RARE DISEASE
Jervell and Lange-Nielsen syndrome
Jervell and Lange-Nielsen syndrome
Jervell and Lange-Nielsen syndrome
Synonyms: Long QT interval-deafness syndrome, Long QT interval-hearing loss syndrome
Synonyms: Long QT interval-deafness syndrome, Long QT interval-hearing loss syndrome
Synonyms: Long QT interval-deafness syndrome, Long QT interval-hearing loss syndrome
Drug discovery
1
drug
With orphan designation
Overview
Jervell and Lange-Nielsen syndrome (JLNS) is a rare autosomal recessive disorder characterized by congenital bilateral sensorineural hearing loss and prolonged QT interval, predisposing to life-threatening ventricular arrhythmias and sudden cardiac death [1][6][13]. Caused by mutations in KCNQ1 (90% of cases) or KCNE1 genes, it disrupts potassium ion channels critical for cardiac repolarization and cochlear function [1][3][6].
Therapies
Cardiac management: First-line β-blockers (nadolol/propranolol) to reduce arrhythmia risk [7][12]. Implantable cardioverter-defibrillators (ICDs) for high-risk patients [3][10][13]. Left cardiac sympathetic denervation (LCSD) in refractory cases [7][13].
Hearing interventions: Cochlear implants for profound deafness [3][13].
Lifestyle: Avoid triggers (exercise, stress) and electrolyte imbalances [3][6].
Categories: rare cardiac diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare otorhinolaryngological diseases
Research Papers
1,387 drug discovery papers about Jervell and Lange-Nielsen syndrome, with 11 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,387 drug discovery papers about Jervell and Lange-Nielsen syndrome, with 11 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-22 | Targeting trafficking defects in long QT syndrome type 2: a phase 2 clinical study with patient-specific cellular validation.
A major component of long QT syndrome (LQTS) is LQT2 due to pathogenic variants in KCNH2, which frequently cause trafficking defects. Despite progress in therapeutic management, there is an unmet clinical need for mechanism-targeted therapies. It has been previously shown, using patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), that lumacaftor (LUM), currently used for cystic fibrosis, can partially correct hERG trafficking. A single-arm phase 2 study was conducted to determine whether LUM could shorten QTc in LQT2 patients with trafficking defects. Sixteen adult patients with genetically confirmed trafficking-defective KCNH2 variants were enrolled. Participants were admitted to hospital and received LUM for 7 days under continuous telemetry. QTc was quantified on serial electrocardiograms and 12-lead Holter recordings. For mechanistic correlation, hiPSC-CMs were generated from the first five participants with distinct genetic variants and assessed for hERG maturation and trafficking. Overall, lumacaftor produced a significant QTc shortening (P < .001). The per-patient change averaged 31 ± 21 ms. Patients with baseline QTc ≥500 ms exhibited the most substantial effect, with 75% achieving reductions ≥40 ms. No ventricular arrhythmias occurred, and adverse effects were primarily gastrointestinal and self-limited. In hiPSC-CMs, LUM restored hERG trafficking in three out of five variants, mirroring the clinical observations. Short-term LUM therapy is safe and yields a significant QTc shortening in LQT2 patients with a trafficking defect. Concordance between cellular and clinical findings reinforces the value of a mechanism-based, variant-informed approach and supports the feasibility of trafficking-correction strategies within a precision-medicine framework for inherited arrhythmia syndromes.
2026-09-16 | Antiemetic-Associated QT Prolongation: A Clinical Review and Risk-Stratified Prescribing Framework for Long QT Syndrome.
Nausea and vomiting accompany pregnancy, gastroenteritis, migraine, the perioperative period, and cytotoxic chemotherapy, and antiemetics are among the most frequently prescribed drugs worldwide. Several antiemetic classes delay ventricular repolarization and prolong the QT interval, a substrate for torsades de pointes (TdP), ventricular fibrillation, and sudden cardiac death. We synthesized the evidence on antiemetic QT liability and translated it into a three-tier, risk-stratified prescribing framework and stepwise clinical algorithm for patients with inherited or acquired long QT syndrome (LQTS) and other torsadogenic risk factors. We conducted a narrative review of PubMed/MEDLINE, EMBASE, and pharmacovigilance sources (FDA Adverse Event Reporting System, CredibleMeds/QTdrugs) through early 2026, prioritizing mechanistic studies, randomized comparisons, disproportionality analyses, and consensus statements on antiemetic QT liability and LQTS management. QT prolongation across antiemetic classes is driven principally by IKr blockade (hERG/KCNH2). Risk is highly heterogeneous within classes: in a 2026 FAERS disproportionality analysis, ondansetron carried a substantially stronger QT-related signal than olanzapine (reporting odds ratio 27.2 vs 8.7), consistent with its dose-dependent effect among 5-HT3 antagonists, which prompted a 2012 FDA restriction on the 32 mg intravenous dose; palonosetron has minimal effect. Neurokinin-1 antagonists, low-risk antihistamines, anticholinergics, and 5-HT4 agonists carry little QT liability, while butyrophenones, phenothiazines, and promethazine carry greater risk. Serious events cluster in patients with electrolyte disturbance, bradycardia, polypharmacy, or underlying LQTS, particularly when QTc exceeds 500 ms or rises more than 60 ms from baseline. Antiemetic-associated arrhythmia is largely preventable. Structured risk assessment, electrolyte correction, ECG monitoring, and a stepwise selection strategy favouring agents with minimal QT liability allow clinicians to manage nausea and vomiting safely, even in high-risk populations.
2026-09-11 | Molecular basis for state-dependent drug block of Kv11.1 (human ether-à-go-go-related gene) potassium channels.
Many structurally and therapeutically diverse drugs block the human ether-à-go-go-related gene (HERG) potassium channel, predisposing patients to an increased risk of arrhythmias and sudden cardiac death. Many of these drugs show state dependence of block, exhibiting a greater preference for block of the inactivated state. Four key residues, ie, T623, S624, Y652, and F656, within the central pore cavity of HERG have been implicated in drug binding. However, whether drugs bind differently to these key residues to dictate preference for binding to the inactivated over the open state is not known. We used the SyncroPatch 384PE, automated patch clamp platform to measure how drug block was impacted by point mutations at these 4 residues when introduced into wild-type (WT) HERG (preferentially occupies the inactivated state) and N588K-HERG (preferentially occupies the open state) channels at depolarized potentials. Mutations to Y652 and F656, which abolished aromatic and hydrophobic characteristics, respectively, reduced drug binding in both WT and N588K backgrounds. The S624A mutation attenuated block by cisapride, astemizole, and quinidine in the WT background but not in the N588K background. We suggest that relative movements between the polar S624 sidechain and the aromatic Y652 sidechains in WT (inactivated) compared with N588K (open) channels can explain preferential binding to the inactivated state. An improved understanding of the structural basis of where and how drugs bind to HERG channels should facilitate efforts to reduce inadvertent HERG drug block during the drug development process. SIGNIFICANCE STATEMENT: A diverse range of drugs block human ether-à-go-go-related gene (HERG) potassium channels, which can have serious side effects, including sudden death. Most problematic drugs bind to the inactivated state of HERG channels. This study shows that the polar side chain of Ser624, at the base of the selectivity filter, is critical for preferential drug block of inactivated compared with open channels. A better understanding of state-dependent drug binding should facilitate efforts to reduce inadvertent HERG drug block.
2026-08-27 | A hERG blocker facilitates K+ channel current by promoting pore opening while blocking.
Many drugs that block voltage-gated K+ channels encoded by the human ether-à-go-go-related gene (hERG) can cause long QT syndrome and life-threatening cardiac arrhythmias, yet the molecular mechanisms that determine this risk remain unclear. A process that may counteract arrhythmogenic hERG block, termed facilitation, is common to many clinically approved hERG blockers, including nifekalant, amiodarone, promethazine, imipramine, nortriptyline, haloperidol, verapamil, carvedilol, metoprolol, propranolol, quinidine, fluoxetine, and chlorpheniramine. Facilitation is an increase in hERG current, under certain conditions, due to these blockers. Here, we propose that an agonism-while-blocking mechanism underpins facilitation. We focus on nifekalant, a class III antiarrhythmic drug and exemplar hERG blocker that induces facilitation. We tested the hypothesis that nifekalant opens hERG channel gates while blocking, and that unblocking of these open-yet-blocked channels results in supranormal hERG current. We developed rate-theory kinetic models to identify features of agonism-while-blocking that produce facilitation. We generated atomistic models that predict that nifekalant blocks the hERG conduction path while modulating the intracellular conduction gate. Voltage-clamp measurements revealed that agonism-while-blocking can result in nifekalant block and facilitation. We speculate that this agonism-while-blocking mechanism contributes to the relative safety of hERG blockers that induce facilitation.
2026-08-12 | ERLAD-hERG axis and L-type calcium channel activation mediate cholesterol-induced acquired long QT syndrome-related cardiotoxicity.
High cholesterol is a key cardiovascular risk factor that can modulate cardiac electrophysiology and promote acquired long QT syndrome (acLQTS)-related cardiotoxicity, a potentially life-threatening condition associated with QT prolongation, torsade de pointes, and sudden cardiac death. This study investigated the effects of cholesterol overload on human Ether-à-go-go-Related Gene (hERG/Kv11.1; encoded by KCNH2) potassium channels and L-type calcium channels (LTCC; mainly Cav1.2/CACNA1C in cardiomyocytes), as well as the underlying mechanisms of acLQTS-related cardiotoxicity, using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), whole-cell patch clamp, quantitative real-time PCR (qRT-PCR), Western blotting, immunoprecipitation, fluorescence imaging, and a high-cholesterol diet guinea pig model with rosuvastatin intervention combined with optical mapping. The results showed that transient cholesterol exposure inhibited hERG tail current amplitude and accelerated channel inactivation, with the effect showing a Y652-dependent component, while also enhancing LTCC activity. Mechanistically, cholesterol overload triggered endoplasmic reticulum (ER) stress, impaired hERG proteostasis, and promoted ER-to-lysosome-associated degradation (ERLAD) of hERG. This process was associated with CANX-mediated recognition of abnormal hERG and FAM134B-LC3B-related autophagic-lysosomal processing, contributing to reduced total hERG expression and membrane-localized mature hERG. FAM134B overexpression partially preserved hERG expression and attenuated cholesterol-induced ER stress/autophagy-related abnormalities. In vivo, rosuvastatin improved lipid profiles and cardiac remodeling in high-cholesterol guinea pigs but was associated with more pronounced action potential duration (APD) and QT interval prolongation under high-cholesterol conditions. These findings suggest that cholesterol overload may increase susceptibility to hERG-related repolarization abnormalities during rosuvastatin exposure and highlight the importance of cholesterol management and electrocardiographic (ECG) monitoring in hypercholesterolemic settings.
gene therapies
2026-09-14 | Variable Expressivity in Long QT Syndrome Type 2 Rabbits Defines a Low Threshold for Therapeutic IKr Restoration.
Long QT syndrome type 2 (LQT2) is caused by pathogenic variants in the hERG potassium channel, resulting in QT prolongation, polymorphic ventricular tachycardia (pVT), and sudden cardiac death. We previously developed a transgenic LQT2 rabbit model that recapitulates the human disease and segregates into two phenotypically distinct lines, LQT2A and LQT2G. Using optical mapping and cardiomyocyte patch clamp, we investigated the electrophysiological basis of variable disease expressivity and its potential future implications for gene therapy. LQT2G hearts were highly arrhythmogenic, with isoproterenol inducing frequent premature ventricular contractions and pVT, whereas LQT2A hearts required additional IKr blockade to reliably trigger arrhythmias. Patch clamp recordings revealed IKr expression in 21% of LQT2A cardiomyocytes at near-wild-type current density, compared with only 5.5% of LQT2G cells exhibiting low IKr. Computer simulations demonstrated that restoration of IKr in >23% of cardiomyocytes fully suppressed early afterdepolarizations through electrotonic coupling. To assess achievable transgene expression, we designed a novel minimally invasive gene delivery method for rabbits. To this end, neonatal wild-type rabbits received three different doses of AAV9 encoding the red-fluorescent reporter mKate2 via jugular vein injection, resulting in viral-load-dependent, regionally distributed mosaic cardiac expression reaching approximately 20%. However, high-dose intravenous AAV9 delivery was associated with dose-dependent hindlimb weakness and dorsal root ganglia pathology, indicating that this administration route is not suitable in rabbits despite achieving biologically sufficient levels of cardiac transduction. Our experimental observations and computational modeling identify ~20% as a plausible range for effective IKr restoration, generating a testable therapeutic hypothesis.
2026-02-28 | A population-based study of trends in cardiac arrest and sudden death owing to long QT syndrome.
Population-based data on long QT syndrome (LQTS) are lacking. New Zealand has a national LQTS registry, molecular autopsy program, and standardized investigation of resuscitated cardiac arrest (RSCA). This study aimed to describe trends in LQTS detection and presentation with RSCA/sudden cardiac death over 24 years. Review of data on registry participants who underwent genetic testing for LQTS presenting between 2000 and 2023. Among 915 diagnosed as having LQTS, 378 probands with a mean corrected QT interval of 512 ± 52 ms presented with sudden cardiac death (26 of 378; 7%), RSCA (82; 21%), syncope or seizure (122; 32%), and incidental/other (148; 40%). Causative genetic variants were found in 165 of 378 probands (44%): 98 KCNQ1 (59%), 41 KCNH2 (25%), 7 SCN5A (4%), and 19 other genes (12%). 593 of 915 participants (65%) were on therapy (beta blocker [565; 62%], implantable cardioverter-defibrillator [134; 16%], and/or left cardiac sympathetic denervation [69; 8%]). 3 likely arrhythmic deaths (0.3%) and 23 appropriate implantable cardioverter-defibrillator shocks (3%) occurred during follow-up (median 12 years). Detections of LQTS/population were 0.5 of 100,000 in 2000, 1.6 of 100,000 in 2009, and 0.4 of 100,000 in 2023. Presentation with RSCA decreased by 10%/y from 2007. Presentation with death decreased by 22%/y from 2014 (P = .026), with no deaths from 2019 to 2023. Decreasing rates of LQTS detection in recent years suggest that most cases have been discovered in New Zealand. Decreasing cardiac arrest and sudden death owing to LQTS is likely related to the success of the overall program.
2026-02-28 | Silencing the Mutant KCNH2 Allele to Reduce the Effects of Long QT Syndrome Type 2.
Long-QT syndrome type 2 (LQTS2), which is associated with life-threatening cardiac arrhythmias, is caused by pathogenic heterozygous loss-of-function mutations in the KCNH2 gene. This gene encodes the pore-forming Kv11.1 α-subunit of the ion channel that carries the rapid delayed rectifier potassium current (IKr). Pathogenic loss-of-function mutations reduce the amplitude of IKr, thereby prolonging the action potential (AP) of ventricular cardiomyocytes, and in turn, the QT interval of the electrocardiogram (ECG). The aim of the present in silico study was to test the extent to which allele-specific suppression ('silencing') of the mutant KCNH2 allele can alleviate the effects of dominant-negative LQTS2 mutations. Two recent and comprehensive models of the electrical activity of a single human ventricular cardiomyocyte, i.e., the 'Bartolucci-Passini-Severi model as published in 2020' and the 'Tomek-Rodriguez model following the O'Hara-Rudy dynamic (ORd) model' (known as the BPS2020 and ToR-ORd models, respectively) were used to assess the effects of mild and severe LQTS2 mutations on the AP duration at 90% repolarization (APD90) and the APD90 restitution obtained with an S1-S2 pacing protocol. For severe mutations, the mutation-induced prolongation of the APD90 at a stimulation rate of 1 Hz is reduced from 166% to 99% in the BPS2020 model and from 111% to 71% in the ToR-ORd model upon 70% suppression of the mutant allele. For mild mutations, this prolongation is reduced from 77% to 44% and from 57% to 34%, respectively. An even greater effect is observed when the mutant KCNH2 allele is inhibited by up to 90%, but the greater suppression is only marginal for mild mutations. The steepness of the mutant APD90 restitution curves is considerably reduced upon suppression, which may exert an anti-arrhythmic effect. Silencing of the mutant allele can substantially, but only partially, counteract the effects of mild or severe LQTS2 mutations on IKr. Allele-specific inhibition of the mutant KCNH2 allele alone is not sufficient to fully treat the effects of LQTS2 mutations and should be accompanied by a replacement gene therapy, creating a suppression-and-replacement ("SupRep") gene therapy.
2025-12-25 | Mapping the Functional Landscape of KCNQ1 to Define Ion Channel Mechanisms and Arrhythmia Risk.
Loss-of-function variants in KCNQ1 are the primary cause of congenital Long QT Syndrome (LQTS), characterized by QT prolongation and increased risk of fatal arrhythmias. The surge in genetic testing continues to uncover vast numbers of variants of uncertain significance in Mendelian disease genes, including KCNQ1. Using four multiplexed assays, we mapped the functional landscape of KCNQ1, identifying trafficking, gating, and dominant negative variants. We provide functional evidence for 13,403 variants, including 1,757 with strong pathogenic and 6,660 with moderate benign evidence. Structure-function analyses revealed variant enrichment in regions regulating trafficking, multimerization, ubiquitylation, and channel gating. Loss-of-function variants showed a risk ratio of 263 (95% CI 241-286) in an LQTS cohort and were significantly associated with QTc prolongation and LQTS diagnoses in biobank participants. By characterizing the functional impact of nearly all KCNQ1 variants, we provide critical insights into arrhythmia mechanisms and open new avenues for precision medicine in LQTS.
2025-10-30 | Gene Therapy for Inherited Cardiac Arrhythmias.
Inherited cardiac arrhythmias are genetic disorders that impact the heart's electrical circuitry. These disorders are caused by inherited mutations and markedly increase the mortality risk of affected individuals. Conventional treatments, such as pharmacological agents for rate and rhythm control or surgical interventions, are often not efficacious and cause long-term complications. Gene therapy has recently emerged as a feasible and potentially curative approach for treating inherited cardiac arrhythmia syndromes. Advancements in elucidating the molecular mechanisms, pinpointing essential candidate genes, and improving gene delivery have rendered gene therapy as a feasible treatment alternative. This review examines recent studies on gene therapy applications in Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, long QT syndrome, familial atrial fibrillation, and arrhythmogenic cardiomyopathy. Additionally, we analyze current advancements in viral and non-viral gene delivery methods, highlighting their therapeutic potential and related challenges.
cell therapies
2026-06-10 | Multidisciplinary management of video-assisted thoracoscopic left cardiac sympathetic denervation in a young child with Jervell and Lange-Nielsen syndrome.
Left cardiac sympathetic denervation (LCSD) via video-assisted thoracoscopy (VATS) is an effective therapy for drug-refractory malignant arrhythmias in congenital long QT syndromes and requires meticulous perioperative planning in children with automatic implantable cardioverter-defibrillators (AICDs). We describe what is likely the first paediatric VATS-LCSD performed in Pakistan. A boy in early childhood with Jervell and Lange-Nielsen syndrome, severe QT prolongation and recurrent ventricular arrhythmias despite beta-blockade and mexiletine had received multiple AICD shocks. Intraoperative management focused on preventing electrocautery-induced AICD activation by applying a magnet to suspend antitachycardia therapies, using external defibrillation pads and ensuring continuous electrophysiology support. Anaesthesia incorporated sevoflurane, dexmedetomidine, cisatracurium and lidocaine, with one-lung ventilation achieved by intentional endobronchial tracheal tube placement. Thoracoscopic excision of the left sympathetic chain (T5-T1), including the lower stellate, was completed uneventfully. The child was extubated in the operating room and discharged the next day without complications.
2026-04-24 | Trigger Type and Breakthrough Cardiac Events in Inherited Arrhythmia Syndromes After Left Cardiac Sympathetic Denervation.
Left cardiac sympathetic denervation (LCSD) confers a strong antifibrillatory effect and provides significant therapeutic efficacy for patients with genetic heart diseases, especially long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). We hypothesize that LCSD's efficacy may differ among patients experiencing adrenergic (AD) vs nonadrenergic (non-AD) triggered symptoms before LCSD. In this study, we sought to evaluate the association between AD and non-AD triggered events and the subsequent risk of breakthrough cardiac events (BCEs) after LCSD. A retrospective review of all previously symptomatic patients with either LQTS or CPVT who underwent LCSD at our institution since 2005 was performed. Data from electronic medical records was abstracted for cardiac event (CE) trigger type (AD or non-AD) before and after LCSD. CEs and BCEs were defined as arrhythmogenic syncope, seizure, appropriate ventricular fibrillation-terminating therapies, and sudden cardiac arrest or death. Among 154 pre-LCSD symptomatic patients (mean age at diagnosis: 15 ± 12 years; follow-up after LCSD: 5.9 ± 4.2 years) with LQTS (n = 105; 68%) or CPVT (n = 49; 32%), 49 patients (32%) had >1 BCE. Post-LCSD BCEs were significantly higher in patients with non-AD triggered CE (n = 30/56; 54%)) compared with patients with AD-triggered CE (n = 19/98; 19%; P < 0.0001). The subset analysis found fewest BCEs in LQT1 patients with AD triggers (OR: 0.24, P < 0.0001). To date, no BCEs have occurred in LQT2, LQT3, or LQT Minor patients with pre-LCSD AD-triggered CEs. There is a marked pre-LCSD phenotypic determinant of LCSD's therapeutic efficacy. Independently from underlying genotype, patients with adrenergic triggers associated with their pre-LCSD symptoms had a greater reduction in disease-mediated BCEs.
2026-02-13 | [Cardiac arrhythmias-Cellular mechanisms, consequences and challenges in the diagnostics using human models].
Cardiac arrhythmias significantly contribute to morbidity and mortality in cardiovascular diseases. Hereditary ion channel disorders, including Brugada syndrome, long/short QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT), represent critical entities with elevated risk of malignant ventricular arrhythmias. Although beta-blockers, ion channel modulators and implantable cardioverter defibrillators (ICD) are available and the indications for them are increasingly based on genetic analyses, variants of uncertain significance (VUS) substantially impair the risk stratification. Atrial tachyarrhythmias, particular atrial fibrillation, can cause an often-reversible arrhythmia-induced cardiomyopathy (AIC). Pathophysiologically, the Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays an important role in atrial and ventricular arrhythmias. It can be activated by various pathological triggers, such as high heart rate, neuroendocrine activation and oxidative stress, the latter often resulting from mechano-energetic uncoupling. The development of effective treatment options for arrhythmia-associated cardiovascular diseases requires the use of human model systems in addition to animal experimental approaches, due to the genetic heterogeneity and systemic comorbidities. Patient-specific cardiac stem cell-models enable the classification of VUS and personalised drug testing. The integration of new methodological approaches into existing animal experimental approaches thus paves the way for functionally validated precision medicine and could fundamentally transform the treatment of both disease patterns.
2025-11-03 | Cardiac sympathetic denervation for refractory ventricular arrhythmias in patients with inherited cardiomyopathies.
Cardiac sympathetic denervation (CSD) is a therapeutic option in patients with recurrent or refractory ventricular arrhythmia (VA). Successful outcomes have largely been established among patients with underlying ischemic cardiomyopathy, patients with nonischemic cardiomyopathy, and young patients diagnosed as having long-QT syndrome or catecholaminergic polymorphic ventricular tachycardia. Patients with inherited cardiomyopathies have a rare prevalence but experience VAs and sudden cardiac death. Herein, we studied the outcomes of CSD on patients with refractory VA and an inherited cardiomyopathy. Data from adult patients with VA referred for CSD were reviewed from 4 tertiary referral centers between 2010 and 2023. Patients with a minimum postoperative follow-up time of 12 months and an inherited cardiomyopathy were included: hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy, or dilated cardiomyopathy. 23 patients with an inherited cardiomyopathy underwent bilateral CSD: 7 patients with hypertrophic cardiomyopathy, 11 patients with arrhythmogenic cardiomyopathy, and 5 patients with dilated cardiomyopathy. The median (interquartile range) follow-up time was 34.5 months (23.1-46.5). The overall success rate of CSD was 48%. When comparing pre- and post-CSD periods, implantable cardioverter-defibrillator shocks decreased by 61% (P < .01). Transplant-free survival at 4 years was 76%. Most of the expected complications resolved upon follow-up. Bilateral CSD significantly reduced implantable cardioverter-defibrillator shocks in patients with inherited cardiomyopathies, demonstrating durable arrhythmia control and favorable long-term transplant-free survival across diverse genetic subtypes.
2025-10-22 | Perioperative management of thoracoscopic left cardiac sympathetic denervation for refractory long QT syndrome: a case report.
Long QT syndrome (LQTS) refractory to standard treatments, including β-blockers and implantable cardioverter-defibrillators (ICDs), has been indicated for left cardiac sympathetic denervation (LCSD) in Europe and the United States. However, the clinical implementation of LCSD remains rarely performed in Japan as it is not covered by national health insurance. A 49-year-old woman with LQTS experienced frequent ICD activations, and β-blocker up-titration was limited due to severe heart failure. As a stellate ganglion block transiently shortened QT interval, LCSD was considered to prevent life-threatening arrhythmic events. Total intravenous anesthesia combined with a left thoracic paravertebral block was used to attenuate sympathetic nervous activation. Thoracoscopic LCSD was performed without arrhythmia or hemodynamic instability. The patient remained stable postoperatively, with no further ICD activations. This case demonstrates the safe perioperative management of LCSD for drug-refractory LQTS by incorporating strategies to minimize QT prolongation and suppress malignant arrhythmias.
proteins
2026-04-17 | Allosteric Mechanisms Underlying Long QT Syndrome Type 2 (LQT2)-Associated Mutations in hERG Channels.
1 Long QT syndrome Type 2 (LQT2) is a genetic disorder caused by missense mutations in the KCNH2 gene that encodes the potassium channel K V 11.1. Previous studies have shown that most K V 11.1 missense mutations with loss-of-function phenotypes result from impaired trafficking from the endoplasmic reticulum to the plasma membrane. To investigate the molecular basis of these defects, we used molecular dynamics simulations to analyze two sets of disease-associated missense mutations: those that suppress and those that maintain normal channel trafficking. We focused initially on the conformational and dynamics differences between wild-type and several mutants of K V 11.1 via molecular dynamics simulations when two K + were placed in the selectivity filter (SF). Our study reveals that missense mutations in the S4 helix allosterically disrupt the selectivity filter, a critical determinant for proper channel trafficking. Trafficking-competent variants largely retained a wild-type selectivity filter structure, whereas trafficking-deficient mutants exhibited pronounced structural perturbations in this region. These findings suggest that certain LQT2-associated missense mutations in KCNH2 impair channel trafficking by compromising the structural integrity of the selectivity filter. We additionally found that second-site variants Y652C in the drug binding vestibule can correct structural defects associated with some mistrafficking variants.
2026-03-02 | Structural differences in Apo-, D132E- and Holo-Calmodulin bound to the IQ domain of the cardiac L-type calcium channel.
Proper regulation of the cardiac L-type calcium channel (CaV1.2) involves calcium-dependent inactivation (CDI) of the channel. CDI is mediated by the calcium-sensing protein calmodulin (CaM), which interacts with the IQ domain of CaV1.2. CaM mutations have been implicated in dangerous cardiac arrhythmias such as long-QT syndrome (LQTS), but it is not clear how structural changes at the CaM-CaV1.2 binding interface can lead to LQTS. In this study, we examine structural differences in holo-, apo- and D132E-CaM bound to the IQ domain of CaV1.2 using molecular dynamics (MD) simulations and molecular mechanics Poisson-Boltzmann surface area (MMPBSA) binding free energy calculations. Calcium (Ca2+) binding to CaM is shown to stabilise key binding interaction triplets in the C-lobe of holo-CaM-CaV1.2. We additionally find that D132E-CaM-CaV1.2 is able to bind with higher affinity than holo-CaM-CaV1.2 due to subtle structural changes taking place at the CaM-CaV1.2 binding interface. The differences in the CaM-CaV1.2 binding interface are larger when calcium is not bound, as opposed to the differences induced by the mutation, which suggests that the D132E mutation may lead to LQTS via defective binding of Ca2+ to CaM as opposed to structural changes occurring at the CaM-CaV1.2 binding interface.
2026-02-19 | Theoretical analysis of low-power optogenetic suppression of action potentials in human ventricular cardiomyocytes expressed with potassium-selective channelrhodopsins.
Effective suppression of cardiac tachyarrhythmias and shortening of action potential duration (APD) remain major challenges in cardiac optogenetics due to the non-selectivity of ion-conducting channelrhodopsins (ChRs). We present a comprehensive theoretical analysis of optogenetic suppression of electrical activity and temporally precise shortening of APD in human ventricular cardiomyocytes (HVCMs) expressed with WiChR and HcKCR1 potassium (K⁺)-selective ChRs that exhibit reversal potentials close to the diastolic membrane potential of the targeted cardiac cells. Our simulations show that K⁺-selective ChRs provide more efficient hyperpolarizing control compared to cation-selective variants. Our computational simulations show that WiChR exhibits action-potential suppression at very low irradiance (4 × 10⁻² mW/mm²), while HcKCR1 could not achieve full suppression at 10 mW/mm². This makes WiChR a much stronger and more effective option for optical inhibition in human ventricular cardiomyocytes. At irradiance of 1 × 101 mW/mm², our simulations show that WiChR hyperpolarizes the membrane to -83.14 mV, closely approaching the K⁺ equilibrium potential, whereas HcKCR1 reached − 82.39 mV. The results are important for the treatment of cardiac arrhythmias and long QT syndrome. This work provides mechanistic insight into low-power optogenetic control of cardiac electrophysiology and offers quantitative predictions to guide future in vitro and in vivo investigations aimed at developing safer and more precise alternatives to electrical pacing and defibrillation technologies.
2025-02-20 | A privileged ER compartment for post-translational heteromeric assembly of an ion channel.
Mechanisms underlying heterotypic subunit assembly of ion channels and other oligomeric complexes are poorly understood. In the human heart, heteromeric assembly of two isoforms encoded by the human ether-à-go-go related gene (hERG) is essential for the normal function of cardiac IKr in ventricular repolarization, with loss of hERG1b contributing to arrhythmias associated with long QT-syndrome (LQTS). While hERG1a homomers traffic efficiently to the plasma membrane, hERG1b homomers are retained in the endoplasmic reticulum (ER). When expressed together, the two subunits avidly associate during biogenesis. Seeking rules specifying heteromeric association, we characterized the fate of hERG1b proteins using confocal and superresolution imaging in fixed and live HeLa cells. We found hERG1b sequestered in punctate intracellular structures when expressed alone in HeLa cells. These puncta, which depend on the presence of an N-terminal "RXR" ER retention signal, represent a privileged ER sub-compartment distinct from that containing ER-retained, type 2 (hERG-based) LQTS mutant proteins, which were rapidly degraded by the proteasome. Introducing hERG1a to cells with preformed hERG1b puncta dissolved these puncta by rescuing extant hERG1b. Rescue occurred by association of fully translated hERG1b with 1a, a surprising finding given previous studies demonstrating cotranslational heteromeric association. We propose that sequestration limits potentially deleterious surface expression of hERG1b homomeric channels while preserving hERG1b for an alternative mode of heteromeric hERG1a/1b channel assembly post-translationally. These findings reveal a surprising versatility of biosynthetic pathways promoting heteromeric assembly.
2024-09-30 | 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.
other
2026-05-19 | Functional characterization and allele-specific RNA interference-based rescue of KCNH2 p.F68C variant associated with long QT syndrome.
Long QT syndrome (LQTS) is an inherited life-threatening cardiac disorder characterized by delayed ventricular repolarization and increased risk of malignant arrhythmias. Among its subtypes, long QT syndrome type 2 (LQT2) is primarily caused by pathogenic variants in KCNH2, which encodes the human ether-à-go-go-related gene (hERG) potassium channel responsible for the rapid delayed rectifier current (IKr). However, the substantial functional heterogeneity among KCNH2 variants poses a major challenge for clinical interpretation and precision intervention. In this study, we sought to functionally characterize KCNH2 p.F68C variant (c.203T > G) identified in a Chinese LQT2 patient and to evaluate the feasibility of RNA interference-based modulation of its functional impact on the hERG channel. Using biochemical and electrophysiological analyses in HEK293T cells, we show that variant p.F68C causes a severe trafficking defect and exerts a dominant-negative effect on wild-type hERG channels, leading to markedly reduced rapid delayed rectifier potassium current (IKr). In contrast to several previously reported Per-Arnt-Sim (PAS) domain variants, the trafficking defect of p.F68C was resistant to reduced culture temperature, chemical chaperones, and pharmacological chaperones. Notably, allele-specific RNA interference selectively suppressed mutant hERG expression, alleviated dominant-negative interference, and partially restored hERG current density without detectable cytotoxicity. Together, these findings establish p.F68C as a loss-of-function KCNH2 variant and highlight allele-specific RNA interference as a variant-directed strategy that may serve as an alternative to suppression-replacement approaches, providing a basis for functional interpretation and precision therapeutic exploration of individual KCNH2 variants.
2025-04-07 | When HERG-caused LQT2 encounters antisense oligonucleotide: is exon 6 skipping therapy plausible?
The unique in-frame exon 6 of the HERG gene as a potential target for antisense oligonucleotide-mediated exon skipping therapy.
2025-01-09 | A PAS-targeting hERG1 activator reduces arrhythmic events in Jervell and Lange-Nielsen syndrome patient-derived hiPSC-CMs.
The hERG1 potassium channel conducts the cardiac repolarizing current, IKr. hERG1 has emerged as a therapeutic target for cardiac diseases marked by prolonged action potential duration (APD). Unfortunately, many hERG1 activators display off-target and proarrhythmic effects that limit their therapeutic potential. A Per-Arnt-Sim (PAS) domain in the hERG1 N-terminus reduces IKr by slowing channel activation and promoting inactivation. Disrupting PAS activity increases IKr and shortens APD in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). We thus hypothesized that the hERG1 PAS domain could represent a therapeutic target to reduce arrhythmogenic potential in a long QT syndrome (LQTS) background. To test this, we measured the antiarrhythmic capacity of a PAS-disabling single-chain variable fragment antibody, scFv2.10, in a hiPSC-CM line derived from a patient with Jervell and Lange Nielsen (JLN) syndrome. JLN is a severe form of LQTS caused by autosomal recessive mutations in KCNQ1. The patient in this study carried compound heterozygous mutations in KCNQ1. Corresponding JLN hiPSC-CMs displayed prolonged APD and early afterdepolarizations (EADs). Disrupting PAS with scFv2.10 increased IKr, shortened APD, and reduced the incidence of EADs. These data demonstrate that the hERG1 PAS domain could serve as a therapeutic target to treat disorders of cardiac electrical dysfunction.
2024-11-04 | Computational analysis of long QT syndrome type 2 and the therapeutic effects of KCNQ1 antibodies.
Long QT interval syndrome (LQTS) is a highly dangerous cardiac disease that can lead to sudden cardiac death; however, its underlying mechanism remains largely unknown. This study is conceived to investigate the impact of two general genotypes of LQTS type 2, and also the therapeutic effects of an emerging immunology-based treatment named KCNQ1 antibody. A multiscale virtual heart is developed, which contains multiple biological levels ranging from ion channels to a three-dimensional cardiac structure with realistic geometry. Critical biomarkers at different biological levels are monitored to investigate the remodeling of cardiac electrophysiology induced by mutations. Simulations revealed multiple important mechanisms that are hard to capture via conventional clinical techniques, including the augmented dispersion of repolarization, the increased vulnerability to arrhythmias, the impaired adaptability in tissue to high heart rates, and so on. An emerging KCNQ1 antibody-based therapy could rescue the prolonged QT interval but did not reduce the vulnerable window. Tiny molecular alterations can lead to cardiac electrophysiological remodeling at multiple biological levels, which in turn contributes to higher susceptibility to lethal arrhythmias in long QT syndrome type 2 patients. The KCNQ1 antibody-based therapy has proarrhythmic risks notwithstanding its QT-rescuing effects.
2024-07-31 | Clinical presentation and genetic characterization of early-onset atrial fibrillation in patients affected by long QT syndrome: A single-center experience.
Early-onset atrial fibrillation (AF) has already been observed in approximately 2% of patients with genetically proven long QT syndrome (LQTS). This frequency is higher than population-based estimates of early-onset AF. However, the concomitant expression of AF in LQTS is likely underestimated. The purpose of this study was to examine the clinical presentation, genetic background, and outcomes of a cohort of patients with LQTS and early-onset AF referred to a single tertiary center. Twenty-seven patients diagnosed with congenital LQTS were included in the study based on the documentation of early-onset (age ≤50 years) clinical or subclinical AF episodes in all available medical records, including standard electrocardiograms, wearable monitor or cardiac implantable electronic devices. Seventeen patients experienced clinical AF during the follow-up period. Subclinical AF was detected in 10 patients through insertable or wearable cardiac monitors. In our series, the mean heart rate during AF episodes was found to be relatively low despite the patients' young age and the low or minimal effective doses of beta-blockers used for QTc interval control. All patients exhibiting LQTS and early-onset AF were genotype positive, carrying mutations in the KCNQ1 (66%), KCNH2, KCNE1, and SCN5A genes. Notably, most of these patients carried the same p.(R231C) mutation in the KCNQ1 gene (59%) and were from the same families, suggesting concurrent expression of familial AF and LQTS. LQTS patients are prone to developing clinical and subclinical AF, even at a younger age. The occurrence of early-onset AF in the LQTS population could be more frequent than previously assumed. AF should be considered as a potential dysrhythmia related to LQTS. Our study emphasizes the importance of carefully researching clinical and/or subclinical episodes of AF through strict heart rhythm monitoring in the LQTS population.
small molecules
2026-09-22 | Targeting trafficking defects in long QT syndrome type 2: a phase 2 clinical study with patient-specific cellular validation.
A major component of long QT syndrome (LQTS) is LQT2 due to pathogenic variants in KCNH2, which frequently cause trafficking defects. Despite progress in therapeutic management, there is an unmet clinical need for mechanism-targeted therapies. It has been previously shown, using patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), that lumacaftor (LUM), currently used for cystic fibrosis, can partially correct hERG trafficking. A single-arm phase 2 study was conducted to determine whether LUM could shorten QTc in LQT2 patients with trafficking defects. Sixteen adult patients with genetically confirmed trafficking-defective KCNH2 variants were enrolled. Participants were admitted to hospital and received LUM for 7 days under continuous telemetry. QTc was quantified on serial electrocardiograms and 12-lead Holter recordings. For mechanistic correlation, hiPSC-CMs were generated from the first five participants with distinct genetic variants and assessed for hERG maturation and trafficking. Overall, lumacaftor produced a significant QTc shortening (P < .001). The per-patient change averaged 31 ± 21 ms. Patients with baseline QTc ≥500 ms exhibited the most substantial effect, with 75% achieving reductions ≥40 ms. No ventricular arrhythmias occurred, and adverse effects were primarily gastrointestinal and self-limited. In hiPSC-CMs, LUM restored hERG trafficking in three out of five variants, mirroring the clinical observations. Short-term LUM therapy is safe and yields a significant QTc shortening in LQT2 patients with a trafficking defect. Concordance between cellular and clinical findings reinforces the value of a mechanism-based, variant-informed approach and supports the feasibility of trafficking-correction strategies within a precision-medicine framework for inherited arrhythmia syndromes.
2026-09-16 | Antiemetic-Associated QT Prolongation: A Clinical Review and Risk-Stratified Prescribing Framework for Long QT Syndrome.
Nausea and vomiting accompany pregnancy, gastroenteritis, migraine, the perioperative period, and cytotoxic chemotherapy, and antiemetics are among the most frequently prescribed drugs worldwide. Several antiemetic classes delay ventricular repolarization and prolong the QT interval, a substrate for torsades de pointes (TdP), ventricular fibrillation, and sudden cardiac death. We synthesized the evidence on antiemetic QT liability and translated it into a three-tier, risk-stratified prescribing framework and stepwise clinical algorithm for patients with inherited or acquired long QT syndrome (LQTS) and other torsadogenic risk factors. We conducted a narrative review of PubMed/MEDLINE, EMBASE, and pharmacovigilance sources (FDA Adverse Event Reporting System, CredibleMeds/QTdrugs) through early 2026, prioritizing mechanistic studies, randomized comparisons, disproportionality analyses, and consensus statements on antiemetic QT liability and LQTS management. QT prolongation across antiemetic classes is driven principally by IKr blockade (hERG/KCNH2). Risk is highly heterogeneous within classes: in a 2026 FAERS disproportionality analysis, ondansetron carried a substantially stronger QT-related signal than olanzapine (reporting odds ratio 27.2 vs 8.7), consistent with its dose-dependent effect among 5-HT3 antagonists, which prompted a 2012 FDA restriction on the 32 mg intravenous dose; palonosetron has minimal effect. Neurokinin-1 antagonists, low-risk antihistamines, anticholinergics, and 5-HT4 agonists carry little QT liability, while butyrophenones, phenothiazines, and promethazine carry greater risk. Serious events cluster in patients with electrolyte disturbance, bradycardia, polypharmacy, or underlying LQTS, particularly when QTc exceeds 500 ms or rises more than 60 ms from baseline. Antiemetic-associated arrhythmia is largely preventable. Structured risk assessment, electrolyte correction, ECG monitoring, and a stepwise selection strategy favouring agents with minimal QT liability allow clinicians to manage nausea and vomiting safely, even in high-risk populations.
2026-09-11 | Molecular basis for state-dependent drug block of Kv11.1 (human ether-à-go-go-related gene) potassium channels.
Many structurally and therapeutically diverse drugs block the human ether-à-go-go-related gene (HERG) potassium channel, predisposing patients to an increased risk of arrhythmias and sudden cardiac death. Many of these drugs show state dependence of block, exhibiting a greater preference for block of the inactivated state. Four key residues, ie, T623, S624, Y652, and F656, within the central pore cavity of HERG have been implicated in drug binding. However, whether drugs bind differently to these key residues to dictate preference for binding to the inactivated over the open state is not known. We used the SyncroPatch 384PE, automated patch clamp platform to measure how drug block was impacted by point mutations at these 4 residues when introduced into wild-type (WT) HERG (preferentially occupies the inactivated state) and N588K-HERG (preferentially occupies the open state) channels at depolarized potentials. Mutations to Y652 and F656, which abolished aromatic and hydrophobic characteristics, respectively, reduced drug binding in both WT and N588K backgrounds. The S624A mutation attenuated block by cisapride, astemizole, and quinidine in the WT background but not in the N588K background. We suggest that relative movements between the polar S624 sidechain and the aromatic Y652 sidechains in WT (inactivated) compared with N588K (open) channels can explain preferential binding to the inactivated state. An improved understanding of the structural basis of where and how drugs bind to HERG channels should facilitate efforts to reduce inadvertent HERG drug block during the drug development process. SIGNIFICANCE STATEMENT: A diverse range of drugs block human ether-à-go-go-related gene (HERG) potassium channels, which can have serious side effects, including sudden death. Most problematic drugs bind to the inactivated state of HERG channels. This study shows that the polar side chain of Ser624, at the base of the selectivity filter, is critical for preferential drug block of inactivated compared with open channels. A better understanding of state-dependent drug binding should facilitate efforts to reduce inadvertent HERG drug block.
2026-08-27 | A hERG blocker facilitates K+ channel current by promoting pore opening while blocking.
Many drugs that block voltage-gated K+ channels encoded by the human ether-à-go-go-related gene (hERG) can cause long QT syndrome and life-threatening cardiac arrhythmias, yet the molecular mechanisms that determine this risk remain unclear. A process that may counteract arrhythmogenic hERG block, termed facilitation, is common to many clinically approved hERG blockers, including nifekalant, amiodarone, promethazine, imipramine, nortriptyline, haloperidol, verapamil, carvedilol, metoprolol, propranolol, quinidine, fluoxetine, and chlorpheniramine. Facilitation is an increase in hERG current, under certain conditions, due to these blockers. Here, we propose that an agonism-while-blocking mechanism underpins facilitation. We focus on nifekalant, a class III antiarrhythmic drug and exemplar hERG blocker that induces facilitation. We tested the hypothesis that nifekalant opens hERG channel gates while blocking, and that unblocking of these open-yet-blocked channels results in supranormal hERG current. We developed rate-theory kinetic models to identify features of agonism-while-blocking that produce facilitation. We generated atomistic models that predict that nifekalant blocks the hERG conduction path while modulating the intracellular conduction gate. Voltage-clamp measurements revealed that agonism-while-blocking can result in nifekalant block and facilitation. We speculate that this agonism-while-blocking mechanism contributes to the relative safety of hERG blockers that induce facilitation.
2026-08-12 | ERLAD-hERG axis and L-type calcium channel activation mediate cholesterol-induced acquired long QT syndrome-related cardiotoxicity.
High cholesterol is a key cardiovascular risk factor that can modulate cardiac electrophysiology and promote acquired long QT syndrome (acLQTS)-related cardiotoxicity, a potentially life-threatening condition associated with QT prolongation, torsade de pointes, and sudden cardiac death. This study investigated the effects of cholesterol overload on human Ether-à-go-go-Related Gene (hERG/Kv11.1; encoded by KCNH2) potassium channels and L-type calcium channels (LTCC; mainly Cav1.2/CACNA1C in cardiomyocytes), as well as the underlying mechanisms of acLQTS-related cardiotoxicity, using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), whole-cell patch clamp, quantitative real-time PCR (qRT-PCR), Western blotting, immunoprecipitation, fluorescence imaging, and a high-cholesterol diet guinea pig model with rosuvastatin intervention combined with optical mapping. The results showed that transient cholesterol exposure inhibited hERG tail current amplitude and accelerated channel inactivation, with the effect showing a Y652-dependent component, while also enhancing LTCC activity. Mechanistically, cholesterol overload triggered endoplasmic reticulum (ER) stress, impaired hERG proteostasis, and promoted ER-to-lysosome-associated degradation (ERLAD) of hERG. This process was associated with CANX-mediated recognition of abnormal hERG and FAM134B-LC3B-related autophagic-lysosomal processing, contributing to reduced total hERG expression and membrane-localized mature hERG. FAM134B overexpression partially preserved hERG expression and attenuated cholesterol-induced ER stress/autophagy-related abnormalities. In vivo, rosuvastatin improved lipid profiles and cardiac remodeling in high-cholesterol guinea pigs but was associated with more pronounced action potential duration (APD) and QT interval prolongation under high-cholesterol conditions. These findings suggest that cholesterol overload may increase susceptibility to hERG-related repolarization abnormalities during rosuvastatin exposure and highlight the importance of cholesterol management and electrocardiographic (ECG) monitoring in hypercholesterolemic settings.
gene therapies
2026-09-14 | Variable Expressivity in Long QT Syndrome Type 2 Rabbits Defines a Low Threshold for Therapeutic IKr Restoration.
Long QT syndrome type 2 (LQT2) is caused by pathogenic variants in the hERG potassium channel, resulting in QT prolongation, polymorphic ventricular tachycardia (pVT), and sudden cardiac death. We previously developed a transgenic LQT2 rabbit model that recapitulates the human disease and segregates into two phenotypically distinct lines, LQT2A and LQT2G. Using optical mapping and cardiomyocyte patch clamp, we investigated the electrophysiological basis of variable disease expressivity and its potential future implications for gene therapy. LQT2G hearts were highly arrhythmogenic, with isoproterenol inducing frequent premature ventricular contractions and pVT, whereas LQT2A hearts required additional IKr blockade to reliably trigger arrhythmias. Patch clamp recordings revealed IKr expression in 21% of LQT2A cardiomyocytes at near-wild-type current density, compared with only 5.5% of LQT2G cells exhibiting low IKr. Computer simulations demonstrated that restoration of IKr in >23% of cardiomyocytes fully suppressed early afterdepolarizations through electrotonic coupling. To assess achievable transgene expression, we designed a novel minimally invasive gene delivery method for rabbits. To this end, neonatal wild-type rabbits received three different doses of AAV9 encoding the red-fluorescent reporter mKate2 via jugular vein injection, resulting in viral-load-dependent, regionally distributed mosaic cardiac expression reaching approximately 20%. However, high-dose intravenous AAV9 delivery was associated with dose-dependent hindlimb weakness and dorsal root ganglia pathology, indicating that this administration route is not suitable in rabbits despite achieving biologically sufficient levels of cardiac transduction. Our experimental observations and computational modeling identify ~20% as a plausible range for effective IKr restoration, generating a testable therapeutic hypothesis.
2026-02-28 | A population-based study of trends in cardiac arrest and sudden death owing to long QT syndrome.
Population-based data on long QT syndrome (LQTS) are lacking. New Zealand has a national LQTS registry, molecular autopsy program, and standardized investigation of resuscitated cardiac arrest (RSCA). This study aimed to describe trends in LQTS detection and presentation with RSCA/sudden cardiac death over 24 years. Review of data on registry participants who underwent genetic testing for LQTS presenting between 2000 and 2023. Among 915 diagnosed as having LQTS, 378 probands with a mean corrected QT interval of 512 ± 52 ms presented with sudden cardiac death (26 of 378; 7%), RSCA (82; 21%), syncope or seizure (122; 32%), and incidental/other (148; 40%). Causative genetic variants were found in 165 of 378 probands (44%): 98 KCNQ1 (59%), 41 KCNH2 (25%), 7 SCN5A (4%), and 19 other genes (12%). 593 of 915 participants (65%) were on therapy (beta blocker [565; 62%], implantable cardioverter-defibrillator [134; 16%], and/or left cardiac sympathetic denervation [69; 8%]). 3 likely arrhythmic deaths (0.3%) and 23 appropriate implantable cardioverter-defibrillator shocks (3%) occurred during follow-up (median 12 years). Detections of LQTS/population were 0.5 of 100,000 in 2000, 1.6 of 100,000 in 2009, and 0.4 of 100,000 in 2023. Presentation with RSCA decreased by 10%/y from 2007. Presentation with death decreased by 22%/y from 2014 (P = .026), with no deaths from 2019 to 2023. Decreasing rates of LQTS detection in recent years suggest that most cases have been discovered in New Zealand. Decreasing cardiac arrest and sudden death owing to LQTS is likely related to the success of the overall program.
2026-02-28 | Silencing the Mutant KCNH2 Allele to Reduce the Effects of Long QT Syndrome Type 2.
Long-QT syndrome type 2 (LQTS2), which is associated with life-threatening cardiac arrhythmias, is caused by pathogenic heterozygous loss-of-function mutations in the KCNH2 gene. This gene encodes the pore-forming Kv11.1 α-subunit of the ion channel that carries the rapid delayed rectifier potassium current (IKr). Pathogenic loss-of-function mutations reduce the amplitude of IKr, thereby prolonging the action potential (AP) of ventricular cardiomyocytes, and in turn, the QT interval of the electrocardiogram (ECG). The aim of the present in silico study was to test the extent to which allele-specific suppression ('silencing') of the mutant KCNH2 allele can alleviate the effects of dominant-negative LQTS2 mutations. Two recent and comprehensive models of the electrical activity of a single human ventricular cardiomyocyte, i.e., the 'Bartolucci-Passini-Severi model as published in 2020' and the 'Tomek-Rodriguez model following the O'Hara-Rudy dynamic (ORd) model' (known as the BPS2020 and ToR-ORd models, respectively) were used to assess the effects of mild and severe LQTS2 mutations on the AP duration at 90% repolarization (APD90) and the APD90 restitution obtained with an S1-S2 pacing protocol. For severe mutations, the mutation-induced prolongation of the APD90 at a stimulation rate of 1 Hz is reduced from 166% to 99% in the BPS2020 model and from 111% to 71% in the ToR-ORd model upon 70% suppression of the mutant allele. For mild mutations, this prolongation is reduced from 77% to 44% and from 57% to 34%, respectively. An even greater effect is observed when the mutant KCNH2 allele is inhibited by up to 90%, but the greater suppression is only marginal for mild mutations. The steepness of the mutant APD90 restitution curves is considerably reduced upon suppression, which may exert an anti-arrhythmic effect. Silencing of the mutant allele can substantially, but only partially, counteract the effects of mild or severe LQTS2 mutations on IKr. Allele-specific inhibition of the mutant KCNH2 allele alone is not sufficient to fully treat the effects of LQTS2 mutations and should be accompanied by a replacement gene therapy, creating a suppression-and-replacement ("SupRep") gene therapy.
2025-12-25 | Mapping the Functional Landscape of KCNQ1 to Define Ion Channel Mechanisms and Arrhythmia Risk.
Loss-of-function variants in KCNQ1 are the primary cause of congenital Long QT Syndrome (LQTS), characterized by QT prolongation and increased risk of fatal arrhythmias. The surge in genetic testing continues to uncover vast numbers of variants of uncertain significance in Mendelian disease genes, including KCNQ1. Using four multiplexed assays, we mapped the functional landscape of KCNQ1, identifying trafficking, gating, and dominant negative variants. We provide functional evidence for 13,403 variants, including 1,757 with strong pathogenic and 6,660 with moderate benign evidence. Structure-function analyses revealed variant enrichment in regions regulating trafficking, multimerization, ubiquitylation, and channel gating. Loss-of-function variants showed a risk ratio of 263 (95% CI 241-286) in an LQTS cohort and were significantly associated with QTc prolongation and LQTS diagnoses in biobank participants. By characterizing the functional impact of nearly all KCNQ1 variants, we provide critical insights into arrhythmia mechanisms and open new avenues for precision medicine in LQTS.
2025-10-30 | Gene Therapy for Inherited Cardiac Arrhythmias.
Inherited cardiac arrhythmias are genetic disorders that impact the heart's electrical circuitry. These disorders are caused by inherited mutations and markedly increase the mortality risk of affected individuals. Conventional treatments, such as pharmacological agents for rate and rhythm control or surgical interventions, are often not efficacious and cause long-term complications. Gene therapy has recently emerged as a feasible and potentially curative approach for treating inherited cardiac arrhythmia syndromes. Advancements in elucidating the molecular mechanisms, pinpointing essential candidate genes, and improving gene delivery have rendered gene therapy as a feasible treatment alternative. This review examines recent studies on gene therapy applications in Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, long QT syndrome, familial atrial fibrillation, and arrhythmogenic cardiomyopathy. Additionally, we analyze current advancements in viral and non-viral gene delivery methods, highlighting their therapeutic potential and related challenges.
cell therapies
2026-06-10 | Multidisciplinary management of video-assisted thoracoscopic left cardiac sympathetic denervation in a young child with Jervell and Lange-Nielsen syndrome.
Left cardiac sympathetic denervation (LCSD) via video-assisted thoracoscopy (VATS) is an effective therapy for drug-refractory malignant arrhythmias in congenital long QT syndromes and requires meticulous perioperative planning in children with automatic implantable cardioverter-defibrillators (AICDs). We describe what is likely the first paediatric VATS-LCSD performed in Pakistan. A boy in early childhood with Jervell and Lange-Nielsen syndrome, severe QT prolongation and recurrent ventricular arrhythmias despite beta-blockade and mexiletine had received multiple AICD shocks. Intraoperative management focused on preventing electrocautery-induced AICD activation by applying a magnet to suspend antitachycardia therapies, using external defibrillation pads and ensuring continuous electrophysiology support. Anaesthesia incorporated sevoflurane, dexmedetomidine, cisatracurium and lidocaine, with one-lung ventilation achieved by intentional endobronchial tracheal tube placement. Thoracoscopic excision of the left sympathetic chain (T5-T1), including the lower stellate, was completed uneventfully. The child was extubated in the operating room and discharged the next day without complications.
2026-04-24 | Trigger Type and Breakthrough Cardiac Events in Inherited Arrhythmia Syndromes After Left Cardiac Sympathetic Denervation.
Left cardiac sympathetic denervation (LCSD) confers a strong antifibrillatory effect and provides significant therapeutic efficacy for patients with genetic heart diseases, especially long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). We hypothesize that LCSD's efficacy may differ among patients experiencing adrenergic (AD) vs nonadrenergic (non-AD) triggered symptoms before LCSD. In this study, we sought to evaluate the association between AD and non-AD triggered events and the subsequent risk of breakthrough cardiac events (BCEs) after LCSD. A retrospective review of all previously symptomatic patients with either LQTS or CPVT who underwent LCSD at our institution since 2005 was performed. Data from electronic medical records was abstracted for cardiac event (CE) trigger type (AD or non-AD) before and after LCSD. CEs and BCEs were defined as arrhythmogenic syncope, seizure, appropriate ventricular fibrillation-terminating therapies, and sudden cardiac arrest or death. Among 154 pre-LCSD symptomatic patients (mean age at diagnosis: 15 ± 12 years; follow-up after LCSD: 5.9 ± 4.2 years) with LQTS (n = 105; 68%) or CPVT (n = 49; 32%), 49 patients (32%) had >1 BCE. Post-LCSD BCEs were significantly higher in patients with non-AD triggered CE (n = 30/56; 54%)) compared with patients with AD-triggered CE (n = 19/98; 19%; P < 0.0001). The subset analysis found fewest BCEs in LQT1 patients with AD triggers (OR: 0.24, P < 0.0001). To date, no BCEs have occurred in LQT2, LQT3, or LQT Minor patients with pre-LCSD AD-triggered CEs. There is a marked pre-LCSD phenotypic determinant of LCSD's therapeutic efficacy. Independently from underlying genotype, patients with adrenergic triggers associated with their pre-LCSD symptoms had a greater reduction in disease-mediated BCEs.
2026-02-13 | [Cardiac arrhythmias-Cellular mechanisms, consequences and challenges in the diagnostics using human models].
Cardiac arrhythmias significantly contribute to morbidity and mortality in cardiovascular diseases. Hereditary ion channel disorders, including Brugada syndrome, long/short QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT), represent critical entities with elevated risk of malignant ventricular arrhythmias. Although beta-blockers, ion channel modulators and implantable cardioverter defibrillators (ICD) are available and the indications for them are increasingly based on genetic analyses, variants of uncertain significance (VUS) substantially impair the risk stratification. Atrial tachyarrhythmias, particular atrial fibrillation, can cause an often-reversible arrhythmia-induced cardiomyopathy (AIC). Pathophysiologically, the Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays an important role in atrial and ventricular arrhythmias. It can be activated by various pathological triggers, such as high heart rate, neuroendocrine activation and oxidative stress, the latter often resulting from mechano-energetic uncoupling. The development of effective treatment options for arrhythmia-associated cardiovascular diseases requires the use of human model systems in addition to animal experimental approaches, due to the genetic heterogeneity and systemic comorbidities. Patient-specific cardiac stem cell-models enable the classification of VUS and personalised drug testing. The integration of new methodological approaches into existing animal experimental approaches thus paves the way for functionally validated precision medicine and could fundamentally transform the treatment of both disease patterns.
2025-11-03 | Cardiac sympathetic denervation for refractory ventricular arrhythmias in patients with inherited cardiomyopathies.
Cardiac sympathetic denervation (CSD) is a therapeutic option in patients with recurrent or refractory ventricular arrhythmia (VA). Successful outcomes have largely been established among patients with underlying ischemic cardiomyopathy, patients with nonischemic cardiomyopathy, and young patients diagnosed as having long-QT syndrome or catecholaminergic polymorphic ventricular tachycardia. Patients with inherited cardiomyopathies have a rare prevalence but experience VAs and sudden cardiac death. Herein, we studied the outcomes of CSD on patients with refractory VA and an inherited cardiomyopathy. Data from adult patients with VA referred for CSD were reviewed from 4 tertiary referral centers between 2010 and 2023. Patients with a minimum postoperative follow-up time of 12 months and an inherited cardiomyopathy were included: hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy, or dilated cardiomyopathy. 23 patients with an inherited cardiomyopathy underwent bilateral CSD: 7 patients with hypertrophic cardiomyopathy, 11 patients with arrhythmogenic cardiomyopathy, and 5 patients with dilated cardiomyopathy. The median (interquartile range) follow-up time was 34.5 months (23.1-46.5). The overall success rate of CSD was 48%. When comparing pre- and post-CSD periods, implantable cardioverter-defibrillator shocks decreased by 61% (P < .01). Transplant-free survival at 4 years was 76%. Most of the expected complications resolved upon follow-up. Bilateral CSD significantly reduced implantable cardioverter-defibrillator shocks in patients with inherited cardiomyopathies, demonstrating durable arrhythmia control and favorable long-term transplant-free survival across diverse genetic subtypes.
2025-10-22 | Perioperative management of thoracoscopic left cardiac sympathetic denervation for refractory long QT syndrome: a case report.
Long QT syndrome (LQTS) refractory to standard treatments, including β-blockers and implantable cardioverter-defibrillators (ICDs), has been indicated for left cardiac sympathetic denervation (LCSD) in Europe and the United States. However, the clinical implementation of LCSD remains rarely performed in Japan as it is not covered by national health insurance. A 49-year-old woman with LQTS experienced frequent ICD activations, and β-blocker up-titration was limited due to severe heart failure. As a stellate ganglion block transiently shortened QT interval, LCSD was considered to prevent life-threatening arrhythmic events. Total intravenous anesthesia combined with a left thoracic paravertebral block was used to attenuate sympathetic nervous activation. Thoracoscopic LCSD was performed without arrhythmia or hemodynamic instability. The patient remained stable postoperatively, with no further ICD activations. This case demonstrates the safe perioperative management of LCSD for drug-refractory LQTS by incorporating strategies to minimize QT prolongation and suppress malignant arrhythmias.
proteins
2026-04-17 | Allosteric Mechanisms Underlying Long QT Syndrome Type 2 (LQT2)-Associated Mutations in hERG Channels.
1 Long QT syndrome Type 2 (LQT2) is a genetic disorder caused by missense mutations in the KCNH2 gene that encodes the potassium channel K V 11.1. Previous studies have shown that most K V 11.1 missense mutations with loss-of-function phenotypes result from impaired trafficking from the endoplasmic reticulum to the plasma membrane. To investigate the molecular basis of these defects, we used molecular dynamics simulations to analyze two sets of disease-associated missense mutations: those that suppress and those that maintain normal channel trafficking. We focused initially on the conformational and dynamics differences between wild-type and several mutants of K V 11.1 via molecular dynamics simulations when two K + were placed in the selectivity filter (SF). Our study reveals that missense mutations in the S4 helix allosterically disrupt the selectivity filter, a critical determinant for proper channel trafficking. Trafficking-competent variants largely retained a wild-type selectivity filter structure, whereas trafficking-deficient mutants exhibited pronounced structural perturbations in this region. These findings suggest that certain LQT2-associated missense mutations in KCNH2 impair channel trafficking by compromising the structural integrity of the selectivity filter. We additionally found that second-site variants Y652C in the drug binding vestibule can correct structural defects associated with some mistrafficking variants.
2026-03-02 | Structural differences in Apo-, D132E- and Holo-Calmodulin bound to the IQ domain of the cardiac L-type calcium channel.
Proper regulation of the cardiac L-type calcium channel (CaV1.2) involves calcium-dependent inactivation (CDI) of the channel. CDI is mediated by the calcium-sensing protein calmodulin (CaM), which interacts with the IQ domain of CaV1.2. CaM mutations have been implicated in dangerous cardiac arrhythmias such as long-QT syndrome (LQTS), but it is not clear how structural changes at the CaM-CaV1.2 binding interface can lead to LQTS. In this study, we examine structural differences in holo-, apo- and D132E-CaM bound to the IQ domain of CaV1.2 using molecular dynamics (MD) simulations and molecular mechanics Poisson-Boltzmann surface area (MMPBSA) binding free energy calculations. Calcium (Ca2+) binding to CaM is shown to stabilise key binding interaction triplets in the C-lobe of holo-CaM-CaV1.2. We additionally find that D132E-CaM-CaV1.2 is able to bind with higher affinity than holo-CaM-CaV1.2 due to subtle structural changes taking place at the CaM-CaV1.2 binding interface. The differences in the CaM-CaV1.2 binding interface are larger when calcium is not bound, as opposed to the differences induced by the mutation, which suggests that the D132E mutation may lead to LQTS via defective binding of Ca2+ to CaM as opposed to structural changes occurring at the CaM-CaV1.2 binding interface.
2026-02-19 | Theoretical analysis of low-power optogenetic suppression of action potentials in human ventricular cardiomyocytes expressed with potassium-selective channelrhodopsins.
Effective suppression of cardiac tachyarrhythmias and shortening of action potential duration (APD) remain major challenges in cardiac optogenetics due to the non-selectivity of ion-conducting channelrhodopsins (ChRs). We present a comprehensive theoretical analysis of optogenetic suppression of electrical activity and temporally precise shortening of APD in human ventricular cardiomyocytes (HVCMs) expressed with WiChR and HcKCR1 potassium (K⁺)-selective ChRs that exhibit reversal potentials close to the diastolic membrane potential of the targeted cardiac cells. Our simulations show that K⁺-selective ChRs provide more efficient hyperpolarizing control compared to cation-selective variants. Our computational simulations show that WiChR exhibits action-potential suppression at very low irradiance (4 × 10⁻² mW/mm²), while HcKCR1 could not achieve full suppression at 10 mW/mm². This makes WiChR a much stronger and more effective option for optical inhibition in human ventricular cardiomyocytes. At irradiance of 1 × 101 mW/mm², our simulations show that WiChR hyperpolarizes the membrane to -83.14 mV, closely approaching the K⁺ equilibrium potential, whereas HcKCR1 reached − 82.39 mV. The results are important for the treatment of cardiac arrhythmias and long QT syndrome. This work provides mechanistic insight into low-power optogenetic control of cardiac electrophysiology and offers quantitative predictions to guide future in vitro and in vivo investigations aimed at developing safer and more precise alternatives to electrical pacing and defibrillation technologies.
2025-02-20 | A privileged ER compartment for post-translational heteromeric assembly of an ion channel.
Mechanisms underlying heterotypic subunit assembly of ion channels and other oligomeric complexes are poorly understood. In the human heart, heteromeric assembly of two isoforms encoded by the human ether-à-go-go related gene (hERG) is essential for the normal function of cardiac IKr in ventricular repolarization, with loss of hERG1b contributing to arrhythmias associated with long QT-syndrome (LQTS). While hERG1a homomers traffic efficiently to the plasma membrane, hERG1b homomers are retained in the endoplasmic reticulum (ER). When expressed together, the two subunits avidly associate during biogenesis. Seeking rules specifying heteromeric association, we characterized the fate of hERG1b proteins using confocal and superresolution imaging in fixed and live HeLa cells. We found hERG1b sequestered in punctate intracellular structures when expressed alone in HeLa cells. These puncta, which depend on the presence of an N-terminal "RXR" ER retention signal, represent a privileged ER sub-compartment distinct from that containing ER-retained, type 2 (hERG-based) LQTS mutant proteins, which were rapidly degraded by the proteasome. Introducing hERG1a to cells with preformed hERG1b puncta dissolved these puncta by rescuing extant hERG1b. Rescue occurred by association of fully translated hERG1b with 1a, a surprising finding given previous studies demonstrating cotranslational heteromeric association. We propose that sequestration limits potentially deleterious surface expression of hERG1b homomeric channels while preserving hERG1b for an alternative mode of heteromeric hERG1a/1b channel assembly post-translationally. These findings reveal a surprising versatility of biosynthetic pathways promoting heteromeric assembly.
2024-09-30 | 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.
other
2026-05-19 | Functional characterization and allele-specific RNA interference-based rescue of KCNH2 p.F68C variant associated with long QT syndrome.
Long QT syndrome (LQTS) is an inherited life-threatening cardiac disorder characterized by delayed ventricular repolarization and increased risk of malignant arrhythmias. Among its subtypes, long QT syndrome type 2 (LQT2) is primarily caused by pathogenic variants in KCNH2, which encodes the human ether-à-go-go-related gene (hERG) potassium channel responsible for the rapid delayed rectifier current (IKr). However, the substantial functional heterogeneity among KCNH2 variants poses a major challenge for clinical interpretation and precision intervention. In this study, we sought to functionally characterize KCNH2 p.F68C variant (c.203T > G) identified in a Chinese LQT2 patient and to evaluate the feasibility of RNA interference-based modulation of its functional impact on the hERG channel. Using biochemical and electrophysiological analyses in HEK293T cells, we show that variant p.F68C causes a severe trafficking defect and exerts a dominant-negative effect on wild-type hERG channels, leading to markedly reduced rapid delayed rectifier potassium current (IKr). In contrast to several previously reported Per-Arnt-Sim (PAS) domain variants, the trafficking defect of p.F68C was resistant to reduced culture temperature, chemical chaperones, and pharmacological chaperones. Notably, allele-specific RNA interference selectively suppressed mutant hERG expression, alleviated dominant-negative interference, and partially restored hERG current density without detectable cytotoxicity. Together, these findings establish p.F68C as a loss-of-function KCNH2 variant and highlight allele-specific RNA interference as a variant-directed strategy that may serve as an alternative to suppression-replacement approaches, providing a basis for functional interpretation and precision therapeutic exploration of individual KCNH2 variants.
2025-04-07 | When HERG-caused LQT2 encounters antisense oligonucleotide: is exon 6 skipping therapy plausible?
The unique in-frame exon 6 of the HERG gene as a potential target for antisense oligonucleotide-mediated exon skipping therapy.
2025-01-09 | A PAS-targeting hERG1 activator reduces arrhythmic events in Jervell and Lange-Nielsen syndrome patient-derived hiPSC-CMs.
The hERG1 potassium channel conducts the cardiac repolarizing current, IKr. hERG1 has emerged as a therapeutic target for cardiac diseases marked by prolonged action potential duration (APD). Unfortunately, many hERG1 activators display off-target and proarrhythmic effects that limit their therapeutic potential. A Per-Arnt-Sim (PAS) domain in the hERG1 N-terminus reduces IKr by slowing channel activation and promoting inactivation. Disrupting PAS activity increases IKr and shortens APD in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). We thus hypothesized that the hERG1 PAS domain could represent a therapeutic target to reduce arrhythmogenic potential in a long QT syndrome (LQTS) background. To test this, we measured the antiarrhythmic capacity of a PAS-disabling single-chain variable fragment antibody, scFv2.10, in a hiPSC-CM line derived from a patient with Jervell and Lange Nielsen (JLN) syndrome. JLN is a severe form of LQTS caused by autosomal recessive mutations in KCNQ1. The patient in this study carried compound heterozygous mutations in KCNQ1. Corresponding JLN hiPSC-CMs displayed prolonged APD and early afterdepolarizations (EADs). Disrupting PAS with scFv2.10 increased IKr, shortened APD, and reduced the incidence of EADs. These data demonstrate that the hERG1 PAS domain could serve as a therapeutic target to treat disorders of cardiac electrical dysfunction.
2024-11-04 | Computational analysis of long QT syndrome type 2 and the therapeutic effects of KCNQ1 antibodies.
Long QT interval syndrome (LQTS) is a highly dangerous cardiac disease that can lead to sudden cardiac death; however, its underlying mechanism remains largely unknown. This study is conceived to investigate the impact of two general genotypes of LQTS type 2, and also the therapeutic effects of an emerging immunology-based treatment named KCNQ1 antibody. A multiscale virtual heart is developed, which contains multiple biological levels ranging from ion channels to a three-dimensional cardiac structure with realistic geometry. Critical biomarkers at different biological levels are monitored to investigate the remodeling of cardiac electrophysiology induced by mutations. Simulations revealed multiple important mechanisms that are hard to capture via conventional clinical techniques, including the augmented dispersion of repolarization, the increased vulnerability to arrhythmias, the impaired adaptability in tissue to high heart rates, and so on. An emerging KCNQ1 antibody-based therapy could rescue the prolonged QT interval but did not reduce the vulnerable window. Tiny molecular alterations can lead to cardiac electrophysiological remodeling at multiple biological levels, which in turn contributes to higher susceptibility to lethal arrhythmias in long QT syndrome type 2 patients. The KCNQ1 antibody-based therapy has proarrhythmic risks notwithstanding its QT-rescuing effects.
2024-07-31 | Clinical presentation and genetic characterization of early-onset atrial fibrillation in patients affected by long QT syndrome: A single-center experience.
Early-onset atrial fibrillation (AF) has already been observed in approximately 2% of patients with genetically proven long QT syndrome (LQTS). This frequency is higher than population-based estimates of early-onset AF. However, the concomitant expression of AF in LQTS is likely underestimated. The purpose of this study was to examine the clinical presentation, genetic background, and outcomes of a cohort of patients with LQTS and early-onset AF referred to a single tertiary center. Twenty-seven patients diagnosed with congenital LQTS were included in the study based on the documentation of early-onset (age ≤50 years) clinical or subclinical AF episodes in all available medical records, including standard electrocardiograms, wearable monitor or cardiac implantable electronic devices. Seventeen patients experienced clinical AF during the follow-up period. Subclinical AF was detected in 10 patients through insertable or wearable cardiac monitors. In our series, the mean heart rate during AF episodes was found to be relatively low despite the patients' young age and the low or minimal effective doses of beta-blockers used for QTc interval control. All patients exhibiting LQTS and early-onset AF were genotype positive, carrying mutations in the KCNQ1 (66%), KCNH2, KCNE1, and SCN5A genes. Notably, most of these patients carried the same p.(R231C) mutation in the KCNQ1 gene (59%) and were from the same families, suggesting concurrent expression of familial AF and LQTS. LQTS patients are prone to developing clinical and subclinical AF, even at a younger age. The occurrence of early-onset AF in the LQTS population could be more frequent than previously assumed. AF should be considered as a potential dysrhythmia related to LQTS. Our study emphasizes the importance of carefully researching clinical and/or subclinical episodes of AF through strict heart rhythm monitoring in the LQTS population.
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Drug Discovery Landscape
1 orphan drug designation for Jervell and Lange-Nielsen syndrome, including 1 approved therapy.
1 orphan drug designation for Jervell and Lange-Nielsen syndrome, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Amiodarone HCl [Cordarone] | small molecules | FDA | Approved | Wyeth-Ayerst Laboratories |
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