred . Conclusions— Although a plethora of tools are available for making pathogenicity predictions over a genome-wide scale, previous tools fail to perform in a robust manner when applied to KCNQ1. The contrasting and favorable results for Q1VarPred suggest a promising approach, where a machine-learning algorithm is tailored to a specific protein target and trained with a functionally validated data set to calibrate informatics tools.

Background— KCNQ1 and KCNE1 assemble to form the slow delayed rectifier ( I Ks ) channel critical for shortening ventricular action potentials during high β-adrenergic tone. However, too much I Ks under basal conditions poses an arrhythmogenic risk. Our objective is to understand how adult ventricular myocytes regulate the I Ks amplitudes under basal conditions and in response to stress. Methods and Results— We express fluorescently tagged KCNQ1 and KCNE1 in adult ventricular myocytes and follow their biogenesis and trafficking paths. We also study the distribution patterns of native KCNQ1 and KCNE1, and their relationship to I Ks amplitudes, in chronically stressed ventricular myocytes, and use COS-7 cell expression to probe the underlying mechanism. We show that KCNQ1 and KCNE1 are both translated in the perinuclear region but traffic by different routes, independent of each other, to their separate subcellular locations. KCNQ1 mainly resides in the jSR (junctional sarcoplasmic reticulum), whereas KCNE1 resides on the cell surface. Under basal conditions, only a small portion of KCNQ1 reaches the cell surface to support the I Ks function. However, in response to chronic stress, KCNQ1 traffics from jSR to the cell surface to boost the I Ks amplitude in a process depending on Ca binding to CaM (calmodulin). Conclusions— In adult ventricular myocytes, KCNE1 maintains a stable presence on the cell surface, whereas KCNQ1 is dynamic in its localization. KCNQ1 is largely in an intracellular reservoir under basal conditions but can traffic to the cell surface and boost the I Ks amplitude in response to stress.

Early diagnosis and risk stratification is of clinical importance in the long QT syndrome (LQTS), however, little genotype-specific data are available regarding fetal LQTS. We investigate third trimester fetal heart rate, routinely recorded within public maternal health care, as a possible marker for LQT1 genotype and phenotype.This retrospective study includes 184 fetuses from 2 LQT1 founder populations segregating p.Y111C and p.R518X (74 noncarriers and 110 KCNQ1 mutation carriers, whereof 13 double mutation carriers). Pedigree-based measured genotype analysis revealed significant associations between fetal heart rate, genotype, and phenotype; mean third trimester prelabor fetal heart rates obtained from obstetric records (gestational week 29-41) were lower per added mutation (no mutation, 143±5 beats per minute; single mutation, 134±8 beats per minute; double mutations, 111±6 beats per minute; P0.0001), and lower in symptomatic versus asymptomatic mutation carriers (122±10 versus 137±9 beats per minute; P0.0001). Strong correlations between fetal heart rate and neonatal heart rate (r=0.700; P0.001), and postnatal QTc (r=-0.762; P0.001) were found. In a multivariable model, fetal genotype explained the majority of variance in fetal heart rate (-10 beats per minute per added mutation; P1.0×10(-23)). Arrhythmia symptoms and intrauterine β-blocker exposure each predicted -7 beats per minute, P0.0001.In this study including 184 fetuses from 2 LQT1 founder populations, third trimester fetal heart rate discriminated between fetal genotypes and correlated with severity of postnatal cardiac phenotype. This finding strengthens the role of fetal heart rate in the early detection and risk stratification of LQTS, particularly for fetuses with double mutations, at high risk of early life-threatening arrhythmias.

Background— Fetal arrhythmias characteristic of long QT syndrome (LQTS) include torsades de pointes (TdP) and/or 2° atrioventricular block, but sinus bradycardia, defined as fetal heart rate Method and Results— Records of subjects exhibiting fetal LQTS arrhythmias were reviewed. Fetal echocardiograms, neonatal ECG, and genetic testing were evaluated. We studied 43 subjects exhibiting fetal LQTS arrhythmias: TdP±2° atrioventricular block (group 1, n=7), isolated 2° atrioventricular block (group 2, n=4), and sinus bradycardia (group 3, n=32). Mutations in known LQTS genes were found in 95% of subjects tested. SCN5A mutations occurred in 71% of group 1, whereas 91% of subjects with KCNQ1 mutations were in group 3. Small numbers of subjects with KCNH2 mutations (n=4) were scattered in all 3 groups. Age at presentation did not differ among groups, and most subjects (n=42) were live-born with gestational ages of 37.5±2.8 weeks (mean±SD). However, those with TdP were typically delivered earlier. Prenatal treatment in group 1 terminated (n=2) or improved (n=4) TdP. The neonatal heart rate–corrected QT interval (mean±SE) of group 1 (664.7±24.9) was longer than neonatal heart rate–corrected QT interval in both group 2 (491.2±27.6; P =0.004) and group 3 (483.1±13.7; P Conclusions— Rhythm phenotypes of fetal LQTS have genotype-suggestive features that, along with heart rate–corrected QT interval duration, may risk stratify perinatal management.

Jervell and Lange–Nielsen syndrome is caused by absence of the voltage-gated potassium current I Ks through either homozygous recessive or compound heterozygous mutations in KCNQ1 or KCNE1 . We report here a case of Jervell and Lange–Nielsen syndrome with typical clinical features in which clinical genetic testing using next-generation sequencing (NGS) revealed only a known single heterozygous KCNQ1 mutation (R518X), but failed to recognize an unusual and complex 52-bp duplication-insertion. This type of variant has not been previously reported in Long QT syndrome (LQTS) and may therefore account for a portion of genetic variant negative cases. A 47-year-old woman with congenital deafness, severe QT prolongation (≥800 ms on Holter monitoring; Figure 1A and 1B), and striking exercise-induced QT lability and torsades de pointes was seen in referral. She had her first episode of syncope at 6 years of age, was reported to have marked QT prolongation, started β-blocker therapy, and was then lost to follow-up. At age 40, she had an episode of syncope while working outdoors in the heat, and β-blocker (propranolol at that time) was continued although she admitted to incomplete compliance because of fatigue. At age 46, she had another syncopal episode and was switched to metoprolol 100 mg daily. An implantable cardioverter-defibrillator was recommended but she declined. During an exercise test to assess the adequacy of β-blockade, she developed marked T wave lability followed by a 40-second, self-terminating episode of torsades de pointes, during which she lost consciousness (Figure 1C). Notably, this T wave instability occurred in an unusual (nonalternans) pattern,1 compatible with temporal variability in repolarization with …

In the past decade, the discovery that cases of ventricular arrhythmias and sudden cardiac death (SCD) in young individuals potentially could be caused by an unrecognized genetic substrate has defined a new subset of cardiac conditions: inherited arrhythmogenic diseases (IADs).1 Although rare in clinical practice, these diseases are more common than previously thought. They represent a challenge for the arrhythmia specialist in terms of diagnosis and clinical management. The correct diagnosis of IADs, as well as the use and interpretation of the results of genetic testing, are not straightforward and require a specific expertise such as that provided by specialized and dedicated centers. Here we will review the general issues arising from the correct interpretation of genetic testing and its indications. We also will focus on the clinical management and use of genetic information in different inherited arrhythmias. The term “channelopathies” defines a group of inherited arrhythmic syndromes caused by mutations on genes encoding for ion channel proteins and proteins that regulate ion channels.1 These mutations disrupt the balance of currents in the cardiac action potential, favoring the onset of life-threatening arrhythmias in the absence of structural heart defects. The long QT syndrome (LQTS) is a heritable channelopathy characterized by an exceedingly prolonged cardiac repolarization that may trigger ventricular arrhythmias and SCD.2 LQTS is one of the first channelopathies in which clinical and genetic features have been discovered, and a large series of patients have been collected and followed over the years.2–4 Thanks to these studies, LQTS management takes into account a patient’s genetic background and has become a paradigm for the use of genetic information applied to the clinical practice.3,4 Long QT syndrome can manifest with syncope and cardiac arrest. These commonly are triggered by adrenergic stress; however, roughly 10% …

Background— β-Adrenergic stimulation is the main trigger for cardiac events in type 1 long-QT syndrome (LQT1). We evaluated a possible association between ion channel response to β-adrenergic stimulation and clinical response to β-blocker therapy according to mutation location. Methods and Results— The study sample comprised 860 patients with genetically confirmed mutations in the KCNQ1 channel. Patients were categorized into carriers of missense mutations located in the cytoplasmic loops (C loops), membrane-spanning domain, C/N terminus, and nonmissense mutations. There were 27 aborted cardiac arrest and 78 sudden cardiac death events from birth through 40 years of age. After multivariable adjustment for clinical factors, the presence of C-loop mutations was associated with the highest risk for aborted cardiac arrest or sudden cardiac death (hazard ratio versus nonmissense mutations=2.75; 95% confidence interval, 1.29–5.86; P =0.009). β-Blocker therapy was associated with a significantly greater reduction in the risk of aborted cardiac arrest or sudden cardiac death among patients with C-loop mutations than among all other patients (hazard ratio=0.12; 95% confidence interval, 0.02–0.73; P =0.02; and hazard ratio=0.82; 95% confidence interval, 0.31–2.13; P =0.68, respectively; P for interaction=0.04). Cellular expression studies showed that membrane spanning and C-loop mutations produced a similar decrease in current, but only C-loop mutations showed a pronounced reduction in channel activation in response to β-adrenergic stimulation. Conclusions— Patients with C-loop missense mutations in the KCNQ1 channel exhibit a high risk for life-threatening events and derive a pronounced benefit from treatment with β-blockers. Reduced channel activation after sympathetic activation can explain the increased clinical risk and response to therapy in patients with C-loop mutations.

Indirect effects of drugs on ion channel expression levels on plasma membrane are focused as the cause of QT prolongation, and we explored the chronic effects of QT-prolonging drugs on the slow component of the delayed-rectifier potassium current (IKs). Chinese Hamster Ovary cells expressing IKs channels were constructed by transfecting KCNQ1/KCNE1 genes, and the IKs values were measured using IonWorks Quattro in the population patch-clamp mode. After 24 hours of treatment with IKs blockers (HMR1556, L-768673, or chromanol 293B) or human Ether-à-go-go related gene channel trafficking inhibitors (amiodarone,17-AAG, brefeldin A, pentamidine, thioridazine, or probucol), brefeldin A, pentamidine, and probucol decreased IKs. Probucol, which is a cholesterol-lowering drug and clinically reported to cause QT prolongation, potently inhibited the IKs in a concentration-dependent manner, with a half maximal inhibitory concentration of 149.1 nM. A reduction in the IKs by 1 μM of probucol was observed beginning 2 hours after treatment, and the current was reduced by about 80% at 24 hours. The activation and deactivation time constants of residual IKs currents became faster compared with that in the vehicle-treatment group. Acute application of probucol did not directly inhibit IKs channels at concentrations of up to 10 μM. Western blotting analysis indicated the reduction of multimeric complex of KCNQ1 proteins by probucol treatment but not monomeric form. These results suggest that chronic probucol treatment may contribute to QT prolongation in humans by decreasing the functional IKs channel complexes.

Background— Current clinical diagnosis of long-QT syndrome (LQTS) includes genetic testing of family members of mutation-positive patients. The present study was designed to assess the clinical course of individuals who are found negative for the LQTS-causing mutation in their families. Methods and Results— Multivariate Cox proportional hazards model was used to assess the risk for cardiac events (comprising syncope, aborted cardiac arrest [ACA], or sudden cardiac death [SCD]) from birth through age 40 years among 1828 subjects from the LQTS Registry who were found negative for their family LQTS-causing mutation. The median QTc of study subjects was 423 ms (interquartile range, 402–442 ms). The cumulative probability of a first syncope through age 40 years was 15%. However, only 2 patients (0.1%) had ACA, and none died suddenly during follow-up. Independent risk factors for syncope in genotype-negative subjects included female sex (hazard ratio [HR], 1.60; P =0.002), prolonged QTc (HR=1.63 per 100 ms increment, P =0.02), family history of ACA or SCD (HR=1.89, P =0.002), and LQT2 versus LQT1 family mutation (HR=1.41, P =0.03). Subgroup analysis showed that the presence of the K897T polymorphism in the LQT2 gene in an affected family was associated with an 11-fold ( P =0.001) increase in the risk of recurrent syncope in genotype-negative subjects. Conclusions— Our findings suggest that cardiac events among genotype-negative family members of LQTS patients are dominated by nonfatal syncopal episodes without occurrence of sudden cardiac death. The risk for nonfatal events in this population may be mediated by the presence of common polymorphisms in LQTS genes.

Paliperidone (9-hydroxyrisperidone) is a second-generation antipsychotic. As observed with risperidone, QT interval prolongation was reported with paliperidone.The aim was to evaluate the effects of paliperidone on cardiac ventricular repolarization.(1) Patch-clamp experiments: Human ether-a-go-go-related gene (HERG)- or KCNQ1 + KCNE1-transfected cells were exposed to 0.1-100 μmol/L paliperidone (N = 39 cells, total) to assess the drug effect on HERG and KCNQ1 + KCNE1 currents. (2) Langendorff perfusion experiments: Hearts isolated from male Hartley guinea pigs (N = 9) were exposed to 0.1 μmol/L paliperidone to assess drug-induced prolongation of monophasic action potential duration measured at 90% repolarization. (3) In vivo cardiac telemetry experiments: Guinea pigs (N = 8) implanted with transmitters were injected a single intraperitoneal dose of 1 mg/kg of paliperidone, and 24-hour electrocardiogram recordings were made.(1) The estimated concentration at which 50% of the maximal inhibitory effect is observed (IC(50)) for paliperidone on HERG current was 0.5276 μmol/L. In contrast, 1 μmol/L paliperidone had hardly any effect on KCNQ1 + KCNE1 current (4.0 ± 1.6% inhibition, N = 5 cells). (2) While pacing the hearts at cycle lengths of 150, 200, or 250 milliseconds, 0.1 μmol/L paliperidone prolonged monophasic action potential duration measured at 90% repolarization by, respectively, 6.1 ± 3.1, 9.8 ± 2.7, and 12.8 ± 2.7 milliseconds. (3) Paliperidone (1 mg/kg) intraperitoneal caused a maximal 15.7 ± 5.3-millisecond prolongation of QTc.Paliperidone prolongs the QT interval by blocking HERG current at clinically relevant concentrations and is potentially unsafe.

Supplemental Digital Content is available in the text, Background: We sought to identify common ion channel single nucleotide polymorphisms (SNPs) associated with the occurrence of sudden cardiac death (SCD) to predict the incidence of SCD in clinical settings. Methods: This study involved a systematic review and meta-analysis of ion channel SNPs and risk of SCD in adults. We searched public databases for studies published up to September 19, 2017. We examined relationships between SNPs in common ion channel genes and the incidence of SCD. Results: We collected data for 22 trials that included a total of 4149 patients who experienced SCD or had a high risk of SCD and assessed these data in our meta-analysis. An allelic model showed that rs11720524 in SCN5A clearly protected against SCD (odds ratio [OR]: 0.76; 95% confidence interval [95% CI]: 0.67–0.85; P

Objectives: The coprevalence, severity, and biomarkers for seizures and arrhythmias in long QT syndrome (LQTS) remain incompletely understood. Methods: Using the Rochester-based LQTS Registry, this study included large cohorts of LQTS1–3 participants (LQTS + , n = 965) and those without a LQTS mutation (LQTS − , n = 936). Results: Compared to LQTS − participants, there was a higher prevalence of LQTS1, LQTS2, and LQTS + participants classified as having seizures ( p + participants with longer corrected QT interval (QT c ) durations were more likely to have seizures. LQTS2 mutations in the KCNH2 pore domain were positive predictors for both arrhythmias and seizures. In contrast, mutations in the cyclic nucleotide binding domain (cNBD) of KCNH2 conferred a negative risk of seizures, but not arrhythmias. LQTS2, KCNH2 -pore, KCNH2 -cNBD, QT c duration, and sex were independent predictors of seizures. LQTS + participants with seizures had significantly longer QT c durations, and a history of seizures was the strongest independent predictor of arrhythmias (hazard ratio 4.09, 95% confidence interval 2.63–6.36, p Conclusions: This study highlights potential biomarkers for neurocardiac electrical abnormalities in LQTS.

Background— Biventricular (BIV) pacing can improve cardiac function in heart failure by altering the mechanical and electric substrates. We investigated the effect of BIV versus right ventricular (RV) pacing on the normal heart. Methods and Results— Male New Zealand White rabbits (n=33) were divided into 3 groups: sham-operated (control), RV pacing, and BIV pacing groups. Four weeks after surgery, the native QT ( P =0.004) interval was significantly shorter in the BIV group compared with the RV or sham-operated groups. Also, compared with rabbits in the RV group, rabbits in the BIV group had shorter RV effective refractory period at all cycle lengths and shorter LV paced QT interval during the drive train of stimuli and close to refractoriness ( P Conclusions— In this rabbit model, we demonstrate a direct effect of BIV but not RV pacing on shortening the native QT interval as well as the paced QT interval during burst pacing and close to the ventricular effective refractory period. These findings underscore the fact that the effect of BIV pacing is partially mediated through direct electric remodeling and may have implications as to the effect of BIV pacing on arrhythmia incidence and burden.

Jervell and Lange-Nielsen syndrome (JLNS) is a rare cause of autosomal recessive inherited deafness. JLNS patients are candidates for cochlear implantation, and represent a group that needs special attention and precautions. The aim of this article is to draw some guidelines for dealing with these patients, and to emphasize the importance of electrocardiography (ECG) screening of congenitally deaf patients. A probable vestibular dysfunction is also discussed.Eight of 273 implanted children (2.9%) at Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway have been diagnosed with JLNS. All the children were evaluated with ECG, six of them before cochlear implantation. Auditory perception was evaluated with the littlEARS Auditory Questionnaire, or with a test battery developed at Rikshospitalet-Radiumhospitalet Medical Center. DNA sequencing was used to screen for mutations in the genes KCNQ1 and KCNE1. The cases are presented and discussed in a retrospective case review.Two of the children are dead. The corrected QT (QTc) interval in the ECG was markedly prolonged in all the children (median QTc, 0.59 sec; range, 0.53-0.65). Six children have more than 1 yr experience with their cochlear implant. Four of them are performing average or above compared with the other implanted children. All the children have mutations in the KCNQ1 gene. Six of our patients have delayed gross motor development, and the remaining two are markedly delayed compared with their older siblings.Cochlear implantation can be performed safely and with good results in children with JLNS, but requires knowledge of the diagnosis and necessary precautions have to be taken. ECG should be taken for all children with congenital deafness, preferably before exposure to strong sound stimuli. Vestibular dysfunction seems to be a part of JLNS, but this needs further investigation.

Previous studies have shown that the gating kinetics of the slow component of the delayed rectifier K + current ( I Ks ) contribute to postrepolarization refractoriness in isolated cardiomyocytes. However, the impact of such kinetics on arrhythmogenesis remains unknown. We surmised that expression of I Ks in rat cardiomyocyte monolayers contributes to wavebreak formation and facilitates fibrillatory conduction by promoting postrepolarization refractoriness. Optical mapping was performed in 44 rat ventricular myocyte monolayers infected with an adenovirus carrying the genomic sequences of KvLQT1 and minK (molecular correlates of I Ks ) and 41 littermate controls infected with a GFP adenovirus. Repetitive bipolar stimulation was applied at increasing frequencies, starting at 1 Hz until loss of 1:1 capture or initiation of reentry. Action potential duration (APD) was significantly shorter in I Ks -infected monolayers than in controls at 1 to 3 Hz ( P I Ks group. Wavelengths in the latter were significantly shorter than in controls at all rotation frequencies. Wavebreaks leading to fibrillatory conduction occurred in 45% of the I Ks reentry episodes but in none of the controls. Moreover, the density of wavebreaks increased with time as long as a stable source sustained the fibrillatory activity. These results provide the first demonstration that I Ks -mediated postrepolarization refractoriness can promote wavebreak formation and fibrillatory conduction during pacing and sustained reentry and may have important implications in tachyarrhythmias.

Stress-dependent regulation of cardiac action potential duration is mediated by the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis. It is accompanied by an increased magnitude of the slow outward potassium ion current, I Ks . KCNQ1 and KCNE1 subunits coassemble to form the I Ks channel. Mutations in either subunit cause long QT syndrome, an inherited cardiac arrhythmia associated with an increased risk of sudden cardiac death. Here we demonstrate that exocytosis of KCNQ1 proteins to the plasma membrane requires the small GTPase RAB11, whereas endocytosis is dependent on RAB5. We further demonstrate that RAB-dependent KCNQ1/KCNE1 exocytosis is enhanced by the serum- and glucocorticoid-inducible kinase 1, and requires phosphorylation and activation of phosphoinositide 3-phosphate 5-kinase and the generation of PI(3,5)P 2 . Identification of KCNQ1/KCNE1 recycling and its modulation by serum- and glucocorticoid-inducible kinase 1-phosphoinositide 3-phosphate 5-kinase -PI(3,5)P 2 provides a mechanistic insight into stress-induced acceleration of cardiac repolarization.

BACKGROUND Atrial fibrillation is a common arrhythmia with multi-factorial pathogenesis. Recently, a single nucleotide polymorphism (G/T) at position 1057 in the KCNE4 gene, resulting in a glutamic acid (Glu, E)/aspartic acid (Asp, D) substitution at position 145 of the KCNE4 peptide, was found in our laboratory to be associated with idiopathic atrial fibrillation (atrial fibrillation more frequent with KCNE4 145D). However, the functional effect of the KCNE4 145E/D polymorphism is still unknown. METHODS We constructed KCNE4 (145E/D) expression plasmids and transiently co-transfected them with the KCNQ1 gene into Chinese hamster ovary-K1 cells and performed whole-cell patch-clamping recording to identify the possible functional consequences of the single nucleotide polymorphism. Quantitative data were analyzed by Student;s t test. Probability values less than 0.05 were considered statistically significant. RESULTS A slowly activating, non-inactivating voltage-dependent current ((24.0 +/- 2.9) pA/pF, at +60 mV)) could be recorded in the cells transfected with KCNQ1 alone. Co-expression of wild type KCNE4 inhibited the KCNQ1 current ((7.3 +/- 1.1) pA/pF)). By contrast, co-expression of KCNE4 (145D) augment the KCNQ1 current ((42.9 +/- 7) pA/pF)). The V(1/2) of activation for the KCNQ1/KCNE4 (145D) current was shifted significantly towards the depolarizing potential compared to that for the KCNQ1 current ((-2.3 +/- 0.2) mv vs (-13.0 +/- 1.5) mv, P < 0.01)) without changing the slope factorkappa. Furthermore, KCNE4 (145D) also affected the activation and deactivation kinetics of KCNQ1 channels. CONCLUSION We provide experimental evidence that the KCNE4 (145E/D) polymorphism exerts the effect of "gain of function" on the KCNQ1 channel. It may underlie the genetic mechanism of atrial fibrillation. Further studies on the functional association between I(Ks) and KCNE4 (145D) polymorphism in cardiac myocytes are suggested.

Background— A paradoxical increase in the uncorrected QT interval during infusion of low-dose epinephrine appears pathognomonic for type 1 long-QT syndrome (LQT1). We sought to determine the diagnostic accuracy of this response among patients referred for clinical evaluation of congenital long-QT syndrome (LQTS). Methods and Results— From 1999 to 2002, 147 genotyped patients (125 untreated and 22 undergoing β-blocker therapy) had an epinephrine QT stress test that involved a 25-minute infusion protocol (0.025 to 0.3 μg · kg −1 · min −1 ). A 12-lead ECG was monitored continuously, and repolarization parameters were measured. The sensitivity, specificity, and positive and negative predictive values for the paradoxical QT response (defined as a ≥30-ms increase in QT during infusion of ≤0.1 μg · kg −1 · min −1 epinephrine) was determined. The 125 untreated patients (44 genotype negative, 40 LQT1, 30 LQT2, and 11 LQT3) constituted the primary analysis. The median baseline corrected QT intervals (QTc) were 444 ms (gene negative), 456 ms (LQT1), 486 ms (LQT2), and 473 ms (LQT3). The median change in QT interval during low-dose epinephrine infusion was −23 ms in the gene-negative group, 78 ms in LQT1, −4 ms in LQT2, and −58 ms in LQT3. The paradoxical QT response was observed in 37 (92%) of 40 patients with LQT1 compared with 18% (gene-negative), 13% (LQT2), and 0% (LQT3; P Conclusions— The epinephrine QT stress test can unmask concealed type 1 LQTS with a high level of accuracy.

Berberine prolongs the duration of cardiac action potentials without affecting resting membrane potential or action potential amplitude. Controversy exists regarding whether berberine exerts this action by preferential block of different components of the delayed rectifying potassium current, I(Kr) and I(Ks). Here we have studied the effects of berberine on hERG (I(Kr)) and KCNQ1/KCNE1 (I(Ks)) channels expressed in HEK-293 cells and Xenopus oocytes. In HEK-293 cells, the IC50 for berberine was 3.1 +/- 0.5 microM on hERG compared with 11 +/- 4% decreases on KCNQ1/KCNE1 channels by 100 microM berberine. Likewise in oocytes, hERG channels were more sensitive to block by berberine (IC50 = 80 +/- 5 microM) compared with KCNQ1/KCNE1 channels (approximately 20% block at 300 microM). hERG block was markedly increased by membrane depolarization. Mutation to Ala of Y652 or F656 located on the S6 domain, or V625 located at the base of the pore helix of hERG decreased sensitivity to block by berberine. An inactivation-deficient mutant hERG channel (G628C/S631C) was also blocked by berberine. Together these findings indicate that berberine preferentially blocks the open state of hERG channels by interacting with specific residues that were previously reported to be important for binding of more potent antagonists.

Mice lacking functional KCNQ1 (previously known as KvLQT1) channels exhibit functional and structural abnormalities that indicate disturbed production of endolymph.Congenital deafness associated with cardiac conduction abnormalities (Jervell and Lange-Nielsen syndrome) is associated with dysfunctional KCNQ1/KCNE1 channel complex. This potassium channel plays a critical role in the production and homeostasis of endolymph by the stria vascularis. A preliminary report documented severe abnormalities of the scala media and vestibular compartments of a single mouse lacking functional KCNQ1 alleles.Hearing thresholds were measured in three Kcnq1 knockout mice, two heterozygous mice, and one wild-type mouse by auditory brainstem response recordings using clicks, after which the temporal bones were removed. After fixation and dehydration, the ears were embedded in araldite, sectioned at 20-microm thickness, stained with toluidine blue on glass slides, and examined with the light microscope.Kcnq1 knockout mice were deaf and demonstrated circling behavior. They exhibited a marked atrophy of the stria vascularis, contraction of the endolymphatic compartments, and collapse and adhesion of surrounding membranes. There was a complete degeneration of the organ of Corti and an associated degeneration of the spiral ganglion.Kcnq1 knockout mice exhibit histopathologic findings that are comparable to those reported in human temporal bone cases of Jervell and Lange-Nielsen syndrome, and provide further evidence that KCNQ1 channel dysfunction can lead to congenital deafness in this syndrome.

Altered myocardial repolarization is one of the important substrates of ventricular tachycardia and fibrillation. The influence of rare gene variants on repolarization is evident in familial long QT syndrome. To investigate the influence of common gene variants on the QT interval we performed a linkage disequilibrium based SNP association study of four candidate genes. Using a two-step design we analyzed 174 SNPs from the KCNQ1, KCNH2, KCNE1, and KCNE2 genes in 689 individuals from the population-based KORA study and 14 SNPs with results suggestive of association in a confirmatory sample of 3277 individuals from the same survey. We detected association to a gene variant in intron 1 of the KCNQ1 gene (rs757092, +1.7 ms/allele, P =0.0002) and observed weaker association to a variant upstream of the KCNE1 gene (rs727957, +1.2 ms/allele, P =0.0051). In addition we detected association to two SNPs in the KCNH2 gene, the previously described K897T variant (rs1805123, −1.9 ms/allele, P =0.0006) and a gene variant that tags a different haplotype in the same block (rs3815459, +1.7 ms/allele, P =0.0004). The analysis of additive effects by an allelic score explained a 10.5 ms difference in corrected QT interval length between extreme score groups and 0.95% of trait variance ( P

The KCNQ1-G589D gene mutation, associated with a long-QT syndrome, has been shown to disrupt yotiao-mediated targeting of protein kinase A and protein phosphatase-1 to the I Ks channel. To investigate how this defect may lead to ventricular arrhythmia during sympathetic stimulation, we use integrative computational models of β-adrenergic signaling, myocyte excitation-contraction coupling, and action potential propagation in a rabbit ventricular wedge. Paradoxically, we find that the KCNQ1-G589D mutation alone does not prolong the QT interval. But when coupled with β-adrenergic stimulation in a whole-cell model, the KCNQ1-G589D mutation induced QT prolongation and transient afterdepolarizations, known cellular mechanisms for arrhythmogenesis. These cellular mechanisms amplified tissue heterogeneities in a three-dimensional rabbit ventricular wedge model, elevating transmural dispersion of repolarization and creating other T-wave abnormalities on simulated electrocardiograms. Increasing heart rate protected both single myocyte and the coupled myocardium models from arrhythmic consequences. These findings suggest that the KCNQ1-G589D mutation disrupts a critical link between β-adrenergic signaling and myocyte electrophysiology, creating both triggers of cardiac arrhythmia and a myocardial substrate vulnerable to such electrical disturbances.

In rat pancreatic acini (RPAs), acetylcholine (ACh) typically induces a tonic depolarization of membrane potential (Vm) via increasing cytoplasmic Ca2+ concentration and subsequent activation of Cl- channels. In this study, to investigate the role of K+ channels during the ACh-induced Cl- secretion, the intracellular Cl- concentration ([Cl-]i) of RPAs was monitored using SPQ, a fluorescent dye quenchable by Cl-, and the effects of K+ channel blockers were examined. Also, the secretion of fluid and enzyme from the whole pancreas of rat was measured. The fluorescence of RPAs loaded with SPQ (FSPQ) was slightly increased by the application of ACh (ACh-Delta FSPQ), indicating net secretion of Cl-. However, the relative change of FSPQ normalized to the control fluorescence (F/F0) of RPAs was only about 20% of the effect observed in rat submandibular gland acinus. The ACh-Delta FSPQ of RPAs was not influenced by the pretreatment with 293B (20 micromol/L), a blocker of KCNQ-type K+ channels. Even the cocktail of K+ channel blockers (10 mmol/L TEA, 3 mmol/L Ba2+, 20 micromol/L 293B) exerted only minute inhibitory effects on ACh-Delta FSPQ in RPAs. In the vascularly perfused rat pancreas, the fluid and enzyme secretion induced by ACh was directly measured. 293B and HMR-1556, both specific blockers of KCNQ1 channel, did not block but even enhanced the secretion of fluid and amylase. These results suggest that the role of KCNQ1 channels may not be essential in the Ca2+-mediated Cl- secretion in rat pancreatic acini.

Background— Long QT syndrome (LQTS) predisposes affected individuals to sudden death from cardiac arrhythmias. Although most LQTS individuals do not have cardiac events, significant phenotypic variability exists within families. Probands can be very symptomatic. The mechanism of this phenotypic variability is not understood. Methods and Results— Genetic analyses of KVLQT1, HERG , KCNE1 , KCNE2 , and SCN5A detected compound mutations in 20 of 252 LQTS probands (7.9%). Carriers of 2 mutations had longer QTc intervals (527±54 versus 489±44 ms; P P P Xenopus oocytes was used to characterize the properties of variant slow delayed rectifier potassium ( I Ks ) channels identified in 7 of the probands. When wild-type and variant subunits were coexpressed in appropriate ratios to mimic the genotype of the proband, the reduction in I Ks density was equivalent to the additive effects of the single mutations. Conclusions— LQTS-associated compound mutations cause a severe phenotype and are more common than expected. Individuals with compound mutations need to be identified, and their management should be tailored to their increased risk for arrhythmias.

Whole-cell patch-clamp techniques were employed to examine the effects of bepridil, a Ca 2 + channel blocker with Vaughan Williams class III action, on a slow component of cardiac delayed rectifier K + current (I K s ), which was reconstituted in HEK293 cells by transfecting KCNQI and KCNEI. Micromolar bepridil inhibited tail currents carried by KCNQI/KCNEI channels in a concentration-dependent manner (IC 5 0 = 5.3 ′ 0.7 μM at -40 mV from 1000 milliseconds test pulse). When the effect of the drug was examined with a short test pulse protocol (250 milliseconds), IC 5 0 became two-fold smaller than that measured with 1000 milliseconds test pulse (2.5 ′ 0.8 μM). The envelope-of-tails protocol was used to assess how the duration of depolarizing pulse affects the drug action on the outward KCNQI/KCNEI channel current. The drug significantly inhibited tail currents more potently during shorter pulses (

We have analyzed the expression of KCNQ genes in murine portal vein myocytes and determined that of the 5 known KCNQ channels, only KCNQ1 was expressed. In addition to the full-length KCNQ1 transcript, a novel spliced form (termed KCNQ1b) was detected that had a 63 amino acid truncation at the C-terminus. KCNQ1b was not detected in heart or brain but represented approximately half the KCNQ1 transcripts expressed in PV. Antibodies specific for KCNQ1a stained cell membranes from portal vein myocytes and HEK cells expressing the channel. However, because the antibodies were generated against an epitope in the deleted, C-terminal portion of the protein, these antibodies did not stain HEK cells expressing KCNQ1b. In murine portal vein myocytes, in the presence of 5 mmol/L 4-aminopyridine, an outwardly rectifying K + current was recorded that was sensitive to linopirdine, a specific blocker of KCNQ channels. Currents produced by the heterologous expression of KCNQ1a or KCNQ1b were inhibited by similar concentrations of linopirdine, and linopirdine prolonged the time-course of the action potential in isolated portal vein myocytes. Our data suggest that these two KCNQ1 splice forms are expressed in murine portal vein and contribute to the delayed rectifier current in these myocytes.

Background —The 2 genes KCNQ1 (LQT1) and HERG (LQT2), encoding cardiac potassium channels, are the most common cause of the dominant long-QT syndrome (LQTS). In addition to QT-interval prolongation, notched T waves have been proposed as a phenotypic marker of LQTS patients. Methods and Results —The T-wave morphology of carriers of mutations in KCNQ1 (n=133) or HERG (n=57) and of 100 control subjects was analyzed from Holter ECG recordings. Averaged T-wave templates were obtained at different cycle lengths, and potential notched T waves were classified as grade 1 (G1) in case of a bulge at or below the horizontal, whatever the amplitude, and as grade 2 (G2) in case of a protuberance above the horizontal. The highest grade obtained from a template defined the notch category of the subject. T-wave morphology was normal in the majority of LQT1 and control subjects compared with LQT2 (92%, 96%, and 19%, respectively, P P HERG . Conclusions —This study provides novel evidence that Holter recording analysis is superior to the 12-lead ECG in detecting G1 and G2 T-wave notches. These repolarization abnormalities are more indicative of LQT2 versus LQT1, with G2 notches being most specific and often reflecting HERG core domain missense mutations.

Background —The long-QT syndrome (LQTS) is a genetically heterogeneous disease in which 4 genes encoding ion-channel subunits have been identified. Most of the mutations have been determined in the transmembrane domains of the cardiac potassium channel genes KCNQ1 and HERG . In this study, we investigated the 3′ part of HERG for mutations. Methods and Results —New specific primers allowed the amplification of the 3′ part of HERG , the identification of 2 missense mutations, S818L and V822 M, in the putative cyclic nucleotide binding domain, and a 1-bp insertion, 3108+1G. Hypokalemia was a triggering factor for torsade de pointes in 2 of the probands of these families. Lastly, in a large family, a maternally inherited G to A transition was found in the splicing donor consensus site of HERG , 2592+1G-A, and a paternally inherited mutation, A341E, was identified in KCNQ1 . The 2 more severely affected sisters bore both mutations. Conclusions —The discovery of mutations in the C-terminal part of HERG emphasizes that this region plays a significant role in cardiac repolarization. Clinical data suggests that these mutations may be less malignant than mutations occurring in the pore region, but they can become clinically significant in cases of hypokalemia. The first description of 2 patients with double heterozygosity associated with a dramatic malignant phenotype implies that genetic analysis of severely affected young patients should include an investigation for >1 mutation in the LQT genes.

Background Mutations that map to the KvLQT1 gene on human chromosome 11 account for more than 50% of inherited long QT syndrome (LQTS). It has been discovered recently that the KvLQT1 and minK proteins functionally interact to generate a current with biophysical properties similar to I Ks , the slowly activating delayed-rectifier cardiac potassium current. Since I Ks modulates the repolarization of cardiac action potentials it is reasonable to hypothesize that mutations in KvLQT1 reduce I Ks , resulting in the prolongation of cardiac action potential duration. Methods and Results We expressed LQTS-associated Kv LQT1 mutants in Xenopus oocytes either individually or in combination with wild-type KvLQT1 or in combination with both wild-type KvLQT1 and minK. Substitutions of alanine with proline in the S2-S3 cytoplasmic loop (A177P) or threonine with isoleucine in the highly conserved signature sequence of the pore (T311I) yield inactive channels when expressed individually, whereas substitution of leucine with phenylalanine in the S5 transmembrane domain (L272F) yields a functional channel with reduced macroscopic conductance. However, all these mutants inhibit wild-type KvLQT1 currents in a dominant-negative fashion. Conclusions In LQTS-affected individuals these mutations would be predicted to result in a diminution of the cardiac I Ks current, subsequent prolongation of cardiac repolarization, and an increased risk of arrhythmias.

Supplemental Digital Content is available in the text, Recently, rs163182 in KCNQ1, rs7612463 in UBE2E2, rs7119 in HMG20A, and rs6815464 in MAEA were discovered as type 2 diabetes (T2D) loci unique to Asians, and rs13342692 in SLC16A11 were newly reported as T2D loci in multiethnicities by genome-wide association (GWA) studies. The aim of the present study is to ascertain the potential associations between these variants and T2D risk in the Chinese population, and characterize diabetic-related quantitative traits underlying these variants. A total of 4268 Chinese Han individuals (1754 patients with T2D and 2514 glucose-tolerant health subjects, age ≥40 years) were genotyped for these 5 variants. All the health individuals underwent an oral glucose tolerance test (OGTT), and measures of insulin release and sensitivity were estimated from insulinogenic, BIGTT, Matsuda, and disposition indices. The associations were determined by using logistic regression analysis. After adjustment for age, sex, and BMI, rs163182 in KCNQ1 (P = 0.002) and rs7612463 in UBE2E2 (P = 0.024) were found to be associated with T2D risk in Chinese Han population. The risk C allele of rs7612463 in UBE2E2 is associated with decreased IGI (P = 0.001), BIGTT-AIR (P = 0.002), CIR (P = 0.002), and DI (P = 0.006). The other 4 variants did not associate with insulin release or sensitivity. UBE2E2 rs7612463 may mediate its diabetogenic impact on insulin response, which highly depends on the impairment of β-cell function.

I Ks , the slowly activating component of the delayed rectifier current, plays a major role in repolarization of the cardiac action potential (AP). Genetic mutations in the α- ( KCNQ1 ) and β- ( KCNE1 ) subunits of I Ks underlie Long QT Syndrome type 1 and 5 (LQT-1 and LQT-5), respectively, and predispose carriers to the development of polymorphic ventricular arrhythmias and sudden cardiac death. β-adrenergic stimulation increases I Ks and results in rate dependent AP shortening, a control system that can be disrupted by some mutations linked to LQT-1 and LQT-5. The mechanisms by which I Ks regulates action potential duration (APD) during β-adrenergic stimulation at different heart rates are not known, nor are the consequences of mutation induced disruption of this regulation. Here we develop a complementary experimental and theoretical approach to address these questions. We reconstituted I Ks in CHO cells (ie, KCNQ1 coexpressed with KCNE1 and the adaptator protein Yotiao) and quantitatively examined the effects of β-adrenergic stimulation on channel kinetics. We then developed theoretical models of I Ks in the absence and presence of β-adrenergic stimulation. We simulated the effects of sympathetic stimulation on channel activation (speeding) and deactivation (slowing) kinetics on the whole cell action potential under different pacing conditions. The model suggests these kinetic effects are critically important in rate-dependent control of action potential duration. We also investigate the effects of two LQT-5 mutations that alter kinetics and impair sympathetic stimulation of I Ks and show the likely mechanism by which they lead to tachyarrhythmias and indicate a distinct role of I KS kinetics in this electrical dysfunction. The full text of this article is available online at http://circres.ahajournals.org.

A drug dose (and con-centration) that produces minimal QT prolongation in onepatient may, in an apparently indistinguishable subject, pro-duce marked QT prolongation and torsade de pointes. Thisvariability in response to an exogenous stressor is paralleledby variability in the extent to which a given mutation in thecongenital long-QT syndrome prolongs QT interval andcauses arrhythmias.