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The aim of this study was to explore the prevalence of likely pathogenic or pathogenic variants and assess the diagnostic yield from genetic testing for cardiac arrhythmias in Norway since 2003. Data from 1991 probands and 2782 relatives were retrospectively collected from the laboratory information management system at Unit for Cardiac and Cardiovascular Genetics, Oslo University hospital. Of 1991 probands, 57.4% were females, age at genetic testing was 33.1 (±22.7) years, and 32.5% were under the age of 18. A likely pathogenic or pathogenic variant (including 14 novel) was detected in 15.4% in total. Of the 2782 relatives, 53.7% were females, age at genetic testing was 35.6 (±22.5) years, 27.3% were under the age of 18, and 45.3% carried the family variant. Probands and relatives combined, 1/3356 persons in the Norwegian population were heterozygous for an arrhythmia‐causing variant. The founder variant p.Q530X (NM_000218.2: c.1588C>T) in KCNQ1 accounted for 34% of all variants in Norway. In conclusion, genetic testing provided a genetic basis of the arrhythmia in 15.4% of the probands. Familial cascade screening identified four times as many variant‐positive relatives, allowing early detection and prompt stratification of arrhythmic risk of those variant carriers. [ABSTRACT FROM AUTHOR]

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]

We report a long QT syndrome 15 whose diagnosis was suspected during foetal life and confirmed at birth and was associated with congenital heart disease. Genetic testing revealed a rare mutation associated with the CALM2 gene. At 23 weeks of gestation, severe foetal sinus bradycardia (∼100 bpm) was detected. In the third trimester, the foetus developed severe right ventricular hypertrophy. At birth, the electrocardiogram showed a long QT interval of 640 ms, and after 1 hour, the newborn showed functional 2:1 atrioventricular block at ventricular rate of 50 bpm. After further pharmacological therapies, epicardial wires were surgically implanted for transient pacing in VVI mode at 90 bpm. Echocardiogram showed aneurysmatic left atrial appendage, dilated right segments, hypertrophied right ventricle, ostium secundum type atrial septal defect, and muscular ventricular septal defect. At two weeks of postpartum, a permanent dual-chamber pacemaker was implanted in the DDD mode and the patient was discharged with a prescription of beta-blockers and calcium therapy.

Background: Long QT syndrome (LQTS) is a sudden death predisposing condition characterized by ECG‐derived prolongation of the QT interval. Previous studies have demonstrated that the supine‐stand test may aid in the diagnosis of LQTS as patients fail to shorten their QT interval in response to standing up. The aim of this study was to evaluate the diagnostic accuracy of ECG data derived from standard protocol, clinically performed treadmill exercise stress tests (TESTs) in their ability to mimic the formal supine‐stand test. Methods: We performed a retrospective review of 478 TESTs from patients evaluated for LQTS. Patients referred for evaluation of LQTS but who were dismissed as normal served as controls. Heart rate & QT values were obtained from standard protocol TESTs. Results: Overall, 243 patients with LQTS (125 LQT1, 63 LQT2, 55 LQT3; 146 [60%] female, mean age at TEST 30 ± 17 years) and 235 controls (142 [60%] female, mean age 24 ± 15 years) were included. The paired ΔQTc (QTcStand‐QTcSupine) was similar between LQTS (−5 ± 26) and controls (−2 ± 25; p =.2). During position change, the QT interval shortened by ≥20 ms in 33% of LQTS patients, remained unchanged in 62%, and increased in 5% of LQTS patients which was similar to controls (shortened in 40%, unchanged in 54%, and increased in 6% of controls; p =.2). Receiver‐operator curve analysis to test the diagnostic ability of supine‐stand ΔQT performed poorly in differentiating LQTS from controls with an of AUC 0.52 (p =.4). Conclusion: TESTs should be used with caution when trying to interpret supine‐stand changes for diagnosis of LQTS. [ABSTRACT FROM AUTHOR]

Congenital long QT syndrome (LQTS) is a hereditary cardiac channelopathy with an estimated prevalence of 1 in 2500. A prolonged resting QT interval corrected for heart rate (QTc interval) remains a key diagnostic component; however, the QTc value may be normal in up to 40% of patients with genotype-positive LQTS and borderline in a further 30%. Provocation of QTc prolongation and T-wave changes may be pivotal to unmasking the diagnosis and useful in predicting genotype. LQTS provocation testing involves assessment of repolarization during and after exercise, in response to changes in heart rate or autonomic tone, with patients with LQTS exhibiting a maladaptive repolarization response. We review the utility and strengths and limitations of 4 forms of provocation testing—stand-up test, exercise stress test, epinephrine challenge, and mental stress test—in diagnosing LQTS and provide some practical guidance for performing provocation testing. Ultimately, exercise testing, when feasible, is the most useful form of provocation testing when considering diagnostic sensitivity and specificity. [ABSTRACT FROM AUTHOR]

Drug-induced QT-prolongation increases the risk of TdP arrhythmia attacks and sudden cardiac death. However, measuring the QT-interval and determining a precise cut-off QT/QTc value that could put a patient at risk of TdP is challenging and influenced by many factors including female sex, drug-free baseline, age, genetic predisposition, and bradycardia. This paper presents a novel approach for intuitively and visually monitoring QT-prolongation showing a potential risk of TdP, which can be adjusted according to patient-specific risk factors, using a pseudo-coloring technique and explainable artificial intelligence (AI). We extended the development and evaluation of an explainable AI-based technique− visualized using pseudo-color on the ECG signal, thus intuitively 'explaining' how its decision was made −to detect QT-prolongation showing a potential risk of TdP according to a cut-off personalized QTc value (using Bazett's ∆ QTc > 60 ms relative to drug-free baseline and Bazett's QTc > 500 ms as examples), and validated its performance using a large number of ECGs (n = 5050), acquired from a clinical trial assessing the effects of four known QT-prolonging drugs versus placebo on healthy subjects. We compared this new personalized approach to our previous study that used a more general approach using the QT-nomogram. The explainable AI-based algorithm can accurately detect QT-prolongation when adjusted to a personalized patient-specific cut-off QTc value showing a potential risk of TdP. Using ∆ QTc > 60 ms relative to drug-free baseline and QTc > 500 ms as examples, the algorithm yielded a sensitivity of 0.95 and 0.79, and a specificity of 0.95 and 0.98, respectively. We found that adjusting pseudo-coloring according to Bazett's ∆QTc > 60 ms relative to a drug-free baseline personalized to each patient provides better sensitivity than using Bazett's QTc > 500 ms, which could underestimate a potentially clinically significant QT-prolongation with bradycardia. [ABSTRACT FROM AUTHOR]

Drug‐induced long QT syndrome (LQTS) and Torsades de Pointes (TdP) are serious concerns in drug development. Although rats are a useful scientific tool, their hearts, unlike larger species, usually do not respond to torsadogenic drugs. Consequently, their resistance to drug‐induced arrhythmias is poorly understood. Here, we challenged rats with rapid delayed rectifier current (Ikr)‐inhibiting antibiotic clarithromycin (CLA), loop diuretic furosemide (FUR) or their combination (CLA + FUR), and examined functional and molecular abnormalities after stimulation with isoproterenol. Clarithromycin and furosemide were administered orally at 12‐h intervals for 7 days. To evaluate electrical instability, electrocardiography (ECG) was recorded either in vivo or ex vivo using the Langendorff‐perfused heart method under basal conditions and subsequently under beta‐adrenergic stimulation. Gene expression was measured using real‐time quantitative PCR in left ventricular tissue. Indeed, FUR and CLA + FUR rats exhibited hypokalemia. CLA and CLA + FUR treatment resulted in drug‐induced LQTS and even an episode of TdP in one CLA + FUR rat. The combined treatment dysregulated gene expression of several ion channels subunits, including KCNQ1, calcium channels and Na+/K + ‐ATPase subunits, while both monotherapies had no impact. The rat with recorded TdP exhibited differences in the expression of ion channel genes compared to the rest of rats within the CLA + FUR group. The ECG changes were not detected in isolated perfused hearts. Hence, we report rapid orchestration of ion channel reprogramming of hearts with QT prolongation induced by simultaneous administration of clarithromycin and furosemide in rats, which may account for their ability to avoid arrhythmias triggered by beta‐adrenergic stimulation. [ABSTRACT FROM AUTHOR]

Calmodulin (CaM) is a highly conserved mediator of calcium (Ca2+)‐dependent signalling and modulates various cardiac ion channels. Genotyping has revealed several CaM mutations associated with long QT syndrome (LQTS). LQTS patients display prolonged ventricular recovery times (QT interval), increasing their risk of incurring life‐threatening arrhythmic events. Loss‐of‐function mutations to Kv7.1 (which drives the slow delayed rectifier potassium current, IKs, a key ventricular repolarising current) are the largest contributor to congenital LQTS (>50% of cases). CaM modulates Kv7.1 to produce a Ca2+‐sensitive IKs, but little is known about the consequences of LQTS‐associated CaM mutations on Kv7.1 function. Here, we present novel data characterising the biophysical and modulatory properties of three LQTS‐associated CaM variants (D95V, N97I and D131H). We showed that mutations induced structural alterations in CaM and reduced affinity for Kv7.1, when compared with wild‐type (WT). Using HEK293T cells expressing Kv7.1 channel subunits (KCNQ1/KCNE1) and patch‐clamp electrophysiology, we demonstrated that LQTS‐associated CaM variants reduced current density at systolic Ca2+ concentrations (1 μm), revealing a direct QT‐prolonging modulatory effect. Our data highlight for the first time that LQTS‐associated perturbations to CaM's structure impede complex formation with Kv7.1 and subsequently result in reduced IKs. This provides a novel mechanistic insight into how the perturbed structure–function relationship of CaM variants contributes to the LQTS phenotype. Key points: Calmodulin (CaM) is a ubiquitous, highly conserved calcium (Ca2+) sensor playing a key role in cardiac muscle contraction.Genotyping has revealed several CaM mutations associated with long QT syndrome (LQTS), a life‐threatening cardiac arrhythmia syndrome.LQTS‐associated CaM variants (D95V, N97I and D131H) induced structural alterations, altered binding to Kv7.1 and reduced IKs.Our data provide a novel mechanistic insight into how the perturbed structure–function relationship of CaM variants contributes to the LQTS phenotype. [ABSTRACT FROM AUTHOR]

Abstract Drug‐induced long QT syndrome (LQTS) and Torsades de Pointes (TdP) are serious concerns in drug development. Although rats are a useful scientific tool, their hearts, unlike larger species, usually do not respond to torsadogenic drugs. Consequently, their resistance to drug‐induced arrhythmias is poorly understood. Here, we challenged rats with rapid delayed rectifier current (Ikr)‐inhibiting antibiotic clarithromycin (CLA), loop diuretic furosemide (FUR) or their combination (CLA + FUR), and examined functional and molecular abnormalities after stimulation with isoproterenol. Clarithromycin and furosemide were administered orally at 12‐h intervals for 7 days. To evaluate electrical instability, electrocardiography (ECG) was recorded either in vivo or ex vivo using the Langendorff‐perfused heart method under basal conditions and subsequently under beta‐adrenergic stimulation. Gene expression was measured using real‐time quantitative PCR in left ventricular tissue. Indeed, FUR and CLA + FUR rats exhibited hypokalemia. CLA and CLA + FUR treatment resulted in drug‐induced LQTS and even an episode of TdP in one CLA + FUR rat. The combined treatment dysregulated gene expression of several ion channels subunits, including KCNQ1, calcium channels and Na+/K + ‐ATPase subunits, while both monotherapies had no impact. The rat with recorded TdP exhibited differences in the expression of ion channel genes compared to the rest of rats within the CLA + FUR group. The ECG changes were not detected in isolated perfused hearts. Hence, we report rapid orchestration of ion channel reprogramming of hearts with QT prolongation induced by simultaneous administration of clarithromycin and furosemide in rats, which may account for their ability to avoid arrhythmias triggered by beta‐adrenergic stimulation.

People diagnosed with genetic heart diseases (GHDs) associated with sudden cardiac death (SCD) have historically been restricted from competitive sports. Recent data documenting return-to-play (RTP) experiences following shared decision making (SDM) suggest that cardiac event rates for athletes with a GHD are lower than previously described, thereby suggesting an opportunity to reconsider this paradigm. The purpose of this study was to evaluate clinical outcomes among National Collegiate Athletic Association Division I university and professional athletes diagnosed with a GHD. A multicenter retrospective analysis was performed to examine demographics, clinical characteristics, RTP outcomes, and cardiac events among elite athletes with a GHD. A total of 76 elite (66%, Division I, 34% professional) athletes (age 19.9 ± 5 years, 28% women) diagnosed with a GHD (hypertrophic cardiomyopathy [53%], long QT syndrome, long QT syndrome [26%]) comprise this cohort. Most athletes were asymptomatic (48 of 76, 63%) before diagnosis and had their GHD detected during routine preparticipation cardiovascular screening. Most athletes (55 of 76, 72%) were initially disqualified from their sport but subsequently opted for unrestricted RTP after comprehensive clinical evaluation and SDM. To date, (mean follow-up 7 ± 6 years), only 1 exercise-related (1.3%) and 2 nonexercise-related GHD-associated adverse cardiac events occurred. There have been no fatalities during follow-up. This is the first study describing the experience of athletes with a known SCD-predisposing GHD who are competing at the elite level. After careful evaluation, risk stratification, and tailoring of their GHD therapy, RTP following SDM appears associated with low, nonfatal events rates at elite levels of sport. [Display omitted] [ABSTRACT FROM AUTHOR]

Congenital long QT syndrome (LQTS) is characterized by a prolonged QT-interval on an electrocardiogram (ECG). An abnormal prolongation in the QT-interval increases the risk for fatal arrhythmias. Genetic variants in several different cardiac ion channel genes, including KCNH2 , are known to cause LQTS. Here, we evaluated whether structure-based molecular dynamics (MD) simulations and machine learning (ML) could improve the identification of missense variants in LQTS-linked genes. To do this, we investigated KCNH2 missense variants in the Kv11.1 channel protein shown to have wild type (WT) like or class II (trafficking-deficient) phenotypes in vitro. We focused on KCNH2 missense variants that disrupt normal Kv11.1 channel protein trafficking, as it is the most common phenotype for LQTS-associated variants. Specifically, we used computational techniques to correlate structural and dynamic changes in the Kv11.1 channel protein PAS domain (PASD) with Kv11.1 channel protein trafficking phenotypes. These simulations unveiled several molecular features, including the numbers of hydrating waters and hydrogen bonding pairs, as well as folding free energy scores, that are predictive of trafficking. We then used statistical and machine learning (ML) (Decision tree (DT), Random forest (RF), and Support vector machine (SVM)) techniques to classify variants using these simulation-derived features. Together with bioinformatics data, such as sequence conservation and folding energies, we were able to predict with reasonable accuracy (≈75%) which KCNH2 variants do not traffic normally. We conclude that structure-based simulations of KCNH2 variants localized to the Kv11.1 channel PASD led to an improvement in classification accuracy. Therefore, this approach should be considered to complement the classification of variant of unknown significance (VUS) in the Kv11.1 channel PASD. [Display omitted] • Long QT syndrome is associated with mutations in the KCNH2 gene. • KCNH2 encodes the Kv11.1 channel, for which mutations in its PASD impair trafficking. • We trained classifiers using bioinformatics and molecular dynamics simulation data. • The classifiers predicted trafficking for known and novel PASD missense mutations. • Classifiers tested on novel variants were in strong agreement with patient ECG data. [ABSTRACT FROM AUTHOR]

Background: Repeated fetal heart rates (FHR) < 3rd percentile for gestational age (GA) with 1:1 atrioventricular conduction (sinus bradycardia) can be a marker for long QT syndrome. We hypothesized that other inherited arrhythmia syndromes might present with fetal sinus bradycardia. Methods: We reviewed pregnancies referred with sinus bradycardia to the Colorado Fetal Care Center between 2013 and 2023. FHR/GA data, family history, medication exposure, normalized isovolumic contraction times (n-IVRT), postnatal genetic testing, and ECGs at 4–6 weeks after birth were reviewed. Results: Twenty-nine bradycardic subjects were evaluated by fetal echocardiography. Five were lost to follow-up, one refused genetic testing, and one had negative genetic testing for any inherited arrhythmia. Six had non-genetic causes of fetal bradycardia with normal prenatal n-IVRT and postnatal QTc. Thirteen carried pathogenic variants in RYR2 (n = 2), HCN4 (n = 2), KCNQ1 (6), and other LQTS genes (n = 4). The postnatal QTc was <470 ms in subjects with RYR2, HCN4, and two of those with KCNQ1 mutations, and >470 ms in subjects with CALM 2, KCNH2, SCN5A, and four of those with KCNQ1 mutations. LQTS and RYR2 mutations were associated with prolonged n-IVRT, but HCN4 was not. Two fetuses died in utero with variants of uncertain significance (CACNA1 and KCNE1). Cascade testing uncovered six affected but undiagnosed parents and confirmed familial inheritance in five. Conclusion: In addition to heralding LQTS, repeated FHR < 3rd percentile for GA is a risk factor for other inherited arrhythmia syndromes. These findings suggest that genetic testing should be offered to infants with a history of FHR < 3rd percentile for GA even if the postnatal ECG demonstrates a normal QTc interval. [ABSTRACT FROM AUTHOR]

Heart diseases such as arrhythmia are the main causes of sudden death. Arrhythmias are typically caused by mutations in specific genes, damage in the cardiac tissue, or due to some chemical exposure. Arrhythmias caused due to mutation is called inherited arrhythmia. Induced arrhythmias are caused due to tissue damage or chemical exposure. Mutations in genes that encode ion channels of the cardiac cells usually result in (dysfunction) improper functioning of the channel. Improper functioning of the ion channel may lead to major changes in the action potential (AP) of the cardiac cells. This further leads to distorted electrical activity of the heart. Distorted electrical activity will affect the ECG that results in arrhythmia. KCNQ1 P535T mutation is one such gene mutation that encodes the potassium ion channel (KV7.1) of the cardiac ventricular tissue. Its clinical significance is not known. This study aims to perform a simulation study on P535T mutation in the KCNQ1 gene that encodes the potassium ion channel KV7.1 in the ventricular tissue grid. The effect of P535T mutation on transmural tissue grids for three genotypes (wild type, heterozygous, and homozygous) of cells are studied and the generated pseudo-ECGs are compared. Results show the delayed repolarization in the cells of ventricular tissue grid. Slower propagation of action potential in the transmural tissue grid is observed in the mutated (heterozygous and homozygous) genotypes. Longer QT interval is also observed in the pseudo-ECG of heterozygous and homozygous genotype tissue grids. From the pseudo-ECGs, it is observed that KCNQ1 P535T mutation leads to Long QT Syndrome (LQTS) which may result in life-threatening arrhythmias, such as Torsade de Pointes (TdP), Jervell and Lange–Nielsen syndrome (JLNS), and Romano–Ward syndrome (RWS). [ABSTRACT FROM AUTHOR]

We report an unusual case of a patient with hypertrophic obstructive cardiomyopathy, anomalous aortic origin of a coronary artery, obesity hypoventilation syndrome, and acquired long QT syndrome who was able to defy the odds of sudden cardiac death in the rarest of circumstances. (Level of Difficulty: Advanced.).

Introduction: Cardiovascular diseases are currently the leading cause of death in the world. Arrhythmias are one of the most common cardiovascular diseases. In arrhythmia, the heartbeat becomes slow, fast, or irregular, which affects the efficiency of the heart, and in this case, the heart may not have enough ability to pump blood. Cardiac arrhythmias are the leading causes of sudden cardiac death in young people, affecting even patients with anatomically normal hearts. Arrhythmia syndromes are ion channel diseases that lead to abnormal electrical properties of the heart. This article examined the genetic causes affecting all types of cardiac arrhythmias. A detailed search was performed on Google Scholar and PubMed to identify research articles related to arrhythmia genetics. All duplicate articles based on the title and articles published before the year 2000 were removed during the screening. Finally, after several rounds of content review of the articles, 50 research articles were selected for this study. Conclusion: It has been found that mutations cause arrhythmias in nuclear genes encoding membrane channels in heart muscle cells. However, the causes of some cases of arrhythmia are unclear and the possibility of multifactorial of these cardiac disorders is raised. The importance of this type of review article, while revealing the relationship between gene loci and types of arrhythmogenic syndromes, is to provide a molecular basis that can provide researchers with new diagnostic methods in addition to echocardiogram.

Abstract Background The c.1124_1127delTTCA p.(Ile375Argfs*43) pathogenic variant is the most frequently identified molecular defect in the KCNQ1 gene in the cardiogenetics clinic of the Antwerp University Hospital. This variant was observed in nine families presenting with either Jervell-Lange-Nielsen syndrome or long QT syndrome (LQTS). Here, we report on the molecular, clinical and functional characterization of the KCNQ1 c.1124_1127delTTCA variant. Results Forty-one heterozygous variant harboring individuals demonstrated a predominantly mild clinical and electrophysiological phenotype, compared to individuals harboring other KCNQ1 pathogenic variants (5% symptomatic before 40 years of age, compared to 24% and 29% in p.(Tyr111Cys) and p.(Ala341Val) variant carriers, respectively, 33% with QTc ≤ 440 ms compared to 10% in p.(Tyr111Cys) and p.(Ala341Val) variant carriers). The LQTS phenotype was most comparable to that observed for the Swedish p.(Arg518*) founder mutation (7% symptomatic at any age, compared to 17% in p.(Arg518*) variant carriers, 33% with QTc ≤ 440 ms compared to 16% in p.(Arg518*) variant carriers). Surprisingly, short tandem repeat analysis did not reveal a common haplotype for all families. One KCNQ1 c.1124_1127delTTCA harboring patient was diagnosed with Brugada syndrome (BrS). The hypothesis of a LQTS/BrS overlap syndrome was supported by electrophysiological evidence for both loss-of-function and gain-of-function (acceleration of channel kinetics) in a heterologous expression system. However, BrS phenotypes were not identified in other affected individuals and allelic KCNQ1 expression testing in patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) showed nonsense mediated decay of the c.1124_1127delTTCA allele. Conclusions The c.1124_1127delTTCA frameshift variant shows a high prevalence in our region, despite not being confirmed as a founder mutation. This variant leads to a mild LQTS phenotype in the heterozygous state. Despite initial evidence for a gain-of-function effect based on in vitro electrophysiological assessment in CHO cells and expression of the KCNQ1 c.1124_1127delTTCA allele in patient blood cells, additional testing in iPSC-CMs showed lack of expression of the mutant allele. This suggests haploinsufficiency as the pathogenic mechanism. Nonetheless, as inter-individual differences in allele expression in (iPSC-) cardiomyocytes have not been assessed, a modifying effect on the BrS phenotype through potassium current modulation cannot be excluded.

Aims Current long QT syndrome (LQTS) therapy, largely based on beta-blockade, does not prevent arrhythmias in all patients; therefore, novel therapies are warranted. Pharmacological inhibition of the serum/glucocorticoid-regulated kinase 1 (SGK1-Inh) has been shown to shorten action potential duration (APD) in LQTS type 3. We aimed to investigate whether SGK1-Inh could similarly shorten APD in LQTS types 1 and 2. Methods and results Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and hiPSC-cardiac cell sheets (CCS) were obtained from LQT1 and LQT2 patients; CMs were isolated from transgenic LQT1, LQT2, and wild-type (WT) rabbits. Serum/glucocorticoid-regulated kinase 1 inhibition effects (300 nM–10 µM) on field potential durations (FPD) were investigated in hiPSC-CMs with multielectrode arrays; optical mapping was performed in LQT2 CCS. Whole-cell and perforated patch clamp recordings were performed in isolated LQT1, LQT2, and WT rabbit CMs to investigate SGK1-Inh (3 µM) effects on APD. In all LQT2 models across different species (hiPSC-CMs, hiPSC-CCS, and rabbit CMs) and independent of the disease-causing variant (KCNH2 -p.A561V/p.A614V/p.G628S/IVS9-28A/G), SGK1-Inh dose-dependently shortened FPD/APD at 0.3–10 µM (by 20–32%/25–30%/44–45%). Importantly, in LQT2 rabbit CMs, 3 µM SGK1-Inh normalized APD to its WT value. A significant FPD shortening was observed in KCNQ1 -p.R594Q hiPSC-CMs at 1/3/10 µM (by 19/26/35%) and in KCNQ1 -p.A341V hiPSC-CMs at 10 µM (by 29%). No SGK1-Inh-induced FPD/APD shortening effect was observed in LQT1 KCNQ1 -p.A341V hiPSC-CMs or KCNQ1 -p.Y315S rabbit CMs at 0.3–3 µM. Conclusion A robust SGK1-Inh-induced APD shortening was observed across different LQT2 models, species, and genetic variants but less consistently in LQT1 models. This suggests a genotype- and variant-specific beneficial effect of this novel therapeutic approach in LQTS. [ABSTRACT FROM AUTHOR]

Background An elegant bedside provocation test has been shown to aid the diagnosis of long‐QT syndrome (LQTS) in a retrospective cohort by evaluation of QT intervals and T‐wave morphology changes resulting from the brief tachycardia provoked by standing. We aimed to prospectively determine the potential diagnostic value of the standing test for LQTS. Methods and Results In adults suspected for LQTS who had a standing test, the QT interval was assessed manually and automated. In addition, T‐wave morphology changes were determined. A total of 167 controls and 131 genetically confirmed patients with LQTS were included. A prolonged heart rate–corrected QT interval (QTc) (men ≥430 ms, women ≥450 ms) at baseline before standing yielded a sensitivity of 61% (95% CI, 47–74) in men and 54% (95% CI, 42–66) in women, with a specificity of 90% (95% CI, 80–96) and 89% (95% CI, 81–95), respectively. In both men and women, QTc≥460 ms after standing increased sensitivity (89% [95% CI, 83–94]) but decreased specificity (49% [95% CI, 41–57]). Sensitivity further increased (P

IntroductionTo perform a meta-analysis to discover the performance of ML algorithms in identifying Congenital long QT syndrome (LQTS).MethodsThe searched databases included Cochrane, EMBASE, Web of Science, and PubMed. Our study considered all English-language studies that reported the detection of LQTS using ML algorithms. Quality was assessed using QUADAS-2 and QUADAS-AI tools. The bivariate mixed effects models were used in our study. Based on genotype data for LQTS, we performed a subgroup analysis.ResultsOut of 536 studies, 8 met all inclusion criteria. The pooled area under the receiving operating curve (SAUROC) for detecting LQTS was 0.95 (95% CI: 0.31–1.00); sensitivity was 0.87 (95% CI: 0.83–0.90), and specificity was 0.91 (95% CI: 0.88–0.93). Additionally, diagnostic odd ratio (DOR) was 65 (95% CI: 39–109). The positive likelihood ratio (PLR) was 9.3 (95% CI: 7.0–12.3) and the negative likelihood ratio (NLR) was 0.14 (95% CI: 0.11–0.20), with very low heterogeneity (I2 = 16%).DiscussionWe found that machine learning can be used to detect features of rare cardiovascular disease like LQTS, thus increasing our understanding of intelligent interpretation of ECG. To improve ML performance in the classification of LQTS subtypes, further research is required.Systematic Review Registrationidentifier PROSPERO CRD42022360122.

Background: Hereditary cardiac arrhythmias result from mutations in various genes encoding ion channels. One major channelopathy is long QT syndrome, which has excel-lent genetic and clinical heterogeneity. Arrhythmogenic right ventricular cardiomyopathy, another hereditary arrhythmia type, also shows high genetic heterogeneity and variable expressivity. Next-generation sequencing is an effective tool to reveal the dis-ease's underlying genetic etiology. Methods: In this study, we performed clinical exome sequencing or gene panel including cardiac arrhythmia and cardiomyopathy-associated genes by next-generation sequencing in 13 unrelated patients. Results: Five pathogenic or likely pathogenic mutations, including three novel mutations, were found in the total cases. Conclusion: This research shows a strong genetic heterogeneity in the disease. In addition, the study revealed that patients with QT interval prolongation on electrocardiogram might also have mutations in genes that are not associated with long QT syndrome, such as MYLK2 and DSG2. Therefore, our data helped expand the molecular scope of long QT syndrome. It is necessary to study with a broad perspective to elucidate the underly-ing molecular etiology in patients with hereditary cardiac arrhythmias.

AimsDiagnosis of Long QT syndrome (LQTS) is based on prolongation of the QT interval corrected for heart rate (QTc) on surface ECG and genotyping. However, up to 25% of genotype positive patients have a normal QTc interval. We recently showed that individualized QT interval (QTi) derived from 24 h holter data and defined as the QT value at the intersection of an RR interval of 1,000 ms with the linear regression line fitted through QT-RR data points of each individual patient was superior over QTc to predict mutation status in LQTS families. This study aimed to confirm the diagnostic value of QTi, fine-tune its cut-off value and evaluate intra-individual variability in patients with LQTS.MethodsFrom the Telemetric and Holter ECG Warehouse, 201 recordings from control individuals and 393 recordings from 254 LQTS patients were analysed. Cut-off values were obtained from ROC curves and validated against an in house LQTS and control cohort.ResultsROC curves indicated very good discrimination between controls and LQTS patients with QTi, both in females (AUC 0.96) and males (AUC 0.97). Using a gender dependent cut-off of 445 ms in females and 430 ms in males, a sensitivity of 88% and specificity of 96% were achieved, which was confirmed in the validation cohort. No significant intra-individual variability in QTi was observed in 76 LQTS patients for whom at least two holter recordings were available (483 ± 36 ms vs. 489 ± 42 ms, p = 0.11).ConclusionsThis study confirms our initial findings and supports the use of QTi in the evaluation of LQTS families. Using the novel gender dependent cut-off values, a high diagnostic accuracy was achieved.

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease, characterized by the presence of unexplained left ventricular hypertrophy. This condition is often associated with electrocardiographic abnormalities including QTc prolongation occurring in 13% of patients. The main explanation for prolonged QTc in HCM is myocardial hypertrophy and the related structural damage. However, other mechanisms, including long QT syndrome (LQTS) genes mutations, may be involved. In the present study we explored the hypothesis of a distinct genetic basis underlying QTc prolongation in HCM by investigating the potential co-inheritance of pathogenic gene variants associated with LQTS and HCM. For this purpose, starting from a cohort of 150 HCM patients carrying pathogenic variants in sarcomere genes, we selected 25 patients carrying a QTc prolongation unexplained by any other cause. The QTc was considered prolonged if greater than 450 ms in males and greater than 470 ms in females. The NGS analysis was performed with Illumina TrueSight Cardio panel genes on Illumina MiniSeq platform. We identified pathogenic/likely pathogenic variants in the KCNQ1 in two patients (c.1781G > A, p. Arg594Gln; c.532G > A, p. Ala178Thr) (8%). Variants of uncertain significance were identified in SCN5A, KCNJ5, AKAP9 and ANK2 in four patients (16%). Although the results are limited by the small number of patients included in the study, they highlight a minor contribution of LQTS genes for QTc prolongation in HCM patients. The screening for ion channel genes mutations may be considered in HCM patients with prolonged QTc unexplained by any other cause. This in-depth molecular diagnosis may contribute to improve risk stratification and treatment planning.

Background: The c.1124_1127delTTCA p.(Ile375Argfs*43) pathogenic variant is the most frequently identified molecular defect in the KCNQ1 gene in the cardiogenetics clinic of the Antwerp University Hospital. This variant was observed in nine families presenting with either Jervell-Lange-Nielsen syndrome or long QT syndrome (LQTS). Here, we report on the molecular, clinical and functional characterization of the KCNQ1 c.1124_1127delTTCA variant. Results: Forty-one heterozygous variant harboring individuals demonstrated a predominantly mild clinical and electrophysiological phenotype, compared to individuals harboring other KCNQ1 pathogenic variants (5% symptomatic before 40 years of age, compared to 24% and 29% in p.(Tyr111Cys) and p.(Ala341Val) variant carriers, respectively, 33% with QTc ≤ 440 ms compared to 10% in p.(Tyr111Cys) and p.(Ala341Val) variant carriers). The LQTS phenotype was most comparable to that observed for the Swedish p.(Arg518*) founder mutation (7% symptomatic at any age, compared to 17% in p.(Arg518*) variant carriers, 33% with QTc ≤ 440 ms compared to 16% in p.(Arg518*) variant carriers). Surprisingly, short tandem repeat analysis did not reveal a common haplotype for all families. One KCNQ1 c.1124_1127delTTCA harboring patient was diagnosed with Brugada syndrome (BrS). The hypothesis of a LQTS/BrS overlap syndrome was supported by electrophysiological evidence for both loss-of-function and gain-of-function (acceleration of channel kinetics) in a heterologous expression system. However, BrS phenotypes were not identified in other affected individuals and allelic KCNQ1 expression testing in patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) showed nonsense mediated decay of the c.1124_1127delTTCA allele. Conclusions: The c.1124_1127delTTCA frameshift variant shows a high prevalence in our region, despite not being confirmed as a founder mutation. This variant leads to a mild LQTS phenotype in the heterozygous state. Despite initial evidence for a gain-of-function effect based on in vitro electrophysiological assessment in CHO cells and expression of the KCNQ1 c.1124_1127delTTCA allele in patient blood cells, additional testing in iPSC-CMs showed lack of expression of the mutant allele. This suggests haploinsufficiency as the pathogenic mechanism. Nonetheless, as inter-individual differences in allele expression in (iPSC-) cardiomyocytes have not been assessed, a modifying effect on the BrS phenotype through potassium current modulation cannot be excluded. [ABSTRACT FROM AUTHOR]

The KCNQ1 gene encodes the α-subunit of the cardiac voltage-gated potassium (Kv) channel KCNQ1, also denoted as Kv7.1 or KvLQT1. The channel assembles with the ß-subunit KCNE1, also known as minK, to generate the slowly activating cardiac delayed rectifier current IKs, a key regulator of the heart rate dependent adaptation of the cardiac action potential duration (APD). Loss-of-function variants in KCNQ1 cause the congenital Long QT1 (LQT1) syndrome, characterized by delayed cardiac repolarization and a QT interval prolongation in the surface electrocardiogram (ECG). Autosomal dominant loss-of-function variants in KCNQ1 result in the LQT syndrome called Romano-Ward syndrome (RWS), while autosomal recessive variants affecting function, lead to Jervell and Lange-Nielsen syndrome (JLNS), associated with deafness. The aim of this study was the characterization of novel KCNQ1 variants identified in patients with RWS to widen the spectrum of known LQT1 variants, and improve the interpretation of the clinical relevance of variants in the KCNQ1 gene. We functionally characterized nine human KCNQ1 variants using the voltage-clamp technique in Xenopus laevis oocytes, from which we report seven novel variants. The functional data was taken as input to model surface ECGs, to subsequently compare the functional changes with the clinically observed QTc times, allowing a further interpretation of the severity of the different LQTS variants. We found that the electrophysiological properties of the variants correlate with the severity of the clinically diagnosed phenotype in most cases, however, not in all. Electrophysiological studies combined with in silico modelling approaches are valuable components for the interpretation of the pathogenicity of KCNQ1 variants, but assessing the clinical severity demands the consideration of other factors that are included, for example in the Schwartz score. [ABSTRACT FROM AUTHOR]

Introduction: QTc prolongation is key in diagnosing long QT syndrome (LQTS), however 25%–50% with congenital LQTS (cLQTS) demonstrate a normal resting QTc. T wave morphology (TWM) can distinguish cLQTS subtypes but its role in acquired LQTS (aLQTS) is unclear. Methods: Electronic databases were searched using the terms "LQTS," "long QT syndrome," "QTc prolongation," "prolonged QT," and "T wave," "T wave morphology," "T wave pattern," "T wave biomarkers." Whole text articles assessing TWM, independent of QTc, were included. Results: Seventeen studies met criteria. TWM measurements included T‐wave amplitude, duration, magnitude, Tpeak‐Tend, QTpeak, left and right slope, center of gravity (COG), sigmoidal and polynomial classifiers, repolarizing integral, morphology combination score (MCS) and principal component analysis (PCA); and vectorcardiographic biomarkers. cLQTS were distinguished from controls by sigmoidal and polynomial classifiers, MCS, QTpeak, Tpeak‐Tend, left slope; and COG x axis. MCS detected aLQTS more significantly than QTc. Flatness, asymmetry and notching, J‐Tpeak; and Tpeak‐Tend correlated with QTc in aLQTS. Multichannel block in aLQTS was identified by early repolarization (ERD30%) and late repolarization (LRD30%), with ERD reflecting hERG‐specific blockade. Cardiac events were predicted in cLQTS by T wave flatness, notching, and inversion in leads II and V5, left slope in lead V6; and COG last 25% in lead I. T wave right slope in lead I and T‐roundness achieved this in aLQTS. Conclusion: Numerous TWM biomarkers which supplement QTc assessment were identified. Their diagnostic capabilities include differentiation of genotypes, identification of concealed LQTS, differentiating aLQTS from cLQTS; and determining multichannel versus hERG channel blockade. [ABSTRACT FROM AUTHOR]

Background: While much is known about the channelopathy disorder Long QT Syndrome (LQTS), the histopathological findings and their implications on the disease have remained largely unexplored to date. In this review, we discuss the background of LQTS and highlight the importance of histological findings in the absence of genetic markers or when genetic testing is unavailable.Materials and methods: Three pediatric cases of LQTS were identified, evaluated histologically, and compared to two adult cases.Results: Histological examination of three pediatric LQTS patients demonstrated fibrotic alterations to the cardiac conduction system with markedly decreased conductive tissue density and volume. Both adult cases revealed fibrosis with similar reductions in tissue volume.Conclusion: When diagnostic methods such as genetic testing are unavailable, histopathology offers clinicians an alternative tool for postmortem diagnosis of LQTS when considered alongside clinical presentation. Confirmation of diagnosis in a proband can prevent the death of relatives in hereditary LQTS. [ABSTRACT FROM AUTHOR]

Abstract Background Congenital long QT syndrome (LQTS) is a rare heart disease caused by various underlying mutations. Most general cardiologists do not routinely see patients with congenital LQTS and may not always recognize the accompanying ECG features. In addition, a proportion of disease carriers do not display obvious abnormalities on their ECG. Combined, this can cause underdiagnosing of this potentially life-threatening disease. Methods This study presents 1D convolutional neural network models trained to identify genotype positive LQTS patients from electrocardiogram as input. The deep learning (DL) models were trained with a large 10-s 12-lead ECGs dataset provided by Amsterdam UMC and externally validated with a dataset provided by University Hospital Leuven. The Amsterdam dataset included ECGs from 10000 controls, 172 LQTS1, 214 LQTS2, and 72 LQTS3 patients. The Leuven dataset included ECGs from 2200 controls, 32 LQTS1, and 80 LQTS2 patients. The performance of the DL models was compared with conventional QTc measurement and with that of an international expert in congenital LQTS (A.A.M.W). Lastly, an explainable artificial intelligence (AI) technique was used to better understand the prediction models. Results Overall, the best performing DL models, across 5-fold cross-validation, achieved on average a sensitivity of 84 ± 2%, 90 ± 2% and 87 ± 6%, specificity of 96 ± 2%, 95 ± 1%, and 92 ± 4%, and AUC of 0.90 ± 0.01, 0.92 ± 0.02, and 0.89 ± 0.03, for LQTS 1, 2, and 3 respectively. The DL models were also shown to perform better than conventional QTc measurements in detecting LQTS patients. Furthermore, the performances held up when the DL models were validated on a novel external cohort and outperformed the expert cardiologist in terms of specificity, while in terms of sensitivity, the DL models and the expert cardiologist in LQTS performed the same. Finally, the explainable AI technique identified the onset of the QRS complex as the most informative region to classify LQTS from non-LQTS patients, a feature previously not associated with this disease. Conclusions This study suggests that DL models can potentially be used to aid cardiologists in diagnosing LQTS. Furthermore, explainable DL models can be used to possibly identify new features for LQTS on the ECG, thus increasing our understanding of this syndrome.

Long QT syndrome (LQTS) is an inherited arrhythmic disorder associated with sudden cardiac death (SCD). This study aimed to identify the clinical and molecular genetic risk factors that contribute to major arrhythmic events (MAEs) in patients with genetically confirmed childhood onset LQTS 1–3. This study was a retrospective double-center study. An MAE was defined as the occurrence of SCD, aborted SCD, appropriate implantable cardioverter defibrillator discharge, or sustained ventricular tachycardia. During a median follow-up of 4.6 years (range 0.1–24.3 years), MAEs occurred in 18 (17.8%) of 101 patients diagnosed with LQTS at a median of 7.7 years (range 0.0–18.0 years) despite the use of beta-blockers in 91.6% of patients at the last follow-up. A multivariate analysis identified a genetic diagnosis of LQTS2 and LQTS3 and variants within the KCNH2 S5-loop-S6 pore region as independent risk factors for MAEs, independent of the QTc value or a history of syncope detected from a univariate analysis. MAEs occur frequently in childhood onset LQTS despite beta-blocker treatment. A detailed molecular genetic diagnosis can contribute to the arrhythmia risk stratification and optimize the use of preventive measures in this vulnerable patient population.

Rui Huang,1,&ast; Yinhua Luo,2,&ast; Yuhua Lei,1 Yuanhong Li1 1Cardiovascular Disease Center, Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, 445000, Hubei Province, People’s Republic of China; 2Department of Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Hubei University of Medicine, Shiyan, 442000, Hubei Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuanhong LiCardiovascular Disease Center, Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, 445000, Hubei Province, People’s Republic of ChinaEmail lyh0101@163.vip.comAbstract: It is reported that the incidence of congenital long QT syndrome (cLQTS) is very low, with the incidence of LQTS caused by transient receptor potential melastatin 4 (TRPM4) being even lower, leading to less research on the gene TRPM4. We reported a case of an elderly male patient presenting with frequent syncopal episodes since the age of 20. Electrocardiography showed sinus bradycardia (mean heart rate 59 beats), prolonged QT interval (540ms), and torsade de pointes. His sister also had experienced an episode of syncope, but his other families had not. A novel mutation in the TRPM4 gene was discovered in this patient and his sister, according to genetic analysis. All in all, we provided a new heterozygous shift mutation (NM_017636: exon4: c.434delC, p. Ala145ValfsTer133) on TRPM4, which has never been reported in the past and thus may hopefully serve as useful feedback information for genetic pathogenesis of cLQTS caused by TRPM4 variants.Keywords: long QT syndrome, LQTS, TRPM4, mutation

Abstract Introduction QTc prolongation is key in diagnosing long QT syndrome (LQTS), however 25%–50% with congenital LQTS (cLQTS) demonstrate a normal resting QTc. T wave morphology (TWM) can distinguish cLQTS subtypes but its role in acquired LQTS (aLQTS) is unclear. Methods Electronic databases were searched using the terms “LQTS,” “long QT syndrome,” “QTc prolongation,” “prolonged QT,” and “T wave,” “T wave morphology,” “T wave pattern,” “T wave biomarkers.” Whole text articles assessing TWM, independent of QTc, were included. Results Seventeen studies met criteria. TWM measurements included T‐wave amplitude, duration, magnitude, Tpeak‐Tend, QTpeak, left and right slope, center of gravity (COG), sigmoidal and polynomial classifiers, repolarizing integral, morphology combination score (MCS) and principal component analysis (PCA); and vectorcardiographic biomarkers. cLQTS were distinguished from controls by sigmoidal and polynomial classifiers, MCS, QTpeak, Tpeak‐Tend, left slope; and COG x axis. MCS detected aLQTS more significantly than QTc. Flatness, asymmetry and notching, J‐Tpeak; and Tpeak‐Tend correlated with QTc in aLQTS. Multichannel block in aLQTS was identified by early repolarization (ERD30%) and late repolarization (LRD30%), with ERD reflecting hERG‐specific blockade. Cardiac events were predicted in cLQTS by T wave flatness, notching, and inversion in leads II and V5, left slope in lead V6; and COG last 25% in lead I. T wave right slope in lead I and T‐roundness achieved this in aLQTS. Conclusion Numerous TWM biomarkers which supplement QTc assessment were identified. Their diagnostic capabilities include differentiation of genotypes, identification of concealed LQTS, differentiating aLQTS from cLQTS; and determining multichannel versus hERG channel blockade.

In most cases, sudden unexplained death (SUD) is caused by hereditary cardiac arrhythmias that standard forensic autopsy procedures cannot prove. For this reason, forensics analysis must apply other methodologies to uncover related factors. For example, postmortem molecular analysis (molecular autopsy) based on next-generation sequencing represents a promising and effective tool for diagnosing SUD. This analysis allows scientists to detect well-known, new, and rare pathogenic exonic variants or those with unknown significance that could be related to the cause of sudden death. Using exome sequencing, we identified rare exon variants in MYBPC3, KCND3, TTN, and ANK3 in a fifteen-year-old male SUD case with negative toxicology analysis and autopsy showing microscopic abnormality of heart fiber disarray. Our findings suggested that this case might be associated with cardiac channelopathy long QT syndrome, type 2, as a potential causative factor.

[Display omitted] [ABSTRACT FROM AUTHOR]

Background: β-Blockers (BBs), sodium channel blockers (SCBs), left cardiac sympathetic denervation (LCSD), and implantable cardioverter-defibrillators (ICDs) are used to prevent or counter long QT syndrome (LQTS)-triggered syncope, seizures, and sudden cardiac death. The spectrum and extent of side effects/complications associated with these guideline-directed therapies (GDTs) remain unknown.Objective: The purpose of this study was to identify the types/prevalence of treatment-associated side effects/complications for patients with the most common LQTS subtypes after GDT.Methods: Retrospective analysis was performed on 1310 patients with type 1, 2, or 3 LQTS evaluated in Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic (average age at the time of diagnosis 22 ± 18 years; average length of follow-up 5 ± 5 years) and treated with ≥1 of the common GDTs for LQTS.Results: BBs were used in 1102 (84%), SCBs in 104 (8%), LCSD in 197 (15%), and an ICD was used in 251 (19%) patients. Overall, 727 (55%) patients reported at least 1 treatment-associated side effect/complication. A total of 490 of 1102 patients treated with BBs (44%) reported side effects, with fatigue (381 [35%]) being the most common; 28 of 104 SCB-treated patients (27%) reported side effects, most common being gastrointestinal distress/vomiting (18 [17%]); 80 of 197 patients (41%) reported side effects after LCSD, most reporting neuropathic pain (57 [29%]); and 129 of 251 patients (51%) experienced ≥1 complication after ICD implantation, including inappropriate shocks (46 [18%]).Conclusion: Although LQTS-triggered sudden cardiac death is uncommon in the properly treated patient, this study demonstrates that contemporary GDTs for LQTS are not innocuous. Their treatment-related side effects are not trivial and should compel an ongoing quest for new LQTS therapies. [ABSTRACT FROM AUTHOR]

Background: Long QT syndrome is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by KCNH2 . Variant classification is difficult, often because of lack of functional data. Moreover, variant-based risk stratification is also complicated by heterogenous clinical data and incomplete penetrance. Here we sought to test whether variant-specific information, primarily from high-throughput functional assays, could improve both classification and cardiac event risk stratification in a large, harmonized cohort of KCNH2 missense variant heterozygotes., Methods: We quantified cell-surface trafficking of 18 796 variants in KCNH2 using a multiplexed assay of variant effect (MAVE). We recorded KCNH2 current density for 533 variants by automated patch clamping. We calibrated the strength of evidence of MAVE data according to ClinGen guidelines. We deeply phenotyped 1458 patients with KCNH2 missense variants, including QTc, cardiac event history, and mortality. We correlated variant functional data and Bayesian long QT syndrome penetrance estimates with cohort phenotypes and assessed hazard ratios for cardiac events., Results: Variant MAVE trafficking scores and automated patch clamping peak tail currents were highly correlated (Spearman rank-order ρ=0.69; n=433). The MAVE data were found to provide up to pathogenic very strong evidence for severe loss-of-function variants. In the cohort, both functional assays and Bayesian long QT syndrome penetrance estimates were significantly predictive of cardiac events when independently modeled with patient sex and adjusted QT interval (QTc); however, MAVE data became nonsignificant when peak tail current and penetrance estimates were also available. The area under the receiver operator characteristic curve for 20-year event outcomes based on patient-specific sex and QTc (area under the curve, 0.80 [0.76-0.83]) was improved with prospectively available penetrance scores conditioned on MAVE (area under the curve, 0.86 [0.83-0.89]) or attainable automated patch clamping peak tail current data (area under the curve, 0.84 [0.81-0.88])., Conclusions: High-throughput KCNH2 variant MAVE data meaningfully contribute to variant classification at scale, whereas long QT syndrome penetrance estimates and automated patch clamping peak tail current measurements meaningfully contribute to risk stratification of cardiac events in patients with heterozygous KCNH2 missense variants.

Objective To investigate the role of Rer1 in hERG potassium channel protein transport,and to study the medicine Baf A1 that may restore abnormal hERG transport. Methods HEK293T cells were transiently transfected with constructed A561V mutant and WT plasmids, the wild-type,mutant and mixed transfection cell models were established.The expressions of hERG and Rer1 were detected by immunofluorescence and Western blot.siRNA was used to knockdown the expression of Rer1 and detect the expression of hERG;Bafilomycin A1,a V-ATPase inhibitor was incubated with 1 mmol/L for 6 hours.Western blot was used to detect the changes of hERG protein before and after the incubation.Patch clamp was used to measure the current of potential functional in mixed transfection cells. Results Compared with the WT group,A561V-mutation could cause trafficking deficient of hERG protein.The PM expression of hERG in mutant group was significantly reduced(P＜0.01).The expression of Rer1 in mutation and mixed transfection groups decreased significantly(P＜0.01).Knockdown of Rer1 promoted the forward transport of mature hERG.Besides,after incubation with Baf A1,the mature hERG protein in WT and mutant groups increased significantly(P＜0.05),while the immature hERG in the mixed transformation group was significantly increased(P＜0.05).Relative density of tail current was elevated following incubation with Baf A1 compared with control. Conclusions Rer1 is involved in the transport of hERG potassium channel and inhibits the forward transport of some abnormal hERG.Baf A1 significantly enhances the tail current density of mixed transfection cells.

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.

We identified a single nucleotide variation (SNV) (c.1264A > G) in the KCNQ1 gene in a 5-year-old boy who presented with a prolonged QT interval. His elder brother and mother, but not sister and father, also had this mutation. This missense mutation leads to a p.Lys422Glu (K422E) substitution in the Kv7.1 protein that has never been mentioned before. We inserted this substitution in an expression plasmid containing Kv7.1 cDNA and studied the electrophysiological characteristics of the mutated channel expressed in CHO-K1, using the whole-cell configuration of the patch-clamp technique. Expression of the mutant Kv7.1 channel in both homo- and heterozygous conditions in the presence of auxiliary subunit KCNE1 results in a significant decrease in tail current densities compared to the expression of wild-type (WT) Kv7.1 and KCNE1. This study also indicates that K422E point mutation causes a dominant negative effect. The mutation was not associated with a trafficking defect; the mutant channel protein was confirmed to localize at the cell membrane. This mutation disrupts the poly-Lys strip in the proximal part of the highly conserved cytoplasmic A–B linker of Kv7.1 that was not shown before to be crucial for channel functioning. [ABSTRACT FROM AUTHOR]

Background: Pathogenic mutations in the KCNH2 gene were associated with long QT syndrome 2 (LQT2), which typically manifest in a prolonged QT interval and may lead to recurrent syncopes, seizure, or sudden death. Limited reports indicated that the KCNH2 mutations would result in LQT2 combined with tetralogy of fallot. Our goal was to present an additional case of LQT2 combined with the tetralogy of fallot in a fetus with a novel KCNH2 mutation. Case presentation: Enrolled in this study was a 23-year-old pregnant woman from Quanzhou Fujian province, China. In her pregnancy, fetal ultrasound anomalies were identified, including tetralogy of fallot, coronary sinus enlargement, and persistent left superior vena cava. No chromosomal abnormality was detected by fetal karyotype analysis. However, 238.1-kb duplication in the 2q14.2 region containing the GLI2 gene was observed in the fetus by chromosomal array analysis, which was inherited from the mother with normal clinical features and interpreted as a variant of uncertain significance (VOUS). Furthermore,whole-exome sequencing (WES) detection identified a novel nonsense c.1907C > G (p.S636*) mutation in the KCNH2 gene in the fetus, and it was classified as a likely pathogenic variant, according to the ACMG guidelines. Parental verification analysis indicated that c.1907C > G (p.S636*) mutation was inherited from the mother. Conclusion: In this study, we believe that 2q14.2 duplication may not be the reason for fetal heart defects; moreover, we described an additional case with KCNH2 gene mutation, which may lead to LQTS and be associated with congenital heart defects. In addition, our study further confirms the application value of the WES technology in prenatal genetic etiology diagnosis of fetuses with structural anomalies and unexplained structural variants. [ABSTRACT FROM AUTHOR]

Provide a brief summary of your article (100–150 words; no references or figures/tables). The synopsis appears only in the table of contents and is often used by indexing services such as PubMed. Genetic arrhythmia syndromes are rare, yet harbor the potential for highly consequential, often unpredictable arrhythmias or sudden death events. There has been historical uncertainty regarding the correct advice to offer to affected patients who are reasonably wanting to participate in sporting and athletic endeavors. In some cases, this had led to abundantly cautious disqualifications, depriving individuals from participation unnecessarily. Societal guidance and expert opinion has evolved significantly over the last decade or 2, along with our understanding of the genetics and natural history of these conditions, and the emphasis has switched toward shared decision making with respect to the decision to participate or not, with patients and families becoming better informed, and willing participants in the decision making process. This review aims to give a brief update of the salient issues for the busy physician concerning these syndromes and to provide a framework for approaching their management in the otherwise aspirational or keen sports participant. [ABSTRACT FROM AUTHOR]

Background: Hereditary cardiac arrhythmias result from mutations in various genes encoding ion channels. One major channelopathy is long QT syndrome, which has excellent genetic and clinical heterogeneity. Arrhythmogenic right ventricular cardiomyopathy, another hereditary arrhythmia type, also shows high genetic heterogeneity and variable expressivity. Next-generation sequencing is an effective tool to reveal the disease's underlying genetic etiology. Methods: In this study, we performed clinical exome sequencing or gene panel including cardiac arrhythmia and cardiomyopathy-associated genes by next-generation sequencing in 13 unrelated patients. Results: Five pathogenic or likely pathogenic mutations, including three novel mutations, were found in the total cases. Conclusion: This research shows a strong genetic heterogeneity in the disease. In addition, the study revealed that patients with QT interval prolongation on electrocardiogram might also have mutations in genes that are not associated with long QT syndrome, such as MYLK2 and DSG2. Therefore, our data helped expand the molecular scope of long QT syndrome. It is necessary to study with a broad perspective to elucidate the underlying molecular etiology in patients with hereditary cardiac arrhythmias. [ABSTRACT FROM AUTHOR]

BackgroundLeft ventricular non-compaction (LVNC) is an abnormality of the myocardium, characterized by prominent left ventricular trabeculae and deep inter-trabecular recesses. Long QT syndrome (LQTS) is a cardiac ion channelopathy presenting with a prolonged QT interval on resting electrocardiogram and is associated with increased susceptibility to sudden death. The association between LVNC and LQTS is uncommon.Case presentationWe report an Italian family with a novel pathogenic KCNH2 variant who presented with clinical features of LVNC and LQTS. The proband came to our attention after two syncopal episodes without prodromal symptoms. His ECG showed QTc prolongation and deep T wave inversion in anterior leads, and the echocardiogram fulfilled LVNC criteria. After that, also his sister was found to have LQTS and LVNC, while his father only presented LQTS.ConclusionsPhysicians should be aware of the possible association between LVNC and LQTS. Even if this association is rare, patients with LVNC should be investigated for LQTS to prevent possible severe or even life-threatening arrhythmic episodes.

Background: Adult long QT syndrome (LQTS) patients have inadequate corrected QT interval (QTc) shortening and an abnormal T-wave response to the sudden heart rate acceleration provoked by standing. In adults, this knowledge can be used to aid an LQTS diagnosis and, possibly, for risk stratification. However, data on the diagnostic value of the standing test in children are currently limited. Objective: To determine the potential value of the standing test to aid LQTS diagnostics in children. Methods: In a prospective cohort including children (≤18 years) who had a standing test, comprehensive analyses were performed including manual and automated QT interval assessments and determination of T-wave morphology changes. Results: We included 47 LQTS children and 86 control children. At baseline, the QTc that identified LQTS children with a 90% sensitivity was 435 ms, which yielded a 65% specificity. A QTc ≥ 490 ms after standing only slightly increased sensitivity (91%, 95% confidence interval [CI]: 80%–98%) and slightly decreased specificity (58%, 95% CI: 47%–70%). Sensitivity increased slightly more when T-wave abnormalities were present (94%, 95% CI: 82%–99%; specificity 53%, 95% CI: 42%–65%). When a baseline QTc ≥ 440 ms was accompanied by a QTc ≥ 490 ms and T-wave abnormalities after standing, sensitivity further increased (96%, 95% CI: 85%–99%) at the expense of a further specificity decrease (41%, 95% CI: 30%–52%). Beat-to-beat analysis showed that 30 seconds after standing, LQTS children had a greater increase in heart rate compared to controls, which was more evidently present in LQTS boys and LQTS type 1 children. Conclusion: In children, the standing test has limited additive diagnostic value for LQTS over a baseline electrocardiogram, while T-wave abnormalities after standing also have limited additional value. The standing test for LQTS should only be used with caution in children.

Background: Congenital long QT syndrome (LQTS) is a rare heart disease caused by various underlying mutations. Most general cardiologists do not routinely see patients with congenital LQTS and may not always recognize the accompanying ECG features. In addition, a proportion of disease carriers do not display obvious abnormalities on their ECG. Combined, this can cause underdiagnosing of this potentially life-threatening disease.Methods: This study presents 1D convolutional neural network models trained to identify genotype positive LQTS patients from electrocardiogram as input. The deep learning (DL) models were trained with a large 10-s 12-lead ECGs dataset provided by Amsterdam UMC and externally validated with a dataset provided by University Hospital Leuven. The Amsterdam dataset included ECGs from 10000 controls, 172 LQTS1, 214 LQTS2, and 72 LQTS3 patients. The Leuven dataset included ECGs from 2200 controls, 32 LQTS1, and 80 LQTS2 patients. The performance of the DL models was compared with conventional QTc measurement and with that of an international expert in congenital LQTS (A.A.M.W). Lastly, an explainable artificial intelligence (AI) technique was used to better understand the prediction models.Results: Overall, the best performing DL models, across 5-fold cross-validation, achieved on average a sensitivity of 84 ± 2%, 90 ± 2% and 87 ± 6%, specificity of 96 ± 2%, 95 ± 1%, and 92 ± 4%, and AUC of 0.90 ± 0.01, 0.92 ± 0.02, and 0.89 ± 0.03, for LQTS 1, 2, and 3 respectively. The DL models were also shown to perform better than conventional QTc measurements in detecting LQTS patients. Furthermore, the performances held up when the DL models were validated on a novel external cohort and outperformed the expert cardiologist in terms of specificity, while in terms of sensitivity, the DL models and the expert cardiologist in LQTS performed the same. Finally, the explainable AI technique identified the onset of the QRS complex as the most informative region to classify LQTS from non-LQTS patients, a feature previously not associated with this disease.Conclusions: This study suggests that DL models can potentially be used to aid cardiologists in diagnosing LQTS. Furthermore, explainable DL models can be used to possibly identify new features for LQTS on the ECG, thus increasing our understanding of this syndrome. [ABSTRACT FROM AUTHOR]

Diurnal oscillations in human cardiac electrophysiology are thought to be under the control of the endogenous circadian clock. The incidence of arrhythmic events in patients with Long QT syndrome (LQTS) varies diurnally. The diurnal variation in QT interval has previously been identified as a potential for error in clinical trials which utilise ECG measurement. We performed a systematic review of clinical trials for LQTS to identify practice around specification of timing information for point electrocardiogram (ECG) measurements, analysis of continual ECG recordings ≥24 h, and drug delivery. Despite guidelines having been issued around the analysis of 24-h ECG recordings, we identify a lack of usage of detailed time of day information in trial design for LQTS studies, which has the potential to affect the interpretation of the results of drug trials. We identify that, in contrast, clinical trials for QT prolonging drugs demonstrate increased incorporation of time of day information of both QT analysis and drug dosing. We provide a visual portal to allow trial designers and clinicians to better understand timing of common cardiac-targeting drugs, and to bear this concept in mind in the design of future clinical trials. [ABSTRACT FROM AUTHOR]