Search

Background: Women with congenital long QT syndrome (LQTS) experience increased cardiac event risk after the onset of adolescence, perhaps stemming from the known modulating effects of sex hormones on the cardiac potassium channels. Objective: We hypothesized that the effect of sex hormones on cardiac ion channel function may modify electrocardiographic (ECG) parameters associated with the propensity for ventricular tachyarrhythmias during the menstrual cycle in women with LQTS. Methods: We prospectively enrolled 65 women with congenital LQTS (type 1 LQTS [LQT1], n = 24 [36.9%]; type 2 LQTS [LQT2], n = 20 [30.8%]) and unaffected female relatives (n = 21 [32.3%]). Patients underwent three 7-day ECG recordings during their menstrual cycles. Simultaneous saliva testing of sex hormone levels was conducted on the first day of each 7-day ECG recording cycle. Results: The mean age was 35 ± 8 years, without a significant difference among the groups. In women with LQT2, linear mixed effects models showed significant inverse correlations of the corrected QT interval with progesterone levels (P < .001) and with the progesterone to estradiol ratio (P < .001). Inverse relationships of the R-R interval with estradiol levels (P = .003) and of the T-wave duration with testosterone levels (P = .014) were also observed in women with LQT2. In contrast, no significant associations were observed between ECG parameters and sex hormone levels in women with LQT1 or unaffected relatives. Conclusion: This is the first study to prospectively assess correlations between repolarization dynamics and sex hormone levels during the menstrual cycle in women with congenital LQTS. Our findings show genotype-specific unique corrected QT dynamics during the menstrual cycle that may affect the propensity for ventricular tachyarrhythmia in women with LQTS, particularly women with LQT2.

Aims Mutation type, location, dominant-negative I Ks reduction, and possibly loss of cyclic adenosine monophosphate (cAMP)-dependent I Ks stimulation via protein kinase A (PKA) influence the clinical severity of long QT syndrome type 1 (LQT1). Given the malignancy of KCNQ1-p.A341V, we assessed whether mutations neighbouring p.A341V in the S6 channel segment could also increase arrhythmic risk. Methods and results Clinical and genetic data were obtained from 1316 LQT1 patients [450 families, 166 unique KCNQ1 mutations, including 277 p.A341V-positive subjects, 139 patients with p.A341-neighbouring mutations (91 missense, 48 non-missense), and 900 other LQT1 subjects]. A first cardiac event represented the primary endpoint. S6 segment missense variant characteristics, particularly cAMP stimulation responses, were analysed by cellular electrophysiology. p.A341-neighbouring mutation carriers had a QTc shorter than p.A341V carriers (477 ± 33 vs. 490 ± 44 ms) but longer than the remaining LQT1 patient population (467 ± 41 ms) (P Conclusion KCNQ1 S6 segment mutations surrounding p.A341 increase arrhythmic risk. p.A341V-specific loss of PKA-dependent I Ks enhancement correlates with its phenotypic severity. Cellular studies providing further insights into I Ks-channel regulation and knowledge of structure-function relationships could improve risk stratification. These findings impact on clinical management.

Background There are conflicting reports with regard to the allele-specific gene suppression effects of single nucleotide polymorphisms (SNPs) in the 3'untranslated region (3'UTR) of the

The electrocardiogram (ECG) empowered clinician scientists to measure the electrical activity of the heart noninvasively to identify arrhythmias and heart disease. Shortly after the standardization of the 12-lead ECG for the diagnosis of heart disease, several families with autosomal recessive (Jervell and Lange-Nielsen Syndrome) and dominant (Romano-Ward Syndrome) forms of long QT syndrome (LQTS) were identified. An abnormally long heart rate-corrected QT-interval was established as a biomarker for the risk of sudden cardiac death. Since then, the International LQTS Registry was established; a phenotypic scoring system to identify LQTS patients was developed; the major genes that associate with typical forms of LQTS were identified; and guidelines for the successful management of patients advanced. In this review, we discuss the molecular and cellular mechanisms for LQTS associated with missense variants in

Aims We report clinical and molecular analysis of an infant presenting with foetal bradycardia and clinical outcome of Jervell and Lange-Nielsen syndrome (JLNS). Methods and results Clinical, electrocardiogram (ECG), and echocardiographic data were collected from members in a three-generation family. Whole exomes were amplified and sequenced for proband. The identified variants were verified in the remaining members. The pathogenicity of candidate variants was predicted using multiple software programmes. A 28-year-old non-consanguineous Chinese woman at 23 weeks’ gestation presenting with sustained foetal bradycardia of 100 b.p.m. Immunological disorders and infection were excluded. The infant was delivered at 37 weeks’ gestation with 2700-g birthweight. QTc was prolonged in both ECG and Holter recording. Hearing tests confirmed bilateral sensorineural hearing loss. Genetic testing demonstrated that the infant carried a novel frameshift c.431delC (p.I145Sfs*92) and a novel nonsense c.1175G>A (p.W392X) compound variants of KCNQ1 inherited from mother and father, respectively, in autosomal recessive inheritance. Only relative II-5 carrying heterozygous KCNQ1-I145Sfs*92 variant had prolonged QTc, while the other carriers did not have prolonged QT, suggesting an autosomal dominant inheritance of LQT1 phenotype with incomplete penetrance in the family. Conclusion We report the novel frameshift KCNQ1-I145Sfs*92 and nonsense KCNQ1-W392X compound variants in autosomal recessive inheritance that caused JLNS presenting as sustained foetal bradycardia for the first time. Meanwhile, KCNQ1-I145Sfs*92 heterozygous variant demonstrated LQT1 phenotype in autosomal dominant inheritance with incomplete penetrance.

Long-QT syndrome type 1 (LQT1) is caused by mutations in

Hysteresis, a ubiquitous regulatory phenomenon, is a salient feature of the adaptation of ventricular repolarization duration to heart rate (HR) change. We therefore compared the QT interval adaptation to rapid HR increase in patients with the long QT syndrome type 1 (LQT1) versus healthy controls because LQT1 is caused by loss-of-function mutations affecting the repolarizing potassium channel current IsubKs/sub, presumably an important player in QT hysteresis. The study was performed in an outpatient hospital setting. HR was increased in LQT1 patients and controls by administering an intravenous bolus of atropine (0.04 mg/kg body weight) for 30 s. RR and QT intervals were recorded by continuous Frank vectorcardiography. Atropine induced transient expected side effects but no adverse arrhythmias. There was no difference in HR response (RR intervals) to atropine between the groups. Although atropine-induced ΔQT was 48% greater in 18 LQT1 patients than in 28 controls (p lt; 0.001), QT adaptation was on average 25% faster in LQT1 patients (measured as the time constant τ for the mono-exponential function and the time for 90% of ΔQT; p lt; 0.01); however, there was some overlap between the groups, possibly a beta-blocker effect. The shorter QT adaptation time to atropine-induced HR increase in LQT1 patients on the group level corroborates the importance of IsubKs/subin QT adaptation hysteresis in humans and shows that LQT1 patients have a disturbed ultra-rapid cardiac memory. On the individual level, the QT adaptation time possibly reflects the effect-size of the loss-of-function mutation, but its clinical implications need to be shown.

Long QT syndrome type 2 (LQT2) is a heart disorder caused by a loss-of-function mutation in the KCNH2 gene that is an essential factor in cardiac repolarization and affects the heart rate. This study has generated a human-induced stem cell line (KSCBi014-A) carrying the KCNH2 (c.453delC) mutation from an LQT2 patient. The non-integrative Sendai virus-mediated induced pluripotent stem cell (iPSC) reprogramming method was used for iPSC line generation. The KSCBi014-A line maintained stem cell-like morphology, normal karyotype, and pluripotency, and could differentiate into three germ layers in vitro.

Congenital long QT syndrome type 1 (LQT1) results from KCNQ1 mutations that cause loss of Kv7.1 channel function, leading to arrhythmias, syncope, and sudden cardiac death. Here, we generated three human-induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMCs) of LQT1 patients carrying pathogenic variants (c.569 G>A, c.585delG, and c.573_577delGCGCT) in KCNQ1. All lines show typical iPSC morphology, high expression of pluripotent markers, normal karyotype, and are able to differentiate into three germ layers in vitro. These lines are valuable resources for studying the pathological mechanisms of LQT1 caused by KCNQ1 mutations.

Long QT syndrome (LQTS) is a rare (1:2500–1:10,000) inherited disorder characterized by the onset of arrhythmogenic syncope, polymorphic ventricular tachycardia, and sudden cardiac death. The aim of this article was to describe an unexpected success with an unusual therapeutic modality of a patient diagnosed with LQTS syndrome (suspected Romano–Ward syndrome) during an 8-year period. A 59-year-old female patient was admitted to the hospital due to chest pain and nausea, and after diagnostic and therapeutical approach, a permanent dual-chamber rate-modulated (DDDR) pacemaker was implanted instead of the implantable cardioverter defibrillator (ICD). During the 8-year period, the patient remained stable, without rhythm disorder. Romano–Ward syndrome as a congenital LQTS carries a high risk of sudden cardiac death and presents an indication for ICD. In this patient, for objective reasons, this could not be performed. Implantation of a DDDR with an appropriate pharmacological therapy, including propranolol, in this case, proved to be a successful therapeutic modality.

Background\ud Left-stellate ganglion stimulation (LSGS) can modify regional dispersion of ventricular refractoriness, promote triggered activity, and reduce the threshold for ventricular fibrillation (VF). Sympathetic hyperactivity precipitates torsades de pointes (TdP) and VF in susceptible patients with long-QT syndrome type 1 (LQT1). We investigated the electromechanical effects of LSGS in a canine model of drug-induced LQT1, gaining novel arrhythmogenic insights.\ud \ud Methods\ud In nine mongrel dogs, the left and right stellate ganglia were exposed for electrical stimulation. ECG, left- and right-ventricular endocardial monophasic action potentials (MAPs) and pressures (LVP, RVP) were recorded. The electromechanical window (EMW; Q to LVP at 90% relaxation minus QT interval) was calculated. LQT1 was mimicked by infusion of the KCNQ1/IKs blocker HMR1556.\ud \ud Results\ud At baseline, LSGS and right-stellate ganglion stimulation (RSGS) caused similar heart-rate acceleration and QT shortening. Positive inotropic and lusitropic effects were more pronounced under LSGS than RSGS. IKs blockade prolonged QTc, triggered MAP-early afterdepolarizations (EADs) and rendered the EMW negative, but no ventricular tachyarrhythmias occurred. Superimposed LSGS exaggerated EMW negativity and evoked TdP in 5/9 dogs within 30 s. Preceding extrasystoles originated mostly from the outflow-tracts region. TdP deteriorated into therapy-refractory VF in 4/5 animals. RSGS did not provoke TdP/VF.\ud \ud Conclusions\ud In this model of drug-induced LQT1, LSGS readily induced TdP and VF during repolarization prolongation and MAP-EAD generation, but only if EMW turned from positive to very negative. We postulate that altered mechano-electric coupling can exaggerate regional dispersion of refractoriness and facilitates ventricular ectopy.

Background: Long QT syndrome (LQTS) is characterized by the prolongation of QT interval, which results in syncope and sudden cardiac death in young people. KCNQ1 is the most common gene responsible for this syndrome. Methods: Molecular investigation was performed by DNA Sanger sequencing in Iranian families with a history of syncope. In silico examinations were performed for predicting the pathogenicity of the novel variant. Results: A novel homozygous KCNQ1 frameshift mutation, c.1426_1429delATGC (M476Pfs*4), was identified, and then the current literatures of five patients were reviewed regarding the LQTS. Conclusion: The novel frameshift mutation has been reported for the first time among the Iranian population. Our finding along with the case series study of LQTS patients illustrates the importance of genetic and case series in precise detection of the frequency of LQTS carriers.

Patient: Male, 54 Final Diagnosis: Recurrent torsades de pointes Symptoms: Sudden cardiac death Medication: — Clinical Procedure: — Specialty: Cardiology Objective: Congenital defects/diseases Background: QT prolongation is a common, easily overlooked clinical problem with potentially dire consequences. Drug-induced and congenital forms are not mutually exclusive, but are treated differently. Here, we present a case of cryptogenic underlying congenital long QT syndrome (cLQTS) successfully treated with isoproterenol, a drug contraindicated in most congenital forms of this condition. Case Report: We present the case of a 54-year-old man who experienced severe QT prolongation after drug administration followed by recurrent episodes of torsade de pointes (TdP) with subsequent ventricular fibrillation (VF) arrest unresponsive to typical therapy. After failing electrolyte repletion, magnesium, amiodarone, and lidocaine, the patient was started on an isoproterenol drip to achieve a heart rate of at least 90 beats per minute (bpm). Isoproterenol resulted in an immediate near-normalization of his QT interval and cessation of his recurrent TdP. The patient was subsequently found to have a mutation of undetermined significance in the KCNQ1 gene, which is implicated in long QT syndrome type 1 (LQT1). Although isoproterenol is contraindicated in LQT1, our patient had an astonishingly therapeutic benefit. Conclusions: After reviewing the electrophysiology of the delayed rectifier potassium current as it relates to long QT syndrome, we propose a mechanism by which our patient’s specific mutation may have allowed him to derive benefit from isoproterenol treatment. We believe that there are patients with variants of LQT1 who can be safely treated with isoproterenol.

We report a case o fhereditary long Q-T syndrome without congenital deafness (Romano-Ward syndrome). In four members of a family, a father and his daughters, the Q-T intervals on the EKG were found to be prolonged. There were no other accompanying familial anomalies such as deafness or a tendency to extracellular hypokalemia The youngest daughter which had the longest. Q-T interval had several Adams-Stokes attacks, and died in the last attack at the age of 23 months. Her two older siblings died at the age of 15 and 10 months with the same typical clinical histories. The eldest daughter, a 12-year old girl, has no clinical symptoms at all, while the fourth child, 5-yeltr old girl has several occasions of near fainting attacks. The EKG of the father showed several runs of supraventricular premature contractions that ceased spontaneously, besides evidence of the prolongation of Q-T interval. The beta-adrenergic blocking drug (propranalol) given in a relatively small maintenance dose, proved to be effective in preventing attacks of the father and the fourth child, despite the unchanged prolongation of the Q-T interval.

Funding Acknowledgements Type of funding sources: None. Background Sudden cardiac death (SCD) is an uncommon event in the absence of structural heart disease. However, ventricular fibrillation (VF) may occur in patients with unknown cardiac disease and a comprehensive work-up is needed to further improve diagnostic. Still, a significant and heterogenous group of patients remains labelled of Idiopathic VF and limited data is available regarding their natural history. Purpose The aim of this study was to evaluate the clinical outcomes of survivors of an aborted sudden cardiac death due to idiopathic VF or pulseless ventricular tachycardia (VT) and to assess possible predictors of recurrence. Methods Patients who survived an idiopathic VF or pulseless VT between 2005 and 2019 referred to a cardiac defibrillator (ICD) implantation were included. Patients were followed for 1 to 15 years (median follow-up of 7 years). Clinical and device data were collected. Results A population of 29 patients, 59% male, with a median age of 50 years (age ranging from 18 to 76) at the time of the aborted SCD was studied. All patients implanted an ICD (69% single chamber, 24% dual chamber and 3% subcutaneous) at the index hospitalization. The initial rhythm was VF in 76% and pulseless VT in 24%. In relation to the context of the arrhythmic event, 48.3% occurred during daily life activities, 13.8% after an emotional stress, 6.9% during efforts and a similar percentage occurred either in rest or asleep. Of note, 12.5% of patients had previous history of syncope. Normal ECG was present in 83% of patients. Family history of SCD was present in 12% of the cases. As for the cardiovascular risk factors, 61.5% had hypertension, 19% dyslipidemia, 17% diabetes, 31% were smokers or previous smokers. Paroxysmal atrial fibrillation was present in 15% of patients. To exclude possible causes of VF, all patients were submitted to coronary angiogram and echocardiogram, 64% to genetic testing, 68% to cardiac magnetic resonance, 20% to electrophysiologic study, 12% to pharmacological provocative test and 4% were submitted to endomyocardial biopsy. At follow-up, an etiological diagnosis was established in 31% of patients: 3 events were attributed to coronary vasospasm, 3 to short coupled polymorphic VT, 1 patient had long QT syndrome, 1 had Brugada syndrome and in 1 patient an ANK2 mutation was identified. As for the clinical outcomes, 8% patients died (from non-arrhythmic causes), 31% patients received appropriate therapies and 19% had unappropriated shocks (of those 60% for sinus tachycardia and 40% for supraventricular tachycardia). Conclusion Etiologic diagnosis and prediction of recurrence of arrhythmic events in patients with idiopathic VF is challenging, even with a long-term follow-up and more sophisticated diagnostic evaluation. Idiopathic VF is a rare but serious condition with recurrence in about one third of patients. Although not free of complications, ICD remains the gold standard of treatment.

Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Ministry of Education, Youth and Sports of the Czech Republic Introduction Loss-of-function variants of the KCNQ1 gene are associated with life-threatening arrhythmogenic long QT syndrome type 1 (LQT1). This gene encodes structure of the slow delayed rectifier potassium channel (IKs). Some functional characteristics of the C-terminal KCNQ1 variant c.1686G > C (p.R562S) have been recently described [1]. However, accumulation of the current under beta-adrenergic stimulation, essential for shortening the action potential duration during exercise, have not been tested. Purpose The aim of this study was to analyse clinical and genetic characteristics of the R562S variant in our patients and to investigate impact of the variant on IKs channel function with a special focus on reactivity of the channels on beta-adrenergic stimulation. Methods The clinical diagnosis was established according to ESC Guidelines including QTc analysis at rest and after exercise. The molecular genetics diagnostics followed according to current practices (the massive parallel sequencing since 2016). The biophysical analysis was performed on Chinese hamster ovary cells (CHO) by the whole cell patch clamp technique at 37 °C. CHO cells were transiently transfected with wild type (WT) and/or R562S human IKs channels (KCNQ1/KCNE1/Yotiao, 1:2:4). Cyclic adenosine monophosphate (cAMP, 200 µM) and okadaic acid (OA, 0.2 µM) in the pipette solution were used to simulate the beta-adrenergic stimulation. In the confocal microscopy experiments, expression of Yotiao was omitted and GFP-tagged KCNQ1 was used. Results The variant R562S-Kv7.1 has been identified in 7 heterozygous carriers from 3 putatively unrelated families in the Czech Republic. The genotype was associated with long QT syndrome phenotype (prolonged QTc, symptoms including syncopes and aborted cardiac arrest) in some of the carriers. The basic functional analysis proved that both homozygous and heterozygous R562S channels are expressed on the cell membrane (confocal microscopy) and carry IKs (whole cell patch clamp) which agrees with the recently published data on this variant. Importantly, reactivity on beta-adrenergic stimulation was absent in both homozygous and heterozygous R562S channels (n = 14 and 8, respectively), but present in the wild-type channels (increase by 51.4 ± 11.1 % at 120-s cAMP/OA diffusion; n = 12). Conclusions The R562S-Kv7.1 variant may be a founder LQT1 variant in our region which will be further investigated in the future. This variant impairs response of IKs channel to beta-adrenergic stimulation. Absence of this essential regulation may considerably aggravate the channel dysfunction and, thus, may result in life-threatening arrhythmias in R562S carriers during exercise.

Next Generation Sequencing has identified many KCNQ1 genetic variants associated with type 1 long QT or Romano-Ward syndrome, most frequently inherited in an autosomal dominant fashion, although recessive forms have been reported. Particularly in the case of missense variants, functional studies of mutants are of aid to establish variant pathogenicity and to understand the mechanistic basis of disease. Two compound heterozygous KCNQ1 mutations (p.A300T and p.P535T) were previously found in a child who suffered sudden death. To provide further insight into the clinical significance and basis for pathogenicity of these variants, different combinations of wildtype, A300T and P535T alleles were co-expressed with the accessory β-subunit minK in HEK293 cells, to analyze colocalization with the plasma membrane and some biophysical phenotypes of homo and heterotetrameric channels using the patch-clamp technique. A300T homotetrameric channels showed left-shifted activation V1/2 as previously observed in Xenopus oocytes, decreased maximum conductance density, slow rise-time300ms, and a characteristic use-dependent response. A300T slow rise-time300ms and use-dependent response behaved as dominant biophysical traits for all allele combinations. The P535T variant significantly decreased maximum conductance density and Kv7.1-minK-plasma membrane colocalization. P535T/A300T heterotetrameric channels showed decreased colocalization with plasma membrane, slow rise-time300ms and the A300T characteristic use-dependent response. While A300T left shifted activation voltage dependence behaved as a recessive trait when co-expressed with WT alleles, it was dominant when co-expressed with P535T alleles.Conclusions: The combination of P535T/A300T channel biophysical properties is compatible with recessive Romano Ward syndrome. Further analysis of other biophysical traits may identify other mechanisms involved in the pathophysiology of this disease.

Background: In patients with long QT syndrome (LQTS), swimming and loud noises have been identified as genotype-specific arrhythmic triggers in LQTS type 1 (LQTS1) and LQTS type 2 (LQTS2), respectively. Objective: The purpose of this study was to compare LQTS group responses to arrhythmic triggers. Methods: LQTS1 and LQTS2 patients were included. Before and after beta-blocker intake, electrocardiograms were recorded as participants (1) were exposed to a loud noise of ∼100 dB; and (2) had their face immersed into cold water. Results: Twenty-three patients (9 LQTS1, 14 LQTS2) participated. In response to noise, LQTS groups showed similarly increased heart rate, but LQTS2 patients had corrected QT interval (Fridericia formula) (QTcF) prolonged significantly more than LQTS1 patients (37 ± 8 ms vs 15 ± 6 ms; P = .02). After intake of beta-blocker, QTcF prolongation in LQTS2 patients was significantly blunted and similar to that of LQTS1 patients (P = .90). In response to simulated diving, LQTS groups experienced a heart rate drop of ∼28 bpm, which shortened QTcF similarly in both groups. After intake of beta-blockers, heart rate dropped to 28 ± 2 bpm in LQTS1 patients and 20 ± 3 bpm in LQTS2, resulting in a slower heart rate in LQTS1 compared with LQTS2 (P = .01). In response, QTcF shortened similarly in LQTS1 and LQTS2 patients (57 ± 9 ms vs 36 ± 7 ms; P = .10). Conclusion: When exposed to noise, LQTS2 patients had QTc prolonged significantly more than did LQTS1 patients. Importantly, beta-blockers reduced noise-induced QTc prolongation in LQTS2 patients, thus demonstrating the protective effect of beta-blockers. In response to simulated diving, LQTS groups responded similarly, but a slower heart rate was observed in LQTS1 patients during simulated diving after beta-blocker intake.

Aims NOS1AP single-nucleotide polymorphisms (SNPs) correlate with QT prolongation and cardiac sudden death in patients affected by long QT syndrome type 1 (LQT1). NOS1AP targets NOS1 to intracellular effectors. We hypothesize that NOS1AP SNPs cause NOS1 dysfunction and this may converge with prolonged action-potential duration (APD) to facilitate arrhythmias. Here we test (i) the effects of NOS1 inhibition and their interaction with prolonged APD in a guinea pig cardiomyocyte (GP-CMs) LQT1 model; (ii) whether pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from LQT1 patients differing for NOS1AP variants and mutation penetrance display a phenotype compatible with NOS1 deficiency. Methods and results In GP-CMs, NOS1 was inhibited by S-Methyl-L-thiocitrulline acetate (SMTC) or Vinyl-L-NIO hydrochloride (L-VNIO); LQT1 was mimicked by IKs blockade (JNJ303) and β-adrenergic stimulation (isoproterenol). hiPSC-CMs were obtained from symptomatic (S) and asymptomatic (AS) KCNQ1-A341V carriers, harbouring the minor and major alleles of NOS1AP SNPs (rs16847548 and rs4657139), respectively. In GP-CMs, NOS1 inhibition prolonged APD, enhanced ICaL and INaL, slowed Ca2+ decay, and induced delayed afterdepolarizations. Under action-potential clamp, switching to shorter APD suppressed ‘transient inward current’ events induced by NOS1 inhibition and reduced cytosolic Ca2+. In S (vs. AS) hiPSC-CMs, APD was longer and ICaL larger; NOS1AP and NOS1 expression and co-localization were decreased. Conclusion The minor NOS1AP alleles are associated with NOS1 loss of function. The latter likely contributes to APD prolongation in LQT1 and converges with it to perturb Ca2+ handling. This establishes a mechanistic link between NOS1AP SNPs and aggravation of the arrhythmia phenotype in prolonged repolarization syndromes.

Type 1 long QT syndrome (LQT1) is caused by loss-of-function variants in theA dual-component suppression-and-replacement (SupRep)In TSA201 cells, KCNQ1-SupRep achieved mutation-independent suppression of wild-typeThis study provides the first proof-of-principle gene therapy for complete correction of long QT syndrome. As a dual-component gene therapy vector, KCNQ1-SupRep successfully suppressed and replaced

In this study we describe the generation and characterization of an human induced pluripotent stem cell (hiPSC) line from a long QT syndrome type 1 (LQT1) patient carrying the KCNQ1 c.940 G > A (p.Gly314Ser) mutation. This patient-specific iPSC line has been obtained by using non-integrational Sendai reprogramming method, expresses pluripotency markers and has the capacity to differentiate into the three germ layers and into spontaneously beating cardiomyocytes (iPSC-CMs).

KCNQ1 encodes the voltage-gated potassium (Kv) channel KCNQ1, also known as KvLQT1 or Kv7.1. Together with its &szlig, subunit KCNE1, also denoted as minK, this channel generates the slowly activating cardiac delayed rectifier current IKs, which is a key regulator of the heart rate dependent adaptation of the cardiac action potential duration (APD). Loss-of-function mutations in KCNQ1 cause congenital long QT1 (LQT1) syndrome, characterized by a delayed cardiac repolarization and a prolonged QT interval in the surface electrocardiogram. Autosomal dominant loss-of-function mutations in KCNQ1 result in long QT syndrome, called Romano&ndash, Ward Syndrome (RWS), while autosomal recessive mutations lead to Jervell and Lange-Nielsen syndrome (JLNS), associated with deafness. Here, we identified a homozygous KCNQ1 mutation, c.1892_1893insC (p.P631fs*20), in a patient with an isolated LQT syndrome (LQTS) without hearing loss. Nevertheless, the inheritance trait is autosomal recessive, with heterozygous family members being asymptomatic. The results of the electrophysiological characterization of the mutant, using voltage-clamp recordings in Xenopus laevis oocytes, are in agreement with an autosomal recessive disorder, since the IKs reduction was only observed in homomeric mutants, but not in heteromeric IKs channel complexes containing wild-type channel subunits. We found that KCNE1 rescues the KCNQ1 loss-of-function in mutant IKs channel complexes when they contain wild-type KCNQ1 subunits, as found in the heterozygous state. Action potential modellings confirmed that the recessive c.1892_1893insC LQT1 mutation only affects the APD of homozygous mutation carriers. Thus, our study provides the molecular mechanism for an atypical autosomal recessive LQT trait that lacks hearing impairment.

Background: Videoscopic left cardiac sympathetic denervation (LCSD) is an effective antifibrillatory, minimally invasive therapy for patients with potentially life-threatening arrhythmia syndromes like long QT syndrome (LQTS). Although initially used primarily for treatment intensification following documented LQTS-associated breakthrough cardiac events while on beta-blockers, LCSD as 1-time monotherapy for certain patients with LQTS requires further evaluation. We are presenting our early experience with LCSD monotherapy for carefully selected patients with LQTS. Methods: Among the 1400 patients evaluated and treated for LQTS, a retrospective review was performed on the 204 patients with LQTS who underwent LCSD at our institution since 2005 to identify the patients where the LCSD served as stand-alone, monotherapy. Clinical data on symptomatic status before diagnosis, clinical, and genetic diagnosis, and breakthrough cardiac events after diagnosis were analyzed to determine efficacy of LCSD monotherapy. Result: Overall, 64 of 204 patients (31%) were treated with LCSD alone (37 [58%] female, mean QTc 466±30 ms, 16 [25%] patients were symptomatic before diagnosis with a mean age at diagnosis 17.3±11.8 years, 5 had [8%] ≥1 breakthrough cardiac event after diagnosis, and mean age at LCSD was 21.1±11.4 years). The primary motivation for LCSD monotherapy was an unacceptable quality of life stemming from beta-blocker related side effects (ie, beta-blocker intolerance) in 56/64 patients (88%). The underlying LQTS genotype was LQT1 in 36 (56%) and LQT2 in 20 (31%). There were no significant LCSD-related surgical complications. With a mean follow-up of 2.7±2.4 years so far, only 3 patients have experienced a nonlethal, post-LCSD breakthrough cardiac event in 180 patient-years. Conclusions: LCSD may be a safe and effective stand-alone therapy for select patients who do not tolerate beta-blockers. However, LCSD is not curative and patient selection will be critical when potentially considering LCSD as monotherapy.

Background Type 1 Long QT Syndrome (LQT1) is an arrhythmogenic disorder, caused by loss-of-function mutations on KCNQ1 gene, coding for Kv7.1 potassium channel. Although LQT1 is described as the most benign form of LQTS, patients still experience arrhythmic events and there is an unmet need for personalized risk stratification. Attempts have been made to correlate the location of mutations with outcome, but the results are unequivocal. Purpose We provide in the present study a new mutation site-specific risk profile obtained from a large cohort of LQT1 patients. Methods We gathered data on 963 patients with the diagnosis of LQT1 and divided the Kv7.1 channel into 5 functional regions: the N-terminus (NT), the voltage sensor (VS, including transmembrane segments S1 to S4), the cytoplasmic loops (CL), the pore (PO, including the transmembrane segments S5, S6 and the S5-S6 extracellular linker), the C-terminus (CT). Results We studied 963 LQT1 patients: 518 (54%) females; average age 20±17 years; mean QTc at baseline ECG 465±38ms. During a mean follow-up of 8±7 years, 172 (18%) patients experienced arrhythmic events: 31 (3%) experienced one or more cardiac arrests, while 141 (15%) experienced one or more syncopal spells. We identified 188 different variants in the KCNQ1 gene, with the following distribution: 15 (8%) in the NT, 33 (18%) in the VS, 27 (14%) in the CL, 43 (23%) in the PO, 70 (37%) in the CT. The frequency of pathogenic variants per number of amino acids (a.a.) was higher in the CL region, as compared to the other domains (1 mutation every 1.4 a.a.). The duration of QTc interval was significantly longer for patients with mutations in the PO region (473±40 ms) and in the CL region (468±38 ms) as compared to the other regions (p Importantly, in a multivariate analysis PO and CL regions were associated with a higher probability of experiencing arrhythmic events (OR 2.89, 95% CI 1.95–4.29, p=0.019 and OR 1.61, 95% CI 1.0–2.49, p=0.05, respectively. Figure) than the other regions. Interestingly, the risk was independent from QTc interval duration. Conclusions Mutations affecting the PO and the CL region of the Kv7.1. channel are associated with a higher probability of experiencing arrhythmic events. This finding is clinically relevant, because it will allow for a more personalized, mutation site-specific risk stratification. Mutation site and arrhythmic events Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Italian Ministry of Research and University Dipartimenti di Eccellenza 2018–2022 grant to the Molecular Medicine Department (University of Pavia)

Background: The heart rate (HR) corrected QT interval (QTc) is crucial for diagnosis and risk stratification in the long QT syndrome (LQTS). Although its use has been questioned in some contexts, Bazett's formula has been applied in most diagnostic and prognostic studies in LQTS patients. However, studies on which formula eliminates the inverse relation between QT and HR are lacking in LQTS patients. We therefore determined which QT correction formula is most appropriate in LQTS patients including the effect of beta blocker therapy and an evaluation of the agreement of the formulae when applying specific QTc limits for diagnostic and prognostic purposes. Methods: Automated measurements from routine 12-lead ECGs from 200 genetically confirmed LQTS patients from two Swedish regions were included (167 LQT1, 33 LQT2). QT correction was performed using the Bazett, Framingham, Fridericia, and Hodges formulae. Linear regression was used to compare the formulae in all patients, and before and after the initiation of beta blocking therapy in a subgroup (n = 44). Concordance analysis was performed for QTc >= 480 ms (diagnosis) and >= 500 ms (prognosis). Results: The median age was 32 years (range 0.1-78), 123 (62%) were female and 52 (26%) were children