RARE DISEASE
Familial long QT syndrome
Familial long QT syndrome
Familial long QT syndrome
Synonyms: Congenital long QT syndrome, LQTS
Synonyms: Congenital long QT syndrome, LQTS
Synonyms: Congenital long QT syndrome, LQTS
Drug discovery
3
drugs
With orphan designations
Overview
Familial long QT syndrome (LQTS) is an inherited cardiac arrhythmia disorder characterized by prolonged ventricular repolarization (QT interval) on ECG, increasing the risk of syncope, torsades de pointes, and sudden cardiac death. Autosomal dominant Romano-Ward syndrome (RWS) accounts for 85% of cases, while autosomal recessive Jervell and Lange-Nielsen syndrome includes congenital deafness. Over 15 genetic subtypes involve ion channel mutations (e.g., KCNQ1, KCNH2, SCN5A), with triggers including exercise, stress, or QT-prolonging medications.
Burden
Therapies
First-line: Non-selective β-blockers (nadolol, propranolol) reduce cardiac events by 53–90% [1][3][13][17].
Adjuncts: Mexiletine (for LQT3), left cardiac sympathetic denervation (LCSD), and implantable cardioverter-defibrillators (ICDs) for high-risk patients [3][5][8].
Lifestyle modifications: Avoid QT-prolonging drugs, strenuous exercise, and electrolyte imbalances [1][6][11].
Categories: rare cardiac diseases, rare genetic diseases
Research Papers
1,682 drug discovery papers about Familial long QT syndrome, with 2 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,682 drug discovery papers about Familial long QT syndrome, with 2 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-06 | Case Report: Overlap of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia in two Chinese children with CALM2-related calmodulinopathy.
Calmodulinopathy is a rare CALM-related hereditary channelopathy presenting with long QT syndrome (LQTS), less commonly with catecholaminergic polymorphic ventricular tachycardia (CPVT) or LQTS/CPVT overlap. It carries high mortality and limited data from Chinese population. We reviewed two Chinese children with CALM2 mutation-related LQTS/CPVT overlap. Clinical data, genetic findings, and treatments were collected; outcomes were obtained via telephone follow-up. A systematic literature review was also performed. Case 1 was a 13-year-old girl with seven exercise-induced syncopal episodes. Sinus rhythm QTc 0.55 s, with bidirectional/polymorphic premature ventricular contractions, and ventricular tachycardia during exercise. A de novo CALM2 p.E140Q mutation was found. She remained event-free on propranolol and propafenone for two years. Case 2 was a 15-year-old boy with onset at 4 years. He experienced > 10 syncopal episodes triggered by recurrent exercise or emotional stress. Initial Holter monitoring revealed sinus bradycardia with a mean heart rate of 70 bpm and a maximum QTc of 0.51 s. A de novo CALM2 p.N98S mutation was found. Despite treatment with propranolol plus mexiletine, syncopal episodes continued, with the QTc interval further prolonged to 0.62 s. The p.E140Q variant is novel, whereas p.N98S has been previously reported. Literature suggests that β-blockers combined with Class Ic drugs may be more effective, and implantable cardioverter defibrillator (ICD) implantation should be considered in cases who respond poorly to medical therapy or survivors of aborted cardiac arrest. Patients who experience recurrent syncope coexisting with significant sinus bradycardia may have more severe phenotypes with higher risk of malignant arrhythmias, warranting earlier or more aggressive evaluation for device therapy. Genetic testing is recommended for suspected pediatric channelopathies with phenotype-guided individualized treatment.
2026-08-04 | Clonidine for ADHD with Comorbid Oppositional Defiant Disorder in a Patient with Congenital Long QT Syndrome
Background: Oppositional defiant disorder (ODD) and attention-deficit/hyperactivity disorder (ADHD) co-occur in roughly half of children with ADHD. Pharmacological management for both disorders typically involves stimulants or antipsychotics. However, in patients with congenital Long QT syndrome (LQTS), the use of stimulants might present an additional clinical risk for ventricular arrhythmias. Alternatives must be sought as the impact of these untreated psychiatric conditions can be significantly limiting to these patients. Case Presentation: A 14-year-old male with ODD and comorbid ADHD was started on risperidone 0.25 mg daily for severe behavioral dysregulation following incidents of serious aggression towards an infant sibling. Electrocardiography demonstrated marked QT prolongation (QTc = 508 ms) and subsequently confirmed a diagnosis of congenital LQTS with a maternal family history over 3 generations. Risperidone was discontinued and nadolol 20 mg daily was initiated by a pediatric cardiologist. After a second psychiatric opinion for persistent ADHD, oppositionality, aggression, and suicide risk, he was started on clonidine, a possible alternative to avoind the use of stimulants or antipsychotics. At the one-month follow-up, parents reported a lessening of impulsivity, physical aggression, and improved emotional self-regulation. He is continuing with psychological and cardiac monitoring. Discussion: This case demonstrated a different approach to treating patients with congenital LQTS and neurodevelopmental disorders when first-line pharmacotherapies present a risk to the patient. Clonidine offered clinical benefits without the risk of arrhythmia that comes with stimulants or antipsychotics. Given the lack of studies done on this population, more controlled studies are needed to study the effects of clonidine on patients with congenital LQTS and ODD with comorbid ADHD. Conclusion: Clonidine may be a promising alternative for treating ADHD and ODD in patients with congenital Long QT syndrome, although further research is needed to confirm its safety and effectiveness.
2026-07-20 | Effects of curcumin and nicorandil on nilotinib-induced QT interval prolongation in rats: A telemetry-based study.
Long QT syndrome (LQTS) is characterized by QT prolongation, ventricular arrhythmias and sudden death. Nilotinib (Nilo), a tyrosine kinase inhibitor used in chronic myeloid leukemia, prolongs QTc mainly through hERG (IKr) channel inhibition. Curcumin (Curc), often co-administered, modulates cardiac ion channels, whereas nicorandil (Nico) acts as a KATP channel opener. This study evaluated the effects of Curc and Nico on Nilo-induced QTc prolongation. Male Sprague-Dawley rats implanted with radiotelemetry transmitters received 10 mg/kg nilotinib (selected as the minimal effective dose based on preliminary dose-finding studies at 10, 30 and 50 mg/kg), 100 mg/kg curcumin, or 10 mg/kg nicorandil, as previously described. Animals were allocated into seven groups: Control, Nilo, Curc, Nico, Nilo+Curc, Nilo+Nico and Nilo+Curc+Nico. ECG, biochemical and histopathological analyses were performed. Data were analyzed using one-way ANOVA followed by Tukey's post hoc test. Nilotinib caused dose-dependent QTc prolongation, with 10 mg/kg as the minimal effective dose (p<0.001). Curcumin further exacerbated QTc prolongation, whereas nicorandil co-administration mitigated this effect. (p<0.001). Nilo also elevated TNF-α and TAS, which were attenuated in combination groups. Nilotinib-induced dose-dependent QTc prolongation was aggravated by curcumin, whereas nicorandil demonstrated a potential protective effect on drug-induced LQTS.
2026-07-16 | Multimodality Risk Stratification in Athletes With Long QT Syndrome.
Long QT syndrome has traditionally led to exercise restriction due to concerns for exertion-triggered arrhythmia and sudden cardiac death. Emerging data, however, support individualized participation guided by genotype and physiologic risk markers. We describe 3 young athletes with distinct genotypes (KCNE1 D85N [long QT syndrome type 5-Lite], KCNQ1 R555H [long QT syndrome type 1], and KCNH2 p.T613M [long QT syndrome type 2]) evaluated through electrocardiography, exercise testing, and echocardiographic assessment of the electromechanical window. The electromechanical window ranged from mildly to severely negative (-11 to -103 ms) and corresponded with phenotypic severity. Personalized management, including selective β-blockade, mexiletine, and device therapy, enabled safe continuation of sports participation in all cases. This case series underscores the role of genotype-specific, multimodality assessment in risk stratifying athletes with long QT syndrome. Integration of individualized therapy, shared decision making, and structured emergency preparedness supports safe athletic participation while maintaining arrhythmic protection and quality of life. Individualized risk assessment including resting and stress electrocardiography, genotype analysis, and electromechanical window measurement provides a more accurate estimate of arrhythmic risk than does resting QTc interval alone. Genotype-guided therapy and structured sports counseling allow most patients with LQTS to safely engage in exercise and even competitive athletics under expert supervision. Shared decision making and emergency preparedness, including automated external defibrillator access and multidisciplinary collaboration, are essential to balancing athletic participation with long-term safety in patients with LQTS.
2026-07-15 | Bisoprolol Treatment and Adherence in Pediatric Patients With Genotype-Positive Long QT Syndrome.
Non-selective beta-blockers, such as propranolol, are highly effective in reducing arrhythmia risk in long QT Syndrome (LQTS). The study aim was to evaluate the use of beta-blockers, especially beta-1-selective bisoprolol, and their efficacy in Finnish children with genotype-positive LQTS type 1 or 2. We retrospectively reviewed the medical records of children with genetically confirmed LQTS1 or LQTS2 diagnosis, who were treated at Tampere University Hospital in Finland between 2006 and 2020. Data on cardiac events, beta-blocker use and adherence, ECG, clinical exercise tests, and genetic testing were collected. Eighty-eight children were diagnosed with a genotype-positive type 1 or 2 LQTS, and 84% of them had a family history of LQTS associated gene mutations. Four Finnish founder mutations accounted for 68% of the cases. At diagnosis, 63% had a normal QTc interval. No cardiac events occurred during follow-up among patients receiving beta-blocker therapy. For children aged 0-7 years, propranolol was the primary medication in 90% of cases, and for > 7-year-olds, bisoprolol was used in 77% of cases. At the last follow-up visit, 87/88 were on beta-blockers, most commonly bisoprolol (66%). Medication adherence was high, with 84% of patients using beta-blockers as prescribed. In clinical exercise tests, maximal heart rate remained < 160 beats per minute in 76% of tests, indicating effective beta-blockade. Cascade screening identified asymptomatic patients, most with normal QTc intervals. Bisoprolol was the most commonly used beta-blocker with good adherence, effective heart rate control, and no cardiac events observed during follow-up among these Finnish children with LQTS.
cell therapies
2026-07-03 | Combined Leadless Pacing and Subcutaneous ICD Therapy in Long QT Syndromes.
Congenital long QT syndrome (LQTS) is associated with ventricular arrhythmias and increased risk of sudden cardiac death. Beta-blockers are first-line therapy, although intolerance may occur. We report a case of a 50-year-old man with LQTS and subcutaneous implantable cardioverter-defibrillator (S-ICD) who experienced recurrent appropriate therapies and beta-blocker intolerance due to bradycardia. An atrial leadless pacemaker was implanted while maintaining the S-ICD, achieving a double-device strategy without intracardiac leads. This approach resulted in QTc shortening, symptom improvement, and complete suppression of further ICD therapies. This strategy may represent a feasible and effective alternative in selected LQTS patients requiring atrial pacing.
2025-12-11 | Atrial-Specific KCNQ1 Channelopathy Drives Arrhythmogenesis and Unmasks Amiodarone Proarrhythmia in a Human iPSC Model
Background : While KCNQ1 mutations (I Ks channel α-subunit) are known to cause long QT syndrome (LQTS) presenting with atrial fibrillation (AF), the underlying mechanisms remain incompletely characterized. Methods : We report a novel KCNQ1 c.625T>C (p.Ser209Pro) mutation identified through whole-exome sequencing and Sanger validation in a LQTS pedigree with atypical AF presentation. Utilizing non-invasive urine-derived epithelial cells, we generated integration-free induced pluripotent stem cells (iPSCs) from patients (S209P-iPSC) and established precise homozygous repair of the mutation via CRISPR/Cas9 to create isogenic controls (GC-iPSC), complemented by healthy control iPSCs (CTRL-iPSC). Critically, we developed an atrial-specific differentiation protocol yielding patient-derived atrial cardiomyocytes (aCMs). Patch-clamp and multi-electrode array electrophysiological analyses revealed prolonged action potential duration and delayed repolarization in mutant aCMs—providing the first direct evidence that KCNQ1 dysfunction drives AF susceptibility through impaired atrial repolarization, resolving a key mechanistic gap in channelopathy-associated arrhythmogenesis. Results : Electrophysiological analysis revealed the KCNQ1 c.625T>C mutation induces a tissue-specific channelopathy: patient-derived aCMs exhibited significantly prolonged field potential duration (FPDc) and reduced I Ks current versus controls – indicating distinct atrial-selective repolarization impairment. Crucially, antiarrhythmic testing uncovered paradoxical responses: amiodarone, though clinically used for AF prevention, exacerbated atrial pathology by further prolonging FPDc in dose-dependent fashion and inducing torsade de pointes-like arrhythmias in mutant atrial cells, whereas nadolol normalized FPDc. This mechanistic discordance manifested clinically where amiodarone failed to terminate AF but induced long QT in familial patients – providing the first direct evidence of KCNQ1-mediated atrial vulnerability to proarrhythmic drug effects. Conclusion : The KCNQ1 c.625T>C mutation causes atrial-specific delayed repolarization via I Ks reduction, driving AF in LQTS. We resolve the amiodarone proarrhythmia paradox and establish CRISPR-edited iPSC-atrial myocytes as a transformative platform for precision antiarrhythmic therapy.
2025-12-06 | Long QT Syndrome With KCNH2/SCN5A Dual Gene Mutation Leading to Electrical Storm.
Long QT syndrome (LQTS) is a genetic ion channel abnormality characterized by a long QT interval and torsades de pointes. Torsades de pointes can progress to ventricular fibrillation and sudden cardiac death, and stressful conditions such as infections can be an acquired trigger of malignant arrhythmias. LQTS due to compound genetic mutations are clinically rare, and its diagnosis and therapy are challenging and require a multidisciplinary comprehensive intervention. A 62-year-old man presented with malignant arrhythmia and shock, triple-vessel coronary artery disease, dual LQT mutations (KCNH2/LQT2 and SCN5A/LQT3), and Gram-negative sepsis. The arrhythmia was successfully controlled by means of emergency defibrillation, temporary pacing, anti-infective therapy, and ultimately the placement of an implantable cardioverter-defibrillator. In this patient, the double gene mutations KCNH2 and SCN5A caused LQTS, which caused electrical storm and mixed shock under infectious stress. Based on the electrocardiographic changes, the dynamic evolution of troponin levels, and genetic testing, LQTS was a more plausible etiology than acute coronary syndrome. An integrated multimodal strategy was used: anti-infective therapy, temporary pacing to shorten the QT interval, and implantable cardioverter-defibrillator placement. This case highlights the value of genetic diagnosis of complex arrhythmias and the need for acute-phase trigger control and long-term treatment. When managing malignant arrhythmias, hereditary channelopathies and infections need to be considered as significant causes. Genetic testing plays an important role in diagnosis, risk assessment, and family management.
2025-07-03 | Catheter Ablation of Triggers and Arrhythmogenic Epicardial Substrates in Patients with QT Prolongation.
Long QT syndrome (LQTS) ablation is currently limited to high-risk or refractory cases, targeting the elimination of triggers such as ventricular premature contraction (VPC). However, the characteristics of the underlying substrate and the role of radiofrequency ablation have not been extensively discussed. Eight symptomatic patients with LQTS (all women; aged 36 ± 10.2 years) underwent 3-D endocardial and epicardial mapping of triggers and/or substrates of ventricular arrhythmias. Genetic testing revealed P1093A mutations in the KCNH2 gene, H558R mutations in the SCN5A gene, and K28E mutations in the KCNH2 gene in three patients, respectively. A total of 13 VPC morphologies were identified, including five right ventricular outflow tract (RVOT) VPCs, one basal lateral RV, two from inferoapical RV, one from the lateral to annulus tricuspid, three from basal lateral LV and one from epicardial site of the lateral mitral annulus. Epicardial voltage mapping revealed moderate to extensive areas of scar and low voltage in all patients. The localized abnormal ventricular activities (LAVAs) were recorded in all patients and were successfully ablated. The corrected QT interval (QTc) shortened after the epicardial LAVA elimination (594.9 ± 85.98 ms vs. 490 ± 67.49 ms, p = 0.001). During a mean follow-up period of 288 ± 147.4 d (range 170-492 d), two patients experienced ventricular tachycardia (VT) /ventricular fibrillation (VF) recurrence. Regional and limited epicardial LAVAs could be identified in patients with LQTS. Radiofrequency ablation of VPC triggers and epicardial LAVAs had a modest effect on preventing future VT/VF recurrences.
2025-04-22 | Induced Pluripotent Stem Cells in Congenital Long QT Syndrome: Research Progress and Clinical Applications
Congenital long QT syndrome (LQTS) is a potentially life-threatening hereditary arrhythmia characterized by a prolonged QT interval on electrocardiogram (ECG) due to delayed ventricular repolarization. This condition predisposes individuals to severe arrhythmic events, including ventricular tachycardia and sudden cardiac death. Traditional approaches to LQTS research and treatment are limited by an incomplete understanding of its gene-specific pathophysiology, variable clinical presentation, and the challenges associated with developing effective, personalized therapies. Recent advances in human induced pluripotent stem cell (iPSC) technology have opened new avenues for elucidating LQTS mechanisms and testing therapeutic strategies. By generating cardiomyocytes from patient-specific iPSCs (iPSC-CMs), it is now possible to recreate the patient’s genetic context and study LQTS in a controlled environment. This comprehensive review describes how iPSC technology deepens our understanding of LQTS and accelerates the development of tailored treatments, as well as ongoing challenges such as incomplete cell maturation and cellular heterogeneity.
gene therapies
2026-06-01 | In vivo trafficking and functional analysis of hERG missense variants in a CRISPR/Cas9-engineered C. elegans model of congenital long-QT syndrome
Abstract Background Loss-of-function variants in KCNH2, which encodes the voltage-gated hERG (Kv11.1) K+ channel, are responsible for congenital long-QT syndrome type 2 (LQT2), a major cause of sudden cardiac death in young individuals. Yet, most hERG missense variants remain of uncertain significance, underscoring the need for scalable functional assays. Heterologous expression systems offer high-throughput assays but lack the native molecular context for hERG biogenesis and rely on overexpression. Induced pluripotent stem cell-derived cardiomyocytes provide a human cardiomyocyte background but are limited by fetal-like electrophysiology, inter-individual genetic variability, and limited scalability. Complex transgenic animals can reproduce the LQT2 phenotype but are limited by their complexity, time requirements and ethical rules. A conserved, scalable and tractable in vivo model is needed to overcome these different limitations. UNC-103, the C. elegans Kv channel ortholog of hERG, exhibits strong conservation in sequence, structure, and key regulators of biogenesis. Methods We developed a CRISPR/Cas9-engineered Caenorhabditis elegans in vivo model of LQT2 using fluorescently tagged UNC-103 knock-in strains. To quantify the trafficking efficiency and functional impact of hERG missense variants, we established an approach combining quantitative confocal imaging with assays of C. elegans egg-laying. Results The model faithfully recapitulated the known profiles of two previously well-characterized LQT2-associated hERG missense variants (G604S and G628S) and enabled in vivo characterization of a novel variant recently identified by our group (G603S). G604S and G603S showed trafficking defects (less then 50% of UNC-103 signal at neuromuscular junctions Figure 1A top, and increased somatic retention in ALM neurons Figure 1B), whereas G628S displayed normal trafficking (Figure 1A bottom). Functionally, G604S and G628S induced severe egg-laying defects, while G603S exhibited a milder phenotypic profile (Figure 2). Conclusions Our CRISPR/Cas9-engineered C. elegans model of LQT2 provides a physiologically relevant and scalable tool for in vivo characterization of hERG missense variants. This approach bridges the gap between in vitro assays and complex transgenic animals and opens new avenues for drug screening in LQT2.
2026-05-27 | Hidden Cardiac Channelopathies in Children Presenting with Syncope and Seizure-like Events.
Background: Cardiac channelopathies are rare but potentially life-threatening disorders that may present with syncope or seizure-like episodes in children, often leading to misdiagnosis and delayed recognition. Other arrhythmia-associated cardiac conditions may also present with similar clinical manifestations and require careful cardiac evaluation. Objective: To evaluate the prevalence of cardiac channelopathies and inherited arrhythmogenic cardiac disorders in pediatric patients presenting with syncope and seizure-like events and to identify associated clinical and electrocardiographic features. Methods: This retrospective cross-sectional study included pediatric patients presenting with syncope, presyncope, seizures, or seizure-like episodes who underwent cardiac evaluation at Ankara Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital between January 2015 and April 2019. Cardiac evaluation was performed using a standard 12-lead electrocardiogram and was complemented by additional investigations, including 24 h Holter monitoring, exercise testing, pharmacological provocation, electrophysiological studies, and genetic analysis, when clinically indicated. Demographic, clinical, and diagnostic parameters were systematically evaluated. Results: A total of 363 patients were included in the final analysis. The mean age was 12.2 ± 4.7 years, and 58.7% were female. The most common diagnosis was vasovagal syncope (n = 160, 44.1%), followed by epilepsy (n = 53, 14.6%). Cardiac channelopathies, and arrhythmogenic right ventricular dysplasia (ARVD) were identified in 18 patients, corresponding to 4.9% of the pediatric cardiology-evaluated patients and 0.82% of the initial screened population. These diagnoses included long QT syndrome (n = 8), Brugada syndrome (n = 3), short QT syndrome (n = 3), catecholaminergic polymorphic ventricular tachycardia (n = 2), ARVD (n = 1), and malignant-type early repolarization (n = 1). Compared with other patients, those with cardiac channelopathies, malignant-type early repolarization, and ARVD more frequently had exercise-related triggers (p < 0.001), ventricular extrasystoles and ventricular tachycardia (p < 0.001), and abnormal exercise test findings (p < 0.001). Conclusions: Cardiac channelopathies are not uncommon in pediatric patients presenting with syncope and seizure-like events and should be considered in the differential diagnosis. Clinical triggers, family history, and electrocardiographic abnormalities may serve as important clues for early identification. A multidisciplinary approach, including detailed cardiac evaluation, is essential to prevent misdiagnosis and reduce the risk of sudden cardiac death.
2026-03-05 | Perinatal management of congenital long QT syndrome: A case of maternal and fetal manifestations
Congenital long QT syndrome (LQTS) encompasses a group of heritable channelopathies characterized by cardiac repolarization dysfunction and an increased risk of ventricular arrhythmias. The three major autosomal dominant subtypes (types I, II, and III) are linked to mutations in cardiac potassium and sodium ion channels, leading to prolonged QTc intervals. Over 75% of cases are attributed to mutations in three primary genes: KCNQ1, KCNH2 (potassium channels) and SCN5A (sodium channels) (1).
2026-01-27 | Genetics of Sudden Cardiac Death.
Cardiomyopathies (DCM, HCM, and ACM) and primary arrhythmogenic disorders (BrS, LQTS, and CPVT) represent the most common causes of sudden cardiac death (SCD) in young individuals. Systematic genome-wide single-nucleotide polymorphism (SNP) analyses and genome-wide association studies (GWASs) have enabled the identification of numerous genetic variants associated with cardiovascular diseases. Body: Genetic testing for cardiomyopathies and inherited channelopathies primarily involves panel testing of genes with definitive and strong evidence of disease association; genes supported by moderate evidence may also be considered. Cardiomyocytes express a variety of proteins implicated in the pathogenesis of genetic cardiomyopathies, including sarcomeric, cytoskeletal, desmosomal, and nuclear envelope proteins. Inherited cardiac channelopathies result from mutations in genes encoding cellular components that influence calcium ion availability or affect membrane ion channels, including sodium, potassium, and calcium channels. Common variants associated with SCD are found in genes encoding cardiac ion channels (e.g., SCN5A, KCNQ1, and KCNH2), calmodulin (CALM2), sarcomeric proteins (MYH7, MYBPC3, TTN, and TNNI3), and desmosomal proteins (RyR2 and DES). This review demonstrates that specific genetic variants are significantly associated with an increased risk of SCD. The evidence underscores the importance of genetic screening and early intervention in individuals with a family history of SCD or other risk factors for inherited cardiac disorders predisposing to SCD. Future research should focus on gene-specific management strategies for familial cardiomyopathies and inherited channelopathies, with the goal of improving targeted genetic therapies and reducing the burden of sudden cardiac death.
2025-12-09 | Spatial and temporal dispersion of ventricular repolarization in pediatric patients with congenital long QT syndrome
Congenital long QT-syndrome (LQTS) is a genetic disorder characterized by prolonged corrected QT-intervals (QTc, Bazett’s formula) longer than 450ms in males and 460 ms in females on the 12-lead surface electrocardiogram (ECG). This syndrome is caused by mutations in genes encoding ion channels, prolonging cardiac repolarization.1 Consequently, LQTS may give rise to life-threatening ventricular tachyarrhythmias and is a leading cause of sudden cardiac death (SCD) in young individuals without structural heart abnormalities.
proteins
2026-03-12 | hERG epitope mimic-decoy peptide corrects autoimmune-long QT syndrome in guinea pigs.
The most investigated form of autoimmune-long-QT-syndrome (LQTS) is caused by circulating anti-Ro/SSA(Sjögren's syndrome-related antigen-A)-52kD antibodies, which cross-react with a specific sequence of the human ether-à-go-go-related (hERG) potassium channel's pore region, reducing the rapid inward-rectifying potassium current (IKr) density. We designed the scaffolded monobody decoy peptide-4, MDP4, comprised of a segment of the hERG extracellular pore region fused to a carrier monobody, aiming to neutralize the circulating anti-Ro/SSA-52kD antibodies cross-reacting with hERG. MDP4 was designed using 3D-structure-based protein engineering and optimized via conformational search and energy minimization. QT-interval prolongation was induced in an established guinea pig model of autoimmune-associated LQTS via injection of Ro/SSA-52kD antigen over 15 days. Upon confirmation of QT-interval prolongation, MDP4 was administered, and electrocardiogram parameters were monitored for 30 days. IKr and action potentials were measured using the patch-clamp technique in guinea pig ventricular cardiomyocytes treated with IgG isolated from the sera of an anti-Ro/SSA-52kD antibody-positive patient with LQTS and Torsades de Pointes. Guinea pigs immunized with Ro/SSA-52kD antigen exhibit QTc prolongation and hERG-cross-reactive anti-Ro/SSA-52kD serum antibodies. In vivo treatment with MDP4 reverses QTc prolongation. MDP4 in vitro treatment of guinea pig ventricular myocytes also reverses IKr inhibition and action potential duration prolongation by anti-Ro/SSA-52kD antibodies from patients with LQTS and Torsades de Pointes. Treatment with MDP4 results in recovery of both the QT-interval prolongation in vivo and IKr inhibition in vitro. MDP4 and other conceptually similar molecules may represent an innovative therapeutic approach for autoimmune LQTS in humans, and, prospectively, for other forms of arrhythmogenic autoimmune cardiac channelopathies.
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.
2026-01-01 | Venom Hymenoptera Immunotherapy in A Patient Affected by Long QT Syndrome
Introduction: Many drugs employed for treating allergic reactions, such as epinephrine and antihistamines, are contraindicated in patients affected by long QT syndrome (LQTS). Moreover, betablocker drugs used for LQTS reduce the efficacy of epinephrine. Patients affected by concomitant LQTS and venom hymenoptera allergy are a difficult challenge for allergologists. This report describes the case of a patient affected by LQTS and allergy to honeybee who was submitted to venom immunotherapy (VIT). Methods: A patient with congenital LQTS and adverse reactions after hymenoptera stings was evaluated at the Azienda Ospedaliera Universitaria Pisana (Pisa, Italy). In vitro and in vivo tests were performed, followed by VIT, according to guidelines. Results: A 40 years-woman affected by congenital LQTS suffered of suspected allergic reaction after a honeybee sting; chlorphenamine and systemic steroid administered by clinician resolved symptoms but induced an intense malaise with QT prolongation. The cardiologist prescribed methoprolol daily. In vivo and in vitro test demonstrated honeybee allergy so we started VIT. VIT allows to protect the patients from both severe allergic reactions and side effects of anti-allergic drugs. We suggest considering LQTS as a selected indication for allergen immunotherapy.
2022-06-14 | Pharmacological activation of the hERG K+ channel for the management of the long QT syndrome: A review
Abstract In the human heart, the rapid delayed rectifier K + current ( I Kr ) contributes significantly to ventricular action potential (AP) repolarization and to set the duration of the QT interval of the surface electrocardiogram (ECG). The pore‐forming (α) subunit of the I Kr channel is encoded by KCNH2 or human ether‐à‐go‐go‐related gene 1 (hERG1). Impairment of hERG function through either gene mutation (congenital) or pharmacological blockade by diverse drugs in clinical use (acquired) can cause a prolongation of the AP duration (APD) reflected onto the surface ECG as a prolonged QT interval or Long QT Syndrome (LQTS). LQTS can increase the risk of triggered activity of ventricular cardiomyocytes and associated life‐threatening arrhythmia. Current treatments all focus on reducing the incidence of arrhythmia or terminating it after its onset but there is to date no prophylactic treatment for the pharmacological management of LQTS. A new class of hERG modulators (agonists) have been suggested through direct interaction with the hERG channel to shorten the action potential duration (APD) and/or increase the postrepolarisation refractoriness period (PRRP) of ventricular cardiomyocytes protecting thereby against triggered activity and associated arrhythmia. Although promising drug candidates, there remain major obstacles to their clinical development. The aim of this review is to summarize the latest advances as well as the limitations of this proposed pharmacotherapy.
2021-07-01 | Role and mechanism of chaperones calreticulin and ERP57 in restoring trafficking to mutant HERG‑A561V protein
Long QT syndrome type 2 is caused by a mutation in the human‑ether‑a‑go‑go‑related gene (HERG) gene encoding the rapidly activating delayed rectifier K‑current. HERG is a key cell membrane glycoprotein; however, whether the maturation process of HERG protein involves key molecules derived from the calnexin (CNX)/calreticulin (CRT) cycle and how these molecules work remains unknown. Using western blotting, the present study screened the key molecules CNX/CRT/endoplasmic reticulum protein 57 (ERP57) involved in this cycle, and it was revealed that the protein expression levels of CNX/CRT/ERP57 in wild‑type (WT)/A561V cells were increased compared with those in WT cells (n=3; P<0.05). Additionally, a co‑immunoprecipitation experiment was used to reveal that the ability of CNX/ERP57/CRT to interact with HERG was significantly increased in A561V and WT/A561V cells (n=3; P<0.05). A plasmid lacking the bb' domain of ERP57 was constructed and it was demonstrated that the key site of ERP57 binding to CRT and immature HERG protein is the bb' domain. The whole‑cell patch‑clamp technique detected that the tail current density increased by 46% following overexpression of CRT and by 53% following overexpression of ERP57 in WT/A561V cells. Overexpression of CRT and ERP57 could increased HERG protein levels on the membrane detected by confocal imaging. Furthermore, overexpression of ERP57 and CRT proteins could restore the HERG‑A561V mutant protein trafficking process and rescue the dominant‑negative suppression of WT. Overall, ERP57/CRT served a crucial role in the HERG‑A561V mutant protein trafficking deficiency and degradation process.
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.
2025-01-09 | 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.
2024-06-07 | Joint effects of CD8A and ICOS in Long QT Syndrome (LQTS) and Beckwith-Wiedemann Syndrome (BWS).
Long QT Syndrome (LQTS) and Beckwith-Wiedemann Syndrome (BWS) are complex disorders with unclear origins, underscoring the need for in-depth molecular investigations into their mechanisms. The main aim of this study is to identify the shared key genes between LQTS and BWS, shedding light on potential common molecular pathways underlying these syndromes. The LQTS and BWS datasets are available for download from the GEO database. Differential expression genes (DEGs) were identified. Weighted gene co-expression network analysis (WGCNA) was used to detect significant modules and central genes. Gene enrichment analysis was performed. CIBERSORT was used for immune cell infiltration analysis. The predictive protein interaction (PPI) network of core genes was constructed using STRING, and miRNAs regulating central genes were screened using TargetScan. Five hundred DEGs associated with Long QT Syndrome and Beckwith-Wiedemann Syndrome were identified. GSEA analysis revealed enrichment in pathways such as T cell receptor signaling, MAPK signaling, and adrenergic signaling in cardiac myocytes. Immune cell infiltration indicated higher levels of memory B cells and naive CD4 T cells. Four core genes (CD8A, ICOS, CTLA4, LCK) were identified, with CD8A and ICOS showing low expression in the syndromes and high expression in normal samples, suggesting potential inverse regulatory roles. The expression of CD8A and ICOS is low in long QT syndrome and Beckwith-Wiedemann syndrome, indicating their potential as key genes in the pathogenesis of these syndromes. The identification of shared key genes between LQTS and BWS provides insights into common molecular mechanisms underlying these disorders, potentially facilitating the development of targeted therapeutic strategies.
2023-12-06 | Proof of concept for monoclonal antibody therapy in a cellular model of acquired long QT syndrome type 3.
Long QT syndrome (LQTS) type 3 although less common than the first two forms, differs in that arrhythmic events are less likely triggered by adrenergic stimuli and are more often lethal. Effective pharmacological treatment is challenged by interindividual differences, mutation dependence, and adverse effects, translating into an increased use of invasive measures (implantable cardioverter-defibrillator, sympathetic denervation) in patients with LQTS type 3. Previous studies have demonstrated the therapeutic potential of polyclonal KCNQ1 antibody for LQTS type 2. Here, we sought to identify a monoclonal KCNQ1 antibody that preserves the electrophysiological properties of the polyclonal form. Using hybridoma technology, murine monoclonal antibodies were generated, and patch clamp studies were performed for functional characterization. We identified a monoclonal KCNQ1 antibody able to normalize cardiac action potential duration and to suppress arrhythmias in a pharmacological model of LQTS type 3 using human-induced pluripotent stem cell-derived cardiomyocytes.NEW & NOTEWORTHY Long QT syndrome is a leading cause of sudden cardiac death in the young. Recent research has highlighted KCNQ1 antibody therapy as a new treatment modality for long QT syndrome type 2. Here, we developed a monoclonal KCNQ1 antibody that similarly restores cardiac repolarization. Moreover, the identified monoclonal KCNQ1 antibody suppresses arrhythmias in a cellular model of long QT syndrome type 3, holding promise as a first-in-class antiarrhythmic immunotherapy.
small molecules
2026-08-06 | Case Report: Overlap of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia in two Chinese children with CALM2-related calmodulinopathy.
Calmodulinopathy is a rare CALM-related hereditary channelopathy presenting with long QT syndrome (LQTS), less commonly with catecholaminergic polymorphic ventricular tachycardia (CPVT) or LQTS/CPVT overlap. It carries high mortality and limited data from Chinese population. We reviewed two Chinese children with CALM2 mutation-related LQTS/CPVT overlap. Clinical data, genetic findings, and treatments were collected; outcomes were obtained via telephone follow-up. A systematic literature review was also performed. Case 1 was a 13-year-old girl with seven exercise-induced syncopal episodes. Sinus rhythm QTc 0.55 s, with bidirectional/polymorphic premature ventricular contractions, and ventricular tachycardia during exercise. A de novo CALM2 p.E140Q mutation was found. She remained event-free on propranolol and propafenone for two years. Case 2 was a 15-year-old boy with onset at 4 years. He experienced > 10 syncopal episodes triggered by recurrent exercise or emotional stress. Initial Holter monitoring revealed sinus bradycardia with a mean heart rate of 70 bpm and a maximum QTc of 0.51 s. A de novo CALM2 p.N98S mutation was found. Despite treatment with propranolol plus mexiletine, syncopal episodes continued, with the QTc interval further prolonged to 0.62 s. The p.E140Q variant is novel, whereas p.N98S has been previously reported. Literature suggests that β-blockers combined with Class Ic drugs may be more effective, and implantable cardioverter defibrillator (ICD) implantation should be considered in cases who respond poorly to medical therapy or survivors of aborted cardiac arrest. Patients who experience recurrent syncope coexisting with significant sinus bradycardia may have more severe phenotypes with higher risk of malignant arrhythmias, warranting earlier or more aggressive evaluation for device therapy. Genetic testing is recommended for suspected pediatric channelopathies with phenotype-guided individualized treatment.
2026-08-04 | Clonidine for ADHD with Comorbid Oppositional Defiant Disorder in a Patient with Congenital Long QT Syndrome
Background: Oppositional defiant disorder (ODD) and attention-deficit/hyperactivity disorder (ADHD) co-occur in roughly half of children with ADHD. Pharmacological management for both disorders typically involves stimulants or antipsychotics. However, in patients with congenital Long QT syndrome (LQTS), the use of stimulants might present an additional clinical risk for ventricular arrhythmias. Alternatives must be sought as the impact of these untreated psychiatric conditions can be significantly limiting to these patients. Case Presentation: A 14-year-old male with ODD and comorbid ADHD was started on risperidone 0.25 mg daily for severe behavioral dysregulation following incidents of serious aggression towards an infant sibling. Electrocardiography demonstrated marked QT prolongation (QTc = 508 ms) and subsequently confirmed a diagnosis of congenital LQTS with a maternal family history over 3 generations. Risperidone was discontinued and nadolol 20 mg daily was initiated by a pediatric cardiologist. After a second psychiatric opinion for persistent ADHD, oppositionality, aggression, and suicide risk, he was started on clonidine, a possible alternative to avoind the use of stimulants or antipsychotics. At the one-month follow-up, parents reported a lessening of impulsivity, physical aggression, and improved emotional self-regulation. He is continuing with psychological and cardiac monitoring. Discussion: This case demonstrated a different approach to treating patients with congenital LQTS and neurodevelopmental disorders when first-line pharmacotherapies present a risk to the patient. Clonidine offered clinical benefits without the risk of arrhythmia that comes with stimulants or antipsychotics. Given the lack of studies done on this population, more controlled studies are needed to study the effects of clonidine on patients with congenital LQTS and ODD with comorbid ADHD. Conclusion: Clonidine may be a promising alternative for treating ADHD and ODD in patients with congenital Long QT syndrome, although further research is needed to confirm its safety and effectiveness.
2026-07-20 | Effects of curcumin and nicorandil on nilotinib-induced QT interval prolongation in rats: A telemetry-based study.
Long QT syndrome (LQTS) is characterized by QT prolongation, ventricular arrhythmias and sudden death. Nilotinib (Nilo), a tyrosine kinase inhibitor used in chronic myeloid leukemia, prolongs QTc mainly through hERG (IKr) channel inhibition. Curcumin (Curc), often co-administered, modulates cardiac ion channels, whereas nicorandil (Nico) acts as a KATP channel opener. This study evaluated the effects of Curc and Nico on Nilo-induced QTc prolongation. Male Sprague-Dawley rats implanted with radiotelemetry transmitters received 10 mg/kg nilotinib (selected as the minimal effective dose based on preliminary dose-finding studies at 10, 30 and 50 mg/kg), 100 mg/kg curcumin, or 10 mg/kg nicorandil, as previously described. Animals were allocated into seven groups: Control, Nilo, Curc, Nico, Nilo+Curc, Nilo+Nico and Nilo+Curc+Nico. ECG, biochemical and histopathological analyses were performed. Data were analyzed using one-way ANOVA followed by Tukey's post hoc test. Nilotinib caused dose-dependent QTc prolongation, with 10 mg/kg as the minimal effective dose (p<0.001). Curcumin further exacerbated QTc prolongation, whereas nicorandil co-administration mitigated this effect. (p<0.001). Nilo also elevated TNF-α and TAS, which were attenuated in combination groups. Nilotinib-induced dose-dependent QTc prolongation was aggravated by curcumin, whereas nicorandil demonstrated a potential protective effect on drug-induced LQTS.
2026-07-16 | Multimodality Risk Stratification in Athletes With Long QT Syndrome.
Long QT syndrome has traditionally led to exercise restriction due to concerns for exertion-triggered arrhythmia and sudden cardiac death. Emerging data, however, support individualized participation guided by genotype and physiologic risk markers. We describe 3 young athletes with distinct genotypes (KCNE1 D85N [long QT syndrome type 5-Lite], KCNQ1 R555H [long QT syndrome type 1], and KCNH2 p.T613M [long QT syndrome type 2]) evaluated through electrocardiography, exercise testing, and echocardiographic assessment of the electromechanical window. The electromechanical window ranged from mildly to severely negative (-11 to -103 ms) and corresponded with phenotypic severity. Personalized management, including selective β-blockade, mexiletine, and device therapy, enabled safe continuation of sports participation in all cases. This case series underscores the role of genotype-specific, multimodality assessment in risk stratifying athletes with long QT syndrome. Integration of individualized therapy, shared decision making, and structured emergency preparedness supports safe athletic participation while maintaining arrhythmic protection and quality of life. Individualized risk assessment including resting and stress electrocardiography, genotype analysis, and electromechanical window measurement provides a more accurate estimate of arrhythmic risk than does resting QTc interval alone. Genotype-guided therapy and structured sports counseling allow most patients with LQTS to safely engage in exercise and even competitive athletics under expert supervision. Shared decision making and emergency preparedness, including automated external defibrillator access and multidisciplinary collaboration, are essential to balancing athletic participation with long-term safety in patients with LQTS.
2026-07-15 | Bisoprolol Treatment and Adherence in Pediatric Patients With Genotype-Positive Long QT Syndrome.
Non-selective beta-blockers, such as propranolol, are highly effective in reducing arrhythmia risk in long QT Syndrome (LQTS). The study aim was to evaluate the use of beta-blockers, especially beta-1-selective bisoprolol, and their efficacy in Finnish children with genotype-positive LQTS type 1 or 2. We retrospectively reviewed the medical records of children with genetically confirmed LQTS1 or LQTS2 diagnosis, who were treated at Tampere University Hospital in Finland between 2006 and 2020. Data on cardiac events, beta-blocker use and adherence, ECG, clinical exercise tests, and genetic testing were collected. Eighty-eight children were diagnosed with a genotype-positive type 1 or 2 LQTS, and 84% of them had a family history of LQTS associated gene mutations. Four Finnish founder mutations accounted for 68% of the cases. At diagnosis, 63% had a normal QTc interval. No cardiac events occurred during follow-up among patients receiving beta-blocker therapy. For children aged 0-7 years, propranolol was the primary medication in 90% of cases, and for > 7-year-olds, bisoprolol was used in 77% of cases. At the last follow-up visit, 87/88 were on beta-blockers, most commonly bisoprolol (66%). Medication adherence was high, with 84% of patients using beta-blockers as prescribed. In clinical exercise tests, maximal heart rate remained < 160 beats per minute in 76% of tests, indicating effective beta-blockade. Cascade screening identified asymptomatic patients, most with normal QTc intervals. Bisoprolol was the most commonly used beta-blocker with good adherence, effective heart rate control, and no cardiac events observed during follow-up among these Finnish children with LQTS.
cell therapies
2026-07-03 | Combined Leadless Pacing and Subcutaneous ICD Therapy in Long QT Syndromes.
Congenital long QT syndrome (LQTS) is associated with ventricular arrhythmias and increased risk of sudden cardiac death. Beta-blockers are first-line therapy, although intolerance may occur. We report a case of a 50-year-old man with LQTS and subcutaneous implantable cardioverter-defibrillator (S-ICD) who experienced recurrent appropriate therapies and beta-blocker intolerance due to bradycardia. An atrial leadless pacemaker was implanted while maintaining the S-ICD, achieving a double-device strategy without intracardiac leads. This approach resulted in QTc shortening, symptom improvement, and complete suppression of further ICD therapies. This strategy may represent a feasible and effective alternative in selected LQTS patients requiring atrial pacing.
2025-12-11 | Atrial-Specific KCNQ1 Channelopathy Drives Arrhythmogenesis and Unmasks Amiodarone Proarrhythmia in a Human iPSC Model
Background : While KCNQ1 mutations (I Ks channel α-subunit) are known to cause long QT syndrome (LQTS) presenting with atrial fibrillation (AF), the underlying mechanisms remain incompletely characterized. Methods : We report a novel KCNQ1 c.625T>C (p.Ser209Pro) mutation identified through whole-exome sequencing and Sanger validation in a LQTS pedigree with atypical AF presentation. Utilizing non-invasive urine-derived epithelial cells, we generated integration-free induced pluripotent stem cells (iPSCs) from patients (S209P-iPSC) and established precise homozygous repair of the mutation via CRISPR/Cas9 to create isogenic controls (GC-iPSC), complemented by healthy control iPSCs (CTRL-iPSC). Critically, we developed an atrial-specific differentiation protocol yielding patient-derived atrial cardiomyocytes (aCMs). Patch-clamp and multi-electrode array electrophysiological analyses revealed prolonged action potential duration and delayed repolarization in mutant aCMs—providing the first direct evidence that KCNQ1 dysfunction drives AF susceptibility through impaired atrial repolarization, resolving a key mechanistic gap in channelopathy-associated arrhythmogenesis. Results : Electrophysiological analysis revealed the KCNQ1 c.625T>C mutation induces a tissue-specific channelopathy: patient-derived aCMs exhibited significantly prolonged field potential duration (FPDc) and reduced I Ks current versus controls – indicating distinct atrial-selective repolarization impairment. Crucially, antiarrhythmic testing uncovered paradoxical responses: amiodarone, though clinically used for AF prevention, exacerbated atrial pathology by further prolonging FPDc in dose-dependent fashion and inducing torsade de pointes-like arrhythmias in mutant atrial cells, whereas nadolol normalized FPDc. This mechanistic discordance manifested clinically where amiodarone failed to terminate AF but induced long QT in familial patients – providing the first direct evidence of KCNQ1-mediated atrial vulnerability to proarrhythmic drug effects. Conclusion : The KCNQ1 c.625T>C mutation causes atrial-specific delayed repolarization via I Ks reduction, driving AF in LQTS. We resolve the amiodarone proarrhythmia paradox and establish CRISPR-edited iPSC-atrial myocytes as a transformative platform for precision antiarrhythmic therapy.
2025-12-06 | Long QT Syndrome With KCNH2/SCN5A Dual Gene Mutation Leading to Electrical Storm.
Long QT syndrome (LQTS) is a genetic ion channel abnormality characterized by a long QT interval and torsades de pointes. Torsades de pointes can progress to ventricular fibrillation and sudden cardiac death, and stressful conditions such as infections can be an acquired trigger of malignant arrhythmias. LQTS due to compound genetic mutations are clinically rare, and its diagnosis and therapy are challenging and require a multidisciplinary comprehensive intervention. A 62-year-old man presented with malignant arrhythmia and shock, triple-vessel coronary artery disease, dual LQT mutations (KCNH2/LQT2 and SCN5A/LQT3), and Gram-negative sepsis. The arrhythmia was successfully controlled by means of emergency defibrillation, temporary pacing, anti-infective therapy, and ultimately the placement of an implantable cardioverter-defibrillator. In this patient, the double gene mutations KCNH2 and SCN5A caused LQTS, which caused electrical storm and mixed shock under infectious stress. Based on the electrocardiographic changes, the dynamic evolution of troponin levels, and genetic testing, LQTS was a more plausible etiology than acute coronary syndrome. An integrated multimodal strategy was used: anti-infective therapy, temporary pacing to shorten the QT interval, and implantable cardioverter-defibrillator placement. This case highlights the value of genetic diagnosis of complex arrhythmias and the need for acute-phase trigger control and long-term treatment. When managing malignant arrhythmias, hereditary channelopathies and infections need to be considered as significant causes. Genetic testing plays an important role in diagnosis, risk assessment, and family management.
2025-07-03 | Catheter Ablation of Triggers and Arrhythmogenic Epicardial Substrates in Patients with QT Prolongation.
Long QT syndrome (LQTS) ablation is currently limited to high-risk or refractory cases, targeting the elimination of triggers such as ventricular premature contraction (VPC). However, the characteristics of the underlying substrate and the role of radiofrequency ablation have not been extensively discussed. Eight symptomatic patients with LQTS (all women; aged 36 ± 10.2 years) underwent 3-D endocardial and epicardial mapping of triggers and/or substrates of ventricular arrhythmias. Genetic testing revealed P1093A mutations in the KCNH2 gene, H558R mutations in the SCN5A gene, and K28E mutations in the KCNH2 gene in three patients, respectively. A total of 13 VPC morphologies were identified, including five right ventricular outflow tract (RVOT) VPCs, one basal lateral RV, two from inferoapical RV, one from the lateral to annulus tricuspid, three from basal lateral LV and one from epicardial site of the lateral mitral annulus. Epicardial voltage mapping revealed moderate to extensive areas of scar and low voltage in all patients. The localized abnormal ventricular activities (LAVAs) were recorded in all patients and were successfully ablated. The corrected QT interval (QTc) shortened after the epicardial LAVA elimination (594.9 ± 85.98 ms vs. 490 ± 67.49 ms, p = 0.001). During a mean follow-up period of 288 ± 147.4 d (range 170-492 d), two patients experienced ventricular tachycardia (VT) /ventricular fibrillation (VF) recurrence. Regional and limited epicardial LAVAs could be identified in patients with LQTS. Radiofrequency ablation of VPC triggers and epicardial LAVAs had a modest effect on preventing future VT/VF recurrences.
2025-04-22 | Induced Pluripotent Stem Cells in Congenital Long QT Syndrome: Research Progress and Clinical Applications
Congenital long QT syndrome (LQTS) is a potentially life-threatening hereditary arrhythmia characterized by a prolonged QT interval on electrocardiogram (ECG) due to delayed ventricular repolarization. This condition predisposes individuals to severe arrhythmic events, including ventricular tachycardia and sudden cardiac death. Traditional approaches to LQTS research and treatment are limited by an incomplete understanding of its gene-specific pathophysiology, variable clinical presentation, and the challenges associated with developing effective, personalized therapies. Recent advances in human induced pluripotent stem cell (iPSC) technology have opened new avenues for elucidating LQTS mechanisms and testing therapeutic strategies. By generating cardiomyocytes from patient-specific iPSCs (iPSC-CMs), it is now possible to recreate the patient’s genetic context and study LQTS in a controlled environment. This comprehensive review describes how iPSC technology deepens our understanding of LQTS and accelerates the development of tailored treatments, as well as ongoing challenges such as incomplete cell maturation and cellular heterogeneity.
gene therapies
2026-06-01 | In vivo trafficking and functional analysis of hERG missense variants in a CRISPR/Cas9-engineered C. elegans model of congenital long-QT syndrome
Abstract Background Loss-of-function variants in KCNH2, which encodes the voltage-gated hERG (Kv11.1) K+ channel, are responsible for congenital long-QT syndrome type 2 (LQT2), a major cause of sudden cardiac death in young individuals. Yet, most hERG missense variants remain of uncertain significance, underscoring the need for scalable functional assays. Heterologous expression systems offer high-throughput assays but lack the native molecular context for hERG biogenesis and rely on overexpression. Induced pluripotent stem cell-derived cardiomyocytes provide a human cardiomyocyte background but are limited by fetal-like electrophysiology, inter-individual genetic variability, and limited scalability. Complex transgenic animals can reproduce the LQT2 phenotype but are limited by their complexity, time requirements and ethical rules. A conserved, scalable and tractable in vivo model is needed to overcome these different limitations. UNC-103, the C. elegans Kv channel ortholog of hERG, exhibits strong conservation in sequence, structure, and key regulators of biogenesis. Methods We developed a CRISPR/Cas9-engineered Caenorhabditis elegans in vivo model of LQT2 using fluorescently tagged UNC-103 knock-in strains. To quantify the trafficking efficiency and functional impact of hERG missense variants, we established an approach combining quantitative confocal imaging with assays of C. elegans egg-laying. Results The model faithfully recapitulated the known profiles of two previously well-characterized LQT2-associated hERG missense variants (G604S and G628S) and enabled in vivo characterization of a novel variant recently identified by our group (G603S). G604S and G603S showed trafficking defects (less then 50% of UNC-103 signal at neuromuscular junctions Figure 1A top, and increased somatic retention in ALM neurons Figure 1B), whereas G628S displayed normal trafficking (Figure 1A bottom). Functionally, G604S and G628S induced severe egg-laying defects, while G603S exhibited a milder phenotypic profile (Figure 2). Conclusions Our CRISPR/Cas9-engineered C. elegans model of LQT2 provides a physiologically relevant and scalable tool for in vivo characterization of hERG missense variants. This approach bridges the gap between in vitro assays and complex transgenic animals and opens new avenues for drug screening in LQT2.
2026-05-27 | Hidden Cardiac Channelopathies in Children Presenting with Syncope and Seizure-like Events.
Background: Cardiac channelopathies are rare but potentially life-threatening disorders that may present with syncope or seizure-like episodes in children, often leading to misdiagnosis and delayed recognition. Other arrhythmia-associated cardiac conditions may also present with similar clinical manifestations and require careful cardiac evaluation. Objective: To evaluate the prevalence of cardiac channelopathies and inherited arrhythmogenic cardiac disorders in pediatric patients presenting with syncope and seizure-like events and to identify associated clinical and electrocardiographic features. Methods: This retrospective cross-sectional study included pediatric patients presenting with syncope, presyncope, seizures, or seizure-like episodes who underwent cardiac evaluation at Ankara Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital between January 2015 and April 2019. Cardiac evaluation was performed using a standard 12-lead electrocardiogram and was complemented by additional investigations, including 24 h Holter monitoring, exercise testing, pharmacological provocation, electrophysiological studies, and genetic analysis, when clinically indicated. Demographic, clinical, and diagnostic parameters were systematically evaluated. Results: A total of 363 patients were included in the final analysis. The mean age was 12.2 ± 4.7 years, and 58.7% were female. The most common diagnosis was vasovagal syncope (n = 160, 44.1%), followed by epilepsy (n = 53, 14.6%). Cardiac channelopathies, and arrhythmogenic right ventricular dysplasia (ARVD) were identified in 18 patients, corresponding to 4.9% of the pediatric cardiology-evaluated patients and 0.82% of the initial screened population. These diagnoses included long QT syndrome (n = 8), Brugada syndrome (n = 3), short QT syndrome (n = 3), catecholaminergic polymorphic ventricular tachycardia (n = 2), ARVD (n = 1), and malignant-type early repolarization (n = 1). Compared with other patients, those with cardiac channelopathies, malignant-type early repolarization, and ARVD more frequently had exercise-related triggers (p < 0.001), ventricular extrasystoles and ventricular tachycardia (p < 0.001), and abnormal exercise test findings (p < 0.001). Conclusions: Cardiac channelopathies are not uncommon in pediatric patients presenting with syncope and seizure-like events and should be considered in the differential diagnosis. Clinical triggers, family history, and electrocardiographic abnormalities may serve as important clues for early identification. A multidisciplinary approach, including detailed cardiac evaluation, is essential to prevent misdiagnosis and reduce the risk of sudden cardiac death.
2026-03-05 | Perinatal management of congenital long QT syndrome: A case of maternal and fetal manifestations
Congenital long QT syndrome (LQTS) encompasses a group of heritable channelopathies characterized by cardiac repolarization dysfunction and an increased risk of ventricular arrhythmias. The three major autosomal dominant subtypes (types I, II, and III) are linked to mutations in cardiac potassium and sodium ion channels, leading to prolonged QTc intervals. Over 75% of cases are attributed to mutations in three primary genes: KCNQ1, KCNH2 (potassium channels) and SCN5A (sodium channels) (1).
2026-01-27 | Genetics of Sudden Cardiac Death.
Cardiomyopathies (DCM, HCM, and ACM) and primary arrhythmogenic disorders (BrS, LQTS, and CPVT) represent the most common causes of sudden cardiac death (SCD) in young individuals. Systematic genome-wide single-nucleotide polymorphism (SNP) analyses and genome-wide association studies (GWASs) have enabled the identification of numerous genetic variants associated with cardiovascular diseases. Body: Genetic testing for cardiomyopathies and inherited channelopathies primarily involves panel testing of genes with definitive and strong evidence of disease association; genes supported by moderate evidence may also be considered. Cardiomyocytes express a variety of proteins implicated in the pathogenesis of genetic cardiomyopathies, including sarcomeric, cytoskeletal, desmosomal, and nuclear envelope proteins. Inherited cardiac channelopathies result from mutations in genes encoding cellular components that influence calcium ion availability or affect membrane ion channels, including sodium, potassium, and calcium channels. Common variants associated with SCD are found in genes encoding cardiac ion channels (e.g., SCN5A, KCNQ1, and KCNH2), calmodulin (CALM2), sarcomeric proteins (MYH7, MYBPC3, TTN, and TNNI3), and desmosomal proteins (RyR2 and DES). This review demonstrates that specific genetic variants are significantly associated with an increased risk of SCD. The evidence underscores the importance of genetic screening and early intervention in individuals with a family history of SCD or other risk factors for inherited cardiac disorders predisposing to SCD. Future research should focus on gene-specific management strategies for familial cardiomyopathies and inherited channelopathies, with the goal of improving targeted genetic therapies and reducing the burden of sudden cardiac death.
2025-12-09 | Spatial and temporal dispersion of ventricular repolarization in pediatric patients with congenital long QT syndrome
Congenital long QT-syndrome (LQTS) is a genetic disorder characterized by prolonged corrected QT-intervals (QTc, Bazett’s formula) longer than 450ms in males and 460 ms in females on the 12-lead surface electrocardiogram (ECG). This syndrome is caused by mutations in genes encoding ion channels, prolonging cardiac repolarization.1 Consequently, LQTS may give rise to life-threatening ventricular tachyarrhythmias and is a leading cause of sudden cardiac death (SCD) in young individuals without structural heart abnormalities.
proteins
2026-03-12 | hERG epitope mimic-decoy peptide corrects autoimmune-long QT syndrome in guinea pigs.
The most investigated form of autoimmune-long-QT-syndrome (LQTS) is caused by circulating anti-Ro/SSA(Sjögren's syndrome-related antigen-A)-52kD antibodies, which cross-react with a specific sequence of the human ether-à-go-go-related (hERG) potassium channel's pore region, reducing the rapid inward-rectifying potassium current (IKr) density. We designed the scaffolded monobody decoy peptide-4, MDP4, comprised of a segment of the hERG extracellular pore region fused to a carrier monobody, aiming to neutralize the circulating anti-Ro/SSA-52kD antibodies cross-reacting with hERG. MDP4 was designed using 3D-structure-based protein engineering and optimized via conformational search and energy minimization. QT-interval prolongation was induced in an established guinea pig model of autoimmune-associated LQTS via injection of Ro/SSA-52kD antigen over 15 days. Upon confirmation of QT-interval prolongation, MDP4 was administered, and electrocardiogram parameters were monitored for 30 days. IKr and action potentials were measured using the patch-clamp technique in guinea pig ventricular cardiomyocytes treated with IgG isolated from the sera of an anti-Ro/SSA-52kD antibody-positive patient with LQTS and Torsades de Pointes. Guinea pigs immunized with Ro/SSA-52kD antigen exhibit QTc prolongation and hERG-cross-reactive anti-Ro/SSA-52kD serum antibodies. In vivo treatment with MDP4 reverses QTc prolongation. MDP4 in vitro treatment of guinea pig ventricular myocytes also reverses IKr inhibition and action potential duration prolongation by anti-Ro/SSA-52kD antibodies from patients with LQTS and Torsades de Pointes. Treatment with MDP4 results in recovery of both the QT-interval prolongation in vivo and IKr inhibition in vitro. MDP4 and other conceptually similar molecules may represent an innovative therapeutic approach for autoimmune LQTS in humans, and, prospectively, for other forms of arrhythmogenic autoimmune cardiac channelopathies.
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.
2026-01-01 | Venom Hymenoptera Immunotherapy in A Patient Affected by Long QT Syndrome
Introduction: Many drugs employed for treating allergic reactions, such as epinephrine and antihistamines, are contraindicated in patients affected by long QT syndrome (LQTS). Moreover, betablocker drugs used for LQTS reduce the efficacy of epinephrine. Patients affected by concomitant LQTS and venom hymenoptera allergy are a difficult challenge for allergologists. This report describes the case of a patient affected by LQTS and allergy to honeybee who was submitted to venom immunotherapy (VIT). Methods: A patient with congenital LQTS and adverse reactions after hymenoptera stings was evaluated at the Azienda Ospedaliera Universitaria Pisana (Pisa, Italy). In vitro and in vivo tests were performed, followed by VIT, according to guidelines. Results: A 40 years-woman affected by congenital LQTS suffered of suspected allergic reaction after a honeybee sting; chlorphenamine and systemic steroid administered by clinician resolved symptoms but induced an intense malaise with QT prolongation. The cardiologist prescribed methoprolol daily. In vivo and in vitro test demonstrated honeybee allergy so we started VIT. VIT allows to protect the patients from both severe allergic reactions and side effects of anti-allergic drugs. We suggest considering LQTS as a selected indication for allergen immunotherapy.
2022-06-14 | Pharmacological activation of the hERG K+ channel for the management of the long QT syndrome: A review
Abstract In the human heart, the rapid delayed rectifier K + current ( I Kr ) contributes significantly to ventricular action potential (AP) repolarization and to set the duration of the QT interval of the surface electrocardiogram (ECG). The pore‐forming (α) subunit of the I Kr channel is encoded by KCNH2 or human ether‐à‐go‐go‐related gene 1 (hERG1). Impairment of hERG function through either gene mutation (congenital) or pharmacological blockade by diverse drugs in clinical use (acquired) can cause a prolongation of the AP duration (APD) reflected onto the surface ECG as a prolonged QT interval or Long QT Syndrome (LQTS). LQTS can increase the risk of triggered activity of ventricular cardiomyocytes and associated life‐threatening arrhythmia. Current treatments all focus on reducing the incidence of arrhythmia or terminating it after its onset but there is to date no prophylactic treatment for the pharmacological management of LQTS. A new class of hERG modulators (agonists) have been suggested through direct interaction with the hERG channel to shorten the action potential duration (APD) and/or increase the postrepolarisation refractoriness period (PRRP) of ventricular cardiomyocytes protecting thereby against triggered activity and associated arrhythmia. Although promising drug candidates, there remain major obstacles to their clinical development. The aim of this review is to summarize the latest advances as well as the limitations of this proposed pharmacotherapy.
2021-07-01 | Role and mechanism of chaperones calreticulin and ERP57 in restoring trafficking to mutant HERG‑A561V protein
Long QT syndrome type 2 is caused by a mutation in the human‑ether‑a‑go‑go‑related gene (HERG) gene encoding the rapidly activating delayed rectifier K‑current. HERG is a key cell membrane glycoprotein; however, whether the maturation process of HERG protein involves key molecules derived from the calnexin (CNX)/calreticulin (CRT) cycle and how these molecules work remains unknown. Using western blotting, the present study screened the key molecules CNX/CRT/endoplasmic reticulum protein 57 (ERP57) involved in this cycle, and it was revealed that the protein expression levels of CNX/CRT/ERP57 in wild‑type (WT)/A561V cells were increased compared with those in WT cells (n=3; P<0.05). Additionally, a co‑immunoprecipitation experiment was used to reveal that the ability of CNX/ERP57/CRT to interact with HERG was significantly increased in A561V and WT/A561V cells (n=3; P<0.05). A plasmid lacking the bb' domain of ERP57 was constructed and it was demonstrated that the key site of ERP57 binding to CRT and immature HERG protein is the bb' domain. The whole‑cell patch‑clamp technique detected that the tail current density increased by 46% following overexpression of CRT and by 53% following overexpression of ERP57 in WT/A561V cells. Overexpression of CRT and ERP57 could increased HERG protein levels on the membrane detected by confocal imaging. Furthermore, overexpression of ERP57 and CRT proteins could restore the HERG‑A561V mutant protein trafficking process and rescue the dominant‑negative suppression of WT. Overall, ERP57/CRT served a crucial role in the HERG‑A561V mutant protein trafficking deficiency and degradation process.
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.
2025-01-09 | 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.
2024-06-07 | Joint effects of CD8A and ICOS in Long QT Syndrome (LQTS) and Beckwith-Wiedemann Syndrome (BWS).
Long QT Syndrome (LQTS) and Beckwith-Wiedemann Syndrome (BWS) are complex disorders with unclear origins, underscoring the need for in-depth molecular investigations into their mechanisms. The main aim of this study is to identify the shared key genes between LQTS and BWS, shedding light on potential common molecular pathways underlying these syndromes. The LQTS and BWS datasets are available for download from the GEO database. Differential expression genes (DEGs) were identified. Weighted gene co-expression network analysis (WGCNA) was used to detect significant modules and central genes. Gene enrichment analysis was performed. CIBERSORT was used for immune cell infiltration analysis. The predictive protein interaction (PPI) network of core genes was constructed using STRING, and miRNAs regulating central genes were screened using TargetScan. Five hundred DEGs associated with Long QT Syndrome and Beckwith-Wiedemann Syndrome were identified. GSEA analysis revealed enrichment in pathways such as T cell receptor signaling, MAPK signaling, and adrenergic signaling in cardiac myocytes. Immune cell infiltration indicated higher levels of memory B cells and naive CD4 T cells. Four core genes (CD8A, ICOS, CTLA4, LCK) were identified, with CD8A and ICOS showing low expression in the syndromes and high expression in normal samples, suggesting potential inverse regulatory roles. The expression of CD8A and ICOS is low in long QT syndrome and Beckwith-Wiedemann syndrome, indicating their potential as key genes in the pathogenesis of these syndromes. The identification of shared key genes between LQTS and BWS provides insights into common molecular mechanisms underlying these disorders, potentially facilitating the development of targeted therapeutic strategies.
2023-12-06 | Proof of concept for monoclonal antibody therapy in a cellular model of acquired long QT syndrome type 3.
Long QT syndrome (LQTS) type 3 although less common than the first two forms, differs in that arrhythmic events are less likely triggered by adrenergic stimuli and are more often lethal. Effective pharmacological treatment is challenged by interindividual differences, mutation dependence, and adverse effects, translating into an increased use of invasive measures (implantable cardioverter-defibrillator, sympathetic denervation) in patients with LQTS type 3. Previous studies have demonstrated the therapeutic potential of polyclonal KCNQ1 antibody for LQTS type 2. Here, we sought to identify a monoclonal KCNQ1 antibody that preserves the electrophysiological properties of the polyclonal form. Using hybridoma technology, murine monoclonal antibodies were generated, and patch clamp studies were performed for functional characterization. We identified a monoclonal KCNQ1 antibody able to normalize cardiac action potential duration and to suppress arrhythmias in a pharmacological model of LQTS type 3 using human-induced pluripotent stem cell-derived cardiomyocytes.NEW & NOTEWORTHY Long QT syndrome is a leading cause of sudden cardiac death in the young. Recent research has highlighted KCNQ1 antibody therapy as a new treatment modality for long QT syndrome type 2. Here, we developed a monoclonal KCNQ1 antibody that similarly restores cardiac repolarization. Moreover, the identified monoclonal KCNQ1 antibody suppresses arrhythmias in a cellular model of long QT syndrome type 3, holding promise as a first-in-class antiarrhythmic immunotherapy.
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Drug Discovery Landscape
3 orphan drug designations for Familial long QT syndrome.
3 orphan drug designations for Familial long QT syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
recombinant self-complementary AAV9 containing a base editor encoding human SCN5A | gene editing enzymes | FDA | 2025-04-15 | — | Hangzhou Rongze Biotechnology Group Co., Ltd. |
N-(4-(4-((2-(dimethylamino)ethyl)amino)-3-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)-2-fluorophenyl)-2,5-difluorobenzenesulfonamide hydrochloride salt | small molecules | FDA | 2024-09-20 | — | Thryv Therapeutics Inc. |
4-(pyrimidin-2-ylmethyl)-7-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-1,4-benzoxazepin-5(2H)-one | small molecules | FDA | 2015-05-04 | — | Gilead Sciences, Inc. |
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