Antipsychotic (AP) use has been associated to QT interval prolongation on the surface electrocardiogram (ECG). Our study aimed to determine the incidence of corrected QT (QTc) interval prolongation among patients admitted to a psychiatric hospitalization unit requiring AP treatment and to assess the relationship between administered dose and QTc interval changes. We enrolled 179 patients admitted to the Hospital Psiquiátrico Departamental Universitario del Valle in Cali, Colombia. ECGs were conducted upon admission, and again at 3 and 7 days postadmission. The QT interval was measured, and QTc interval correction was performed using Bazzet's formula. QTc interval prolongation at time points B or C was observed in 9.5% of patients. Clozapine was the most common AP associated with QTc interval prolongation (20.59%), followed by olanzapine (15.38%). The relative risk of QT interval prolongation with clozapine compared to haloperidol was 4.17 (95% confidence interval, 1.14-15.17, P  = 0.02). AP use upon hospital admission was linked to early (within 3 days) QTc interval prolongation. Clozapine and olanzapine were associated with a greater increase in QTc interval compared to haloperidol, indicating a need for rigorous electrocardiographic monitoring with their use.

Excitable cells - including neurons, muscle cells and cardiac myocytes - are unique in expressing high densities of voltage-gated sodium (NaV) channels. This molecular adaptation enables these cells to produce action potentials, and is essential to their function. With the advent of the molecular revolution, the concept of 'the' sodium channel has been supplanted by understanding that excitable cells in mammals can express any of nine different forms of sodium channels (NaV1.1-NaV1.9). Selective expression in particular types of cells, together with a key role in controlling action potential firing, makes some of these NaV subtypes especially attractive molecular targets for drug development. Although these different channel subtypes display a common overall structure, differences in their amino acid sequences have provided a basis for the development of subtype-specific drugs. This approach has resulted in exciting progress in the development of drugs for epilepsy, cardiac disorders and pain. In this Review, we discuss recent progress in the development of drugs that selectively target each of the sodium channel subtypes.

Continuous monitoring of physiological activities within the internal regions of three-dimensional (3D) organoids holds significant promise for advancing organoid-based research. However, conventional methods are constrained to capturing signals from the peripheral surfaces of organoids, limiting insights into internal dynamics. Here, we present a soft 3D bioelectrode platform for continuous intraorganoid signal monitoring. These bioelectrodes, formed via 3D printing of liquid metal, are designed with customizable geometric parameters, including height and diameter, to adapt to various organoid structures. The tissue-comparable softness of the electrodes minimizes damage to cardiac organoids, ensuring a stable interface for reliable signal recording even under dynamic deformations caused by rhythmic contractions or displacements in aqueous environments. The array configuration enables simultaneous electrocardiogram (ECG) recordings from 32 organoids. Demonstrating real-time monitoring of drug-induced ECG responses, this scalable platform highlights its potential for high-throughput drug screening.

Long QT syndrome type 2 (LQT2) is an arrythmia caused by loss-of-function mutations in KCNH2, leading to impaired Kv11.1 channel function.

To better understand LQT2, we examined the electrophysiological differences related to the G53S variant, which is located within the PAS domain of KCNH2, using patient-specific human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hiPSC-CMs).

We generated hiPSC-CMs from a patient harboring the KCNH2G53S variant and a healthy control using non-integrative Sendai virus-mediated reprogramming. Their electrophysiological properties were assessed using microelectrode arrays (MEA), and Ca2+ dynamics were characterized using Fluo-4 dye.

The patient harboring KCNH2G53S experienced aborted sudden cardiac death at 22 years of age, was diagnosed with LQT, and had an implantable cardioverter-defibrillator (ICD) implanted. KCNH2G53S hiPSC-CMs expressed less KCNH2 than normal CMs. Transcriptomic analysis of KCNH2G53S hiPSC-CMs revealed 3,857 differentially expressed genes, highlighting significant changes in pathways related to LQT2 development. Action potential duration was significantly longer in KCNH2G53S hiPSC-CMs than in control (545.3 ± 176.3 ms vs. 339.9 ± 44.5 ms; P = 0.019). Corrected field potential duration was significantly longer in KCNH2G53S hiPSC-CMs than in control (318.0 ± 66.3 ms vs. 234.5 ± 21.0 ms; P = 0.015), indicating altered electrophysiology. KCNH2G53S hiPSC-CMs exhibited significantly increased calcium transient amplitude and prolonged calcium wave duration under isoproterenol stimulation, indicating exacerbated abnormal calcium handling.

Our analysis of hiPSC-CMs carrying a heterozygous KCNH2G53S mutation, which showed abnormal electrophysiology and impaired calcium handling, provides a basis for developing improved management strategies for patients with LQT2.

Long QT syndrome (LQTS) presents a group of inheritable channelopathies with prolonged ventricular repolarization, leading to syncope, ventricular tachycardia, and sudden death. Differentiating LQTS genotypes is crucial for targeted management and treatment, yet conventional genetic testing remains costly and time-consuming. This study aims to improve the distinction between LQTS genotypes, particularly LQT3, through a novel electrocardiogram (ECG)-based approach. Patients with LQT3 are at elevated risk due to arrhythmia triggers associated with rest and sleep. Employing a database of genotyped long QT syndrome E-HOL-03-0480-013 ECG signals, we introduced two innovative parameterization techniques-area under the ECG curve and wave transformation into the unit circle-to classify LQT3 against LQT1 and LQT2 genotypes. Our methodology utilized single-lead ECG data with a 200 Hz sampling frequency. The support vector machine (SVM) model demonstrated the ability to discriminate LQT3 with a recall of 90% and a precision of 81%, achieving an F1-score of 0.85. This parameterization offers a potential substitute for genetic testing and is practical for low frequencies. These single-lead ECG data could enhance smartwatches' functionality and similar cardiovascular monitoring applications. The results underscore the viability of ECG morphology-based genotype classification, promising a significant step towards streamlined diagnosis and improved patient care in LQTS.

Antiseizure medications (ASMs) are the primary treatment for epilepsy. However, adverse cardiac effects of ASMs can occur, related to their effects on lipid metabolism, raising ischemic heart disease risk; or specific actions on cardiac ion channels, increasing cardiac arrhythmia risk. Select ASMs, particularly enzyme inducers used at higher doses or for longer durations, can adversely affect lipids or cause metabolic changes, and thereby increase the risk for ischemic heart disease. These metabolic and potentially proarrhythmic actions may contribute to the increased cardiovascular morbidity and mortality that occur in epilepsy. Many ASMs block sodium channels or affect the QT interval, which can lead to proarrhythmia, particularly when used in combination with other medications or given to vulnerable populations. While ASMs are rarely reported to cause cardiac arrhythmias directly, population data raise concerns that cardiac arrhythmias and sudden cardiac death may be more common in epilepsy, and that sodium channel blocking ASMs in particular, might contribute. It is also possible that some cases of sudden cardiac death could be misclassified as sudden unexpected death in epilepsy (SUDEP), leading to an underestimation of the cardiovascular risk in this population. Cardiovascular risk factors, such as smoking and a sedentary lifestyle, are also associated with epilepsy, and should also be addressed. This summary is a narrative review of the literature, clarifies which ASMs tend to have more cardiovascular effects, and provides practical suggestions for medication management and monitoring from neurology and cardiology perspectives.

Long QT syndrome (LQTS), an inherited cardiac arrhythmia syndrome with congenital and drug-induced presentations and known monogenic and polygenic contributions, represents a significant clinical challenge due to its complex genetic underpinning and propensity for fatal arrhythmias. In this study, we generated induced pluripotent stem cells (iPSCs) reprogrammed from peripheral blood mononuclear cells (PBMCs) of six patients with extreme polygenic scores for short and long corrected QT intervals. This patient-specific approach will enable us to better understand variable expressivity and penetrance of LQTS, using rigorously validated iPSC lines serve as a vital resource for elucidating the molecular mechanisms underlying LQTS.

FHL2 (Four-and-a-half LIM domain protein 2) is a crucial factor involved in cardiac morphogenesis, the process by which the heart develops its complex structure. It is expressed in various tissues during embryonic development, including the developing heart, and has been shown to play important roles in cell proliferation, differentiation, and migration. FHL2 interacts with multiple proteins to regulate cardiac development as a coactivator or a corepressor. It is involved in cardiac specification and determination of cell fate, cardiomyocyte growth, cardiac remodeling, myofibrillogenesis, and the regulation of HERG channels. Targeting FHL2 has therapeutic implications as it could improve cardiac function, control arrhythmias, alleviate heart failure, and maintain cardiac integrity in various pathological conditions. The identification of FHL2 as a signature gene in atrial fibrillation suggests its potential as a diagnostic marker and therapeutic target for this common arrhythmia.

Congenital long-QT syndrome (LQTS) is most often associated with pathogenic variants in KCNQ1 encoding the pore-forming voltage-gated potassium channel subunit of the slow delayed rectifier current ( I Ks ). Generation of I Ks requires assembly of KCNQ1 with an auxiliary subunit encoded by KCNE1 , which is also associated with LQTS but causality of autosomal dominant disease is disputed. By contrast, KCNE1 is an accepted cause of recessive type 2 Jervell and Lange-Nielson syndrome (JLN2). The functional consequences of most KCNE1 variants have not been determined and the population prevalence of JLN2 is unknown. Methods : We determined the functional properties of 95 KCNE1 variants co-expressed with KCNQ1 in heterologous cells using high-throughput voltage-clamp recording. Experiments were conducted with each KCNE1 variant expressed in the homozygous state and then a subset was studied in the heterozygous state. The carrier frequency of JLN2 was estimated by considering the population prevalence of dysfunctional variants. Results : There is substantial overlap between disease-associated and population KCNE1 variants. When examined in the homozygous state, 68 KCNE1 variants exhibited significant differences in at least one functional property compared to WT KCNE1, whereas 27 variants did not significantly affect function. Most dysfunctional variants exhibited loss-of-function properties. We observed no evidence of dominant-negative effects. Most variants were scored as variants of uncertain significance (VUS) and inclusion of functional data resulted in revised classifications for only 14 variants. The population carrier frequency of JLN2 was calculated as 1 in 1034. Peak current density and activation voltage-dependence but no other biophysical properties were correlated with findings from a mutational scan of KCNE1. Conclusions : Among 95 disease-associated or population KCNE1 variants, many exhibit abnormal functional properties but there was no evidence of dominant-negative behaviors. Using functional data, we inferred a population carrier frequency for recessive JLN2. This work helps clarify the pathogenicity of KCNE1 variants.

Dravet syndrome (DS) is a severe and catastrophic epilepsy with childhood onset. The incidence and prevalence of sudden unexpected death in epilepsy (SUDEP) are significantly higher in DS patients than in general epileptic populations. Although extensive research conducted, the underlying mechanisms of SUDEP occurring in DS patients remain unclear. This review focuses on the link between DS and SUDEP and analyzes the potential pathogenesis. We summarize the genetic basis of DS and SUDEP and elucidate the pathophysiological mechanisms of SUDEP in DS. Furthermore, given the drug-resistant nature of this disorder, the pharmacological approach has limited efficacy and often causes side effects, therefore, the non-pharmacological approaches and precise treatment can reduce the risk of SUDEP in this condition, open a new window to cure this disease, and provide a widened landscape of treatment options for patients.

Whether it is reasonable to program ATP in patients with electrical heart disease (EHD) or hypertrophic cardiomyopathy (HCM) is not thoroughly clarified. Aim of the study was to define the types of ventricular arrhythmias and evaluate the safety and efficacy of ATP activation in these patients.

A total of 154 patients (53.9 % male, 64.9 % secondary prevention) with EHD or HCM, who had an implanted cardioverter defibrillator (ICD) with ATP activated, were included in this retrospective analysis; comprising a median of 65.0 months of follow-up. In 39/154 (25.3 %) patients appropriate ICD therapy was delivered during the follow-up. Patients with HCM had a significantly higher incidence rate of monomorphic VTs than patients with EHD (0.21 versus 0.01 per month, 0 < 0.001). ATP terminated monomorphic VT with an efficacy of 88,2 % in 94.9 % of the occurring episodes. The incidence rate per month of torsade de pointes (TdP) tachycardia and VF was significantly higher in patients with EHD versus HCM (0.04 vs. 0.001, p=<0.001; 0.06 vs. 0.007, p=<0.001). The termination of TdP tachycardia and VF was associated with ATP in 14.0 % and 0 % (ATP efficacy of 28.3 % and 0 % respectively). The implantation for secondary prevention was associated with the occurrence of appropriate ICD therapy during the follow-up period (OR 3.94 [95%CI 1.53-10.14], p = 0.005).

Ventricular tachycardias in patients with HCM are primarily monomorphic and can be effectively terminated with ATP. In patients with EHD, TdP tachycardias and VF occur more frequently and are preferentially terminated by ICD shock.

Sudden cardiac death represents a significant diagnostic challenge for forensic pathologists, particularly in inherited arrhythmia syndromes or cardiomyopathies resulting from genetic defects. Molecular autopsies can reveal the underlying molecular etiology in such cases. In this study, we investigated a family with a history of sudden cardiac death to elucidate the molecular basis responsible for sudden cardiac death. The proband underwent a comprehensive forensic examination. Family members received thorough clinical evaluations, including electrocardiogram, Holter monitoring, echocardiography, and cardiac magnetic imaging. Whole exome sequencing and genetic analysis were performed on the deceased and her parents. In addition, Western blotting and patch-clamp recordings were employed to evaluate the expression and function of the mutant protein in vitro. Forensic examination diagnosed arrhythmogenic right ventricular cardiomyopathy (ARVC) as the cause of sudden death. Genetic analysis identified a novel missense mutation in SCN5A (p.V1323L), which was assessed as likely pathogenic by the ACMG guideline. Another family member carrying the mutation manifested long QT syndrome and mild cardiac fibrosis. The cellular electrophysiological study demonstrated that the mutation resulted in an enhanced late sodium current, suggesting it was a gain-of-function mutation. This study characterizes a novel SCN5A mutation that putatively causes long QT syndrome and may contribute to the development of ARVC. Our work expands the pathogenic spectrum of SCN5A variants and underscores the importance of molecular autopsy in sudden death cases, especially in those with suspected genetic disorders.

The electrocardiogram (ECG) is a widely used, non-invasive tool for diagnosing a range of cardiovascular conditions, including arrhythmia and heart disease-related structural changes. Despite its critical role in clinical care, racial and ethnic differences in ECG readings are often underexplored or inadequately addressed in research. Variations in key ECG parameters, such as PR interval, QRS duration, QT interval, and T-wave morphology, have been noted across different racial groups. However, the limited research in this area has hindered the development of diagnostic criteria that account for these differences, potentially contributing to healthcare disparities, as ECG interpretation algorithms largely developed from major population data may lead to misdiagnoses or inappropriate treatments for minority groups. This review aims to help cardiac researchers and cardiovascular specialists better understand, explore, and address the impact of racial and ethnic differences in ECG readings. By identifying potential causes-ranging from genetic factors to environmental influences-and exploring the resulting disparities in healthcare outcomes, we propose strategies such as the development of race-specific ECG norms, the application of artificial intelligence (AI) to improve diagnostic accuracy, and the diversification of ECG databases. Through these efforts, the medical community can advance toward more personalized and equitable cardiovascular care.

Long QT syndrome (LQTS) is a potentially lethal medical condition that might never be diagnosed and cause sudden cardiac death. It is mainly caused by mutation in electrolyte transporter genes. Due to the significant difference in the treatment approach of heart block and other rhythm disorders that mimic this condition, it is necessary to discriminate these conditions. The occurrence of pseudo-block in electrocardiography features but without disturbance in the function of the conduction system can mask the definite diagnosis of the real underlying disorder, and this issue leads to the selection of an unfavorable treatment protocol and sometimes the sudden death of the patient.

We described an infant who showed evidence of atrioventricular (AV) block in initial electrocardiography (ECG) on his first day, but in further evaluations, the final diagnosis of LQTS was raised. The patient recovered after performing the treatment protocol, which included Mexiletine and beta-blockers. After the genetic test of the parents and the patient, it was determined that a defective allele of the gene had caused the condition.

Our report shows the importance of timely differentiation between heart block and LQTS in neonates and choosing the correct treatment approach to faster patient recovery and prevent sudden death.

Primary diagnosis of LQTS in neonates might not be a straightforward process due to resembling AV pseudo-block and can cause misleading diagnosis and treatment. Long QT syndrome has several nonspecific presentations. They might be asymptomatic until adulthood and be diagnosed after sudden cardiac death. Preventive measures such as timely initiation of medications, ICD or PPM implantation, and continuous observation by caregivers are the mainstay of survival and quality of life improvement.

Congenital long QT syndrome (LQTS) is a genetic disorder causing prolonged QT intervals and an increased risk of arrhythmias and sudden cardiac death. With 25% of cases lacking known genetic mutations, diagnosis and treatment can be challenging. We present a successfully managed case of late-onset genotype-negative phenotype-positive LQTS presenting as palpitations, complicated by a single event of polymorphic ventricular tachycardia, followed by a review of the literature. This case underscores the gaps in understanding congenital long QT syndrome, especially in genotype-negative cases, and highlights the need for ongoing research for risk assessment and effective management to prevent fatal cardiac events.

A well-balanced ion channel trafficking machinery is paramount for the normal electromechanical function of the heart. Ion channel variants and many drugs can alter the cardiac action potential and lead to arrhythmias by interfering with mechanisms like ion channel synthesis, trafficking, gating, permeation, and recycling. A case in point is the Long QT syndrome (LQTS), a highly arrhythmogenic disease characterized by an abnormally prolonged QT interval on ECG produced by variants and drugs that interfere with the action potential. Disruption of ion channel trafficking is one of the main sources of LQTS. We review some molecular pathways and mechanisms involved in cardiac ion channel trafficking. We highlight the importance of channelosomes and other macromolecular complexes in helping to maintain normal cardiac electrical function, and the defects that prolong the QT interval as a consequence of variants or the effect of drugs. We examine the concept of "interactome mapping" and illustrate by example the multiple protein-protein interactions an ion channel may undergo throughout its lifetime. We also comment on how mapping the interactomes of the different cardiac ion channels may help advance research into LQTS and other cardiac diseases. Finally, we discuss how using human induced pluripotent stem cell technology to model ion channel trafficking and its defects may help accelerate drug discovery toward preventing life-threatening arrhythmias. Advancements in understanding ion channel trafficking and channelosome complexities are needed to find novel therapeutic targets, predict drug interactions, and enhance the overall management and treatment of LQTS patients.

Obesity is associated with abnormal repolarization manifested by QT interval prolongation, and oxidative stress is an important link between obesity and arrhythmias. However, the underlying electrophysiological and molecular mechanisms remain unclear. The aim of this study is to evaluate the role of obesity in potassium current in ventricular myocytes and the potential mechanism of NADPH oxidase 2 (Nox2). We investigated the effect of Nox2 on cardiac repolarization without compromising its expression and function in other systems using mice with conditional cardiac-specific deletions of Nox2 (knockout [KO]). Wild-type, KO, and Flox littermate mice were randomized to either the control or high-fat diet (HFD) groups. Surface electrocardiograms were recorded to analyze repolarization in vivo. Whole-cell patch-clamp techniques were used to evaluate the electrophysiological phenotype of isolated myocytes in vitro. Western blotting was performed to assess protein expression levels. Compared with the control mice, the HFD group had a prolonged QTc. The consequences of an HFD were not attributed to delayed rectifier K+ and inward-rectifier K+ currents but were associated with reduced peak outward KV and fast transient outward K+ currents. Downregulated expression of KV4.2 and KChIP2, comprising functional Ito channel pore-forming (α) and accessory (β) subunits, was detected in HFD mice. Nox2-KO reversed the effect of obesity on Ipeak and Ito amplitude. Our data demonstrate that obesity mediates impaired cardiac repolarization in mice, manifested by QTc at the whole organism level and action potential duration at the cellular level, and correlated with Nox2. The electrophysiological and molecular aspects of this phenomenon were mediated by repolarizing outward K+ currents.

Congenital long QT syndrome (LQTS) is characterized by delayed ventricular repolarization, predisposing to potentially lethal ventricular arrhythmias. The variability in disease severity among patients remains largely unexplored, underscoring the limitations of current risk stratification methods.

We aimed to evaluate the potential utility of electrocardiographic markers from the exercise stress test (EST) in identifying patients with high-risk LQTS.

The study, which considered patients with LQTS type 1 and LQTS type 2, comprised a discovery cohort of 695 and a validation cohort of 635 patients.

The change in corrected QT (QTc) interval between rest and recovery (between rest and 3-4 minutes into the recovery period, called recovery-rest ΔQTc) was consistently greater in symptomatic patients. Sensitivity analyses performed on EST data obtained on and off β-blockers as well as upon distinguishing between patients with a baseline QTc interval below and those above 470 ms demonstrated consistent findings. The association of recovery-rest ΔQTc with cardiac events remained significant in a subanalysis focusing on future events (ie, occurring after the EST). An optimal recovery-rest ΔQTc cutoff was determined for LQTS type 1 (35 ms) and LQTS type 2 (16 ms) separately and was shown to be significantly associated with cardiac events.

Our findings suggest that in patients with LQTS, dynamic QT interval measures obtained during the EST are associated with lifetime arrhythmic events and events after the EST. Such measures can be helpful in identifying a higher-risk subset of patients with LQTS in order to optimize their management. Further research may confirm these findings in larger cohorts and explore the potential benefit of combining genetic and EST data for more precise risk stratification.

Patients with rare genetic diseases frequently experience significant diagnostic delays. Routinely collected data in the electronic health record (EHR) may be used to help identify patients at risk of undiagnosed conditions. Long QT syndrome (LQTS) is a rare inherited cardiac condition associated with significant morbidity and premature mortality. In this study, we examine LQTS as an exemplar disease to assess if clinical features recorded in the primary care EHR can be used to develop and validate a predictive model to aid earlier detection.

1495 patients with an LQTS diagnostic code and 7475 propensity-score matched controls were identified from 10.5 million patients' electronic primary care records in the UK's Clinical Practice Research Datalink (CPRD). Associated clinical features recorded before diagnosis (with p < 0.05) were incorporated into a multivariable logistic regression model, the final model was determined by backwards regression and validated by bootstrapping to determine model optimism.

The mean age at LQTS diagnosis was 58.4 (SD 19.41). 18 features were included in the final model. Discriminative accuracy, assessed by area under the curve (AUC), was 0.74, (95% CI 0.73, 0.75) (optimism 6%). Features occurring at significantly greater frequency before diagnosis included: epilepsy, palpitations, syncope, collapse, mitral valve disease and irritable bowel syndrome.

This study demonstrates the potential to develop primary care prediction models for rare conditions, like LQTS, in routine primary care records and highlights key considerations including disease suitability, finding an appropriate linked dataset, the need for accurate case ascertainment and utilising an approach to modelling suitable for rare events.

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.

Genetic overdiagnosis of long QT syndrome (LQTS) becomes a critical concern due to the high clinical significance of DNA diagnosis. Current guidelines for LQTS genetic testing recommend a limited scope and strict referral based on the Schwartz score. Nevertheless, LQTS may be underdiagnosed in patients with borderline phenotypes. We aimed to evaluate the total yield of rare variants in cardiac genes in LQTS patients. The cohort of 82 patients with LQTS referral diagnosis underwent phenotyping, Schwartz score counting, and exome sequencing. We assessed known LQTS genes for diagnostics, as per guidelines, and a broader set of genes for research. Diagnostic testing yield reached 75% in index patients; all causal variants were found in KCNQ1, KCNH2, and SCN5A genes. Research testing of 248 heart-related genes achieved a 50% yield of molecular diagnosis in patients with a low Schwartz score (<3.5). In patients with LQTS-causing variants, each additional rare variant in heart-related genes added 0.94 points to the Schwartz score (p value = 0.04), reflecting the more severe disease in such patients than in those with causal variants but without additional findings. We conclude that the current LQTS genetic diagnosis framework is highly specific but may lack sensitivity for patients with a Schwartz score <3.5. Improving referral criteria for these patients could enhance DNA diagnosis. Also, our results suggest that additional variants in cardiac genes may affect the severity of the disease in the carriers of LQTS-causing variants, which may aid in identifying new modifier genes.

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.

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.

In this case report, we present a 24-year-old woman with a previous diagnosis of epilepsy who was admitted to the hospital following loss of consciousness (LOC). It was initially assumed that this was an epileptic seizure based on her previous diagnosis of epilepsy; however, a review of her electrocardiograms (ECGs) revealed a prolonged QT interval. She was admitted to the cardiology ward for continuous ECG monitoring and subsequently developed self-limiting torsades de pointes (TDP). A diagnosis of congenital long QT syndrome (LQTS) was established, her anticonvulsant treatment was withdrawn, and she was managed with nadolol, mexiletine, and an implantable cardioverter defibrillator (ICD). This case underscores the importance of excluding cardiac disease with secondary anoxic seizures in patients with apparent epilepsy and in particular the need for all patients to have a baseline 12-lead ECG as part of their initial assessment.

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.

Genetic testing for cardiac channelopathies is the standard of care. However, many rare genetic variants remain classified as variants of uncertain significance (VUS) due to lack of epidemiological and functional data. Whether deep protein language models may aid in VUS resolution remains unknown. Here, we set out to compare how 2 deep protein language models perform at VUS resolution in the 3 most common long-QT syndrome-causative genes compared with the gold-standard patch clamp.

A total of 72 rare nonsynonymous VUS (9 KCNQ1, 19 KCNH2, and 50 SCN5A) were engineered by site-directed mutagenesis and expressed in either HEK293 cells or TSA201 cells. Whole-cell patch-clamp technique was used to functionally characterize these variants. The protein language models, evolutionary scale modeling, version 1b and AlphaMissense, were used to predict the variant effect of missense variants and compared with patch clamp.

Considering variants in all 3 genes, the evolutionary scale modeling, version 1b model had a receiver operating characteristic curve-area under the curve of 0.75 (P=0.0003). It had a sensitivity of 88% and a specificity of 50%. AlphaMissense performed well compared with patch-clamp with an receiver operating characteristic curve-area under the curve of 0.85 (P<0.0001), sensitivity of 80%, and specificity of 76%.

Deep protein language models aid in VUS resolution with high sensitivity but lower specificity. Thus, these tools cannot fully replace functional characterization but can aid in reducing the number of variants that may require functional analysis.

Sudden, unexpected deaths are extremely difficult for families, especially when the victim is a child. Most sudden deaths occur due to cardiovascular issues, and a smaller number (approximately one-quarter) are attributed to other causes, such as epilepsy. The medicinal and non-medicinal use of the synthetic opioid fentanyl, which can cause breathing problems, is frequently involved in these deaths. It is also being found more often in autopsies of sudden death cases, and the number of overdose deaths from illicit drugs containing fentanyl is increasing. There are cases in which it is mixed with other drugs. A gene known as the KCNH2 gene or human ether-a-go-go-related gene (hERG), involved in the heart's electrical activity, can be related to abnormal heart rhythms. This gene, along with others, may play a role in sudden deaths related to fentanyl use. In response, we have examined the scientific literature on genetic variations in the KCNH2 gene that can cause sudden death, the impact of fentanyl on this process, and the potential benefits of genetic testing for the victims to offer genetic counseling for their family members.

Aluminum phosphide (AlP) is the main component of rice tablets (a pesticide), which produces phosphine gas (PH3) when exposed to stomach acid. The most important symptoms of PH3 toxicity include, lethargy, tachycardia, hypotension, and cardiac shock. It was shown that Iodine can chemically react with PH3, and the purpose of this study is to investigate the protective effects of Lugol solution in poisoning with rice tablets. Five doses (12, 15, 21, 23, and 25 mg/kg) of AlP were selected, for calculating its lethal dose (LD50). Then, the rats were divided into 4 groups: AlP, Lugol, AlP + Lugol, and Almond oil (as a control). After 4 h, the blood pressure and electrocardiogram (ECG) were recorded, and blood samples were obtained for biochemical tests, then liver, lung, kidney, heart, and brain tissues were removed for histopathological examination. The results of the blood pressure showed no significant changes (P > 0.05). In ECG, the PR interval showed a significant decrease in the AlP + Lugol group (P < 0.05). In biochemical tests, LDH, Ca2+, Creatinine, ALP, Mg2+, and K+ represented significant decreases in AlP + Lugol compared to the AlP group (P < 0.05). Also, the administration of Lugol's solution to AlP-poisoned rats resulted in a significant decrease in malondialdehyde levels and a significant increase in catalase activity (P < 0.05). Histopathological evaluation indicates that Lugol improves changes in the lungs, kidneys, brain, and heart. Our results showed that the Lugol solution could reduce tissue damage and oxidative stress in AlP-poisoned rats. We assume that the positive effects of Lugol on pulmonary and cardiac tissues are due to its ability to react directly with PH3.

Electromechanical reciprocity - comprising electro-mechanical (EMC) and mechano-electric coupling (MEC) - provides cardiac adaptation to changing physiological demands. Understanding electromechanical reciprocity and its impact on function and heterogeneity in pathological conditions - such as (drug-induced) acquired long QT syndrome (aLQTS) - might lead to novel insights in arrhythmogenesis. Our aim is to investigate how electrical changes impact on mechanical function (EMC) and vice versa (MEC) under physiological conditions and in aLQTS. To measure regional differences in EMC and MEC in vivo, we used tissue phase mapping cardiac MRI and a 24-lead ECG vest in healthy (control) and IKr-blocker E-4031-induced aLQTS rabbit hearts. MEC was studied in vivo by acutely increasing cardiac preload, and ex vivo by using voltage optical mapping (OM) in beating hearts at different preloads. In aLQTS, electrical repolarization (heart rate corrected RT-interval, RTn370) was prolonged compared to control (P < 0.0001) with increased spatial and temporal RT heterogeneity (P < 0.01). Changing electrical function (in aLQTS) resulted in significantly reduced diastolic mechanical function and prolonged contraction duration (EMC), causing increased apico-basal mechanical heterogeneity. Increased preload acutely prolonged RTn370 in both control and aLQTS hearts (MEC). This effect was more pronounced in aLQTS (P < 0.0001). Additionally, regional RT-dispersion increased in aLQTS. Motion-correction allowed us to determine APD-prolongation in beating aLQTS hearts, but limited motion correction accuracy upon preload-changes prevented a clear analysis of MEC ex vivo. Mechano-induced RT-prolongation and increased heterogeneity were more pronounced in aLQTS than in healthy hearts. Acute MEC effects may play an additional role in LQT-related arrhythmogenesis, warranting further mechanistic investigations. KEY POINTS: Electromechanical reciprocity comprising excitation-contraction coupling (EMC) and mechano-electric feedback loops (MEC) is essential for physiological cardiac function. Alterations in electrical and/or mechanical heterogeneity are known to have potentially pro-arrhythmic effects. In this study, we aimed to investigate how electrical changes impact on the mechanical function (EMC) and vice versa (MEC) both under physiological conditions (control) and in acquired long QT syndrome (aLQTS). We show that changing the electrical function (in aLQTS) results in significantly altered mechanical heterogeneity via EMC and, vice versa, that increasing the preload acutely prolongs repolarization duration and increases electrical heterogeneity, particularly in aLQTS as compared to control. Our results substantiate the hypothesis that LQTS is an ‛electro-mechanical', rather than a 'purely electrical', disease and suggest that acute MEC effects may play an additional role in LQT-related arrhythmogenesis.

A novel approach to treating heart failures was developed with the introduction of iPSC technology. Knowledge in regenerative medicine, developmental biology, and the identification of illnesses at the cellular level has exploded since the discovery of iPSCs. One of the most frequent causes of mortality associated with cardiovascular disease is the loss of cardiomyocytes (CMs), followed by heart failure. A possible treatment for heart failure involves restoring cardiac function and replacing damaged tissue with healthy, regenerated CMs. Significant strides in stem cell biology during the last ten years have transformed the in vitro study of human illness and enhanced our knowledge of the molecular pathways underlying human disease, regenerative medicine, and drug development. We seek to examine iPSC advancements in disease modeling, drug discovery, iPSC-Based cell treatments, and purification methods in this article.

To evaluate improvement in knowledge and clinical behaviour among healthcare professionals after attendance at paediatric epilepsy training (PET) courses.

Since 2005, 1-day PET courses have taught evidence-based paediatric epilepsy management to doctors and nurses in low-, middle-, and high-income countries. A cohort study was performed of 7528 participants attending 252 1-day PET courses between 2005 and 2020 in 17 low-, middle-, and high-income countries, and which gathered data from participants immediately after the course and then 6 months later. Training outcomes were measured prospectively in three domains (reaction, learning, and behaviour) using a mixed-methods approach involving a feedback questionnaire, a knowledge quiz before and after the course, and a 6-month survey.

Ninety-eight per cent (7217 of 7395) of participants rated the course as excellent or good. Participants demonstrated knowledge gain, answering a significantly higher proportion of questions correctly after the course compared to before the course (88% [47 883 of 54 196], correct answers/all quiz answers, vs 75% [40 424 of 54 196]; p < 0.001). Most survey responders reported that the course had improved their epilepsy diagnosis and management (73% [311 of 425]), clinical service (68% [290 of 427]), and local epilepsy training (68% [290 of 427]).

This was the largest evaluation of a global epilepsy training course. Participants reported high course satisfaction, showed knowledge gain, and described improvements in clinical behaviour 6 months later. PET supports the global reduction in the epilepsy 'treatment gap' as promoted by the World Health Organization.

The human ether-a-go-go-related gene (hERG) encodes the Kv11.1 (or hERG) channel that conducts the rapidly activating delayed rectifier potassium current (IKr). Naturally occurring mutations in hERG impair the channel function and cause long QT syndrome type 2. Many missense hERG mutations lead to a lack of channel expression on the cell surface, representing a major mechanism for the loss-of-function of mutant channels. While it is generally thought that a trafficking defect underlies the lack of channel expression on the cell surface, in the present study, we demonstrate that the trafficking defective mutant hERG G601S can reach the plasma membrane but is unstable and quickly degrades, which is akin to WT hERG channels under low K+ conditions. We previously showed that serine (S) residue at 624 in the innermost position of the selectivity filter of hERG is involved in hERG membrane stability such that substitution of serine 624 with threonine (S624T) enhances hERG stability and renders hERG insensitive to low K+ culture. Here, we report that the intragenic addition of S624T substitution to trafficking defective hERG mutants G601S, N470D, and P596R led to a complete rescue of the function of these otherwise loss-of-function mutant channels to a level similar to the WT channel, representing the most effective rescue means for the function of mutant hERG channels. These findings not only provide novel insights into hERG mutation-mediated channel dysfunction but also point to the critical role of S624 in hERG stability on the plasma membrane.

Long QT syndrome (LQTS) has been reported in older patients with advanced non-small cell lung cancer (NSCLC) following the use of osimertinib, the third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). However, there have not been analytic epidemiology studies on this topic. We aimed to compare the risk of LQTS between osimertinib and first/second-generation EGFR-TKIs in older patients with advanced NSCLC.

This retrospective observational study used the 2006-2019 Surveillance, Epidemiology, and End Results (SEER)-Medicare data and included older patients with advanced NSCLC who were treated with either osimertinib or first/second-generation EGFR-TKIs during 2007-2017. Inverse probability of treatment weighting (IPTW) was used to balance the two groups with propensity scores estimated based on the patients' socioeconomic and clinical characteristics. Crude incidence rate (IR) and adjusted hazard ratio (HR) of the primary outcome, incident LQTS, were estimated.

A total of 545 and 1,135 patients were included in the osimertinib and first/second-generation EGFR-TKI groups, which increased to 1,614 and 1,659, respectively, after IPTW. The osimertinib group had a higher IR of LQTS (2.62 per 100 person-years, 95% CI 2.03-3.38) compared to the first/second-generation EGFR-TKI group (1.33 per 100 person-years, 95% CI 0.92-1.92). After adjusting for covariates, the osimertinib group had a higher risk of LQTS than the first/second-generation EGFR-TKI group, with an HR of 1.94 (95% CI 1.23-3.08). The increased LQTS risk in the osimertinib group was even higher in females, whites and patients aged ≥ 75.

Given the elevated risk of LQTS associated with osimertinib user, close monitoring for cardiac rhythm irregularities of high-risk patients following initiation of EGFR-TKI is recommended.

Long QT Syndrome (LQTS) is a genetic heart disorder that can induce cardiac arrhythmias. The most prevalent subtype, LQT1, stems from rare variants in the KCNQ1 gene. Utilizing induced pluripotent stem cells (iPSCs) enables detailed cellular studies and personalized medicine approaches for this life-threatening condition. We generated two LQT1 iPSC lines with single nucleotide nonsense mutations, c.1031 C > T and c.1121 T > A in KCNQ1. Both lines exhibited typical iPSC morphology, expressed high levels of pluripotent markers, maintained normal karyotype, and possessed the capability to differentiate into three germ layers. These cell lines serve as important tools for investigating the biological mechanisms underlying LQT1 due to mutations in the KCNQ1 gene.

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.

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.

A systematic search of PubMed, Embase, and Cochrane Library databases was conducted to identify relevant studies published up to April 2024.

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, β-blockers, potassium channel openers, device therapy, and surgical interventions.

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.

Arrhythmias are disturbances in the normal rhythm of the heart and account for significant cardiovascular morbidity and mortality worldwide. Historically, preclinical research has been anchored in animal models, though physiological differences between these models and humans have limited their clinical translation. The discovery of human induced pluripotent stem cells (iPSC) and subsequent differentiation into cardiomyocyte has led to the development of new in vitro models of arrhythmias with the hope of a new pathway for both exploration of pathogenic variants and novel therapeutic discovery.

The authors describe the latest two-dimensional in vitro models of arrhythmias, several examples of the use of these models in drug development, and the role of gene editing when modeling diseases. They conclude by discussing the use of three-dimensional models in the study of arrythmias and the integration of computational technologies and machine learning with experimental technologies.

Human iPSC-derived cardiomyocytes models have significant potential to augment disease modeling, drug discovery, and toxicity studies in preclinical development. While there is initial success with modeling arrhythmias, the field is still in its nascency and requires advances in maturation, cellular diversity, and readouts to emulate arrhythmias more accurately.

This study was performed to clarify the clinical findings of pediatric patients diagnosed with long QT syndrome (LQTS) through electrocardiographic screening programs and to predict their outcome using Holter electrocardiographic approaches.

This retrospective study included pediatric patients with a Schwartz score of ≥3.5 who visited the National Hospital Organization Kagoshima Medical Center between April 2005 and March 2019. Resting 12-lead and Holter electrocardiograms were recorded at every visit. The maximum resting QTc and maximum Holter QTc values among all recordings were used for statistical analyses. To test the prognostic value of QTc for the appearance of cardiac events after the first hospital visit, receiver operating characteristic curves were used to calculate the area under the curve (AUC). Among 207 patients, 181 (87%) were diagnosed through screening programs. The prevalence of cardiac events after the first hospital visit was 4% (8/207). Among QTc at diagnosis, maximum resting QTc, and maximum Holter QTc, only maximum Holter QTc value was a predictor (P=0.02) of cardiac events after the hospital visit in multivariate regression analysis. The AUC of the maximum Holter QTc was significantly superior to that of maximum resting QTc.

The maximum Holter QTc value can be used to predict the appearance of symptoms in pediatric patients with LQTS.