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.

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.

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.

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.

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.

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.

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.

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.

Targeting the IKs Channel PKA Phosphorylation Axis to Restore Its Function in High-Risk LQT1 Variants.

BACKGROUND: The KCNQ1+KCNE1 (IKs) potassium channel plays a crucial role in cardiac adaptation to stress, in which ß-adrenergic stimulation phosphorylates the IKs channel through the cyclic adenosine monophosphate (cAMP)/PKA (protein kinase A) pathway. Phosphorylation increases the channel current and accelerates repolarization to adapt to an increased heart rate. Variants in KCNQ1 can cause long-QT syndrome type 1 (LQT1), and those with defective cAMP effects predispose patients to the highest risk of cardiac arrest and sudden death. However, the molecular connection between IKs channel phosphorylation and channel function, as well as why high-risk LQT1 mutations lose cAMP sensitivity, remain unclear. METHODS: Regular patch clamp and voltage clamp fluorometry techniques were utilized to record pore opening and voltage sensor movement of wild-type and mutant KCNQ1/IKs channels. The clinical phenotypic penetrance of each LQT1 mutation was analyzed as a metric for assessing their clinical risk. The patient-specific-induced pluripotent stem-cell model was used to test mechanistic findings in physiological conditions. RESULTS: By systematically elucidating mechanisms of a series of LQT1 variants that lack cAMP sensitivity, we identified molecular determinants of IKs channel regulation by phosphorylation. These key residues are distributed across the N-terminus of KCNQ1 extending to the central pore region of IKs. We refer to this pattern as the IKs channel PKA phosphorylation axis. Next, by examining LQT1 variants from clinical databases containing 10 579 LQT1 carriers, we found that the distribution of the most high-penetrance LQT1 variants extends across the IKs channel PKA phosphorylation axis, demonstrating its clinical relevance. Furthermore, we found that a small molecule, ML277, which binds at the center of the phosphorylation axis, rescues the defective cAMP effects of multiple high-risk LQT1 variants. This finding was then tested in high-risk patient-specific induced pluripotent stem cell-derived cardiomyocytes, where ML277 remarkably alleviates the beating abnormalities. CONCLUSIONS: Our findings not only elucidate the molecular mechanism of PKA-dependent IKs channel phosphorylation but also provide an effective antiarrhythmic strategy for patients with high-risk LQT1 variants.

What an anesthesiologist should know about pediatric arrhythmias.

Identifying and treating pediatric arrhythmias is essential for pediatric anesthesiologists. Pediatric patients can present with narrow or wide complex tachycardias, though the former is more common. Patients with inherited channelopathies or cardiomyopathies are at increased risk. Since most pediatric patients present for anesthesia without a baseline electrocardiogram, the first identification of an arrhythmia may occur under general anesthesia. Supraventricular tachycardia, the most common pediatric tachyarrhythmia, represents a broad category of predominately narrow complex tachycardias. Stimulating events including intubation, vascular guidewire manipulation, and surgical stimulation can trigger episodes. Valsalva maneuvers are unreliable as treatment, making adenosine or other intravenous antiarrhythmics the preferred acute therapy. Reentrant tachycardias are the most common supraventricular tachycardia in pediatric patients, including atrioventricular reciprocating tachycardia (due to a distinct accessory pathway) and atrioventricular nodal reentrant tachycardia (due to an accessory pathway within the atrioventricular node). Patients with ventricular preexcitation, often referred to as Wolff-Parkinson-White syndrome, have a wide QRS with short PR interval, indicating antegrade conduction through the accessory pathway. These patients are at risk for sudden death if atrial fibrillation degenerates into ventricular fibrillation over a high-risk accessory pathway. Automatic tachycardias, such as atrial tachycardia and junctional ectopic tachycardia, are causes of supraventricular tachycardia in pediatric patients, the latter most typically noted after cardiac surgery. Patients with inherited arrhythmia syndromes, such as congenital long QT syndrome, are at risk of developing ventricular arrhythmias such as polymorphic ventricular tachycardia (Torsades de Pointes) which can be exacerbated by QT prolonging medications. Patients with catecholaminergic polymorphic ventricular tachycardia are at particular risk for developing bidirectional ventricular tachycardia or ventricular fibrillation during exogenous or endogenous catecholamine surges. Non-selective beta blockers are first line for most forms of long QT syndrome as well as catecholaminergic polymorphic ventricular tachycardia. Anesthesiologists should review the impact of medications on the QT interval and transmural dispersion of repolarization, to limit increasing the risk of Torsades de Pointes in patients with long QT syndrome. This review explores the key anesthetic considerations for these arrhythmias.

Implantable loop recorder uncovered torsades de pointes in long-QT syndrome type 1 with multi cause of syncope.

An implantable loop recorder (ILR) is now widely used for differential diagnosis of unexplained syncope or recurrent syncope with unknown causes. In the inherited arrhythmia syndromes, ILR may be useful for management of the therapeutic strategies; however, there is no obvious evidence to uncover arrhythmic syncope by ILR in long-QT syndrome (LQTS) patients. Here we experienced a 19-year-old female patient with LQTS type 1 who had recurrent syncope even after beta-blocker therapy but no arrhythmias were documented, and some episodes might be due to non-cardiogenic causes. Implantable cardioverter defibrillator (ICD) therapy was also recommended; however, she could not accept ICD but was implanted with ILR for further continuous monitoring. Two years later, she suffered syncope during a brief run, and ILR recorded an electrocardiogram at that moment. Thus a marked QT interval prolongation as well as T-wave alternance resulting in development of torsades de pointes could be detected. Although ILR is just a diagnostic tool but does not prevent sudden cardiac death, most arrhythmic events in LQTS are transient and sometimes hard to be diagnosed as arrhythmic syncope. ILR may provide direct supportive evidence to select the optimal therapeutic strategy in cases where syncope is difficult to diagnose. Learning objective: Long-QT syndrome (LQTS) patients often suffer recurrent syncope even after beta-blocker therapy, but torsades de pointes (TdP) is not always detected by standard 12­lead electrocardiogram or Holter monitoring, and some syncope might be non-cardiogenic. In this case, implantable loop recorder (ILR) documented the evidence of QT interval prolongation and beat-by-beat T-wave alternance subsequent TdP. Thus, ILR may provide useful evidence for the optimal treatment strategy in LQTS cases where syncope is difficult to diagnose.

Neurocardiac pathologies associated with potassium channelopathies.

Voltage-gated potassium channels are expressed throughout the human body and are essential for physiological functions. These include delayed rectifiers, A-type channels, outward rectifiers, and inward rectifiers. They impact electrical function in the heart (repolarization) and brain (repolarization and stabilization of the resting membrane potential). KCNQx and KCNHx encode Kv7.x and Kv11.x proteins, which form delayed rectifier potassium channels. KCNQx and KCNHx channelopathies are associated with both cardiac and neuronal pathologies. These include electrocardiographic abnormalities, cardiac arrhythmias, sudden cardiac death (SCD), epileptiform discharges, seizures, bipolar disorder, and sudden unexpected death in epilepsy (SUDEP). Due to the ubiquitous expression of KCNQx and KCNHx channels, abnormalities in their function can be particularly harmful, increasing the risk of sudden death. For example, KCNH2 variants have a dual role in both cardiac and neuronal pathologies, whereas KCNQ2 and KCNQ3 variants are associated with severe and refractory epilepsy. Recurrent and uncontrolled seizures lead to secondary abnormalities, which include autonomics, cardiac electrical function, respiratory drive, and neuronal electrical activity. Even with a wide array of anti-seizure therapies available on the market, one-third of the more than 70 million people worldwide with epilepsy have uncontrolled seizures (i.e., intractable/drug-resistant epilepsy), which negatively impact neurodevelopment and quality of life. To capture the current state of the field, this review examines KCNQx and KCNHx expression patterns and electrical function in the brain and heart. In addition, it discusses several KCNQx and KCNHx variants that have been clinically and electrophysiologically characterized. Because these channel variants are associated with multi-system pathologies, such as epileptogenesis, Kv7 channel modulators provide a potential anti-seizure therapy, particularly for people with intractable epilepsy. Ultimately an increased understanding of the role of Kv channels throughout the body will fuel the development of innovative, safe, and effective therapies for people at a high risk of sudden death (SCD and SUDEP).

QTc Interval Prolongation as an Adverse Event of Azole Antifungal Drugs: Case Report and Literature Review.

QTc prolongation and torsade de pointes (TdP) are significant adverse events linked to azole antifungals. Reports on QTc interval prolongation caused by these agents are limited. In this study, we report a case of a 77-year-old male with cardiovascular disease who experienced QTc prolongation and subsequent TdP while being treated with fluconazole for Candida albicans-induced knee arthritis. Additionally, a literature review was conducted on cases where QTc prolongation and TdP were triggered as adverse events of azole antifungal drugs. The case study detailed the patient's experience, whereas the literature review analyzed cases from May 1997 to February 2023, focusing on patient demographics, underlying diseases, antifungal regimens, concurrent medications, QTc changes, and outcomes. The review identified 16 cases, mainly in younger individuals (median age of 29) and women (75%). Fluconazole (63%) and voriconazole (37%) were the most common agents. Concurrent medications were present in 75% of cases, and TdP occurred in 81%. Management typically involved discontinuing or switching antifungals and correcting electrolytes, with all patients surviving. Risk assessment and concurrent medication review are essential before starting azole therapy. High-risk patients require careful electrocardiogram monitoring to prevent arrhythmias. Remote monitoring may enhance safety for patients with implanted devices. Further studies are needed to understand risk factors and management strategies.

Novel KCNQ1 Q234K variant, identified in patients with long QT syndrome and epileptiform activity, induces both gain- and loss-of-function of slowly activating delayed rectifier potassium currents.

Introduction: KCNQ1 and KCNE1 form slowly activating delayed rectifier potassium currents (IKs). Loss-of-function of IKs by KCNQ1 variants causes type-1 long QT syndrome (LQTS). Also, some KCNQ1 variants are reported to cause epilepsy. Segment 4 (S4) of voltage-gated potassium channels has several positively-charged amino acids that are periodically aligned, and acts as a voltage-sensor. Intriguingly, KCNQ1 has a neutral-charge glutamine at the third position (Q3) in the S4 (Q234 position in KCNQ1), which suggests that the Q3 (Q234) may play an important role in the gating properties of IKs. We identified a novel KCNQ1 Q234K (substituted for a positively-charged lysine) variant in patients (a girl and her mother) with LQTS and epileptiform activity on electroencephalogram. The mother had been diagnosed with epilepsy. Therefore, we sought to elucidate the effects of the KCNQ1 Q234K on gating properties of IKs. Methods: Wild-type (WT)-KCNQ1 and/or Q234K-KCNQ1 were transiently expressed in tsA201-cells with KCNE1 (E1) (WT + E1-channels, Q234K + E1-channels, and WT + Q234K + E1-channels), and membrane currents were recorded using whole-cell patch-clamp techniques. Results: At 8-s depolarization, current density (CD) of the Q234K + E1-channels or WT + Q234K + E1-channels was significantly larger than the WT + E1-channels (WT + E1: 701 ± 59 pA/pF; Q234K + E1: 912 ± 50 pA/pF, p < 0.01; WT + Q234K + E1: 867 ± 48 pA/pF, p < 0.05). Voltage dependence of activation (VDA) of the Q234K + E1-channels or WT + Q234K + E1-channels was slightly but significantly shifted to depolarizing potentials in comparison to the WT + E1-channels ([V1/2] WT + E1: 25.6 ± 2.6 mV; Q234K + E1: 31.8 ± 1.7 mV, p < 0.05; WT + Q234K + E1: 32.3 ± 1.9 mV, p < 0.05). Activation rate of the Q234K + E1-channels or WT + Q234K + E1-channels was significantly delayed in comparison to the WT + E1-channels ([half activation time] WT + E1: 664 ± 37 ms; Q234K + E1: 1,417 ± 60 ms, p < 0.01; WT + Q234K + E1: 1,177 ± 71 ms, p < 0.01). At 400-ms depolarization, CD of the Q234K + E1-channels or WT + Q234K + E1-channels was significantly decreased in comparison to the WT + E1-channels (WT + E1: 392 ± 42 pA/pF; Q234K + E1: 143 ± 12 pA/pF, p < 0.01; WT + Q234K + E1: 209 ± 24 pA/pF, p < 0.01) due to delayed activation rate and depolarizing shift of VDA. Conclusion: The KCNQ1 Q234K induced IKs gain-of-function during long (8-s)-depolarization, while loss of-function during short (400-ms)-depolarization, which indicates that the variant causes LQTS, and raises a possibility that the variant may also cause epilepsy. Our data provide novel insights into the functional consequences of charge addition on the Q3 in the S4 of KCNQ1.