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Journal articles on the topic 'LQT1'

Author: Grafiati

Published: 9 March 2023

Last updated: 10 March 2023

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1

Gao, Yuanfeng, Wenling Liu, Cuilan Li, Xiaoliang Qiu, Xuguang Qin, Baojing Guo, Xueqin Liu, et al. "Common Genotypes of Long QT Syndrome in China and the Role of ECG Prediction." Cardiology 133, no. 2 (October 24, 2015): 73–78. http://dx.doi.org/10.1159/000440608.

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Objectives: Genetic testing, a gold standard for long QT syndrome (LQTS) diagnosis, is time-consuming and costly when all the 15 candidate genes are screened. Since genotype-specific ECG patterns are present in most LQT1-3 mutation carriers, we tested the utility of ECG-guided genotyping in a large cohort of Chinese LQTS patients. Methods and Results: We enrolled 230 patients (26 ± 17 years, 66% female) with a clinical diagnosis of LQTS. Genotypes were predicted as LQT1-3 based on the presence of ECG patterns typical for each genotype in 200 patients (85 LQT1, 110 LQT2 and 5 LQT3). Family-based genotype prediction was also conducted if gene-specific ECG patterns were found in other affected family members. Mutational screening identified 104 mutations (44% novel), i.e. 46 KCNQ1, 54 KCNH2 and 4 SCN5A mutations. The overall predictive accuracy of ECG-guided genotyping was 79% (157/200) and 79% (67/85), 78% (86/110) and 80% (4/5) for LQT1, LQT2 and LQT3, respectively. The predictive accuracy was 98% (42/43) when family-based ECG assessment was performed. Conclusions: From this large-scale genotyping study, we found that LQT2 is the most common genotype among the Chinese. Family-based ECG-guided genotyping is highly accurate. ECG-guided genotyping is time- and cost-effective. We therefore recommend it as an optimal approach for the genetic diagnosis of LQTS.

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Paavonen, K. J., H. Swan, K. Piippo, L. Hokkanen, P. Laitinen, M. Viitasalo, L. Toivonen, and K. Kontula. "Response of the QT interval to mental and physical stress in types LQT1 and LQT2 of the long QT syndrome." Heart 86, no. 1 (July 1, 2001): 39–44. http://dx.doi.org/10.1136/hrt.86.1.39.

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OBJECTIVETo study and compare the effects of mental and physical stress on long QT syndrome (LQTS) patients.DESIGNCase–control study.MAIN OUTCOME MEASURESQT intervals were measured from lead V3. Serum potassium and plasma catecholamine concentrations were also monitored.PATIENTS16 patients with type 1 LQTS (LQT1), 14 with type 2 LQTS (LQT2), both groups asymptomatic, and 14 healthy control subjects.INTERVENTIONSThree types of mental stress tests and a submaximal exercise stress test.RESULTSHeart rate responses to mental stress and exercise were similar in all groups. During mental stress, the mean QT interval shortened to a similar extent in controls (–29 ms), LQT1 patients (–34 ms), and LQT2 patients (–30 ms). During exercise, the corresponding QT adaptation to exercise stress was more pronounced (p < 0.01) in healthy controls (–47 ms) than in LQT1 (–38 ms) or LQT2 patients (–38 ms). During exercise changes in serum potassium concentrations were correlated to changes in QT intervals in controls, but not in LQTS patients. LQT1 and LQT2 patients did not differ in serum potassium, catecholamine or heart rate responses to mental or physical stress.CONCLUSIONSQT adaptation to mental and exercise stress in healthy people and in patients with LQTS is different. In healthy people QT adaptation is more sensitive to physical than to mental stress while no such diverging pattern was seen in asymptomatic LQTS patients.

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Harmer, S. C., and A. Tinker. "The role of abnormal trafficking of KCNE1 in long QT syndrome 5." Biochemical Society Transactions 35, no. 5 (October 25, 2007): 1074–76. http://dx.doi.org/10.1042/bst0351074.

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LQTS (long QT syndrome) is an important cause of cardiac sudden death. LQTS is characterized by a prolongation of the QT interval on an electrocardiogram. This prolongation predisposes the individual to torsade-de-pointes and subsequent sudden death by ventricular fibrillation. Mutations in a number of genes that encode ion channels have been implicated in LQTS. Hereditary mutations in the α- and β-subunits, KCNQ1 and KCNE1 respectively, of the K+ channel pore IKs are the commonest cause of LQTS and account for LQTS types 1 and 5 respectively (LQT1 and LQT5). Recently, it has been shown that disease pathogenesis in LQT1 can be influenced by the abnormal trafficking of KCNQ1. In comparison, whether defective trafficking of KCNE1 plays a role in LQT5 is less well established.

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Paci, Michelangelo, Simona Casini, Milena Bellin, Jari Hyttinen, and Stefano Severi. "Large-Scale Simulation of the Phenotypical Variability Induced by Loss-of-Function Long QT Mutations in Human Induced Pluripotent Stem Cell Cardiomyocytes." International Journal of Molecular Sciences 19, no. 11 (November 13, 2018): 3583. http://dx.doi.org/10.3390/ijms19113583.

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Loss-of-function long QT (LQT) mutations inducing LQT1 and LQT2 syndromes have been successfully translated to human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) used as disease-specific models. However, their in vitro investigation mainly relies on experiments using small numbers of cells. This is especially critical when working with cells as heterogeneous as hiPSC-CMs. We aim (i) to investigate in silico the ionic mechanisms underlying LQT1 and LQT2 hiPSC-CM phenotypic variability, and (ii) to enable massive in silico drug tests on mutant hiPSC-CMs. We combined (i) data of control and mutant slow and rapid delayed rectifying K+ currents, IKr and IKs respectively, (ii) a recent in silico hiPSC-CM model, and (iii) the population of models paradigm to generate control and mutant populations for LQT1 and LQT2 cardiomyocytes. Our four populations contain from 1008 to 3584 models. In line with the experimental in vitro data, mutant in silico hiPSC-CMs showed prolonged action potential (AP) duration (LQT1: +14%, LQT2: +39%) and large electrophysiological variability. Finally, the mutant populations were split into normal-like hiPSC-CMs (with action potential duration similar to control) and at risk hiPSC-CMs (with clearly prolonged action potential duration). At risk mutant hiPSC-CMs carried higher expression of L-type Ca2+, lower expression of IKr and increased sensitivity to quinidine as compared to mutant normal-like hiPSC-CMs, resulting in AP abnormalities. In conclusion, we were able to reproduce the two most common LQT syndromes with large-scale simulations, which enable investigating biophysical mechanisms difficult to assess in vitro, e.g., how variations of ion current expressions in a physiological range can impact on AP properties of mutant hiPSC-CMs.

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Borowiec, Karolina, Mirosław Kowalski, Magdalena Kumor, Joanna Duliban, Witold Śmigielski, Piotr Hoffman, and Elżbieta Katarzyna Biernacka. "Prolonged left ventricular contraction duration in apical segments as a marker of arrhythmic risk in patients with long QT syndrome." EP Europace 22, no. 8 (June 12, 2020): 1279–86. http://dx.doi.org/10.1093/europace/euaa107.

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Abstract Aims Long QT syndrome (LQTS) is an inherited cardiac ion channelopathy predisposing to life-threatening ventricular arrhythmias and sudden cardiac death. The aim of this study was to investigate left ventricular mechanical abnormalities in LQTS patients and establish a potential role of strain as a marker of arrhythmic risk. Methods and results We included 47 patients with genetically confirmed LQTS (22 LQT1, 20 LQT2, 3 LQT3, and 2 SCN3B) and 25 healthy controls. A history of cardiac events was present in 30 LQTS subjects. Tissue Doppler and speckle tracking echocardiography were performed and contraction duration was measured by radial and longitudinal strain. The radial strain characteristic was subdivided into two planes — the basal and the apical. Left ventricular ejection fraction and global longitudinal strain were normal in LQTS patients. Mean contraction duration was longer in LQTS patients compared with controls in regard to basal radial strain (491 ± 57 vs. 437 ± 55 ms, P < 0.001), apical radial strain (450 ± 53 vs. 407 ± 53 ms, P = 0.002), and longitudinal strain (445 ± 34 vs. 423 ± 43 ms, P = 0.02). Moreover, contraction duration obtained from apical radial strain analysis was longer in symptomatic compared with asymptomatic LQTS mutation carriers (462 ± 49 vs. 429 ± 55 ms, P = 0.024), as well as in subject with mutations other than LQT1 considered to be at higher risk (468 ± 50 vs. 429 ± 49 ms, P = 0.01). Conclusion Myocardial contraction duration is prolonged for both radial and longitudinal directions in LQTS patients. Regional left ventricular function analysis may contribute to risk stratification. Apical radial deformation seems to select subjects at higher risk of arrhythmic events.

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Odening, Katja E., Malcolm Kirk, Michael Brunner, Ohad Ziv, Peem Lorvidhaya, Gong Xin Liu, Lorraine Schofield, et al. "Electrophysiological studies of transgenic long QT type 1 and type 2 rabbits reveal genotype-specific differences in ventricular refractoriness and His conduction." American Journal of Physiology-Heart and Circulatory Physiology 299, no. 3 (September 2010): H643—H655. http://dx.doi.org/10.1152/ajpheart.00074.2010.

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We have generated transgenic rabbits lacking cardiac slow delayed-rectifier K+ current [ IKs; long QT syndrome type 1 (LQT1)] or rapidly activating delayed-rectifier K+ current [ IKr; long QT syndrome type 2 (LQT2)]. Rabbits with either genotype have prolonged action potential duration and QT intervals; however, only LQT2 rabbits develop atrioventricular (AV) blocks and polymorphic ventricular tachycardia. We therefore sought to characterize the genotype-specific differences in AV conduction and ventricular refractoriness in LQT1 and LQT2 rabbits. We carried out in vivo electrophysiological studies in LQT1, LQT2, and littermate control (LMC) rabbits at baseline, during isoproterenol infusion, and after a bolus of dofetilide and ex vivo optical mapping studies of the AV node/His-region at baseline and during dofetilide perfusion. Under isoflurane anesthesia, LQT2 rabbits developed infra-His blocks, decremental His conduction, and prolongation of the Wenckebach cycle length. In LQT1 rabbits, dofetilide altered the His morphology and slowed His conduction, resulting in intra-His block, and additionally prolonged the ventricular refractoriness, leading to pseudo-AV block . The ventricular effective refractory period (VERP) in right ventricular apex and base was significantly longer in LQT2 than LQT1 ( P < 0.05) or LMC ( P < 0.01), with a greater VERP dispersion in LQT2 than LQT1 rabbits. Isoproterenol reduced the VERP dispersion in LQT2 rabbits by shortening the VERP in the base more than in the apex but had no effect on VERP in LQT1. EPS and optical mapping experiments demonstrated genotype-specific differences in AV conduction and ventricular refractoriness. The occurrence of infra-His blocks in LQT2 rabbits under isoflurane and intra-His block in LQT1 rabbits after dofetilide suggest differential regional sensitivities of the rabbit His-Purkinje system to drugs blocking IKr and IKs.

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Joutsijoki, Henry, Kirsi Penttinen, Martti Juhola, and Katriina Aalto-Setälä. "Separation of HCM and LQT Cardiac Diseases with Machine Learning of Ca2+ Transient Profiles." Methods of Information in Medicine 58, no. 04/05 (November 2019): 167–78. http://dx.doi.org/10.1055/s-0040-1701484.

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Abstract Background Modeling human cardiac diseases with induced pluripotent stem cells not only enables to study disease pathophysiology and develop therapies but also, as we have previously showed, it can offer a tool for disease diagnostics. We previously observed that a few genetic cardiac diseases can be separated from each other and healthy controls by applying machine learning to Ca2+ transient signals measured from iPSC-derived cardiomyocytes (CMs). Objectives For the current research, 419 hypertrophic cardiomyopathy (HCM) transient signals and 228 long QT syndrome (LQTS) transient signals were measured. HCM signals included data recorded from iPSC-CMs carrying either α-tropomyosin, i.e., TPM1 (HCMT) or MYBPC3 or myosin-binding protein C (HCMM) mutation and LQTS signals included data recorded from iPSC-CMs carrying potassium voltage-gated channel subfamily Q member 1 (KCNQ1) mutation (long QT syndrome 1 [LQT1]) or KCNH2 mutation (long QT syndrome 2 [LQT2]). The main objective was to study whether and how effectively HCMM and HCMT can be separated from each other as well as LQT1 from LQT2. Methods After preprocessing those Ca2+ signals where we computed peak waveforms we then classified the two mutations of both disease pairs by using several different machine learning methods. Results We obtained excellent classification accuracies of 89% for HCM and even 100% for LQT at their best. Conclusion The results indicate that the methods applied would be efficient for the identification of these genetic cardiac diseases.

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Chakova, N. N., S. M. Komissarova, E. A. Zasim, T. V. Dolmatovich, E. S. Rebeko, S. S. Niyazova, E. V. Zaklyazminskaya, L. I. Plashchinskaya, and M. V. Dudko. "Spectrum of mutations and their phenotypic manifestations in children and adults with long QT syndrome." Russian Journal of Cardiology 26, no. 10 (November 22, 2021): 4704. http://dx.doi.org/10.15829/1560-4071-2021-4704.

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Aim. To determine the spectrum of mutations in the genes responsible for the long QT syndrome (LQTS) and study their phenotypic manifestations in patients with LQTS in different age groups.Materials and methods. The study included 35 unrelated probands with a clinical diagnosis of LQTS: 23 adults (8 men) and 12 children (9 boys). There were following clinical features: syncope — 54%, positive family history for SCD — 29%, implanted cardioverter defibrillator (ICD) — 46%. All participants underwent 12-lead electrocardiography (ECG), 24-hour Holter monitoring, genealogical analysis, echocardiography and cardiac MRI. The genetic study was performed by nextgeneration sequencing (NGS) using the MiSeq system (Illumina). The quantitative comparison of two unrelated groups was carried out using the nonparametric MannWhitney U-test. The differences were considered significant at p<0,05.Results. In the examined group of 35 probands, 23 genetic variants of pathogenicity class IV and V (hereinafter referred to as) were identified. The molecular genetic variant of the disease was verified in 66% of probands. At the same time, the detection of mutations in the group with early manifestation (children) was significantly higher: 83% (10 out of 12 children) vs 57% in adults (13 out of 23). Rare genetic variants of uncertain significance (VUS, class III pathogenicity) were detected in 4 probands (11%). In the groups of children and adults with LQT1, LQT2 and LQT3, the sex distribution deviated from the 1:1 ratio. Among children, two-thirds were boys, among adults — the same proportion was represented by women. Disease manifestation time, QTc duration and adverse events risk depended on the genetic type of LQTS, intragenic localization of mutations and sex. In children, all 4 missense mutations in the KCNQ1 gene were located in transmembrane domain, and in adults, 4 mutations were in the transmembrane domain and three — in the C-terminal domain of the protein. LQT1 in boys was characterized by early manifestation, while QTc did not exceed 500 ms and there were no adverse outcomes. Two women out of 7 adults with LQT1 with mutations in the transmembrane domain had na ICD (QTc >520 ms). All patients with LQT2 (4 children, 4 adults) had QTc >500 ms. At the same time, 2 children and 3 women had an ICD. LQT3 was diagnosed only in the children subgroup (2 boys, with QTc of 510 ms and QTc of 610 ms); one of them died suddenly despite beta-blocker therapy. Four adult patients, carriers of class III pathogenicity variants, had QTc <500 ms and delayed disease manifestation (after 30 years). Three of them had episodes of clinical death with subsequent resuscitation and implantation of cardioverter defibrillator.Conclusion. The average diagnostic efficiency of mutation identification using NGS in patients with clinically manifest LQTS was 66%. At the same time, mutations were more common in the children’s group. In genotype-positive probands, the risk of adverse outcomes correlated with sex, age and the genetic variant of disease. The greatest number of adverse outcomes was observed in carriers of mutations in both KCNH2 (LQT2) and SCN5A (LQT3) genes. Variants with unknown clinical significance were identified in 4 probands (11%), which potentially allowed to confirm the diagnosis after functional tests.

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Odening, Katja E., Omar Hyder, Leonard Chaves, Lorraine Schofield, Michael Brunner, Malcolm Kirk, Manfred Zehender, Xuwen Peng, and Gideon Koren. "Pharmacogenomics of anesthetic drugs in transgenic LQT1 and LQT2 rabbits reveal genotype-specific differential effects on cardiac repolarization." American Journal of Physiology-Heart and Circulatory Physiology 295, no. 6 (December 2008): H2264—H2272. http://dx.doi.org/10.1152/ajpheart.00680.2008.

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Anesthetic agents prolong cardiac repolarization by blocking ion currents. However, the clinical relevance of this blockade in subjects with reduced repolarization reserve is unknown. We have generated transgenic long QT syndromes type 1 (LQT1) and type 2 (LQT2) rabbits that lack slow delayed rectifier K+ currents ( IKs) or rapidly activating K+ currents ( IKr) and used them as a model system to detect the channel-blocking properties of anesthetic agents. Therefore, LQT1, LQT2, and littermate control (LMC) rabbits were administered isoflurane, thiopental, midazolam, propofol, or ketamine, and surface ECGs were analyzed. Genotype-specific heart rate correction formulas were used to determine the expected QT interval at a given heart rate. The QT index (QTi) was calculated as percentage of the observed QT/expected QT. Isoflurane, a drug that blocks IKs, prolonged the QTi only in LQT2 and LMC but not in LQT1 rabbits. Midazolam, which blocks inward rectifier K+ current ( IK1), prolonged the QTi in both LQT1 and LQT2 but not in LMC. Thiopental, which blocks both IKs and IK1, increased the QTi in LQT2 and LMC more than in LQT1. By contrast, ketamine, which does not block IKr, IKs, or IK1, did not alter the QTi in any group. Finally, anesthesia with isoflurane or propofol resulted in lethal polymorphic ventricular tachycardia (pVT) in three out of nine LQT2 rabbits. Transgenic LQT1 and LQT2 rabbits could serve as an in vivo model in which to examine the pharmacogenomics of drug-induced QT prolongation of anesthetic agents and their proarrhythmic potential. Transgenic LQT2 rabbits developed pVT under isoflurane and propofol, underlining the proarrhythmic risk of IKs blockers in subjects with reduced IKr.

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Diamant, Ulla-Britt, Farzad Vahedi, Annika Winbo, Annika Rydberg, Eva-Lena Stattin, Steen M. Jensen, and Lennart Bergfeldt. "Electrophysiological phenotype in the LQTS mutations Y111C and R518X in the KCNQ1 gene." Journal of Applied Physiology 115, no. 10 (November 15, 2013): 1423–32. http://dx.doi.org/10.1152/japplphysiol.00665.2013.

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Long QT syndrome is the prototypical disorder of ventricular repolarization (VR), and a genotype-phenotype relation is postulated. Furthermore, although increased VR heterogeneity (dispersion) may be important in the arrhythmogenicity in long QT syndrome, this hypothesis has not been evaluated in humans and cannot be tested by conventional electrocardiography. In contrast, vectorcardiography allows assessment of VR heterogeneity and is more sensitive to VR alterations than electrocardiography. Therefore, vectorcardiography was used to compare the electrophysiological phenotypes of two mutations in the LQT1 gene with different in vitro biophysical properties, and with LQT2 mutation carriers and healthy control subjects. We included 99 LQT1 gene mutation carriers (57 Y111C, 42 R518X) and 19 LQT2 gene mutation carriers. Potassium channel function is in vitro most severely impaired in Y111C. The control group consisted of 121 healthy subjects. QRS, QT, and T-peak to T-end (Tp-e) intervals, measures of the QRS vector and T vector and their relationship, and T-loop morphology parameters were compared at rest. Apart from a longer heart rate-corrected QT interval (QT heart rate corrected according to Bazett) in Y111C mutation carriers, there were no significant differences between the two LQT1 mutations. No signs of increased VR heterogeneity were observed among the LQT1 and LQT2 mutation carriers. QT heart rate corrected according to Bazett and Tp-e were longer, and the Tp-e-to-QT ratio greater in LQT2 than in LQT1 and the control group. In conclusion, there was a marked discrepancy between in vitro potassium channel function and in vivo electrophysiological properties in these two LQT1 mutations. Together with previous observations of the relatively low risk for clinical events in Y111C mutation carriers, our results indicate need for cautiousness in predicting in vivo electrophysiological properties and the propensity for clinical events based on in vitro assessment of ion channel function alone.

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Zumhagen, Sven, Alexis Vrachimis, Lars Stegger, Peter Kies, Christian Wenning, Marko Ernsting, Jovanca Müller, et al. "Impact of presynaptic sympathetic imbalance in long-QT syndrome by positron emission tomography." Heart 104, no. 4 (September 1, 2017): 332–39. http://dx.doi.org/10.1136/heartjnl-2017-311667.

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ObjectiveWe investigated the impact of cardiac presynaptic norepinephrine recycling in patients with long-QT syndrome (LQTS) using positron emission tomography (PET) with 11C-meta-hydroxyephedrine ([11C]mHED-PET).Methods[11C]mHED-PET was performed in 25 patients with LQTS (LQT1: n=14; LQT2: n=11) and 20 healthy controls and correlated with clinical parameters. [11C]mHED-PET images were analysed for global and regional retention indices (RI) and washout rates (WO) reflecting dynamic parameters of the tracer activity.ResultsGlobal and regional RI values were similar between patients with LQTS and controls. Although the global WO rates were similar between these groups, regional WO rates were on average higher in the lateral left ventricle (LV) wall in patients with LQTS (dose, mean ±SD; 0.08±0.14 vs 0.00%±0.09% min–1; p=0.033). In addition, patients with LQTS with a longer QTc interval showed a higher global WO rate. Clinical symptoms correlated with higher global WO rates. In the presence of normal global WO rates, asymptomatic LQTS patients showed higher global RI values.ConclusionThe increased regional WO rate of [11C]mHED in the lateral LV suggests an imbalance of presynaptic catecholamine reuptake and release, resulting in a higher synaptic catecholamine concentration, in particular in LQT1 patients. This might enhance β-adrenoceptor signalling and thereby aggravate inherited ion channel dysfunction and may facilitate occurrence of ventricular tachyarrhythmias. Detection of regional differences in LV sympathetic nervous function may modify disease expression and potentially serve as a non-invasive risk marker in congenital LQTS.Trial registration number2006-002767-41;Results.

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Komissarova, S. M., N. N. Chakova, E. S. Rebeko, T. V. Dolmatovich, and S. S. Niyazova. "Clinical characteristics of patients with various genetic types of long QT syndrome." Journal of Arrhythmology 29, no. 1 (March 28, 2022): 7–16. http://dx.doi.org/10.35336/va-2022-1-02.

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The aim of the study is to evaluate clinical characteristics, including adverse events and outcomes, in patients with various genetic types of long QT syndrome (LQTS).Material and methods. We examined 24 patients with a clinical diagnosis of LQTS, observed in the for 5 years. The clinical and instrumental study included registration of electrocardiography (ECG), Holter monitoring, collection of a genealogical history with an ECG assessment of all family members and identification of cases of sudden cardiac death (SCD) in the family or the presence of a family form of the disease, echocardiography and cardiac magnetic resonance imaging to exclude structural changes in the myocardium. The search for mutations in the coding sequences of genes associated with the development of channelopathy and other hereditary heart rhythm disorders was carried out by next generation sequencing (NGS).Results. Mutations in 4 genes associated with LQTS (KCNQ1, KCNH2, CACNA1C, ANK2) were detected in 18 out of 24 (75.0%) patients. Mutations in the KCNQ1, KCNH2 and CACNA1C genes were detected in 14 (58.0%) patients. In 4 out of 24 (17%) patients, two or more variants of clinical significance (VUS) were detected in the genes associated with LQTS and hereditary arrhythmias, 6 patients had no genetic changes. The most severe form of the disease with pronounced clinical manifestations and episodes of clinical death with subsequent resuscitation measures, as well as a significant increase in the QTc interval exceeding 500 ms, was observed in patients with LQT2 and multiple mutations. Implantation of a cardioverter-defibrillator (CD) was required in 14 (58.3%) patients, including 11 (78.56%) - for secondary prevention of SCD and 3 (21.4%) - for primary prevention.Conclusion. A comparative analysis between different genetic types of LQTS (LQT1; LQT2; patients with multiple VUS) showed that in patients with LQT1 syndrome, despite the early manifestation of the disease and the presence of syncopal conditions, life-threatening arrhythmias, SCD and the frequency of CD implantation were significantly less often recorded than in other LQTS. The most severe form of the disease with pronounced clinical manifestations, episodes of clinical death with subsequent resuscitation and CD implantation was observed both in the group of probands with LQT2 and in patients with several nucleotide variants (VUS), one of which was in the CACNA1C or ANK2 genes.

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Cordeiro, Jonathan M., Guillermo J. Perez, Nicole Schmitt, Ryan Pfeiffer, Vladislav V. Nesterenko, Elena Burashnikov, Christian Veltmann, et al. "Overlapping LQT1 and LQT2 phenotype in a patient with long QT syndrome associated with loss-of-function variations in KCNQ1 and KCNH2." Canadian Journal of Physiology and Pharmacology 88, no. 12 (December 2010): 1181–90. http://dx.doi.org/10.1139/y10-094.

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Long QT syndrome (LQTS) is an inherited disorder characterized by prolonged QT intervals and potentially life-threatening arrhythmias. Mutations in 12 different genes have been associated with LQTS. Here we describe a patient with LQTS who has a mutation in KCNQ1 as well as a polymorphism in KCNH2. The proband (MMRL0362), a 32-year-old female, exhibited multiple ventricular extrasystoles and one syncope. Her ECG (QT interval corrected for heart rate (QTc) = 518ms) showed an LQT2 morphology in leads V4–V6 and LQT1 morphology in leads V1–V2. Genomic DNA was isolated from lymphocytes. All exons and intron borders of 7 LQTS susceptibility genes were amplified and sequenced. Variations were detected predicting a novel missense mutation (V110I) in KCNQ1, as well as a common polymorphism in KCNH2 (K897T). We expressed wild-type (WT) or V110I Kv7.1 channels in CHO-K1 cells cotransfected with KCNE1 and performed patch-clamp analysis. In addition, WT or K897T Kv11.1 were also studied by patch clamp. Current–voltage (I-V) relations for V110I showed a significant reduction in both developing and tail current densities compared with WT at potentials >+20 mV (p < 0.05; n = 8 cells, each group), suggesting a reduction in IKs currents. K897T- Kv11.1 channels displayed a significantly reduced tail current density compared with WT-Kv11.1 at potentials >+10 mV. Interestingly, channel availability assessed using a triple-pulse protocol was slightly greater for K897T compared with WT (V0.5 = –53.1 ± 1.13 mV and –60.7 ± 1.15 mV for K897T and WT, respectively; p < 0.05). Comparison of the fully activated I-V revealed no difference in the rectification properties between WT and K897T channels. We report a patient with a loss-of-function mutation in KCNQ1 and a loss-of-function polymorphism in KCNH2. Our results suggest that a reduction of both IKr and IKs underlies the combined LQT1 and LQT2 phenotype observed in this patient.

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Kutyifa, Valentina, Usama A. Daimee, Scott McNitt, Bronislava Polonsky, Charles Lowenstein, Kris Cutter, Coeli Lopes, Wojciech Zareba, and Arthur J. Moss. "Clinical aspects of the three major genetic forms of long QT syndrome (LQT1, LQT2, LQT3)." Annals of Noninvasive Electrocardiology 23, no. 3 (March 5, 2018): e12537. http://dx.doi.org/10.1111/anec.12537.

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Lorca, Rebeca, Alejandro Junco-Vicente, Alicia Pérez-Pérez, Isaac Pascual, Yvan Rafael Persia-Paulino, Francisco González-Urbistondo, Elías Cuesta-Llavona, et al. "KCNH2 p.Gly262AlafsTer98: A New Threatening Variant Associated with Long QT Syndrome in a Spanish Cohort." Life 12, no. 4 (April 8, 2022): 556. http://dx.doi.org/10.3390/life12040556.

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Long QT syndrome (LQTS) is an inherited (autosomal dominant) channelopathy associated with susceptibility to ventricular arrhythmias due to malfunction of ion channels in cardiomyocytes, that could lead to sudden death (SD). Most pathogenic variants are in the main 3 genes: KCNQ1 (LQT1), KCNH2 (LQT2) and SCN5A (LQT3). Efforts to improve the understanding of the genotype-phenotype relationship are essential to improve the medical clinical practice. In this study, we identified all index patients referred for NGS genetic sequencing due to LQTS, in a Spanish cohort, who were carriers of a new pathogenic variant (KCNH2 p.Gly262AlafsTer98). Genetic and clinical family screening was performed in order to describe its phenotypic characteristics. We identified 22 relatives of Romani ethnicity, who were carriers of the variant. Penetrance reached a 100% and adherence to medical treatment was low. There was a high rate of clinical events, particularly arrhythmic events and SD (1 in every 4 patients presented syncope, 1 presented an aborted SD, 2 obligated carriers suffered SD before the age of 40 and 4 out of 6 carriers of an implantable cardioverter-defibrillator (ICD) had appropriate ICD therapies. Correct adherence to medical treatment in all carriers should be specially encouraged in this population. ICD implantation decision in non-compliant patients, and refusing left cardiac sympathetic denervation, should be carefully outweighed.

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Oertli, Annemarie, Susanne Rinné, Robin Moss, Stefan Kääb, Gunnar Seemann, Britt-Maria Beckmann, and Niels Decher. "Molecular Mechanism of Autosomal Recessive Long QT-Syndrome 1 without Deafness." International Journal of Molecular Sciences 22, no. 3 (January 23, 2021): 1112. http://dx.doi.org/10.3390/ijms22031112.

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KCNQ1 encodes the voltage-gated potassium (Kv) channel KCNQ1, also known as KvLQT1 or Kv7.1. Together with its ß-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–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.

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Shimizu, Wataru, Takashi Noda, Hiroshi Takaki, Noritoshi Nagaya, Kazuhiro Satomi, Takashi Kurita, Kazuhiro Suyama, et al. "Diagnostic value of epinephrine test for genotyping LQT1, LQT2, and LQT3 forms of congenital long QT syndrome." Heart Rhythm 1, no. 3 (September 2004): 276–83. http://dx.doi.org/10.1016/j.hrthm.2004.04.021.

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SY, RAYMOND W., ISHVINDER S. CHATTHA, GEORGE J. KLEIN, LORNE J. GULA, ALLAN C. SKANES, RAYMOND YEE, MATTHEW T. BENNETT, and ANDREW D. KRAHN. "Repolarization Dynamics During Exercise Discriminate Between LQT1 and LQT2 Genotypes." Journal of Cardiovascular Electrophysiology 21, no. 11 (October 29, 2010): 1242–46. http://dx.doi.org/10.1111/j.1540-8167.2010.01788.x.

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Kekenes-Huskey, Peter M., Don E. Burgess, Bin Sun, Daniel C. Bartos, Ezekiel R. Rozmus, Corey L. Anderson, Craig T. January, Lee L. Eckhardt, and Brian P. Delisle. "Mutation-Specific Differences in Kv7.1 (KCNQ1) and Kv11.1 (KCNH2) Channel Dysfunction and Long QT Syndrome Phenotypes." International Journal of Molecular Sciences 23, no. 13 (July 2, 2022): 7389. http://dx.doi.org/10.3390/ijms23137389.

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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 KCNQ1 (LQT1) and KCNH2 (LQT2). We move beyond the “benign” to a “pathogenic” binary classification scheme for different KCNQ1 and KCNH2 missense variants and discuss gene- and mutation-specific differences in K+ channel dysfunction, which can predispose people to distinct clinical phenotypes (e.g., concealed, pleiotropic, severe, etc.). We conclude by discussing the emerging computational structural modeling strategies that will distinguish between dysfunctional subtypes of KCNQ1 and KCNH2 variants, with the goal of realizing a layered precision medicine approach focused on individuals.

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Takaki, Tadashi, Azusa Inagaki, Kazuhisa Chonabayashi, Keiji Inoue, Kenji Miki, Seiko Ohno, Takeru Makiyama, Minoru Horie, and Yoshinori Yoshida. "Optical Recording of Action Potentials in Human Induced Pluripotent Stem Cell-Derived Cardiac Single Cells and Monolayers Generated from Long QT Syndrome Type 1 Patients." Stem Cells International 2019 (March 6, 2019): 1–12. http://dx.doi.org/10.1155/2019/7532657.

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Induced pluripotent stem cells (iPSCs) from type 1 long QT (LQT1) patients can differentiate into cardiomyocytes (CMs) including ventricular cells to recapitulate the disease phenotype. Although optical recordings using membrane potential dyes to monitor action potentials (APs) were reported, no study has investigated the disease phenotypes of cardiac channelopathy in association with the cardiac subtype at the single-cell level. We induced iPSC-CMs from three control and three LQT1 patients. Single-cell analysis using a fast-responding dye confirmed that ventricular cells were the dominant subtype (control-iPSC-CMs: 98%, 88%, 91%; LQT1-iPSC-CMs: 95%, 79%, 92%). In addition, LQT1-iPSC-ventricular cells displayed an increased frequency of early afterdepolarizations (pvalue=0.031). Cardiomyocyte monolayers constituted mostly of ventricular cells derived from LQT1-iPSCs showed prolonged AP duration (APD) (pvalue=0.000096). High-throughput assays using cardiomyocyte monolayers in 96-well plates demonstrated that IKr inhibitors prolonged APDs in both control- and LQT1-iPSC-CM monolayers. We confirmed that the optical recordings of APs in single cells and monolayers derived from control- and LQT1-iPSC-CMs can be used to assess arrhythmogenicity, supporting the feasibility of membrane potential dye-based high-throughput screening to study ventricular arrhythmias caused by genetic channelopathy or cardiotoxic drugs.

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Winbo, Annika, Suganeya Ramanan, Emily Eugster, Annika Rydberg, Stefan Jovinge, Jonathan R. Skinner, and Johanna M. Montgomery. "Functional hyperactivity in long QT syndrome type 1 pluripotent stem cell-derived sympathetic neurons." American Journal of Physiology-Heart and Circulatory Physiology 321, no. 1 (July 1, 2021): H217—H227. http://dx.doi.org/10.1152/ajpheart.01002.2020.

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Here, we present the first study of patient-derived LQT1 sympathetic neurons that are norepinephrine secreting, and electrophysiologically functional, in vitro. Our data reveal a novel LQT1 sympathetic neuronal phenotype of increased neurotransmission and excitability. The identified sympathetic neuronal hyperactivity phenotype is of particular relevance as it could contribute to the mechanisms underlying sympathetically triggered arrhythmia in LQT1.

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Shimizu, Wataru, and Charles Antzelevitch. "Differential effects of beta-adrenergic agonists and antagonists in LQT1, LQT2 and LQT3 models of the long QT syndrome." Journal of the American College of Cardiology 35, no. 3 (March 2000): 778–86. http://dx.doi.org/10.1016/s0735-1097(99)00582-3.

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Dotzler, Steven M., C. S. John Kim, William A. C. Gendron, Wei Zhou, Dan Ye, J. Martijn Bos, David J. Tester, Michael A. Barry, and Michael J. Ackerman. "Suppression-Replacement KCNQ1 Gene Therapy for Type 1 Long QT Syndrome." Circulation 143, no. 14 (April 6, 2021): 1411–25. http://dx.doi.org/10.1161/circulationaha.120.051836.

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Background: Type 1 long QT syndrome (LQT1) is caused by loss-of-function variants in the KCNQ1 -encoded K v 7.1 potassium channel α-subunit that is essential for cardiac repolarization, providing the slow delayed rectifier current. No current therapies target the molecular cause of LQT1. Methods: A dual-component suppression-and-replacement (SupRep) KCNQ1 gene therapy was created by cloning a KCNQ1 short hairpin RNA and a short hairpin RNA-immune KCNQ1 cDNA modified with synonymous variants in the short hairpin RNA target site, into a single construct. The ability of KCNQ1-SupRep gene therapy to suppress and replace LQT1-causative variants in KCNQ1 was evaluated by means of heterologous expression in TSA201 cells. For a human in vitro cardiac model, induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) were generated from 4 patients with LQT1 (KCNQ1-Y171X, -V254M, -I567S, and -A344A/spl) and an unrelated healthy control. CRISPR-Cas9 corrected isogenic control iPSC-CMs were made for 2 LQT1 lines (correction of KCNQ1-V254M and KCNQ1-A344A/spl). FluoVolt voltage dye was used to measure the cardiac action potential duration (APD) in iPSC-CMs treated with KCNQ1-SupRep. Results: In TSA201 cells, KCNQ1-SupRep achieved mutation-independent suppression of wild-type KCNQ1 and 3 LQT1-causative variants (KCNQ1-Y171X, -V254M, and -I567S) with simultaneous replacement of short hairpin RNA-immune KCNQ1 as measured by allele-specific quantitative reverse transcription polymerase chain reaction and Western blot. Using FluoVolt voltage dye to measure the cardiac APD in the 4 LQT1 patient-derived iPSC-CMs, treatment with KCNQ1-SupRep resulted in shortening of the pathologically prolonged APD at both 90% and 50% repolarization, resulting in APD values similar to those of the 2 isogenic controls. Conclusions: This 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 KCNQ1 to normal wild-type levels. In TSA201 cells, cotransfection of LQT1-causative variants and KCNQ1-SupRep caused mutation-independent suppression and replacement of KCNQ1 . In LQT1 iPSC-CMs, KCNQ1-SupRep gene therapy shortened the APD, thereby eliminating the pathognomonic feature of LQT1.

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Rinné, Susanne, Annemarie Oertli, Claudia Nagel, Philipp Tomsits, Tina Jenewein, Stefan Kääb, Silke Kauferstein, Axel Loewe, Britt Maria Beckmann, and Niels Decher. "Functional Characterization of a Spectrum of Novel Romano-Ward Syndrome KCNQ1 Variants." International Journal of Molecular Sciences 24, no. 2 (January 10, 2023): 1350. http://dx.doi.org/10.3390/ijms24021350.

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The KCNQ1 gene encodes the α-subunit of the cardiac voltage-gated potassium (Kv) channel KCNQ1, also denoted as Kv7.1 or KvLQT1. The channel assembles with the ß-subunit KCNE1, also known as minK, to generate the slowly activating cardiac delayed rectifier current IKs, a key regulator of the heart rate dependent adaptation of the cardiac action potential duration (APD). Loss-of-function variants in KCNQ1 cause the congenital Long QT1 (LQT1) syndrome, characterized by delayed cardiac repolarization and a QT interval prolongation in the surface electrocardiogram (ECG). Autosomal dominant loss-of-function variants in KCNQ1 result in the LQT syndrome called Romano-Ward syndrome (RWS), while autosomal recessive variants affecting function, lead to Jervell and Lange-Nielsen syndrome (JLNS), associated with deafness. The aim of this study was the characterization of novel KCNQ1 variants identified in patients with RWS to widen the spectrum of known LQT1 variants, and improve the interpretation of the clinical relevance of variants in the KCNQ1 gene. We functionally characterized nine human KCNQ1 variants using the voltage-clamp technique in Xenopus laevis oocytes, from which we report seven novel variants. The functional data was taken as input to model surface ECGs, to subsequently compare the functional changes with the clinically observed QTc times, allowing a further interpretation of the severity of the different LQTS variants. We found that the electrophysiological properties of the variants correlate with the severity of the clinically diagnosed phenotype in most cases, however, not in all. Electrophysiological studies combined with in silico modelling approaches are valuable components for the interpretation of the pathogenicity of KCNQ1 variants, but assessing the clinical severity demands the consideration of other factors that are included, for example in the Schwartz score.

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Vaglio, Martino, Jean-Philippe Couderc, Scott McNitt, Xiaojuan Xia, Wojciech Zareba, and Arthur J. Moss. "Heart rate bin method for identifying repolarization changes in LQT1 and LQT2 patients." Journal of Electrocardiology 39, no. 4 (October 2006): S151. http://dx.doi.org/10.1016/j.jelectrocard.2006.05.019.

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Noda, T. "Gene-specific response of dynamic ventricular repolarization to sympathetic stimulation in LQT1, LQT2 and LQT3 forms of congenital long QT syndrome." European Heart Journal 23, no. 12 (June 15, 2002): 975–83. http://dx.doi.org/10.1053/euhj.2001.3079.

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VIITASALO, MATTI, KRISTIAN J. PAAVONEN, HEIKKI SWAN, KIMMO KONTULA, and LAURI TOIVONEN. "Effects of Epinephrine on Right Ventricular Monophasic Action Potentials in the LQT1 Versus LQT2 Form of Long QT Syndrome: Preferential Enhancement of “Triangulation” in LQT1." Pacing and Clinical Electrophysiology 28, no. 3 (February 25, 2005): 219–27. http://dx.doi.org/10.1111/j.1540-8159.2005.09404.x.

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Eldstrom, Jodene, Hongjian Xu, Daniel Werry, Congbao Kang, Matthew E. Loewen, Amanda Degenhardt, Shubhayan Sanatani, Glen F. Tibbits, Charles Sanders, and David Fedida. "Mechanistic basis for LQT1 caused by S3 mutations in the KCNQ1 subunit of IKs." Journal of General Physiology 135, no. 5 (April 26, 2010): 433–48. http://dx.doi.org/10.1085/jgp.200910351.

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Long QT interval syndrome (LQTS) type 1 (LQT1) has been reported to arise from mutations in the S3 domain of KCNQ1, but none of the seven S3 mutations in the literature have been characterized with respect to trafficking or biophysical deficiencies. Surface channel expression was studied using a proteinase K assay for KCNQ1 D202H/N, I204F/M, V205M, S209F, and V215M coexpressed with KCNE1 in mammalian cells. In each case, the majority of synthesized channel was found at the surface, but mutant IKs current density at +100 mV was reduced significantly for S209F, which showed ∼75% reduction over wild type (WT). All mutants except S209F showed positively shifted V1/2’s of activation and slowed channel activation compared with WT (V1/2 = +17.7 ± 2.4 mV and τactivation of 729 ms at +20 mV; n = 18). Deactivation was also accelerated in all mutants versus WT (126 ± 8 ms at −50 mV; n = 27), and these changes led to marked loss of repolarizing currents during action potential clamps at 2 and 4 Hz, except again S209F. KCNQ1 models localize these naturally occurring S3 mutants to the surface of the helices facing the other voltage sensor transmembrane domains and highlight inter-residue interactions involved in activation gating. V207M, currently classified as a polymorphism and facing lipid in the model, was indistinguishable from WT IKs. We conclude that S3 mutants of KCNQ1 cause LQTS predominantly through biophysical effects on the gating of IKs, but some mutants also show protein stability/trafficking defects, which explains why the kinetic gain-of-function mutation S209F causes LQT1.

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Viitasalo, Matti, Lasse Oikarinen, Heikki Väänänen, Heikki Swan, Kirsi Piippo, Kimmo Kontula, Hal V. Barron, Lauri Toivonen, and Melvin M. Scheinman. "Differentiation between LQT1 and LQT2 patients and unaffected subjects using 24-hour electrocardiographic recordings." American Journal of Cardiology 89, no. 6 (March 2002): 679–85. http://dx.doi.org/10.1016/s0002-9149(01)02339-6.

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Cócera-Ortega, Lucía, Ronald Wilders, Selina C. Kamps, Benedetta Fabrizi, Irit Huber, Ingeborg van der Made, Anouk van den Bout, et al. "shRNAs Targeting a Common KCNQ1 Variant Could Alleviate Long-QT1 Disease Severity by Inhibiting a Mutant Allele." International Journal of Molecular Sciences 23, no. 7 (April 6, 2022): 4053. http://dx.doi.org/10.3390/ijms23074053.

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Long-QT syndrome type 1 (LQT1) is caused by mutations in KCNQ1. Patients heterozygous for such a mutation co-assemble both mutant and wild-type KCNQ1-encoded subunits into tetrameric Kv7.1 potassium channels. Here, we investigated whether allele-specific inhibition of mutant KCNQ1 by targeting a common variant can shift the balance towards increased incorporation of the wild-type allele to alleviate the disease in human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs). We identified the single nucleotide polymorphisms (SNP) rs1057128 (G/A) in KCNQ1, with a heterozygosity of 27% in the European population. Next, we determined allele-specificity of short-hairpin RNAs (shRNAs) targeting either allele of this SNP in hiPSC-CMs that carry an LQT1 mutation. Our shRNAs downregulated 60% of the A allele and 40% of the G allele without affecting the non-targeted allele. Suppression of the mutant KCNQ1 allele by 60% decreased the occurrence of arrhythmic events in hiPSC-CMs measured by a voltage-sensitive reporter, while suppression of the wild-type allele increased the occurrence of arrhythmic events. Furthermore, computer simulations based on another LQT1 mutation revealed that 60% suppression of the mutant KCNQ1 allele shortens the prolonged action potential in an adult cardiomyocyte model. We conclude that allele-specific inhibition of a mutant KCNQ1 allele by targeting a common variant may alleviate the disease. This novel approach avoids the need to design shRNAs to target every single mutation and opens up the exciting possibility of treating multiple LQT1-causing mutations with only two shRNAs.

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Charisopoulou, Dafni, George Koulaouzidis, Lucy F. Law, Annika Rydberg, and Michael Y. Henein. "Exercise Induced Worsening of Mechanical Heterogeneity and Diastolic Impairment in Long QT Syndrome." Journal of Clinical Medicine 10, no. 1 (December 24, 2020): 37. http://dx.doi.org/10.3390/jcm10010037.

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Background: Electromechanical heterogeneities due to marked dispersion of ventricular repolarisation and mechanical function have been associated with symptoms in long QT syndrome (LQTS) patients; Aim: To examine the exercise response of longitudinal LV systolic and diastolic myocardial function and synchronicity in LQTS patients and its relationship with symptoms; Methods: Forty seven (age 45 ± 15 yrs, 25 female, 20 symptomatic) LQTS patients and 35 healthy individuals underwent an exercise test (Bruce protocol). ECG and echo parameters were recorded at rest, peak exercise (p.e.), and recovery; Results: LQTS patients had prolonged and markedly dispersed myocardial contraction, delayed early relaxation phase, and significantly decreased filling time at all exercise phases. Unlike controls, these electromechanical disturbances deteriorated further with exercise, during which additional decrease of the LV diastolic myocardial function and attenuated LV stroke volume were noted. Such abnormal responses to exercise were seen to a greater degree in symptomatic patients and in the LQT1 subgroup and improved with B-blocker therapy. Worsening myocardial contraction dispersion at p.e. was the strongest discriminator for previous clinical events, and its discriminating power excelled further by adding early relaxation delay; Conclusions: Electromechanical disturbances were shown to worsen during exercise in LQTS patients and were more pronounced in those with previous arrhythmic events.

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Liu, Gong-Xin, and Gideon Koren. "Differential Conditions for EAD and Triggered Activity in Cardiomyocytes Derived from Transgenic LQT1 and LQT2 Rabbits." Biophysical Journal 98, no. 3 (January 2010): 527a. http://dx.doi.org/10.1016/j.bpj.2009.12.2861.

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Krumerman, Andrew, Xiaohong Gao, Jin-Song Bian, Yonathan F. Melman, Anna Kagan, and Thomas V. McDonald. "An LQT mutant minK alters KvLQT1 trafficking." American Journal of Physiology-Cell Physiology 286, no. 6 (June 2004): C1453—C1463. http://dx.doi.org/10.1152/ajpcell.00275.2003.

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Cardiac IKs, the slowly activated delayed-rectifier K+ current, is produced by the protein complex composed of α- and β-subunits: KvLQT1 and minK. Mutations of genes encoding KvLQT1 and minK are responsible for the hereditary long QT syndrome (loci LQT1 and LQT5, respectively). MinK-L51H fails to traffic to the cell surface, thereby failing to produce effective IKs. We examined the effects that minK-L51H and an endoplasmic reticulum (ER)-targeted minK (minK-ER) exerted over the electrophysiology and biosynthesis of coexpressed KvLQT1. Both minK-L51H and minK-ER were sequestered primarily in the ER as confirmed by lack of plasma membrane expression. Glycosylation and immunofluorescence patterns of minK-L51H were qualitatively different for minK-ER, suggesting differences in trafficking. Cotransfection with the minK mutants resulted in reduced surface expression of KvLQT1 as assayed by whole cell voltage clamp and immunofluorescence. MinK-L51H reduced current amplitude by 91% compared with wild-type (WT) minK/KvLQT1, and the residual current was identical to KvLQT1 without minK. The phenotype of minK-L51H on IKs was not dominant because coexpressed WT minK rescued the current and surface expression. Collectively, our data suggest that ER quality control prevents minK-L51H/KvLQT1 complexes from trafficking to the plasma membrane, resulting in decreased IKs. This is the first demonstration that a minK LQT mutation is capable of conferring trafficking defects onto its associated α-subunit.

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Kandori, Akihiko, Wataru Shimizu, Miki Yokokawa, Takeshi Maruo, Hideaki Kanzaki, Satoshi Nakatani, Shiro Kamakura, et al. "Detection of spatial repolarization abnormalities in patients with LQT1 and LQT2 forms of congenital long-QT syndrome." Physiological Measurement 23, no. 4 (August 6, 2002): 603–14. http://dx.doi.org/10.1088/0967-3334/23/4/301.

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Yamaguchi, Yoshiaki, Koichi Mizumaki, Kunihiro Nishida, Jotaro Iwamoto, Yosuke Nakatani, Naoya Kataoka, and Hiroshi Inoue. "Different Dynamic Aspects of the Repolarization Morphology between LQT1 and LQT2 Forms of Congenital Long QT Syndrome." Journal of Arrhythmia 27, Supplement (2011): PE3_025. http://dx.doi.org/10.4020/jhrs.27.pe3_025.

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Bianchi, Laura, Silvia G. Priori, Carlo Napolitano, Krystyna A. Surewicz, Adrienne T. Dennis, Mirella Memmi, Peter J. Schwartz, and Arthur M. Brown. "Mechanisms of I Ks suppression in LQT1 mutants." American Journal of Physiology-Heart and Circulatory Physiology 279, no. 6 (December 1, 2000): H3003—H3011. http://dx.doi.org/10.1152/ajpheart.2000.279.6.h3003.

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Mutations in the cardiac potassium ion channel gene KCNQ1 (voltage-gated K+ channel subtype KvLQT1) cause LQT1, the most common type of hereditary long Q-T syndrome. KvLQT1 mutations prolong Q-T by reducing the repolarizing cardiac current [slow delayed rectifier K+ current ( I Ks )], but, for reasons that are not well understood, the clinical phenotypes may vary considerably even for carriers of the same mutation, perhaps explaining the mode of inheritance. At present, only currents expressed by LQT1 mutants have been studied, and it is unknown whether abnormal subunits are transported to the cell surface. Here, we have examined for the first time trafficking of KvLQT1 mutations and correlated the results with the I Ks currents that were expressed. Two missense mutations, S225L and A300T, produced abnormal currents, and two others, Y281C and Y315C, produced no currents. However, all four KvLQT1 mutations were detected at the cell surface. S225L, Y281C, and Y315C produced dominant negative effects on wild-type I Ks current, whereas the mutant with the mildest dysfunction, A300T, did not. We examined trafficking of a severe insertion deletion mutant Δ544 and detected this protein at the cell surface as well. We compared the cellular and clinical phenotypes and found a poor correlation for the severely dysfunctional mutations.

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Liu, Gong-Xin, Bum-Rak Choi, Ohad Ziv, Weiyan Li, Enno de Lange, Zhilin Qu, and Gideon Koren. "Differential conditions for early after-depolarizations and triggered activity in cardiomyocytes derived from transgenic LQT1 and LQT2 rabbits." Journal of Physiology 590, no. 5 (January 27, 2012): 1171–80. http://dx.doi.org/10.1113/jphysiol.2011.218164.

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Takenaka, Kotoe, Tomohiko Ai, Wataru Shimizu, Atsushi Kobori, Tomonori Ninomiya, Hideo Otani, Tomoyuki Kubota, Hiroshi Takaki, Shiro Kamakura, and Minoru Horie. "Exercise Stress Test Amplifies Genotype-Phenotype Correlation in the LQT1 and LQT2 Forms of the Long-QT Syndrome." Circulation 107, no. 6 (February 18, 2003): 838–44. http://dx.doi.org/10.1161/01.cir.0000048142.85076.a2.

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Takenaka, K., A. Tomohiko, and W. Shimizu. "Exercise stress test amplifies genotype-phenotype correlation in the LQT1 and LQT2 forms of the long-QT syndrome." ACC Current Journal Review 12, no. 3 (May 2003): 81. http://dx.doi.org/10.1016/s1062-1458(03)00202-2.

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Vaglio, Martino, Jean-Philippe Couderc, Scott McNitt, Xiaojuan Xia, Arthur J. Moss, and Wojciech Zareba. "A quantitative assessment of T-wave morphology in LQT1, LQT2, and healthy individuals based on Holter recording technology." Heart Rhythm 5, no. 1 (January 2008): 11–18. http://dx.doi.org/10.1016/j.hrthm.2007.08.026.

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Shimizu, Wataru, and Charles Antzelevitch. "Effects of a K + Channel Opener to Reduce Transmural Dispersion of Repolarization and Prevent Torsade de Pointes in LQT1, LQT2, and LQT3 Models of the Long-QT Syndrome." Circulation 102, no. 6 (August 8, 2000): 706–12. http://dx.doi.org/10.1161/01.cir.102.6.706.

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Siebrands, Cornelia C., Stephan Binder, Ulrike Eckhoff, Nicole Schmitt, and Patrick Friederich. "Long QT 1 Mutation KCNQ1A344VIncreases Local Anesthetic Sensitivity of the Slowly Activating Delayed Rectifier Potassium Current." Anesthesiology 105, no. 3 (September 1, 2006): 511–20. http://dx.doi.org/10.1097/00000542-200609000-00015.

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Background Anesthesia in patients with long QT syndrome (LQTS) is a matter of concern. Congenital LQTS is most frequently caused by mutations in KCNQ1 (Kv7.1), whereas drug-induced LQTS is a consequence of HERG (human ether-a-go-go-related gene) channel inhibition. The aim of this study was to investigate whether the LQT1 mutation A344V in the S6 region of KCNQ1, at a position corresponding to the local anesthetic binding site in HERG, may render drug insensitive KCNQ1 channels into a toxicologically relevant target of these pharmacologic agents. This may suggest that LQTS constitutes not only a nonspecific but also a specific pharmacogenetic risk factor for anesthesia. Methods The authors examined electrophysiologic and pharmacologic properties of wild-type and mutant KCNQ1 channels. The effects of bupivacaine, ropivacaine, and mepivacaine were investigated using two-electrode voltage clamp and whole cell patch clamp recordings. Results The mutation A344V induced voltage-dependent inactivation in homomeric KCNQ1 channels and shifted the voltage dependence of KCNQ1/KCNE1 channel activation by +30 mV. The mutation furthermore increased the sensitivity of KCNQ1/KCNE1 channels for bupivacaine 22-fold (KCNQ1wt/KCNE1: IC50 = 2,431 +/- 582 microM, n = 20; KCNQ1A344V/KCNE1: IC50 = 110 +/- 9 microM, n = 24). Pharmacologic effects of the mutant channels were dominant when mutant and wild-type channels were coexpressed. Simulation of cardiac action potentials with the Luo-Rudy model yielded a prolongation of the cardiac action potential duration and induction of early afterdepolarizations by the mutation A344V that were aggravated by local anesthetic intoxication. Conclusions The results indicate that certain forms of the LQTS may constitute a specific pharmacogenetic risk factor for regional anesthesia.

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Christ, Torsten, András Horvath, and Thomas Eschenhagen. "LQT1-phenotypes in hiPSC: Are we measuring the right thing?" Proceedings of the National Academy of Sciences 112, no. 16 (March 20, 2015): E1968. http://dx.doi.org/10.1073/pnas.1503347112.

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Paavonen, K. J. "Response of the QT interval to mental and physical stress in types LQT1 and LQT2 of the long QT syndrome." Heart 86, no. 1 (July 1, 2001): 39–44. http://dx.doi.org/10.1136/heart.86.1.39.

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Odening, Katja E., Malcolm Kirk, Peem Lorvidhaya, Michael Brunner, Omar Hyder, Jason Centracchio, Lorraine Schofield, et al. "Transgenic LQT1 and LQT2 rabbits provide a new model for safety screening for IKr or IKs blocking propensity of drugs." Journal of Pharmacological and Toxicological Methods 58, no. 2 (September 2008): 148–49. http://dx.doi.org/10.1016/j.vascn.2008.05.015.

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Jindal, Hitesh K., Elisabeth Merchant, James A. Balschi, Yajie Zhangand, and Gideon Koren. "Proteomic analyses of transgenic LQT1 and LQT2 rabbit hearts elucidate an increase in expression and activity of energy producing enzymes." Journal of Proteomics 75, no. 17 (September 2012): 5254–65. http://dx.doi.org/10.1016/j.jprot.2012.06.034.

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Liu, Judy F., Ilan Goldenberg, Arthur J. Moss, Wataru Shimizu, Arthur A. Wilde, Nynke Hofman, Scott McNitt, et al. "Phenotypic Variability in Caucasian and Japanese Patients with Matched LQT1 Mutations." Annals of Noninvasive Electrocardiology 13, no. 3 (July 2008): 234–41. http://dx.doi.org/10.1111/j.1542-474x.2008.00226.x.

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Bartos, Daniel C., Jennifer L. Smith, Jennifer A. Kilby, Craig T. January, and Brian P. Delisle. "Wild-Type KCNQ1 Modulates the Gating of the LQT1 Mutation R231C." Biophysical Journal 96, no. 3 (February 2009): 380a. http://dx.doi.org/10.1016/j.bpj.2008.12.2847.

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Peroz, David, Shehrazade Dahimène, Isabelle Baró, Gildas Loussouarn, and Jean Mérot. "LQT1-associated Mutations Increase KCNQ1 Proteasomal Degradation Independently of Derlin-1." Journal of Biological Chemistry 284, no. 8 (December 29, 2008): 5250–56. http://dx.doi.org/10.1074/jbc.m806459200.

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Hartle, Cassandra M., Jonathan Z. Luo, Ann N. Stepanchick, Uyenlinh L. Mirshahi, Dustin N. Hartzel, Kandamurugu Manickam, Michael F. Murray, and Tooraj Mirshahi. "Combining Population Whole Exome Sequencing and Functional Analysis to Detect LQT1." Biophysical Journal 114, no. 3 (February 2018): 123a. http://dx.doi.org/10.1016/j.bpj.2017.11.701.

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