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Objective: The safest and most effective exercise stress tests (EST) modalities for long QT syndrome (LQTS) are currently unknown. The main objective was to explore the effects of EST on the corrected QT interval (QTc) in patients with LQTS, and to compare the effects of different EST modalities (cycle ergometer vs treadmill). Data Sources: Systematic searches were performed in September 2022 in accordance with the PRISMA statement through PubMed, Medline, EBM Reviews, Embase, and Web of Science. Main Results: A total of 1728 patients with LQTS, whether congenital or acquired, without any age restrictions (pediatric age#18 years and adult age.19 years), and 2437 control subjects were included in the 49 studies. The QT interval data were available for 15 studies. Our analyses showed that the QT interval prolonged in a similar manner using either a cycle ergometer or a treadmill (standardized mean difference [SMD] 5 1.89 [95% CI, 1.07-2.71] vs SMD 5 1.46 [95% CI, 0.78-2.14], respectively). Therefore, it seems that either modality may be used to evaluate patients with LQTS. Conclusions: The methodology for the measurement of the QT interval was very heterogeneous between studies, which inevitably influenced the quality of the analyses. Hence, researchers should proceed with caution when exploring and interpreting data in the field of exercise and LQTS. [ABSTRACT FROM AUTHOR]

Introduction: Although prior studies indicate that a QTc > 500 ms on a single baseline 12‐lead electrocardiogram (ECG) is associated with significantly increased risk of arrhythmic events in long QT syndrome (LQTS), less is known about the risk of persistent QT prolongation. We sought to determine QTc persistence and its prognostic effect on breakthrough cardiac events (BCEs) among pediatric patients treated for LQTS. Methods: We performed a retrospective analysis of 433 patients with LQTS evaluated, risk‐stratified, and undergoing active guideline‐based LQTS treatment between 1999 and 2019. BCEs were defined as arrhythmogenic syncope/seizure, sudden cardiac arrest (SCA), appropriate VF‐terminating ICD shock, and sudden cardiac death (SCD). Results: During the median follow‐up of 5.5 years (interquartile range [IQR] = 3–9), 32 (7%) patients experienced a total of 129 BCEs. A maximum QTc threshold of 520 ms and median QTc threshold of 490 ms were determined to be strong predictors for BCEs. A landmark analysis controlling for age, sex, genotype, and symptomatic status demonstrated models utilizing both the median QTc and maximum QTc demonstrated the highest discriminatory value (c‐statistic = 0.93–0.95). Patients in the high‐risk group (median QTc > 490 ms and maximum QTc > 520 ms) had a significantly lower BCE free survival (70%–81%) when compared to patients in both medium‐risk (93%–97%) and low‐risk (98%–99%) groups. Conclusions: The risk of BCE among patients treated for LQTS increases not only based upon their maximum QTc, but also their median QTc (persistence of QTc prolongation). Patients with a maximum QTc > 520 ms and median QTc > 490 ms over serial 12‐lead ECGs are at the highest risk of BCE while on guideline‐directed medical therapy. [ABSTRACT FROM AUTHOR]

QT prolongation is related to the development of ventricular arrhythmias such as Torsade de Pointes (TdP) that can lead to sudden cardiac death. Several drugs used in the treatment of patients with advanced cancer may induce QT prolongation due to their interference with cardiac ion channels. Some patients may be at higher risk if predisposing factors are present. Herein we present the case of a patient with advanced cancer under anti-tumor treatment with radical intention that developed a reversible drug-induced QT prolongation when simultaneously treated with methadone, haloperidol and fluoxetine that presented with chest pain and bradycardia. An approach to cancer patients at risk for drug-induced QT prolongation is discussed highlighting the need of a thorough medication review with a special focus in the patient with polypharmacy. [ABSTRACT FROM AUTHOR]

Background: There is no consensus for assessment and management of patients with serious mental illness (SMI) who are at risk for cardiac morbidity and mortality due to antipsychotic-associated QTc prolongation. Objective: The objective of this review was to assess methods for risk scoring, QT correction calculation, and clinical management in SMI patients with antipsychotic-associated QTc prolongation. Methods: A search was performed in PubMed for case reports that described QTc prolongation in adult patients with schizophrenia or bipolar disorder prescribed an antipsychotic. Reports published in North America between 2000 and 2020 were eligible. The Mayo, Tisdale, and RISQ-PATH scoring tools were applied to cases to categorize risk level. Results: Seventeen cases were included. Most patients were prescribed a second-generation antipsychotic for schizophrenia, with baseline and maximum QTc values of 429 milliseconds and 545 milliseconds, respectively. The Mayo scoring tool identified 17 (100%) cases as "high risk," Tisdale identified 9 (53%) cases as "moderate risk" and 7 (41%) cases as "low risk," while RISQ-PATH identified 9 (53%) cases as "not low risk" and 8 (47%) cases as "low risk." Three cases reported the QT correction formula utilized (18%). The most common intervention to address antipsychotic-associated QTc prolongation was switching to a different antipsychotic (35%). Approximately one third of patients experienced Torsades de Pointes. Conclusion: There is a lack of standardization for antipsychotic-associated QTc prolongation risk assessment and management in patients with SMI. This review provides real-world data representing actual clinical practice. [ABSTRACT FROM AUTHOR]

Many drugs are associated with QT prolongation and certain patient factors can increase this effect, leading to a significant risk of arrhythmias. This article describes the drug and patient factors that can lead to QT prolongation and discusses how the risks can be reduced. [ABSTRACT FROM AUTHOR]

A diagnosis of congenital long QT interval syndrome based on history and electrocardiogram was made in a child in the absence of readily available genetic testing. A genotype 3 (LQT3) was suspected after exclusion of other variants as the child was non-responsive to beta-blocker and sodium channel blocker medication. As the child continues to show episodic bradycardia, polymorphic ventricular ectopy, and T-wave alternans, a single-chamber automated implantable cardioverter-defibrillator implantation was done successfully. This report highlights how the diagnosis of LQT3 was arrived at as well as the anesthetic challenges in the management of patients with LQTS. [ABSTRACT FROM AUTHOR]

Managing the risks and consequences of long QT syndrome can be challenging. Multiple factors contribute to the prolongation of the heart-rate corrected QT (QTc) interval including many drug-drug and drug-disease state interactions. Current literature is often focused on avoiding dysrhythmias with limited guidance on acute management strategies. Here we describe a case of QTc prolongation to 616 msec (Bazett's formula) in the setting of chronic dofetilide overdose due to a possible prescription error. Our case was complicated by alcohol withdrawal and electrolyte disturbances that progressed to patient cardiac arrest in the emergency department. Dofetilide overdose was identified through pharmacist-initiated medication reconciliation and lidocaine was recommended as an alternative to amiodarone during advanced cardiac life support (ACLS). This case highlights the importance of reviewing outpatient medication records as well as avoiding drug-drug interactions during ACLS. Due to the potential for additive QTc prolongation, we recommend using lidocaine as the preferred antiarrhythmic in ACLS algorithms where drug induced QTc prolongation is suspected. [ABSTRACT FROM AUTHOR]

Background: The effectiveness of implantable cardioverter-defibrillators (ICDs) on reducing mortality has not been well studied in patients with long QT syndrome (LQTS).Objectives: This study aimed to assess the survival benefits of ICDs in the overall LQTS population and in subgroups defined by ICD indications.Methods: This study included 3,035 patients (597 with ICD) from the Rochester LQTS Registry with a QTc ≥470 milliseconds or confirmed LQTS mutation. Using multivariable Cox proportional hazards models, the risk of all-cause mortality, all-cause mortality before age 50 years, and sudden cardiac death (SCD) were estimated as functions of time-dependent ICD therapy. Indication subgroups examined included patients with: 1) nonfatal cardiac arrest; 2) syncope while on beta-blockers; and 3) a QTc ≥500 milliseconds and syncope while off beta-blockers.Results: During the 118,837 person-years of follow-up, 389 patients died (137 before age 50 years, and 116 experienced SCD). In the entire population, patients with ICDs had a lower risk of death (HR: 0.54; 95% CI: 0.34-0.86), death before age 50 years (HR: 0.29; 95% CI: 0.14-0.61), and SCD (HR: 0.22; 95% CI: 0.09-0.55) than patients without ICDs did. Patients with ICDs also had a lower risk of mortality among the 3 indication subgroups (HR: 0.14; 95% CI: 0.06-0.34; HR: 0.27; 95% CI: 0.10-0.72; and HR: 0.42; 95% CI: 0.19-0.96, respectively).Conclusions: ICD therapy was associated with a lower risk of all-cause mortality, all-cause mortality before age 50 years, and SCD in the LQTS population, as wells as with a lower risk of all-cause mortality in indication subgroups. This study provides evidence supporting ICD implantation in patients with high-risk LQTS. [ABSTRACT FROM AUTHOR]

Background: Type 1 long QT syndrome (LQT1) is caused by loss-of-function variants in the KCNQ1-encoded Kv7.1 potassium channel α-subunit that is essential for cardiac repolarization, providing the slow delayed rectifier current. No current therapies target the molecular cause of LQT1.Methods: A dual-component suppression-and-replacement (SupRep) KCNQ1 gene therapy was created by cloning a KCNQ1 short hairpin RNA and a short hairpin RNA-immune KCNQ1 cDNA modified with synonymous variants in the short hairpin RNA target site, into a single construct. The ability of KCNQ1-SupRep gene therapy to suppress and replace LQT1-causative variants in KCNQ1 was evaluated by means of heterologous expression in TSA201 cells. For a human in vitro cardiac model, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated from 4 patients with LQT1 (KCNQ1-Y171X, -V254M, -I567S, and -A344A/spl) and an unrelated healthy control. CRISPR-Cas9 corrected isogenic control iPSC-CMs were made for 2 LQT1 lines (correction of KCNQ1-V254M and KCNQ1-A344A/spl). FluoVolt voltage dye was used to measure the cardiac action potential duration (APD) in iPSC-CMs treated with KCNQ1-SupRep.Results: In TSA201 cells, KCNQ1-SupRep achieved mutation-independent suppression of wild-type KCNQ1 and 3 LQT1-causative variants (KCNQ1-Y171X, -V254M, and -I567S) with simultaneous replacement of short hairpin RNA-immune KCNQ1 as measured by allele-specific quantitative reverse transcription polymerase chain reaction and Western blot. Using FluoVolt voltage dye to measure the cardiac APD in the 4 LQT1 patient-derived iPSC-CMs, treatment with KCNQ1-SupRep resulted in shortening of the pathologically prolonged APD at both 90% and 50% repolarization, resulting in APD values similar to those of the 2 isogenic controls.Conclusions: This study provides the first proof-of-principle gene therapy for complete correction of long QT syndrome. As a dual-component gene therapy vector, KCNQ1-SupRep successfully suppressed and replaced KCNQ1 to normal wild-type levels. In TSA201 cells, cotransfection of LQT1-causative variants and KCNQ1-SupRep caused mutation-independent suppression and replacement of KCNQ1. In LQT1 iPSC-CMs, KCNQ1-SupRep gene therapy shortened the APD, thereby eliminating the pathognomonic feature of LQT1. [ABSTRACT FROM AUTHOR]

Keywords: Editorials; arrhythmias, cardiac; death, sudden, cardiac; long QT syndrome EN Editorials arrhythmias, cardiac death, sudden, cardiac long QT syndrome 2416 2419 4 12/23/20 20201222 NES 201222 B Article, see p 2405 b Long QT syndrome (LQTS) can no longer be viewed as a medical curiosity, of interest only to arrhythmia specialists. For those quitting sports to avoid the need for therapy, strict avoidance of QT-prolonging medications, and close ECG surveillance to verify that their normalized QT remains normal, is prudent until we learn more about this new form of LQTS. Mexiletine shortens the QT interval in patients with potassium channel-mediated type 2 long QT syndrome. [Extracted from the article]

The diagnosis of long QT syndrome (LQTS) in utero presents many challenges for clinicians, and there is high risk for intrauterine fetal demise as life-threatening arrhythmias develop secondary to QT prolongation. We describe a challenging case of a fetus presenting with sinus bradycardia and second-degree atrioventricular block with episodes of ventricular tachycardia. A prenatal diagnosis of LQTS was suspected given the fetal echocardiographic findings of a short ventricular relaxation time, due to extremely prolonged refractory period. The patient was delivered emergently due to Torsade's with hydrops, with ongoing arrhythmia despite medical management requiring implantation of pacemaker and sympathectomy. Early recognition of LQTS is important to optimize fetal survival with prompt medical management. [ABSTRACT FROM AUTHOR]

Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility.Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score.Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P<5×10-8) near NOS1AP, KCNQ1, and KLF12, and 1 missense variant in KCNE1(p.Asp85Asn) at the suggestive threshold (P<10-6). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (rg=0.40; P=3.2×10-3). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P<0.005).Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS. [ABSTRACT FROM AUTHOR]

Background: Patients with long QT syndrome (LQTS) are predisposed to life-threatening arrhythmias. A delay in cardiac repolarization is characteristic of the disease. Pharmacotherapy, implantable cardioverter-defibrillators, and left cardiac sympathetic denervation are part of the current treatment options, but no targeted therapy for LQTS exists to date. Previous studies indicate that induced autoimmunity against the voltage-gated KCNQ1 K+ channels accelerates cardiac repolarization.Objectives: However, a causative relationship between KCNQ1 antibodies and the observed electrophysiological effects has never been demonstrated, and thus presents the aim of this study.Methods: The authors purified KCNQ1 antibodies and performed whole-cell patch clamp experiments as well as single-channel recordings on Chinese hamster ovary cells overexpressing IKs channels. The effect of purified KCNQ1 antibodies on human cardiomyocytes derived from induced pluripotent stem cells was then studied.Results: The study demonstrated that KCNQ1 antibodies underlie the previously observed increase in repolarizing IKs current. The antibodies shift the voltage dependence of activation and slow the deactivation of IKs. At the single-channel level, KCNQ1 antibodies increase the open time and probability of the channel. In models of LQTS type 2 (LQTS2) using human induced pluripotent stem cell-derived cardiomyocytes, KCNQ1 antibodies reverse the prolonged cardiac repolarization and abolish arrhythmic activities.Conclusions: Here, the authors provide the first direct evidence that KCNQ1 antibodies act as agonists on IKs channels. Moreover, KCNQ1 antibodies were able to restore alterations in cardiac repolarization and most importantly to suppress arrhythmias in LQTS2. KCNQ1 antibody therapy may thus present a novel promising therapeutic approach for LQTS2. [ABSTRACT FROM AUTHOR]

Background: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration.Methods: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death.Results: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P<0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR] 11.6 [95% CI, 2.6-52.2]; P=0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3-10.8], P=0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%).Conclusions: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients. [ABSTRACT FROM AUTHOR]

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Introduction: The epinephrine challenge has been proposed to improve the diagnosis of congenital long QT syndrome (LQTS). The aim of the study was to evaluate the diagnostic reliability of the epinephrine provocative test for LQTS diagnosis, taking into consideration intra‐ and interobserver variability in the interpretation of the test. Methods and Results: A retrospective analysis of 79 consecutive epinephrine provocative tests was conducted. Epinephrine was administered following a standardized protocol at two doses: 0.05 and 0.10 µg kg−1 min−1. Electrocardiograms were blindly read twice by three different operators at ≥1‐week interval. QT and RR intervals were collected at rest and at each dose, as well as final operator interpretation of the test. There was a high interobserver reproducibility of corrected QT measurements with an intraclass correlation (ICC) of 0.74 (95% confidence interval, 0.66‐0.80) but a low interobserver reproducibility on the final interpretation with a κ of 0.31. Intraobserver reproducibility of corrected QT was very good (ICC 0.93; 0.91‐0.95), but still resulted in an only moderate intraobserver reproducibility in the final diagnosis (κ of 0.47). Perceived certainty of at least 1 reading by 2 operators (N = 62 tests) increased interobserver reproducibility compared with baseline (κ = 0.43). Conclusion: Inter‐ and intraobserver agreement in the interpretation of the epinephrine provocation test for LQTS is poor to modest. Complexity in interpretation varies from one case to the next. The low reliability of this test encourages a reconsideration of its importance in the clinical management of patients with suspected LQTS. [ABSTRACT FROM AUTHOR]

The diagnosis of epilepsy is incorrect in up to 20% of cases so should be revisited if attacks are not responding to treatment. We present a case of long QT syndrome that remained undiagnosed in the epilepsy clinic for 15 years until a near-fatal arrhythmia revealed the diagnosis and allowed effective treatment of her attacks. We hope this near miss raises awareness of long QT syndrome as a potentially fatal, rare but treatable condition that neurologists must consider in people with a label of refractory epilepsy. We provide practical pointers to increase the chance of early diagnosis and explore the impact of a late diagnosis for the patient and her family. [ABSTRACT FROM AUTHOR]

Intrathoracic impedance was remotely monitored from preconception to postpartum in a woman with an implantable cardioverter defibrillator. At 6 and 20 weeks, two significant changes were recorded, suggestive for thoracic fluid accumulation. After normal outcome, postpartum intrathoracic impedance returned to preconception values. The obtained results from this case report show that these measurements can be obtained with an implanted device. Current devices for measuring cardiac output by impedance technique allow evaluating thoracic fluid changes non-invasively. As such, non-invasive impedance monitoring may be a potential new method for continuous monitoring of maternal vascular changes during any time window between preconception and postpartum, to be assessed in a large cross sectional observational study. [ABSTRACT FROM AUTHOR]

Abstract: Background: Incorporation of QTc in clinical decision support systems requires accurate QT‐interval correction, also during common electrocardiogram abnormalities as ventricular conduction defects (VCD). We compared the performance and predictive value of QT correction formulas to design a patient‐specific QT correction algorithm (QTcA). Methods: The first ECG in adult patients with sinus rhythm (SR), atrial fibrillation (AF), and ventricular pacing (VP) was collected retrospectively. QT correction was performed with Bazett (QTcB), Fridericia (QTcFri), Framingham, Hodges, and Rautaharju (QTcR) formulas. Correction formulas were compared using QTc/RR linear regression. Adjusted Cox regression was performed to predict 1‐year all‐cause mortality. Results: A total of 49,737 patients were included (70.0% SR, 24.1% AF, 5.9% VP, 11.1% VCD). Overall 1‐year all‐cause mortality rate was 11.8%. In patients without VCD or VP, QTcFri showed significantly better heart rate correction, both overall (P < 0.001) and in subgroups by heart rate (bradycardia P ≤ 0.001, normal P ≤ 0.050, tachycardia P ≤ 0.010). Furthermore, QTcFri improved mortality prediction significantly when compared to QTcB (P < 0.001). Patients with VCD or VP QTcR, including correction for QRS duration, had a significant better heart rate correction than QTcB (P ≤ 0.010) and improved mortality prediction significantly compared to all other formulas (P < 0.001). Implementing QTcA, designed based on QTcFri and QTcR depending on the presence of VCD or VP, reduced the patients considered to be at risk by 61.1% when compared to QTcB. Conclusions: A patient‐specific QT correction algorithm would combine accurate heart rate correction, improved predictive value of mortality, and a reduction of patients considered to be at risk. [ABSTRACT FROM AUTHOR]

The article focuses on the congenital long QT syndrome (LQTS) and arrhythmogenic right ventricular cardiomyopathy which leads to sudden cardiac arrest (SCD). It talks about genetic mutations being the cause to LQTS and other cardiac disorders. It tells about the disorder being managed by making changes in the lifestyle, following proper medication and staying away from sources of loud sudden noises.

Flecainide suppresses cardiac tachyarrhythmias including paroxysmal atrial fibrillation, supraventricular tachycardia and arrhythmic long QT syndromes (LQTS), as well as the Ca2+ -mediated, catecholaminergic polymorphic ventricular tachycardia (CPVT). However, flecainide can also exert pro-arrhythmic effects most notably following myocardial infarction and when used to diagnose Brugada syndrome (BrS). These divergent actions result from its physiological and pharmacological actions at multiple, interacting levels of cellular organization. These were studied in murine genetic models with modified Nav channel or intracellular ryanodine receptor (RyR2)-Ca2+ channel function. Flecainide accesses its transmembrane Nav 1.5 channel binding site during activated, open, states producing a use-dependent antagonism. Closing either activation or inactivation gates traps flecainide within the pore. An early peak INa related to activation of Nav channels followed by rapid de-activation, drives action potential (AP) upstrokes and their propagation. This is diminished in pro-arrhythmic conditions reflecting loss of function of Nav 1.5 channels, such as BrS, accordingly exacerbated by flecainide challenge. Contrastingly, pro-arrhythmic effects attributed to prolonged AP recovery by abnormal late INaL following gain-of-function modifications of Nav 1.5 channels in LQTS3 are reduced by flecainide. Anti-arrhythmic effects of flecainide that reduce triggering in CPVT models mediated by sarcoplasmic reticular Ca2+ release could arise from its primary actions on Nav channels indirectly decreasing [Ca2+ ]i through a reduced [Na+ ]i and/or direct open-state RyR2-Ca2+ channel antagonism. The consequent [Ca2+ ]i alterations could also modify AP propagation velocity and therefore arrhythmic substrate through its actions on Nav 1.5 channel function. This is consistent with the paradoxical differences between flecainide actions upon Na+ currents, AP conduction and arrhythmogenesis under circumstances of normal and increased RyR2 function.Linked Articles: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc. [ABSTRACT FROM AUTHOR]

Abstract: Since its initial description by Jervell and Lange‐Nielsen in 1957, the congenital long QT syndrome (LQTS) has been the most investigated cardiac ion channelopathy. Although congenital LQTS continues to remain the domain of cardiologists, cardiac electrophysiologists, and specialized centers, the by far more frequent acquired drug‐induced LQTS is the domain of all physicians and other members of the health care team who are required to make therapeutic decisions. This report will review the electrophysiological mechanisms of LQTS and torsade de pointes, electrocardiographic characteristics of acquired LQTS, its clinical presentation, management, and future directions in the field. [ABSTRACT FROM AUTHOR]

QT prolongation was perceived as a major antiarrhythmic mechanism, but soon became a surrogate for torsades de pointes (TdP) instead. Drugs that prolong the QT interval range from having potent torsadogenic activity to no proarrhythmic action and even antiarrhythmic effects. Blockade of hERG channels is the primary cause of TdP, but blockade/activation of other channels can also be torsadogenic. TdP is primarily caused by disturbances of TRIaD, but disturbance of wavelength can also contribute to TdP (where TRIaD is triangulation, reverse use dependence, instability and dispersion, and wavelength equals conduction velocity times effective refractory period). The above proarrhythmic parameters do not only result in TdP, but can also lead to ventricular tachycardia (VT) and ventricular fibrillation (VF). Note that QT prolongation (not listed as a causal factor) yields many false positives (potentially depriving patients from much needed drugs) and false negatives (potentially exposing patients to lethal arrhythmias). Thus, drug-induced QT prolongation is a bad surrogate for TdP, VT or VF; it is high time to move away from an oversimplified and erroneous surrogate. [ABSTRACT FROM AUTHOR]

Background/Aims: High-fat diet (HFD) causes cardiac electrical remodeling and increases the risk of ventricular arrhythmias. Aloe-emodin (AE) is an anthraquinone component isolated from rhubarb and has a similar chemical structure with emodin. The protective effect of emodin against cardiac diseases has been reported in the literature. However, the cardioprotective property of AE is still unknown. The present study investigated the effect of AE on HFD-induced QT prolongation in rats. Methods: Adult male Wistar rats were randomly divided into three groups: control, HFD, and AE-treatment groups. Normal diet was given to rats in the control group, high-fat diet was given to rats in HFD and AE-treatment groups for a total of 10 weeks. First, HFD rats and AE-treatment rats were fed with high-fat diet for 4 weeks to establish the HFD model. Serum total cholesterol and triglyceride levels were measured to validate the HFD model. Afterward, AE-treatment rats were intragastrically administered with 100 mg/kg AE each day for 6 weeks. Electrocardiogram monitoring and whole-cell patch-clamp technique were applied to examine cardiac electrical activity, action potential and inward rectifier K+ current (IK1), respectively. Neonatal rat ventricular myocytes (NRVMs) were subjected to cholesterol and/or AE. Protein expression of Kir2.1 was detected by Western blot and miR-1 level was examined by real-time PCR in vivo and in vitro, respectively. Results: In vivo, AE significantly shortened the QT interval, action potential duration at 90% repolarization (APD90) and resting membrane potential (RMP), which were markedly elongated by HFD. AE increased IK1 current and Kir2.1 protein expression which were reduced in HFD rats. Furthermore, AE significantly inhibited pro-arrhythmic miR-1 in the hearts of HFD rats. In vitro, AE decreased miR-1 expression levels resulting in an increase of Kir2.1 protein levels in cholesterol-enriched NRVMs. Conclusions: AE prevents HFD-induced QT prolongation by repressing miR-1 and upregulating its target Kir2.1. These findings suggest a novel pharmacological role of AE in HFD-induced cardiac electrical remodeling. [ABSTRACT FROM AUTHOR]

Background The polyphenol resveratrol and its metabolite piceatannol have beneficial health effects including antiarrhythmic properties in ischemia/reperfusion. The objective of this study was to determine potential antiarrhythmic effects in acquired long-QT-syndrome (LQTS). Methods and results 26 rabbit hearts were isolated and Langendorff-perfused. The I Kr -blocker sotalol (100 μM) was infused to mimic LQTS-2. Hearts were assigned to two groups. Sotalol significantly prolonged action potential duration (APD 90 ) and QT-interval in both groups (group 1:APD 90 : + 18 ms, p < 0.01;QT: + 59 ms, p < 0.01; group 2: APD 90 : + 22 ms, p < 0.01; QT: + 30 ms, p < 0.01) and also significantly increased dispersion of repolarization (group 1: + 21 ms, p < 0.01; group 2: + 23 ms, p < 0.01). Thereafter, hearts were additionally perfused either with resveratrol (50 μM, group 1, n = 14) or with piceatannol (10 μM, group 2, n = 12). Administration of resveratrol significantly reduced APD 90 (− 29 ms, p < 0.01), QT-interval(− 60 ms, p < 0.01) and dispersion of repolarization (− 26 ms, p < 0.01). In contrast, piceatannol did not significantly alter APD 90 (± 0 ms) but shortened QT-interval (− 19 ms, p < 0.01) and increased dispersion of repolarization (+ 15 ms, p < 0.01). With sotalol, 7 of 14 bradycardic, AV-blocked hearts in group 1 and 8 of 12 in group 2 showed early afterdepolarizations (EAD) after lowering potassium concentration (p < 0.01each). Polymorphic ventricular tachycardia (PVT) occurred in 5 of 14 (p < 0.05) and 4 of 12 hearts (p = 0.09) with a total number of 42 (p < 0.05) and 44 episodes (p = 0.07), respectively. Additional infusion of resveratrol reduced EAD (2 of 14, p = 0.11) and PVT (1 of 14 hearts, p = 0.16, 3 episodes, p < 0.05). Piceatannol did not suppress EAD or TdP (EAD in 9 of 12 and TdP in 7 of 12 hearts,50 episodes). Conclusion Resveratrol showed beneficial antiarrhythmic properties in acquired LQTS. Underlying mechanism is a substantial decrease dispersion of repolarization leading to a suppression of triggered activity. [ABSTRACT FROM AUTHOR]

Background Long QT Syndrome type 2 (LQT2) is caused by mutations in the KCNH2 gene that encodes for the α-subunit (hERG) of the ion channel conducting the rapid delayed rectifier potassium current (I Kr ). We have previously identified a disease causing mutation (IVS9-28A/G) in the branch point of the splicing of KCNH2 intron 9. However, the mechanism through which this mutation causes the disease is unknown. Methods and results We generated human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from fibroblasts of two IVS9-28A/G mutation carriers. IVS9-28A/G iPSC-CMs showed prolonged repolarization time, mimicking what observed at the ECG level in the same patients. The expression of the full-length ERG1a isoform resulted reduced, whereas the C-terminally truncated ERG 1aUSO isoform was upregulated in mutant iPSC-CMs, with consequent alteration of the physiological ERG 1aUSO /ERG1a ratio. Importantly, we observed an impairment of hERG trafficking to the cell membrane. The severity of the alterations in hERG expression and trafficking correlated with the clinical severity of the disease in the two patients under study. Finally, we were able to revert the trafficking defect and reduce the repolarization duration in LQT2 iPSC-CMs using the proteasome inhibitor ALLN. Conclusion Our results highlight the key role of the KCNH2 intron 9 branch point in the regulation of KCNH2 isoform expression and hERG channel function, and allow to categorize the IVS9-28A/G mutation as LQT2 class 2 mutation. These findings may result in a more personalized clinical management of IVS9-28A/G mutation carriers. [ABSTRACT FROM AUTHOR]

Background and Purpose: Activators of Kv 11.1 (hERG) channels have potential utility in the treatment of acquired and congenital long QT (LQT) syndrome. Here, we describe a new hERG channel activator, 5-(((1H-indazol-5-yl)oxy)methyl)-N-(4-(trifluoromethoxy)phenyl)pyrimidin-2-amine (ITP-2), with a chemical structure distinct from previously reported compounds.Experimental Approach: Conventional electrophysiological methods were used to assess the effects of ITP-2 on hERG1a and hERG1a/1b channels expressed heterologously in HEK-293 cells.Key Results: ITP-2 selectively increased test pulse currents (EC50 1.0 μM) and decreased tail currents. ITP-2 activated hERG1a homomeric channels primarily by causing large depolarizing shifts in the midpoint of voltage-dependent inactivation and hyperpolarizing shifts in the voltage-dependence of activation. In addition, ITP-2 slowed rates of inactivation and made recovery from inactivation faster. hERG1a/1b heteromeric channels showed reduced sensitivity to ITP-2 and their inactivation properties were differentially modulated. Effects on midpoint of voltage-dependent inactivation and rates of inactivation were less pronounced for hERG1a/1b channels. Effects on voltage-dependent activation and activation kinetics were not different from hERG1a channels. Interestingly, hERG1b channels were inhibited by ITP-2. Inactivation-impairing mutations abolished activation by ITP-2 and led to inhibition of hERG channels. ITP-2 exerted agonistic effect from extracellular side of the membrane and could activate one of the arrhythmia-associated trafficking-deficient LQT2 mutants.Conclusions and Implications: ITP-2 may serve as another novel lead molecule for designing robust activators of hERG channels. hERG1a/1b gating kinetics were differentially modulated by ITP-2 leading to altered sensitivity. ITP-2 is capable of activating an LQT2 mutant and may be potentially useful in the development of LQT2 therapeutics. [ABSTRACT FROM AUTHOR]

Background: Long QT syndrome (LQTS) is a potentially lethal cardiac channelopathy with a 1% to 5% annual risk of LQTS-triggered syncope, aborted cardiac arrest, or sudden cardiac death.Objectives: This study sought to evaluate LQTS outcomes from a single center in the contemporary era.Methods: The authors conducted a retrospective study comprising the 606 patients with LQTS (LQT1 in 47%, LQT2 in 34%, and LQT3 in 9%) who were evaluated in Mayo Clinic's Genetic Heart Rhythm Clinic from January 1999 to December 2015. Breakthrough cardiac events (BCEs) were defined as LQTS-attributable syncope or seizures, aborted cardiac arrest, appropriate ventricular fibrillation-terminating implantable cardioverter-defibrillator shocks, and sudden cardiac death.Results: There were 166 (27%) patients who were symptomatic prior to their first Mayo Clinic evaluation. Median age at first symptom was 12 years. Treatment strategies included no active therapy in 47 (8%) patients, beta-blockers alone in 350 (58%) patients, implantable cardioverter-defibrillators alone in 25 (4%) patients, left cardiac sympathetic denervation alone in 18 (3%) patients, and combination therapy in 166 (27%) patients. Over a median follow-up of 6.7 (IQR: 3.9 to 9.8) years, 556 (92%) patients have not experienced an LQTS-triggered BCE. Only 8 of 440 (2%) previously asymptomatic patients have experienced a single BCE. In contrast, 42 of 166 (25%) previously symptomatic patients have experienced ≥1 BCE. Among the 30 patients with ≥2 BCEs, 2 patients have died and 3 LQT3 patients underwent cardiac transplantation.Conclusions: Although outcomes have improved markedly, further optimization of treatment strategies is still needed given that 1 in 4 previously symptomatic patients experienced at least 1 subsequent, albeit nonlethal, LQTS-triggered cardiac event. [ABSTRACT FROM AUTHOR]

Objectives: Implantable cardioverter defibrillator (ICD) treatment is effective among long QT syndrome (LQTS) patients at a high risk of sudden cardiac death. Previous studies show that the international guidelines are not always followed, and that risk stratification may be based on genotype rather than individual risk profile. We analysed data from the Swedish ICD & Pacemaker Registry and medical records to examine how international guidelines were followed with regards to phenotype and genotype.Methods and Results: ICD treatment was used in 150 Swedish LQTS patients from 1989-2013. The annual number of implantations increased over the study period. A total of 109 patients were included in the analysis. Most patients (91%) were symptomatic before the implantation. Seventy percent of patients who received ICD treatment met the 2006 Class I or Class IIa recommendations for LQTS treatment. Thirty-one percent of the LQT3 patients received ICD treatment despite being asymptomatic. Among LQT1 patients, 45% received ICD treatment after syncope despite beta-blockers.Conclusions: Thirty percent of Swedish LQTS patients with ICD received the treatment without a strong indication based on international guidelines. LQT3 patients were over-represented among asymptomatic patients. Many LQT1 patients received ICD despite the known effect of beta-blockers in this group. [ABSTRACT FROM AUTHOR]

Female sex is an independent risk factor for development of torsade de pointes (TdP) arrhythmias not only in congenital long QT syndromes but also in acquired long QT syndromes. Clinical and experimental evidences suggest that the gender differences may be due to, at least in part, gender differences in regulation of rate-corrected QT (QT C ) interval between men and women. In adult women, both QT C interval and arrhythmic risks in TdP alter cyclically during menstrual cycle, suggesting a critical role of female sex hormones in cardiac repolarization process. These gender differences in fundamental cardiac electrophysiology result from variable ion channel expression and diverse sex hormonal regulation via long term genomic and acute non-genomic actions, and sex differences in drug responses and metabolisms. In particular, non-genomic actions of testosterone and progesterone on cardiac ion channels are likely to contribute to the gender differences in cardiac repolarization processes. This review summarizes current knowledge on sex hormonal regulation of cardiac ion channels which contribute to cardiac repolarization processes and its implication for gender differences in drug-induced long QT syndromes. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 5‐year‐old girl with a with a history of recurrent episodes of loss of consciousness. Topics discussed include the electrocardiogram (ECG) taken for the patient; diagnosis of congenital long‐QT syndrome (LQTS) in the patient; and the single‐chamber permanent pacemaker implantation (AAIR) performed on the patient. Also mentioned is the disappearance of QT alternans and T‐wave alternans (TWA).

Background and Purpose: Enhanced late Na+ current (late INa ) in the myocardium is pro-arrhythmic. Inhibition of this current is a promising strategy to stabilize ventricular repolarization and suppress arrhythmias. Here, we describe GS-6615, a selective inhibitor of late INa , already in clinical development for the treatment of long QT syndrome 3 (LQT3).Experimental Approach: The effects of GS-6615 to inhibit late INa , versus other ion currents to shorten the ventricular action potential duration (APD), monophasic APD (MAPD) and QT interval, and decrease to the incidence of ventricular arrhythmias was determined in rabbit cardiac preparations. To mimic the electrical phenotype of LQT3, late INa was increased using the sea anemone toxin (ATX-II).Key Results: GS-6615 inhibited ATX-II enhanced late INa in ventricular myocytes (IC50  = 0.7 μM), shortened the ATX-II induced prolongation of APD, MAPD, QT interval, and decreased spatiotemporal dispersion of repolarization and ventricular arrhythmias. Inhibition by GS-6615 of ATX-II enhanced late INa was strongly correlated with shortening of myocyte APD and isolated heart MAPD (R2  = 0.94 and 0.98 respectively). In contrast to flecainide, GS-6615 had the minimal effects on peak INa . GS-6615 did not decrease the maximal upstroke velocity of the action potential (Vmax) nor widen QRS intervals.Conclusions and Implications: GS-6615 was a selective inhibitor of late INa , stabilizes the ventricular repolarization and suppresses arrhythmias in a model of LQT3. The concentrations at which the electrophysiological effects of GS-6615 were observed are comparable to plasma levels associated with QTc shortening in patients with LQT3, indicating that these effects are clinically relevant. [ABSTRACT FROM AUTHOR]

Background: QT interval-prolonging drug-drug interactions (QT-DDIs) may increase the risk of life-threatening arrhythmia. Despite guidelines for testing from regulatory agencies, these interactions are usually discovered after drugs are marketed and may go undiscovered for years.Objectives: Using a combination of adverse event reports, electronic health records (EHR), and laboratory experiments, the goal of this study was to develop a data-driven pipeline for discovering QT-DDIs.Methods: 1.8 million adverse event reports were mined for signals indicating a QT-DDI. Using 1.6 million electrocardiogram results from 380,000 patients in our institutional EHR, these putative interactions were either refuted or corroborated. In the laboratory, we used patch-clamp electrophysiology to measure the human ether-à-go-go-related gene (hERG) channel block (the primary mechanism by which drugs prolong the QT interval) to evaluate our top candidate.Results: Both direct and indirect signals in the adverse event reports provided evidence that the combination of ceftriaxone (a cephalosporin antibiotic) and lansoprazole (a proton-pump inhibitor) will prolong the QT interval. In the EHR, we found that patients taking both ceftriaxone and lansoprazole had significantly longer QTc intervals (up to 12 ms in white men) and were 1.4 times more likely to have a QTc interval above 500 ms. In the laboratory, we found that, in combination and at clinically relevant concentrations, these drugs blocked the hERG channel. As a negative control, we evaluated the combination of lansoprazole and cefuroxime (another cephalosporin), which lacked evidence of an interaction in the adverse event reports. We found no significant effect of this pair in either the EHR or in the electrophysiology experiments. Class effect analyses suggested this interaction was specific to lansoprazole combined with ceftriaxone but not with other cephalosporins.Conclusions: Coupling data mining and laboratory experiments is an efficient method for identifying QT-DDIs. Combination therapy of ceftriaxone and lansoprazole is associated with increased risk of acquired long QT syndrome. [ABSTRACT FROM AUTHOR]

Congenital long QT syndrome (LQTS) is a rare genetic disorder that has been associated with various genetic mutations including life-threatening cardiac arrhythmias and sudden death. Left thoracoscopic sympathectomy is an effective treatment for patients who are refractory to medical therapy or who need frequent epicardial internal cardio defibrillator intervention. The authors report three cases, one adult and two children, who underwent successful left thoracoscopic sympathectomy. All three patients remained clinically stable without arrhythmias through 3 months of follow-up. It is suggested in the literature that 77% of patients experienced immediate relief of symptoms. The results of this case report suggest that left thoracoscopic sympathectomy is a safe and effective approach for treating patients with LQTS. [ABSTRACT FROM PUBLISHER]

Study objective Controlled hypotension is a preferred method in various surgical operations, but limited data are available for the effects of drug combinations that are used to ensure the desired level of hypotension on cardiac repolarization. Design Randomized, prospective, double-blinded study. Patients The study comprised 65 patients undergoing septorhinoplasty surgery under general anesthesia. Interventions Group S received sevoflurane inhalation alone, group R received sevoflurane and remifentanil, and group N received sevoflurane and nitroglycerine in a way that a mean arterial pressure of 60 ± 5 mm Hg was achieved. Measurements Electrocardiogram was performed before induction (T1), 30 minutes after induction (T2), and 5 minutes after extubation (T3). Corrected QT (QTc), QT dispersion (QTd), and corrected Tp-e (Tp-ec) intervals and Tp-e/corrected QT (Tp-e/QTc) ratio were calculated. Main results QTc prolongation was observed at T2 and T3 in all groups, but only QTc prolongation at T2 was statistically significant in group S ( P > .05). Significant prolongation of QTd interval at T2 and T3 was observed in group S ( P < .05). In all groups, Tp-ec decreased at T2. However Tp-ec decrease was not statistically significant in group S ( P = .103) and group R ( P = .058). Tp-e/QTc was significantly decreased on T2 in all 3 groups, and it was returned to baseline at T3 ( P < .05). Conclusion The present study demonstrated that none of the 3 hypotensive anesthesia methods has an overall negative effect on Tp-e and Tp-e/QTc. Therefore, we conclude that all 3 methods can be used safely in terms of proarrhythmic risk, but increased sevoflurane consumption may require more attention due to significant prolongation of QTc and QTd. [ABSTRACT FROM AUTHOR]

Background and Purpose: Exposure-response (ER) modelling (concentration-QTc analysis) is gaining as much acceptance as the traditional by-time analysis of the placebo-adjusted change from baseline in the QTc interval (ΔΔQTcF). It has been postulated that intensive ECG analysis and ER modelling during early-phase drug development could be a cost-effective approach of estimating QT liability of a new drug, in a small number of subjects.Experimental Approach: We used a highly automated analysis of ECGs from 46 subjects from a crossover thorough QT/QTc study to detect ΔΔQTcF with moxifloxacin. Using these data, we also simulated (bootstrapped) 1000 datasets of a parallel study with eight subjects receiving moxifloxacin and eight others receiving placebo.Key Results: The slope from the concentration-QTc analysis for moxifloxacin in 46 subjects was 4.12 ms of ΔΔQTcF per μg(-1) mL(-1) ; at mean Cmax of 2.95 μg·mL(-1) , estimated ΔΔQTcF was 13.4 ms (90% confidence interval 11.3, 15.4 ms). In the 1000 simulated datasets, in 996 datasets, ER modelling showed that the upper bound of the 90% confidence interval for ΔΔQTcF at geometric mean Cmax exceeded 10 ms. In 895 of these 996 datasets, the slope of the ER relationship was statistically significantly positive. Thus, with a small sample size (eight subjects on active drug and eight on placebo), moxifloxacin-induced QTc prolongation was demonstrated using ER analysis with statistical power of >80%.Conclusions and Implications: Our study adds to the growing body of data supporting intensive ECG collection and analysis in early-phase studies to estimate QT liability. [ABSTRACT FROM AUTHOR]

Background: Long QT syndrome type 3 (LQT3) is a lethal disease caused by gain-of-function mutations in the SCN5A gene, coding for the alpha-subunit of the sodium channel NaV1.5. Mexiletine is used to block late sodium current and to shorten QT interval in LQT3 patients.Objectives: The aim of this study was to determine whether mexiletine prevents arrhythmic events (arrhythmic syncope, aborted cardiac arrest, or sudden cardiac death) in LQT3 patients.Methods: The endpoint of this retrospective cohort study, which studied consecutive LQT3 patients who were referred to our center and treated with mexiletine, was to evaluate the antiarrhythmic efficacy of mexiletine by comparing the number of arrhythmic events per patient and the annual rate of arrhythmic events during observation periods of equal duration before and after the beginning of therapy with mexiletine.Results: The study population comprised 34 LQT3 patients, 19 (56%) of whom were male. The median age at beginning of treatment with mexiletine was 22 years, and median QTc interval before therapy 509 ms. The median duration of oral mexiletine therapy was 36 months, at an average daily dose of 8 ± 0.5 mg/kg. Mexiletine significantly shortened QTc (by 63 ± 6 ms; p < 0.0001) and reduced the percentage of patients with arrhythmic events (from 22% to 3%; p = 0.031), the mean number of arrhythmic events per patient (from 0.43 ± 0.17 to 0.03 ± 0.03; p = 0.027), and the annual rate of arrhythmic events (from 10.3% to 0.7%; p = 0.0097).Conclusions: Besides shortening QTc interval, mexiletine caused a major reduction of life-threatening arrhythmic events in LQT3 patients, thus representing an efficacious therapeutic strategy. [ABSTRACT FROM AUTHOR]

ADHD Therapy in LQTS Introduction Stimulants are the mainstay therapy for attention deficit/hyperactivity disorder (ADHD) and are associated with adrenergic side effects. There are limited data on the clinical course of patients treated for ADHD who have long-QT syndrome (LQTS), for which β-blockade is the goal of therapy. Methods LQTS patients from the Rochester-based LQTS Registry (open-enrollment between 1979 and 2003; follow-up from 1979 to present) treated with stimulant or nonstimulant ADHD medications (n = 48) were compared to a 2:1 age-, gender-, and QTc-duration matched LQTS control group not exposed to ADHD medications (n = 96). Kaplan-Meier and Cox proportional hazards regression analyses were used to evaluate risk of cardiac events (syncope, aborted cardiac arrest, and sudden cardiac death) in LQTS patients treated with ADHD medications. Results During a mean follow-up of 7.9 ± 5.4 years after initiation of ADHD medication at a mean age 10.7 ±7.3 years, there was a 62% cumulative probability of cardiac events in the ADHD treatment group compared to 28% in the matched LQTS control group (P < 0.001). Time-dependent use of ADHD medication was associated with an increased risk for cardiac events (HR = 3.07; P = 0.03) in the multivariate Cox model adjusted for time-dependent β-blocker use and prior cardiac events. Subgroup gender analyses showed that time-dependent ADHD medication was associated with an increased risk in male LQTS patients (HR = 6.80, P = 0.04). Conclusions LQTS patients treated with ADHD medications have increased risk for cardiac events, particularly syncope, and this risk is augmented in males. The findings highlight the importance of heightened surveillance for LQTS patients on ADHD medications. [ABSTRACT FROM AUTHOR]

Inherited long QT syndrome (LQTS) is an electrical heart disorder that manifests with syncope, seizures, and increased risk of torsades de pointes and sudden cardiac death. Dominant-negative current suppression is a mechanism by which pathogenic proteins disrupt the function of ion channels in inherited LQTS. However, current approaches for the management of inherited LQTS are inadequate. RNA interference (RNAi) is a powerful technique that is able to suppress or silence the expression of mutant genes. RNAi may be harnessed to knock out mRNAs that code for toxic proteins, and has been increasingly recognized as a potential therapeutic intervention for a range of conditions. The present study reviews the literature for RNAi-based therapeutics in the treatment of inherited LQTS. Furthermore, this review discusses the combined use of RNAi with the emerging technology of induced pluripotent stem cells for the treatment of inherited LQTS. In addition, key challenges that must be overcome prior to RNAi-based therapies becoming clinically applicable are addressed. In summary, RNAi-based therapy is potentially a powerful therapeutic intervention, although a number of difficulties remain unresolved. [ABSTRACT FROM AUTHOR]

Background and Purpose We aimed to characterize the pharmacology and electrophysiology of N-[3-(1 H-benzimidazol-2-yl)-4-chloro-phenyl]pyridine-3-carboxamide ( AZSMO-23), an activator of the human ether-a-go-go-related gene ( hERG)-encoded K+ channel ( Kv11.1). Experimental Approach Automated electrophysiology was used to study the pharmacology of AZSMO-23 on wild-type ( WT), Y652 A, F656 T or G628 C/ S631 C hERG, and on other cardiac ion channels. Its mechanism of action was characterized with conventional electrophysiology. Key Results AZSMO-23 activated WT hERG pre-pulse and tail current with EC50 values of 28.6 and 11.2 μM respectively. At 100 μM, pre-pulse current at +40 mV was increased by 952 ± 41% and tail current at −30 mV by 238 ± 13% compared with vehicle values. The primary mechanism for this effect was a 74.5 mV depolarizing shift in the voltage dependence of inactivation, without any shift in the voltage dependence of activation. Structure-activity relationships for this effect were remarkably subtle, with close analogues of AZSMO-23 acting as hERG inhibitors. AZSMO-23 blocked the mutant channel, hERG Y652 A, but against another mutant channel, hERG F656 T, its activator activity was enhanced. It inhibited activity of the G628 C/ S631 C non-inactivating hERG mutant channel. AZSMO-23 was not hERG selective, as it blocked hKv4.3- hKChIP2.2, hCav3.2 and hKv1.5 and activated hCav1.2/β2/α2δ channels. Conclusion and Implications The activity of AZSMO-23 and those of its close analogues suggest these compounds may be of value to elucidate the mechanism of type 2 hERG activators to better understand the pharmacology of this area from both a safety perspective and in relation to treatment of congenital long QT syndrome. [ABSTRACT FROM AUTHOR]

Objective: To assess older age and female sex, 2 of the major risk factors for potentially fatal cardiac arrhythmias or sudden cardiac death in patients prescribed psychotropics, within the context of electrocardiographic evidence of time between start of Q wave and end of T wave (QT) interval prolongation, which is an indicator of an increased risk for potentially fatal cardiac arrhythmias. Method: The literature on the relation between age, sex, and QT interval with respect to psychotropic drugs was reviewed. Results: The QT interval must be corrected (QTc) for heart rate. Because slower heart rates prolong and faster heart rates shorten the QT interval, people with faster heart rates may have a prolonged QT interval that is not apparent until the correction is performed. QTc values for apparently healthy post-pubertal people are less than 450 ms for males and less than 470 ms for females. The longer QT intervals in women may account for their increased risk of potentially fatal cardiac arrhythmias on psychotropics. QTc increases with increasing age. Assessment of QTc in older people is especially important to identify people with a longer QTc who are more likely to attain a serious QT level with drugs that prolong QTc. The age-related increase in QTc is more evident in men than women, suggesting that male sex does not afford protection against potentially fatal arrhythmias at older age. Conclusion: The association of increasing age and female sex with greater QT intervals indicates the need to have an increased awareness of the QTc prior to use of these psychotropics and to evaluate the QTc after initiation of therapy. [ABSTRACT FROM AUTHOR]

Long QT syndrome is the most commonly recognised cause of sudden cardiac death in children. W i t h a prevalence of 1 in 2000, family screening is identifying large numbers of hitherto asymptomatic gene carriers in the community, about a third of w h om have a normal QT interval. The mainstay of treatment is long term uninterrupted beta blocker therapy, a treatment w i t h many potential side effects. This article reviews the evidence and suggests a cohort w h o may, after assessment in a specialised cardiacgenetic clinic, be spared this treatment because of very low baseline risk. These are asymptomatic boys and prepubertal girls w i t h a heart rate corrected QT interval persistently less than 4 7 0 ms w h o do not indulge in high risk activities (especially swimming) and do not have a missense mutation in the c-loop region of the KCNQ1 (long QT 1) gene. [ABSTRACT FROM AUTHOR]

Long QT syndrome (LQTS) is characterised by both the depolarisation and repolarisation disorder of cardiac muscle cells. Cardiac resynchronising therapy (CRT) is an important treatment option for patients with chronic heart failure (CHF) when echocardiographic and electrocardiographic criteria are met. Although CRT was introduced in clinical practice 10 years ago, doubts related to application of this treatment method persist because of its potential proarrhythmogenic effect. This is a case describing a 66-year-old Caucasian female with LQTS coexisting with a left bundle branch branch block (LBBB) and an implantable single-cavity cardioverter-defibrillator (ICD VR), who had repeated appropriate high-energy treatments. The upgrade to resynchronisation therapy defibrillator (CRT-D) significantly reduced frequency of ventricular tachycardia and the need for electrical therapies. The normalisation of the left ventricle size, as seen on echo examination, and the improvement of heart failure symptoms were also observed. [ABSTRACT FROM AUTHOR]

Long QT syndrome is a genetic disorder associated with life threatening ventricular arrhythmias and sudden death. This inherited arrhythmic disorder exhibits genetic heterogeneity, incomplete penetrance, and variable expressivity. During the past two decades there have been major advancements in understanding the genotype-phenotype correlations in LQTS. This genotype-phenotype relationship can lead to improved management of LQTS. However, development of genotype-specific or mutation-specific management strategies is very challenging. This review describes the pathophysiology of LQTS, genotype-phenotype correlations, and focuses on the management of LQTS. In general, the treatment of LQTS consists of lifestyle modifications, medical therapy with beta-blockers, device and surgical therapy. We further summarize current data on the efficacy of pharmacological treatment options for the three most prevalent LQTS variants including beta-blockers in LQT1, LQT2 and LQT3, sodium channel blockers and ranolazine for LQT3, potassium supplementation and spironolactone for LQT2, and possibly sex hormone-based therapy for LQT2. [ABSTRACT FROM AUTHOR]

The mechanisms underlying drug induced QT prolongation and the immediate treatment of torsade de pointes have been extensively studied but the post-acute management of the Acquired Long QT Syndrome (ALQTS) remains to be addressed. We aimed to review the state of the art data regarding risk stratification, arrhythmic prevention and treatment of patients with ALQTS. A comprehensive review of the scientific data collectable from MEDLINE, EMBASE and COCHRANE (from inception to April 2013) was performed, and descriptive and qualitative information was extracted from the most relevant manuscripts. QT prolonging drugs are widely used in hospital clinical practice, and several studies have shown a high prevalence of QT interval prolongation in patients admitted to hospital and a high rate of prescription of QT interval prolonging drugs to patients presenting with QT interval prolongation. Therefore, the acute and post-acute management of ALQTS is of the utmost importance. Avoidance of offending triggers, electrocardiographic screening, pacing at a relatively fast lower rate limit and using pause prevention programming (preferably with concomitant β blocker treatment), implantable defibrillators in the highest risk patients, genetic testing and counselling in selected cases, and family screening are among the potentially applicable strategies. The latter is justifiable by the fact that some studies unveiled a surprisingly similar positive mutation rate in drug induced LQTS compared with congenital LQTS, supporting the hypothesis that the former can be regarded as a latent form of the latter. Drug challenge with D,L-sotalol in suspected LQTS and treatment with a carvedilol analogue, verapamil or an Ikr activating drug are still in need of further investigation. The post-acute management of patients with ALQTS has received scarce attention in the past, probably due to the fact that it is considered a reversible phenomenon in most cases. Considering the relatively high risk of arrhythmic recurrence in the highest risk ALQTS patients, effective preventive and treatment strategies are warranted, and further research is needed. [ABSTRACT FROM AUTHOR]

Abstract: Andersen–Tawil syndrome (ATS) is a rare hereditary multisystem disorder. Ventricular arrhythmias, periodic paralysis and dysmorphic features constitute the classic triad of ATS symptoms. The expressivity of these symptoms is, however, extremely variable, even within single ATS affected families, and not all ATS patients present with the full triad of symptoms. ATS patients may show a prolongation of the QT interval, which explains the classification as long QT syndrome type 7 (LQT7), and specific neurological or neurocognitive defects. In ATS type 1 (ATS1), the syndrome is associated with a loss-of-function mutation in the KCNJ2 gene, which encodes the Kir2.1 inward rectifier potassium channel. In ATS type 2 (ATS2), which does not differ from ATS1 in its clinical symptoms, the genetic defect is unknown. Consequently, ATS2 comprises all cases of ATS in which genetic testing did not reveal a mutation in KCNJ2. The loss-of-function mutations in KCNJ2 in ATS1 affect the excitability of both skeletal and cardiac muscle, which underlies the cardiac arrhythmias and periodic paralysis associated with ATS. Thus far, the molecular mechanism of the dysmorphic features is only poorly understood. In this review, we summarize the clinical symptoms, the underlying genetic and molecular defects, and the management and treatment of ATS. [Copyright &y& Elsevier]

The author discusses the developments in the treatment of ventricular tachycardia and long QT syndrome (LQTS). Also cited are the study which examined the effectiveness of intentional permanent atrial pacing (IPAP), how IPAP reduce breakthrough cardiac events (BCE) in both adult and child patients, and the results in high-risk patients with Andersen-Tawil syndrome and Jervell and Lange-Nielsen syndrome.

Abstract: Impaired ventricular repolarization can lead to long QT syndrome (LQT), a proarrhythmic disease with high risk of developing lethal ventricular tachyarrhythmias. The compound ICA-105574 is a recently developed hERG activator and it enhances I Kr current with very high potency by removing the channel inactivation. The present study was designed to investigate antiarrhythmic properties of ICA-105574. For comparison, the effects of another compound NS1643 was in-parallel assessed, which also acts primarily to attenuate channel inactivation with moderate potency. We found that both ICA-105574 and NS1643 concentration-dependently shortened action potential duration (APD) in ventricular myocytes, and QT/QTc intervals in isolated guinea-pig hearts. ICA-105574, but not NS1643, completely prevented ventricular arrhythmias in intact guinea-pig hearts caused by I Kr and I Ks inhibitors, although both ICA-105574 and NS1643 could reverse the drug-induced prolongation of APD in ventricular myocytes. Reversing prolongation of QT/QTc intervals and antagonizing the increases in transmural dispersion of repolarization and instability of the QT interval induced by I Kr and I Ks inhibitors contributed to antiarrhythmic effect of ICA-105574. Meanwhile, ICA-105574 at higher concentrations showed a potential proarrhythmic risk in normal hearts. Our results suggest that ICA-105574 has more efficient antiarrhythmic activity than NS1643. However, its potential proarrhythmic risk implies that benefits and risks should be seriously taken into consideration for further developing this type of hERG activators. [Copyright &y& Elsevier]

Background and Purpose Zolpidem, a short-acting hypnotic drug prescribed to treat insomnia, has been clinically associated with acquired long QT syndrome ( LQTS) and torsade de pointes ( TdP) tachyarrhythmia. LQTS is primarily attributed to reduction of cardiac human ether-a-go-go-related gene ( hERG)/ IKr currents. We hypothesized that zolpidem prolongs the cardiac action potential through inhibition of hERG K+ channels. Experimental Approach Two-electrode voltage clamp and whole-cell patch clamp electrophysiology was used to record hERG currents from Xenopus oocytes and from HEK 293 cells. In addition, hERG protein trafficking was evaluated in HEK 293 cells by Western blot analysis, and action potential duration ( APD) was assessed in human-induced pluripotent stem cell ( hiPSC)-derived cardiomyocytes. Key Results Zolpidem caused acute hERG channel blockade in oocytes ( IC50 = 61.5 μM) and in HEK 293 cells (IC50 = 65.5 μM). Mutation of residues Y652 and F656 attenuated hERG inhibition, suggesting drug binding to a receptor site inside the channel pore. Channels were blocked in open and inactivated states in a voltage- and frequency-independent manner. Zolpidem accelerated hERG channel inactivation but did not affect I- V relationships of steady-state activation and inactivation. In contrast to the majority of hERG inhibitors, hERG cell surface trafficking was not impaired by zolpidem. Finally, acute zolpidem exposure resulted in APD prolongation in hiPSC-derived cardiomyocytes. Conclusions and Implications Zolpidem inhibits cardiac hERG K+ channels. Despite a relatively low affinity of zolpidem to hERG channels, APD prolongation may lead to acquired LQTS and TdP in cases of reduced repolarization reserve or zolpidem overdose. [ABSTRACT FROM AUTHOR]