A mild phenotype associated with KCNQ1 p.V205M mediated long QT syndrome in First Nations children of Northern British Columbia: effect of additional variants and considerations for management.

Introduction: Congenital Long QT Syndrome (LQTS) is common in a First Nations community in Northern British Columbia due to the founder variant KCNQ1 p.V205M. Although well characterized molecularly and clinically in adults, no data have been previously reported on the pediatric population. The phenotype in adults has been shown to be modified by a splice site variant in KCNQ1 (p.L353L). The CPT1A p.P479L metabolic variant, also common in Northern Indigenous populations, is associated with hypoglycemia and infant death. Since hypoglycemia can affect the corrected QT interval (QTc) and may confer risk for seizures (also associated with LQTS), we sought to determine the effect of all three variants on the LQTS phenotype in children within our First Nations cohort. Methods: As part of a larger study assessing those with LQTS and their relatives in a Northern BC First Nation, we assessed those entering the study from birth to age 18 years. We compared the corrected peak QTc and potential cardiac events (syncope/seizures) of 186 children from birth to 18 years, with and without the KCNQ1 (p.V205M and p.L353L) and CPT1A variants, alone and in combination. Linear and logistic regression and student t-tests were applied as appropriate. Results: Only the KCNQ1 p.V205M variant conferred a significant increase in peak QTc 23.8 ms (p < 0.001) above baseline, with females increased by 30.1 ms (p < 0.001) and males by 18.9 ms (p < 0.01). There was no evidence of interaction effects with the other two variants studied. Although the p.V205M variant was not significantly associated with syncope/seizures, the odds of having a seizure/syncope were significantly increased for those homozygous for CPT1A p.P479L compared to homozygous wild type (Odds Ratio [OR]3.0 [95% confidence interval (CI) 1.2-7.7]; p = 0.019). Conclusion: While the KCNQ1 p.V205M variant prolongs the peak QTc, especially in females, the CPT1A p.P479L variant is more strongly associated with loss of consciousness events. These findings suggest that effect of the KCNQ1 p.V205M variant is mild in this cohort, which may have implications for standard management. Our findings also suggest the CPT1A p.P479L variant is a risk factor for seizures and possibly syncope, which may mimic a long QT phenotype.

Generation of induced pluripotent stem cell lines from patients with LQT1 caused by heterozygous mutations in the KCNQ1 gene.

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

Targeted activation of human ether-à-go-go-related gene channels rescues electrical instability induced by the R56Q+/- long QT syndrome variant.

AIMS: Long QT syndrome type 2 (LQTS2) is associated with inherited variants in the cardiac human ether-à-go-go-related gene (hERG) K+ channel. However, the pathogenicity of hERG channel gene variants is often uncertain. Using CRISPR-Cas9 gene-edited hiPSC-derived cardiomyocytes (hiPSC-CMs), we investigated the pathogenic mechanism underlying the LQTS-associated hERG R56Q variant and its phenotypic rescue by using the Type 1 hERG activator, RPR260243. METHODS AND RESULTS: The above approaches enable characterization of the unclear causative mechanism of arrhythmia in the R56Q variant (an N-terminal PAS domain mutation that primarily accelerates channel deactivation) and translational investigation of the potential for targeted pharmacologic manipulation of hERG deactivation. Using perforated patch clamp electrophysiology of single hiPSC-CMs, programmed electrical stimulation showed that the hERG R56Q variant does not significantly alter the mean action potential duration (APD90). However, the R56Q variant increases the beat-to-beat variability in APD90 during pacing at constant cycle lengths, enhances the variance of APD90 during rate transitions, and increases the incidence of 2:1 block. During paired S1-S2 stimulations measuring electrical restitution properties, the R56Q variant was also found to increase the variability in rise time and duration of the response to premature stimulations. Application of the hERG channel activator, RPR260243, reduces the APD variance in hERG R56Q hiPSC-CMs, reduces the variability in responses to premature stimulations, and increases the post-repolarization refractoriness. CONCLUSION: Based on our findings, we propose that the hERG R56Q variant leads to heterogeneous APD dynamics, which could result in spatial dispersion of repolarization and increased risk for re-entry without significantly affecting the average APD90. Furthermore, our data highlight the antiarrhythmic potential of targeted slowing of hERG deactivation gating, which we demonstrate increases protection against premature action potentials and reduces electrical heterogeneity in hiPSC-CMs.

Ethnic and racial differences in Asian populations with ion channelopathies associated with sudden cardiac death.

Cardiovascular diseases are associated with several morbidities and are the most common cause of worldwide disease-related fatalities. Studies show that treatment and outcome-related differences for cardiovascular diseases disproportionately affect minorities in the United States. The emergence of ethnic and racial differences in sudden cardiac death (SCD) and related ion channelopathies complicates cardiovascular disease prevention, diagnosis, management, prognosis, and treatment objectives for patients and physicians alike. This review compiles and synthesizes current research in cardiac ion channelopathies and genetic disorders in Asian populations, an underrepresented population in cardiovascular literature. We first present a brief introduction to SCD, noting relevant observations and statistics from around the world, including Asian populations. We then examined existing differences between Asian and White populations in research, treatment, and outcomes related to cardiac ion channelopathies and SCD, showing progression in thought and research over time for each ion channelopathy. The review also identifies research that explored phenotypic abnormalities, device usage, and risk of death in Asian patients. We touch upon the unique genetic risk factors in Asian populations that lead to cardiac ion channelopathies and SCD while comparing them to White and Western populations, particularly in the United States, where Asians comprise approximately 7% of the total population. We also propose potential solutions such as improving early genetic screening, addressing barriers affecting access to medical care and device utilization, physician training, and patient education on risks.

Case report: Torsade de pointes induced by the bigeminy result from retrograde ventriculoatrial activation in VVI pacing and resolved by intentional atrial pacing.

Introduction: While pacing has been used for long QT syndrome (LQTs), the optimal pacing modality is controversial. Case: We report a woman with bradycardia and a recently implanted single-chamber pacemaker experienced multiple syncope. No device dysfunction was found. Multiple Torsade de Pointes (TdP) induced by the bigeminy result from retrograde ventriculoatrial (VA) activation in VVI pacing were demonstrated in the scenario of previously unidentified LQTs. Replacement for a dual-chamber ICD and intentional atrial pacing eliminated the VA conduction and symptoms. Conclusion: Pacing without atrioventricular sequence might be catastrophic in LQTs. Atrial pacing and atrioventricular synchrony should be highlighted.

Precision medicine for long QT syndrome: patient-specific iPSCs take the lead.

Long QT syndrome (LQTS) is a detrimental arrhythmia syndrome mainly caused by dysregulated expression or aberrant function of ion channels. The major clinical symptoms of ventricular arrhythmia, palpitations and syncope vary among LQTS subtypes. Susceptibility to malignant arrhythmia is a result of delayed repolarisation of the cardiomyocyte action potential (AP). There are 17 distinct subtypes of LQTS linked to 15 autosomal dominant genes with monogenic mutations. However, due to the presence of modifier genes, the identical mutation may result in completely different clinical manifestations in different carriers. In this review, we describe the roles of various ion channels in orchestrating APs and discuss molecular aetiologies of various types of LQTS. We highlight the usage of patient-specific induced pluripotent stem cell (iPSC) models in characterising fundamental mechanisms associated with LQTS. To mitigate the outcomes of LQTS, treatment strategies are initially focused on small molecules targeting ion channel activities. Next-generation treatments will reap the benefits from development of LQTS patient-specific iPSC platform, which is bolstered by the state-of-the-art technologies including whole-genome sequencing, CRISPR genome editing and machine learning. Deep phenotyping and high-throughput drug testing using LQTS patient-specific cardiomyocytes herald the upcoming precision medicine in LQTS.

Diagnostic accuracy of the 12-lead electrocardiogram in the first 48 hours of life for newborns of a parent with congenital long QT syndrome.

BACKGROUND: Long QT syndrome (LQTS) is an autosomal dominant disorder characterized by a prolonged QT interval. Electrocardiographic (ECG) screening in the first 48 hours of life may be misleading, even in newborns with a genotype-positive LQTS parent. OBJECTIVE: The purpose of this study was to determine the ECG's diagnostic accuracy in the first 48 hours of life for neonates born to a parent with LQTS. METHODS: We conducted a retrospective review of all neonates born at Mayo Clinic to a parent with ≥1 pathogenic variant in a LQTS-causative gene who had least 1 ECG in the first 48 hours and genetic test results were available. The sensitivity and specificity of the diagnostic ECG were calculated using Bazett's heart rate-corrected QT (QTc) thresholds of 440, 450, 460, and 470 ms. RESULTS: Overall, 74 newborns (36 females [49%]) were included (mean QTc interval on the first ECG 489 ± 54 ms; 50 [68%] LQTS genotype-positive). The mean QTc interval in the first 48 hours for neonates that ultimately were genotype-positive was greater (506 ± 52 ms) than that for genotype-negative neonates (455 ± 41 ms) (P = .0004). When using a recommended threshold QTc interval of ≥440 ms, 6 of 50 genotype-positive neonates (12%) were missed (underdiagnosed) and 17 of 24 genotype-negative neonates (71%) were overdiagnosed (sensitivity 88%; specificity 29%). CONCLUSION: The newborn ECG should not be used in isolation to make the diagnosis of LQTS since it will result in many misclassifications. Genetic testing must be initiated before discharge, and proper anticipatory guidance is vital while awaiting test results.

Frequent torsades de pointes in a child with novel AKAP9 mutation: A case report and literature review.

Introduction: The aim of the present study is to report the diagnosis and treatment of a rare case of frequent torsades de pointes (Tdp) in a child with a novel AKAP9 mutation. A 13-year-old girl suffered from repeated syncope and frequent Tdp. An electrocardiogram (ECG) showed frequent multisource premature ventricular contractions with the R-ON-T phenomenon. The QTc ranged from 410 to 468 ms. The genetic test indicated a heterozygous mutation, namely, c.11714T > C (p.M3905T), in the AKAP9 gene, which is a controversial gene in long QT syndrome. After treatment with propranolol, recurrent syncope occurred, and the patient received an implantable cardioverter defibrillator (ICD). Due to frequent electrical storms at home, the child was additionally treated with propafenone to prevent arrhythmia. The antitachycardia pacing (ATP) function in the ICD was turned off, and the threshold of ventricular tachycardia (VT) assessment was adjusted from 180 beats/min to 200 beats/min. The patient was followed up for 12 months without malignant arrhythmia and electric shock. Conclusion: Genetic testing may be a useful tool to determine the origin of channelopathy, but the results should be interpreted in combination with the actual situation. Rational parameter settings for the ICD and application of antiarrhythmic drugs can reduce the mortality rates of children.

Descripción de dos familias con síndrome de QT largo / Description of 2 families with long QT syndrome

Resumen El síndrome de QT largo representa un grupo de desórdenes electrofisiológicos cardiacos, caracterizados por la prolongación del intervalo QT, que se asocian a muerte súbita, taquicardias ventriculares y síncope. Se presenta el caso de dos familias con la descripción clínica de los afectados, el estudio genético y el respectivo manejo, y se hace una breve actualización de la literatura sobre el síndrome de QT largo.

Abstract Long QT syndrome represents a group of electrophysiologic disorders characterized by a prolongation in the QT interval that are associated with sudden death, ventricular tachycardia and syncope. We present 2 families describing the clinical presentation, the genetic study and their respective treatment also there is a brief review about long QT syndrome.

Off-label use of chloroquine, hydroxychloroquine, azithromycin and lopinavir/ritonavir in COVID-19 risks prolonging the QT interval by targeting the hERG channel.

Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses an enormous challenge to the medical system, especially the lack of safe and effective COVID-19 treatment methods, forcing people to look for drugs that may have therapeutic effects as soon as possible. Some old drugs have shown clinical benefits after a few small clinical trials that attracted great attention. Clinically, however, many drugs, including those currently used in COVID-19, such as chloroquine, hydroxychloroquine, azithromycin, and lopinavir/ritonavir, may cause cardiotoxicity by acting on cardiac potassium channels, especially hERG channel through their off-target effects. The blocking of the hERG channel prolongs QT intervals on electrocardiograms; thus, it might induce severe ventricular arrhythmias and even sudden cardiac death. Therefore, while focusing on the efficacy of COVID-19 drugs, the fact that they block hERG channels to cause arrhythmias cannot be ignored. To develop safer and more effective drugs, it is necessary to understand the interactions between drugs and the hERG channel and the molecular mechanism behind this high affinity. In this review, we focus on the biochemical and molecular mechanistic aspects of drug-related blockade of the hERG channel to provide insights into QT prolongation caused by off-label use of related drugs in COVID-19, and hope to weigh the risks and benefits when using these drugs.

PARP inhibitor-induced torsades de pointes in long QT syndrome: a case report.

BACKGROUND: Poly ADP-ribose polymerase (PARP) inhibitors target pathogenic BRCA mutations in chemotherapy-resistant malignancies. PARP inhibitors cause modest dose-dependent QT prolongation in the setting of a normal baseline QT interval. CASE SUMMARY: We describe a case of PARP inhibitor-induced torsades de pointes (TdP) in an 86-year-old gentleman prescribed rucaparib due to chemotherapy-resistant, metastatic prostate cancer with pre-existing long QT, with an apparent dose-dependent increase in QT interval. The patient presented with syncope and recurrent TdP requiring direct cardioversion reversion (200 J biphasic) and an isoprenaline infusion (2 µg/min). There were no other QT prolonging agents and no electrolyte or metabolic disturbance to account for this arrhythmia. Improvement in QT interval was observed within 72 h of rucaparib cessation. DISCUSSION: PARP inhibitors cause a modest, dose-dependent increase in QT interval in patients with a normal baseline. The safety of PARP inhibitors in patients with pre-existing long QT has not been evaluated. This is the first reported case of rucaparib-associated TdP in a patient with pre-existing long QT, highlighting the amplified effect of this agent in individuals with pre-existing QT prolongation and the risk of fatal arrhythmias.

Feasibility of analysis of the SCN5A gene in paraffin embedded samples in sudden infant death cases at the Pretoria Medico-Legal Laboratory, South Africa.

To determine variations in the SCN5A gene linked to inherited cardiac arrhythmogenic disorders in sudden, unexplained infant death (SUID) cases examined at the Pretoria Medico-Legal Laboratory, South Africa. A retrospective study was conducted on SUID cases and controls, analyzing DNA extracted from archived formalin-fixed, paraffin-embedded (FFPE) myocardial tissue samples as well as blood samples. A total of 48 FFPE tissue samples (cases), 10 control FFPE tissue samples and nine control blood samples were included. DNA extracted from all samples was used to test for variations in the SCN5A gene by using high resolution melt (HRM) real-time PCR and sequencing. Genetic analysis showed 31 different single nucleotide variants in the entire study population (n = 67). Five previously reported variants of known pathogenic significance, and 14 variants of benign clinical significance, were identified. The study found 12 different variants in the cases that were not published in any database or literature and were considered novel. Of these novel variants, two were predicted as "probably damaging" with a high level of certainty (found in four case samples), one (identified in another case sample) was predicted to be "possibly damaging" with a 50% chance of being disease-causing, and nine were predicted to be benign. This study shows the significant added value of using genetic testing in determining the cause of death in South African SUID cases. Considering the high heritability of these arrhythmic disorders, post mortem genetic testing could play an important role in the understanding of the pathogenesis thereof and could also aid in the diagnosis and treatment of family members at risk, ultimately preventing similar future cases.

The role of sympathectomy in long QT syndrome.

Long QT syndrome (LQTS) is an uncommon and potentially fatal cardiac channelopathy. Treatment options can be medical with ß-blockers or surgical with implantable cardioverter defibrillator (ICD) implantations and left cardiac sympathetic denervation (LCSD). Purpose of this paper is through a literature review to identify the management algorithm and the role of sympathectomy in LQTS.

A novel KCNQ1 nonsense variant in the isoform-specific first exon causes both jervell and Lange-Nielsen syndrome 1 and long QT syndrome 1: a case report.

BACKGROUND: According to previous KCNQ1 (potassium channel, voltage gated, KQT-like subfamily, member 1) gene screening studies, missense variants, but not nonsense or frame-shift variants, cause the majority of long QT syndrome (LQTS; Romano-Ward syndrome [RWS]) 1 cases. Several missense variants are reported to cause RWS by a dominant-negative mechanism, and some KCNQ1 variants can cause both Jervell and Lange-Nielsen Syndrome (JLNS; in an autosomal recessive manner) and LQTS1 (in an autosomal dominant manner), while other KCNQ1 variants cause only JLNS. The human KCNQ1 gene is known to have two transcript isoforms (kidney isoform and pancreas isoform), and both isoforms can form a functional cardiac potassium channel. CASE PRESENTATION: Here, we report a novel nonsense KCNQ1 variant causing not only JLNS, but also significant QTc prolongation identical to RWS in an autosomal dominant manner. Our case study supports that haploinsufficiency in the KCNQ1 gene is causative of significant QTc prolongation identical to RWS. Interestingly, the nonsense variant (NM_000218.2:c.115G > T [p.Glu39X]) locates in exon 1a of KCNQ1, which is a kidney-isoform specific exon. The variant is located closer to the N-terminus than previously identified nonsense or frame-shift variants. CONCLUSION: To the best of our knowledge, this is the first report showing that a nonsense variant in exon 1a of KCNQ1, which is the kidney-isoform specific exon, causes JLNS. Our findings may be informative to the genetic pathogenesis of RWS and JLNS caused by KCNQ1 variants.

Mutation analysis for the detection of long QT-syndrome (LQTS) associated SNPs.

Congenital long QT-syndrome (LQTS) is an inherited cardiac arrhythmia, which is characterized by a prolonged QT interval which predisposes to sudden cardiac death due to ventricular arrhythmias. The altered functions are based on different mutations in LQTS-associated genes. In this study, we performed a mutation analysis for the detection of 125 LQTS-associated single nucleotide polymorphisms (SNPs) focused on the genes KCNQ1, KCNH2, and SCN5A by using the SNaPshot multiplex minisequencing technique. Furthermore, we investigated 152 autopsy-negative cases from younger adults and infants, as well as samples from patients with clinically suspicion for LQTS, in which we found two types of variations.

Is Symptomatic Long QT Syndrome Associated with Depression in Women and Men?

We examined whether long QT syndrome (LQTS) mutation carrier status or symptomatic LQTS are associated with depression, and whether there are sex differences in these potential relationships. The sample comprised 782 participants (252 men). Of the 369 genetically defined LQTS mutation carriers, 169 were symptomatic and 200 were asymptomatic. The control group consisted of 413 unaffected relatives. Depression was assessed using the Beck Depression Inventory-II (BDI-II). No association was found for LQTS mutation carrier status with depression. The multinomial logistic regression showed that LQTS mutation carrier men with arrhythmic events scored higher on depression compared with the control group, even when adjusting for age, ß-blockers, antidepressants, and social support (OR = 1.09, 95 % CI [1.02, 1.15], p = .007). The binary logistic regression comparing symptomatic and asymptomatic LQTS mutation carriers showed that symptomatic LQTS was associated with depression in men (OR = 1.10, 95 % CI [1.03, 1.19], p = .009). The results were unchanged when additionally adjusted for education. These findings suggest that symptomatic LQTS is associated with depression in men but not in women. Overall, however, depression is more frequent in women than men. Thus, regular screening for depression in LQTS mutation carriers and their unaffected family members can be important.

The link between abnormal calcium handling and electrical instability in acquired long QT syndrome--Does calcium precipitate arrhythmic storms?

Release of Ca(2+) ions from sarcoplasmic reticulum (SR) into myocyte cytoplasm and their binding to troponin C is the final signal form myocardial contraction. Synchronous contraction of ventricular myocytes is necessary for efficient cardiac pumping function. This requires both shuttling of Ca(2+) between SR and cytoplasm in individual myocytes, and organ-level synchronization of this process by means of electrical coupling among ventricular myocytes. Abnormal Ca(2+) release from SR causes arrhythmias in the setting of CPVT (catecholaminergic polymorphic ventricular tachycardia) and digoxin toxicity. Recent optical mapping data indicate that abnormal Ca(2+) handling causes arrhythmias in models of both repolarization impairment and profound bradycardia. The mechanisms involve dynamic spatial heterogeneity of myocardial Ca(2+) handling preceding arrhythmia onset, cell-synchronous systolic secondary Ca(2+) elevation (SSCE), as well as more complex abnormalities of intracellular Ca(2+) handling detected by subcellular optical mapping in Langendorff-perfused hearts. The regional heterogeneities in Ca(2+) handling cause action potential (AP) heterogeneities through sodium-calcium exchange (NCX) activation and eventually overwhelm electrical coupling of the tissue. Divergent Ca(2+) dynamics among different myocardial regions leads to temporal instability of AP duration and - on the patient level - in T wave lability. Although T-wave alternans has been linked to cardiac arrhythmias, non-alternans lability is observed in pre-clinical models of the long QT syndrome (LQTS) and CPVT, and in LQTS patients. Analysis of T wave lability may provide a real-time window on the abnormal Ca(2+) dynamics causing specific arrhythmias such as Torsade de Pointes (TdP).

Regulation of the human ether-a-go-go-related gene (hERG) potassium channel by Nedd4 family interacting proteins (Ndfips).

The cardiac electrical disorder long QT syndrome (LQTS) pre-disposes affected individuals to ventricular arrhythmias and sudden death. Dysfunction of the human ether-a-go-go-related gene (hERG)-encoded rapidly activating delayed rectifier K(+) channel (IKr) is a major cause of LQTS. The expression of hERG channels is controlled by anterograde trafficking of newly synthesized channels to and retrograde degradation of existing channels from the plasma membrane. We have previously shown that the E3 ubiquitin (Ub) ligase Nedd4-2 (neural precursor cell expressed developmentally down-regulated protein 4-2) targets the PY motif of hERG channels to initiate channel degradation. Although both immature and mature hERG channels contain the PY motif, Nedd4-2 selectively mediates the degradation of mature hERG channels. In the present study, we demonstrate that Nedd4-2 is directed to specific cellular compartments by the Nedd4 family interacting proteins, Nedd4 family-interacting protein 1 (Ndfip1) and Ndfip2. Ndfip1 is primarily localized in the Golgi apparatus where it recruits Nedd4-2 to mediate the degradation of mature hERG proteins during channel trafficking to the plasma membrane. Although Ndfip2 directs Nedd4-2 to the Golgi apparatus, it also recruits Nedd4-2 to the multivesicular bodies (MVBs), which may impair MVB function and impede the degradation of mature hERG proteins mediated by Nedd4-2. These findings extend our understanding of hERG channel regulation and provide information which may be useful for the rescue of impaired hERG function in LQTS.

Upgrade from ICD to CRT-D: clinical and haemodynamic impact of biventricular pacing in a patient with acquired long QT syndrome.

Long QT syndrome (LQTS) is characterised by both the depolarisation and repolarisation disorder of cardiac muscle cells. Cardiac resynchronising therapy (CRT) is an important treatment option for patients with chronic heart failure (CHF) when echocardiographic and electrocardiographic criteria are met. Although CRT was introduced in clinical practice 10 years ago, doubts related to application of this treatment method persist because of its potential proarrhythmogenic effect. This is a case describing a 66-year-old Caucasian female with LQTS coexisting with a left bundle branch branch block (LBBB) and an implantable single-cavity cardioverter-defibrillator (ICD VR), who had repeated appropriate high-energy treatments. The upgrade to resynchronisation therapy defibrillator (CRT-D) significantly reduced frequency of ventricular tachycardia and the need for electrical therapies. The normalisation of the left ventricle size, as seen on echo examination, and the improvement of heart failure symptoms were also observed.