The Best ECG Lead for Predicting the Risk of Drug-Induced Torsade De Pointes Using Corrected QT Interval: A Comparative Prognostic Study.

Introduction: Torsade de pointes (TdP) is a deadly complication from drug-induced QT prolongation. Each of the 12 lead of an electrocardiogram (ECG) has a different length of QT interval, and thus might have a different performance in TdP prediction. This study aimed to determine the best ECG lead or set of leads in this regard. Methods: This is a comparative prognostic accuracy study using a two-gate data gathering design. The population in this study was from two sources, a case group (Patients who had drug-induced TdP, which were identified through a systematic Medline search) and a control group (those who overdosed on QT-prolonging drugs, which included patients who were under the consultation of Medical Toxicology Services). The areas under the receiver operating characteristic curve (AUROC) of heart rate-corrected QT (QTc) in each single ECG lead and of a mean/median QTc from a set of ECG leads (17 index test) in predicting the risk of TdP were calculated and compared with each other, trying to find the best lead for this propose. QTc Interval measurements were done by four investigators (Interrater reliabilities 0.95). Results: Finally, we included 136 and 148 ECGs from TdP cases and controls, respectively. V3 lead had the highest frequency of longest QTc interval, among the leads. The lead having the longest QTc yielded the greatest AUROC in predicting TdP regardless of QT correction formulas (QTcFRA=0.9915, QTcRTH=0.9893, QTcBZT=0.9904). The mean QTc of 3 leads (lead II, plus any two of leads V2-V4), and a median QTc of 6 leads (I, II, aVF, V2, V4, V6) provided similar overall performance for TdP prediction (regardless of the type of QTc formula). Conclusion: The longest QTc provided the greatest AUROC in predicting drug-induced TdP, however, the longest QTc is not located in a fixed individual lead in any patient. A less time-consuming method with comparable performance to that of the longest QTc was to use a mean QTc from 3 leads (lead II, plus any two of leads V2-V4). The potential clinical impact of this finding needs to be verified in a prospective cohort study.

Rapid Return to Play After Extravascular Implantable Cardioverter-Defibrillator Implantation in a Competitive Runner.

We present a case of long QT syndrome type 2 in a competitive runner who underwent implantation of a primary prevention extravascular implantable cardioverter defibrillator with a rapid return to partial activity within 2 weeks and a return to full activity within 4 weeks of implantation without affecting wound healing or device function.

Frequency and Outcomes Associated with Non-Adherence to Guideline-Based Recommendations for an Implantable Cardioverter-Defibrillator in Patients with Congenital Long QT Syndrome.

BACKGROUND: Guideline-directed device therapy (GDDT) for long QT syndrome (LQTS) has evolved over the years and indications for an implantable cardioverter defibrillator (ICD) vary amongst professional cardiac societies. OBJECTIVE: To identify the subset of patients with LQTS who satisfied a class I or class II 2022 European Society of Cardiology (ESC) guideline-based recommendation for an ICD and determine the outcomes among those patients who received an ICD compared to those treated without an ICD. METHODS: Retrospective analysis of 2,861 patients with either LQT1, LQT2 or LQT3 to identify patients meeting contemporary recommendations for GDDT. Basic demographics, clinical characteristics, and frequency/type of breakthrough cardiac events (BCEs) were extracted, and outcomes/complications were compared between patients treated with an ICD compared to those treated without one. RESULTS: Among the 290 patients (approximately 10%) who met a guideline-based recommendation, 53 (18%) satisfied a Class I/level B indication for an ICD, 56 (19%) a Class I/level C indication, 19 (7%) a Class IIA/level C indication, and 165 (55%) a Class IIB/level B indication. However, the majority 156/290 (54%) did not receive an ICD. Among those who received an ICD, 55/134 (41%) experienced ≥ 1 appropriate ventricular fibrillation (VF)-terminating ICD therapy while ICD-related complications occurred in 13 patients (10%). Of those who were treated without an ICD, only 6/154 patients (4%) had non-lethal BCEs, which was significantly lower compared to the ICD group (p<0.001). CONCLUSION: With over 1200 years of combined follow-up, the experience and evidence from our two LQTS specialty centers suggests that many patients who satisfy a recommendation for an ICD based upon the latest 2022 ESC Guidelines may not need one. This is particularly true when the indication stemmed from a BCE while on BB therapy or in asymptomatic patients with an increased '1-2-3 LQTS risk score'.

Quercetin is a foe in the heart by targeting the hERG potassium channel.

Objectives: Quercetin is a plant flavonoid known for its pharmacological activities, such as antioxidant, anti-inflammatory, and anti-cancer properties. However, there is limited information available regarding its potential toxicities. A previous study showed that quercetin can inhibit human ether-a-go-related gene (hERG, also named KCNH2) currents, which may lead to long QT syndrome, torsade de pointes (TdP), and even sudden cardiac death. This study aimed to investigate the effects of quercetin on hERG and its potential mechanism. Materials and Methods: hERG currents and action potential duration (APD) were assessed using the patch clamp technique. Molecular docking was employed to elucidate the binding sites between quercetin and hERG. Transfection of wild-type or mutant plasmids was used to verify the results of molecular docking. Western blot was performed to determine the expression levels of hERG, transcription factor SP1, molecular chaperones HSP70 and HSP90, phosphorylated E3 ubiquitin ligase p-Nedd4-2, serum- and glucocorticoid-inducible kinase (SGK1), and phosphatidylinositol 3-kinase (PI3K). Immunoprecipitation was conducted to evaluate hERG ubiquitination. Results: Quercetin acutely blocked hERG current by binding to F656 amino acid residue, subsequently accelerating channel inactivation. Long-term incubation of quercetin accelerates Nedd4-2-mediated ubiquitination degradation of hERG channels by inhibiting the PI3K/SGK1 signaling pathway. Moreover, the APD of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) is significantly prolonged by 30 µM quercetin. Conclusion: Quercetin has a potential risk of proarrhythmia, which provided useful information for the usage and development of quercetin as a medication.

Mechanisms underlying spontaneous termination of Torsade de Pointes in an experimental model of long QT syndrome.

BACKGROUND: Torsade de pointes (TdP) represents a complex polymorphic ventricular tachycardia. While the triggering mechanisms of early afterdepolarization and increased dispersion of repolarization are well investigated, the sudden self-limiting termination remains poorly understood. OBJECTIVE: Analysis of TdP to investigate factors causing spontaneous termination. METHODS: We used a large data set of Langendorff experiments in isolated rabbit hearts in which drug-induced QT prolongation, bradycardia and hypokalemia provoke TdP. We included 427 episodes with typical TdP characteristics of polymorphic, self-terminating beats and twisting QRS complexes occurring in the presence of abnormal QT prolongation due to various different QT prolonging agents. The use of eight monophasic action potential catheters allowed the characterization of action potential duration, configuration, and dispersion of repolarization beyond the capabilities of the surface ECG. To identify possible mechanisms of arrhythmia termination, the initial, midpoint, and terminal three ventricular complexes were analyzed for each episode. RESULTS: An abrupt decrease in spatial dispersion over the course of a TdP episode was identified as a precursor for termination of TdP. Within the last three beats, a sudden significant decrease in dispersion of repolarization was observed as a predictor of termination. In parallel, there was a decrease in action potential duration (APD90) before termination. Also, a change in action potential configuration (APD90/50 ratio) in terms of loss of action potential dome with restitution of action potential triangulation was observed. CONCLUSION: In more than 400 TdP episodes homogenization of myocardial repolarization with the recovery of action potential configuration determines the termination of TdP episodes.

Defining Cardiomyocyte Repolarization Response to Pharmacotherapy in Long-QT Syndrome Type 3.

BACKGROUND: Long-QT syndrome is a primary cardiac ion channelopathy predisposing a patient to ventricular arrhythmia through delayed repolarization on the resting ECG. We aimed to establish a patient-specific, human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes model of long-QT syndrome type 3 (LQT3) using clustered regularly interspaced palindromic repeats (CRISPR/Cas9), for disease modeling and drug challenge. METHODS AND RESULTS: HiPSCs were generated from a patient with LQT3 harboring an SCN5A pathogenic variant (c.1231G>A; p.Val411Met), and an unrelated healthy control. The same SCN5A pathogenic variant was engineered into the background healthy control hiPSCs via CRISPR/Cas9 gene editing to generate a second disease model of LQT3 for comparison with an isogenic control. All 3 hiPSC lines were differentiated into cardiomyocytes. Both the patient-derived LQT3 (SCN5A+/-) and genetically engineered LQT3 (SCN5A+/-) hiPSC-derived cardiomyocytes showed significantly prolonged cardiomyocyte repolarization compared with the healthy control. Mexiletine, a cardiac voltage-gated sodium channel (NaV1.5) blocker, shortened repolarization in both patient-derived LQT3 and genetically engineered LQT3 hiPSC-derived cardiomyocytes, but had no effect in the control. Notably, calcium channel blockers nifedipine and verapamil showed a dose-dependent shortening of repolarization, rescuing the phenotype. Additionally, therapeutic drugs known to prolong the corrected QT in humans (ondansetron, clarithromycin, and sotalol) demonstrated this effect in vitro, but the LQT3 clones were not more disproportionately affected compared with the control. CONCLUSIONS: We demonstrated that patient-derived and genetically engineered LQT3 hiPSC-derived cardiomyocytes faithfully recapitulate pathologic characteristics of LQT3. The clinical significance of such an in vitro model is in the exploration of novel therapeutic strategies, stratifying drug adverse reaction risk and potentially facilitating a more targeted, patient-specific approach in high-risk patients with LQT3.

Clinical Features, Long-Term Prognosis, and Clinical Management of Genotype-Negative Long QT Syndrome Patients.

BACKGROUND: Approximately 15% to 20% of patients clinically diagnosed with long QT syndrome (LQTS) are genotype-negative (GEN-). Whether they have a different arrhythmic risk or should be managed differently remains unclear, often leading to incomplete treatment. OBJECTIVES: The purpose of this study was to compare clinical aspects of GEN- and genotype-positive (GEN+) LQTS patients. METHODS: We retrospectively evaluated 832 LQTS patients genetically screened in Japan (n = 347) and Italy (n = 485), including 698 with a disease-causing variant in the KCNQ1, KCNH2, and SCN5A genes (GEN+), and 134 without variants in these LQTS-related genes (GEN-). RESULTS: At diagnosis, the Japanese patients were more often probands (86% vs 60%), symptomatic (39% vs 18%), and of younger age than the Italian patients; conversely, they used less ß-blockers (65% vs 95%), more rarely had a family history (FH) of LQTS (42% vs 73%), and had more cardiac events during follow-up (13% vs 4%) (P < 0.001 for all comparisons). Within the Japanese cohort, the GEN- had more cardiac arrests, used less ß-blockers, and had much less FH for LQTS compared their GEN+ counterpart. The Italian cohort was more homogeneous, with just more LQTS FH among the GEN+. QTc shortening (close to 30 ms in all groups) during follow-up was similar between Japanese and Italian patients, irrespective of their being GEN+ or GEN-. In both cohorts, during an average follow-up of 6 and 7 years, respectively, GEN+ and GEN- patients showed a comparable clinical outcome. CONCLUSIONS: Arrhythmic risk is similar between GEN+ and GEN- LQTS patients; they should be managed and treated in the same way.

Torsades de Pointes electrical storm in children with KCNH2 mutations.

Congenital long QT syndrome (LQTS) is a genetic heart disorder, which may lead to life-threatening arrhythmias, especially in children. Here, we reported two children who were initially misdiagnosed with epilepsy and experienced Torsades de Pointes (TdP) cardiac electrical storm (ES). Through whole exome sequencing (WES), we identified two Potassium voltage-gated channel subfamily H member 2 (KCHN2) mutations (c.1841 C > T and c.1838 C > T) respectively in a 6-year-old boy and a 13-year-old girl. Clinical data indicated that the QT interval was significantly prolonged, the T-wave pattern of chest V5-V6 leads and limb leads were inverted. Our study suggests that patients with epilepsy, especially those refractory epilepsy with atypical features, need comprehensive evaluation of cardiovascular function. KCNH2 mutation in pore region, QT interval prolongation and T wave inversion are high risk factors for ES. For LQT2 patients with ES, Nadolol and left cardiac sympathetic denervation are indicated, sometimes with an ICD.

Congenital Long QT Syndrome Unmasked by Albuterol in an Adolescent with Asthma.

BACKGROUND: Patients with congenital long QT syndrome (LQTS) are prone to ventricular dysrhythmia but may be initially asymptomatic with a normal QTc interval on resting electrocardiogram (ECG). Albuterol is listed as a medication that poses a "special risk" to patients with congenital LQTS, but its effects have been rarely described. We present a case of previously unknown, asymptomatic congenital LQTS unmasked by albuterol in an adolescent with asthma. CASE REPORT: A 12-year-old girl with a history of asthma presented to the emergency department (ED) with shortness of breath, wheezing, and tachycardia for 24 h, consistent with acute asthma exacerbation. She received two doses of her home albuterol inhaler 2 h prior to presentation. Initial ECG demonstrated a QTc of 619 ms. Her remaining history, clinical examination, and laboratory workup, including electrolytes, were unremarkable. She was observed with cardiac monitoring before being discharged from the ED in stable condition for next-day outpatient pediatric cardiology follow-up. Resting office ECGs revealed QTcs from 440-470 ms. Exercise stress test revealed QTc prolongation of 520 ms and 500 ms at minute-2 and minute-4 of recovery, respectively. Genetic testing revealed heterozygous pathogenic variants in KCNQ1, consistent with type 1 LQTS. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Albuterol may be a cause of marked QTc prolongation in ED patients with underlying congenital LQTS, which can be a diagnostic clue in previously unidentified patients. Extreme QTc prolongation also serves as an indication in the ED for Cardiology consultation, laboratory evaluation for electrolyte imbalances, and observation with cardiac monitoring.

Peripartum management of cardiac arrhythmias: a narrative review.

Cardiac arrhythmias are responsible for a significant portion of cardiovascular disease among pregnant people. As the incidence of arrhythmias in pregnancy continues to increase, anesthesiologists who care for obstetric patients should be experts managing arrhythmias in pregnancy. This article examines the most common arrhythmias encountered in pregnancy, including risk factors, diagnosis, and management strategies. Peripartum monitoring and labor analgesia recommendations are discussed. Additionally, management of cardioversion, management of pacemakers and implantable cardioverter-defibrillators, and advanced cardiac life support in the setting of pregnancy is reviewed.

Relevance of accurate QT correction in the assessment of long QT syndrome.

BACKGROUND: Long QT syndrome (LQTS) is a genetic cardiac disease, where the corrected QT (QTc) interval is prolonged. It can cause arrhythmias and lead to a sudden cardiac death. Duration of the QT interval depends on the heart rate and this dependency is treated with QT correction. However, the current QT correction methods have well known problems and limitations. OBJECTIVE: We study the relevance of QT correction method in evaluating the risk of LQTS. We evaluate the reliability of the present and recently developed QT correction methods to discriminate LQTS subjects from healthy controls. METHODS: We use the clinically prevalent QT correction methods, particularly Bazett and Fridericia, in comparison with the recently developed AccuQT method. The data of healthy controls and LQTS subjects is extracted from the Rochester THEW database. The analysis accounts for sex, major LQTS subtypes, and beta-blocker treatment. RESULTS: QT values corrected with AccuQT discriminate the healthy and LQTS samples with the best accuracy, leading to (TP, TN) = (0.87, 0.65) with the conventional 450 ms threshold for LQTS. Fridericia correction yields lower sensitivity (0.71), but comparable balanced accuracy, whereas Bazett shows significantly less accurate results due to overcorrection at lower heart rates. CONCLUSION: The selected QT correction method is important in the identification of LQTS. In particular, the use of Bazett correction should be questioned. Fridericia correction yields good results with respect to its simplicity. AccuQT has the best accuracy out of all the methods for LQTS discrimination. For practical applicability, however, AccuQT needs further validation in realistic clinical conditions.

Roles of Atrial Arrhythmias in Triggering Torsade de Pointes in Patients With Acquired Long-QT Syndrome.

BACKGROUND: Little is known about the role of atrial arrhythmias (AAs) in triggering Torsade de Pointes (TdP) in patients with long-QT syndrome (LQTS). The aim of this study was to examine the contribution of AAs to the development of TdP in acquired LQTS patients. METHODS: The initiation patterns of 81 episodes of TdP obtained from 34 consecutive acute acquired LQTS patients (14 men, median age, 69 years; median QTc, 645.5 ms) with documented TdP were analyzed. The initiation mode of TdP was divided into 3 categories: (1) preceding short-long sequence (SLS); (2) sudden R-on-T phenomenon without preceding SLS; and (3) increased atrial rate. The patients were divided into 2 groups based on the presence or absence of AAs-induced TdP; AAs-induced (n=18) and non-AAs-induced (n=16) groups. The association of clinical/ECG characteristics and TdP frequency after initiating conventional therapy with AAs-induced TdP was evaluated. The groups were compared using the Mann-Whitney U test or Fisher exact test. RESULTS: AAs-induced group comprised 52.9% (18/34) of the patients studied. TdP was preceded by AAs-initiated SLSs in 41.2% (14/34) of the patients and was directly induced by R-on-T AAs (AAs coincidentally encountered a vulnerable repolarizing region during the T wave) in 23.5% (8/34). AAs triggered 48 (59.3%) of the 81 TdP episodes. AAs-initiated SLSs in 67.8% (40/59) of the SLS-induced TdP episodes. R-on-T AAs accounted for 23.5% (19/81) of the TdP episodes. AAs-induced group experienced TdP after initiating therapy more frequently than non-AAs-induced group (2.5 versus 1 event, P=0.008). AAs-induced group exhibited macroscopic T-wave alternans more frequently than non-AAs-induced group (6 versus 0, P=0.02). CONCLUSIONS: AAs play a key role in triggering TdP in more than half of patients with acute acquired LQTS and can increase TdP frequency after initiating therapy. Thus, AAs are not benign but rather can be life-threatening in patients with acute acquired LQTS.

Idiopathic Ventricular Fibrillation - Just How Much Idiopathic is it?

Idiopathic ventricular fibrillation is diagnosed in survivors of sudden cardiac death that has been caused by ventricular fibrillation without known structural or electrical abnormalities, even after extensive investigation. It is a common cause of sudden death in young adults. Although idiopathic ventricular fibrillation is a diagnosis of exclusion, in many cases only a partial investigation algorithm is performed. The aim of this review is to present a comprehensive diagnostic evaluation algorithm with a focus on diagnostic assessment of inherited arrhythmic syndromes and genetic background.

Long QT Syndrome With Drugs Used in the Management of Arrhythmias: A Systematic Review.

Long QT syndrome (LQTS) is a severe cardiac disorder characterized by an abnormally prolonged QTc interval on an electrocardiogram (ECG), which can result in life-threatening irregular heart rhythms. The use of certain medications, particularly anti-arrhythmic drugs such as quinidine, sotalol, and amiodarone, can lead to acquired LQTS by prolonging the QT interval through the inhibition of specific ion channels responsible for heart repolarization, which may present symptoms like fainting, seizures, and sudden cardiac arrest. This systematic review, conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, focused on analyzing the association between Long QT syndrome and drugs utilized for managing arrhythmias, involving a thorough examination of six selected studies from an initial pool of 68 articles. It was found that antiarrhythmic drugs such as amiodarone, sotalol, dofetilide, procainamide, quinidine, and flecainide have the potential to cause QT prolongation as a side effect, which is often influenced by factors including dosage, coexisting medical conditions, electrolyte imbalances, and other risk factors. Prolonged QT interval significantly elevates the risk of a life-threatening arrhythmia called torsade de pointes. The management of this side effect typically involves reducing the medication dosage or discontinuing it altogether and, in some cases, employing selective beta blockers. However, further research is essential to improve the understanding and implementation of strategies to prevent and manage QT prolongation caused by antiarrhythmic drugs. Additional clinical studies are warranted to enhance knowledge and provide comprehensive guidelines to healthcare practitioners regarding the appropriate use of these medications. Close monitoring of the QT interval is recommended for patients receiving anti-arrhythmic therapy, and consideration should be given to patient-specific risk factors for LQTS, including age, sex, and electrolyte imbalances.

Low foetal heart rate, a potentially ominous finding: case report.

Background: Congenital long QT syndrome (LQTS) type 1 is characterized by abnormally prolonged ventricular repolarization caused by inherited defects in cardiac potassium channels. Patients are predisposed to ventricular arrhythmias and even sudden cardiac death. In some cases, foetal sinus bradycardia is the only sign, making prenatal diagnosis challenging. Physicians should be aware of this subtle presentation of LQTS. Early diagnosis and proactive treatment are crucial for preventing unexpected cardiac events. Case summary: A healthy and asymptomatic 25-year-old pregnant woman was referred to our institute for cardiac evaluation after persistent foetal sinus bradycardia was detected during repeated ultrasounds, despite the absence of any foetal morphological or functional cardiac anomalies. After a thorough assessment, the mother was diagnosed with LQTS type 1, as confirmed by molecular genetic testing. Appropriate management, including maternal medication and increased surveillance, was initiated. The infant was delivered safely, and his electrocardiogram revealed a significantly prolonged QTc interval. Genetic testing confirmed the maternally inherited variant in KCNQ1 gene, and beta-blocker therapy was started. No arrhythmic events were noted. Discussion: Detection and careful stratification of foetal heart rate (FHR) is crucial in every pregnancy. Foetal bradycardia can be caused by both maternal and foetal factors. Persistent low FHR should raise a high suspicion for LQTS. The condition may also present with atrioventricular blocks, torsades de pointes, or sudden intrauterine foetal demise. Accurate and early diagnosis of LQTS is essential for implementing appropriate management strategies, which include vigilant monitoring, effective medical treatment, careful planning of delivery, and post-natal care.

Intraoperative QTc interval interpretation: Effects of anaesthesia, ECG, correction formulae, sex, and current limits: A Prospective Observational Study.

BACKGROUND: Severe QT interval prolongation requires monitoring QTc intervals during anaesthesia with recommended therapeutic interventions at a threshold of 500 ms. The need for 12-lead ECG and lack of standardisation limit such monitoring. We determined whether automated continuous intraoperative QTc monitoring with 5-lead ECG measures QTc intervals comparable to 12-lead ECG and whether the interpretation of QTc intervals depends on the correction formulae and the patient's sex. We compared intraoperative QTc times to QTc times from resting ECGs of a population from the same region, to substantiate the hypothesis that patients under general anaesthesia may need specific treatment thresholds. METHODS: In this prospective observational study, intraoperative QT/QTc intervals were automatically recorded using 12 and 5-lead ECG in 100 patients (44% males). QTc values were analysed for sex and formula-specific aspects after correction for heart rate according to Bazett, Fridericia, Hodges, Framingham, Charbit and QTcRAS, and compared to a regional community-based cohort. The level of significance was set to α = 0.05. RESULTS: QT interval duration was not significantly different between 12-lead and 5-lead ECG (difference - 0.09 ms ± 8.5 ms, p = 0.793). The QTc interval duration significantly differed between the correction formulae (p < 0.001) and between sexes (p < 0.001). Mean intraoperative QTc duration was higher than in resting ECGs from a large community-based population with the same regional background (438 vs. 417 ms). The incidence of prolonged values >500 ms significantly depended on the correction formula (p < 0.001) and was up to tenfold higher in women versus men. CONCLUSION: Intraoperative QTc interval measurement using a 5-lead ECG is valid. Correction formulae and gender influence the intraoperative QTc interval duration and the incidence of pathologically prolonged values according to current limits. The consideration and definition of sex-specific normal limits for QTc times under general anaesthesia, therefore, warrant further investigation.

Comprehensive characterization of long QT syndrome-associated genes in cancer and development of a robust prognosis model.

Cancer is the leading public health problem worldwide. However, the side effects accompanying anti-cancer therapies, particularly those pertaining to cardiotoxicity and adverse cardiac events, have been the hindrances to treatment progress. Long QT syndrome (LQTS) is one of the major clinic manifestations of the anti-cancer drug associated cardiac dysfunction. Therefore, elucidating the relationship between the LQTS and cancer is urgently needed. Transcriptomic sequencing data and clinic information of 10,531 patients diagnosed with 33 types of cancer was acquired from TCGA database. A pan-cancer applicative gene prognostic model was constructed based on the LQTS gene signatures. Meanwhile, transcriptome data and clinical information from various cancer types were collected from the GEO database to validate the robustness of the prognostic model. Furthermore, the expression level of transcriptomes and multiple clinical features were integrated to construct a Nomo chart to optimize the prognosis model. The ssGSEA analysis was employed to analysis the correlation between the LQTS gene signatures, clinic features and cancer associated signalling pathways. Our findings revealed that patients with lower LQTS gene signatures enrichment levels exhibit a poorer prognosis. The correlation of enrichment levels with the typical pathways was observed in multiple cancers. Then, based on the 17 LQTS gene signatures, we construct a prognostic model through the machine-learning approaches. The results obtained from the validation datasets and training datasets indicated that our prognostic model can effectively predict patient outcomes across diverse cancer types. Finally, we integrated this model with clinical features into a nomogram, demonstrating its potential as a valuable prognostic tool for cancer patients. Our study sheds light on the intricate relationship between LQTS and cancer pathways. A LQTS feature based clinic decision tool was developed aiming to enhance precision treatment of cancer.

Decoding polyubiquitin regulation of KV7. 1 functional expression with engineered linkage-selective deubiquitinases.

Protein posttranslational modification with distinct polyubiquitin linkage chains is a critical component of the 'ubiquitin code' that universally regulates protein expression and function to control biology. Functional consequences of diverse polyubiquitin linkages on proteins are mostly unknown, with progress hindered by a lack of methods to specifically tune polyubiquitin linkages on individual proteins in live cells. Here, we bridge this gap by exploiting deubiquitinases (DUBs) with preferences for hydrolyzing different polyubiquitin linkages: OTUD1 - K63; OTUD4 - K48; Cezanne - K11; TRABID - K29/K33; and USP21 - non-specific. We developed a suite of engineered deubiquitinases (enDUBs) comprised of DUB catalytic domains fused to a GFP-targeted nanobody and used them to investigate polyubiquitin linkage regulation of an ion channel, YFP-KCNQ1. Mass spectrometry of YFP-KCNQ1 expressed in HEK293 cells indicated channel polyubiquitination with K48 (72%) and K63 (24%) linkages being dominant. NEDD4-2 and ITCH both decreased KCNQ1 functional expression but with distinctive polyubiquitination signatures. All enDUBs reduced KCNQ1 ubiquitination but yielded unique effects on channel expression, surface density, ionic currents, and subcellular localization. The pattern of outcomes indicates K11, K29/K33, and K63 chains mediate net KCNQ1-YFP intracellular retention, but achieved in different ways: K11 promotes ER retention/degradation, enhances endocytosis, and reduces recycling; K29/K33 promotes ER retention/degradation; K63 enhances endocytosis and reduces recycling. The pattern of enDUB effects on KCNQ1-YFP differed in cardiomyocytes, emphasizing ubiquitin code mutability. Surprisingly, enDUB-O4 decreased KCNQ1-YFP surface density suggesting a role for K48 in forward trafficking. Lastly, linkage-selective enDUBs displayed varying capabilities to rescue distinct trafficking-deficient long QT syndrome type 1 mutations. The results reveal distinct polyubiquitin chains control different aspects of KCNQ1 functional expression, demonstrate ubiquitin code plasticity, and introduce linkage-selective enDUBs as a potent tool to help demystify the polyubiquitin code.

From genes to clinical management: A comprehensive review of long QT syndrome pathogenesis and treatment.

Background: Long QT syndrome (LQTS) is a rare cardiac disorder characterized by prolonged ventricular repolarization and increased risk of ventricular arrhythmias. This review summarizes current knowledge of LQTS pathogenesis and treatment strategies. Objectives: The purpose of this study was to provide an in-depth understanding of LQTS genetic and molecular mechanisms, discuss clinical presentation and diagnosis, evaluate treatment options, and highlight future research directions. Methods: A systematic search of PubMed, Embase, and Cochrane Library databases was conducted to identify relevant studies published up to April 2024. Results: LQTS involves mutations in ion channel-related genes encoding cardiac ion channels, regulatory proteins, and other associated factors, leading to altered cellular electrophysiology. Acquired causes can also contribute. Diagnosis relies on clinical history, electrocardiographic findings, and genetic testing. Treatment strategies include lifestyle modifications, ß-blockers, potassium channel openers, device therapy, and surgical interventions. Conclusion: Advances in understanding LQTS have improved diagnosis and personalized treatment approaches. Challenges remain in risk stratification and management of certain patient subgroups. Future research should focus on developing novel pharmacological agents, refining device technologies, and conducting large-scale clinical trials. Increased awareness and education are crucial for early detection and appropriate management of LQTS.