• The Korean Journal of Physiology and Pharmacology
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• v.13 no.3
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• pp.215-220
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• 2009

Chlorpheniramine is a potent first-generation histamine $H_1$ receptor antagonist that can increase action potential duration and induce QT prolongation in several animal models. Since block of cardiac human ether-a-go-go-related gene (hERG) channels is one of leading causes of acquired long QT syndrome, we investigated the acute effects of chlorpheniramine on hERG channels to determine the electrophysiological basis for its proarrhythmic potential. We examined the effects of chlorpheniramine on the hERG channels expressed in Xenopus oocytes using two-microelectrode voltage-clamp techniques. Chlorpheniramine induced a concentration-dependent decrease of the current amplitude at the end of the voltage steps and hERG tail currents. The $IC_{50}$ of chlorpheniramine-dependent hERG block in Xenopus oocytes decreased progressively relative to the degree of depolarization. Chlorpheniramine affected the channels in the activated and inactivated states but not in the closed states. The S6 domain mutations Y652A and F656A partially attenuated (Y652A) or abolished (F656A) the hERG current block. These results suggest that the $H_1$ antihistamine, chlorpheniramine is a blocker of the hERG channels, providing a molecular mechanism for the drug-induced arrhythmogenic side effects.

• Clinical and Experimental Pediatrics
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• v.58 no.7
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• pp.263-266
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• 2015

Purpose: Ventricular repolarization is assessed using the QT interval corrected by the heart rate (QTc) via an electrocardiogram (ECG). Prolonged QTc is associated with an increased risk of arrhythmias and cardiac mortality. As there have been few reports regarding the effects of hyperthyroidism on ventricular repolarization, we studied the association between serum free thyroxine (free T4 [fT4]) and thyroid stimulating hormone (TSH) levels and the QTc interval. Methods: Thirty-eight patients with hyperthyroidism (<30 years old) were included, and we used their clinical records and available ECGs (between August 2003 and August 2011) to evaluate the association between their fT4 and TSH levels and their QTc interval. In addition, we studied the ECGs of 72 age-matched patients with no hyperthyroidism (control group) and compared their data with that from the patients group. Results: The QTc duration in patients with hyperthyroidism was significantly prolonged compared to that in the control subjects (P<0.001). In addition, the number of hyperthyroid patients with abnormal prolonged QTc was significantly higher than that in the control group (P<0.001). Among the patients with hyperthyroidism, patients with prolonged QTc and borderline QTc had higher fT4 levels and there was positive correlation between their fT4 levels and their QTc interval (P<0.05). However, no correlation was observed between their TSH levels and their QTc interval. Conclusion: We report that hyperthyroidism is associated with QTc prolongation. The correlation between the fT4 levels and the QTc interval suggests that thyroid status is associated with QTc values and the risk of cardiac mortality.

• The Korean Journal of Physiology and Pharmacology
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• v.6 no.1
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• pp.1-7
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• 2002

Congenital Long QT syndrome (LQTs) is a relatively rare pathologic disorder but results frequently in sudden cardiac death. Of the six LQTs that have been clinically described, five have been worked out for their genetic and biophysical profile. Most are generated by mutations which cause a loss of function in two delayed $K^+$ currents, $i_{Ks}\;and\;i_{Kr}.$ One syndrome is generated by mutations in the $Na^+$ channel which causes essentially a gain of function in the channel. Clinically the syndromes are characterized by slowed repolarization of the cardiac ventricular action potential and the occurrence of typical arrhythmias with undulating peaks in the electrocardiogram, called Torsade de Pointes. Arrhythmias are initiated by early or delayed afterdepolarizations and continue as reentry. Triggers for cardiac events are exercise (swimming; LQT1), emotion (arousal; LQT2) and rest/sleep (LQT3). ${\beta}-blockers$ have a high efficacy in the treatment of LQT1 and LQT2. In LQT3 their use is questionable. The study of congenital LQTsyndromes is a remarkable example of how basic and clinical science converge and take profit of each other's contribution.

• Journal of Chest Surgery
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• v.44 no.1
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• pp.61-63
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• 2011

Implantable cardioverter defibrillator (ICD) can be a crucial therapeutic modality for pediatric patients with congenital heart disease, Brugada syndrome, long QT syndrome and cardiomyopathy. Because transvenous implantation of ICD is mostly unfeasible for pediatric patients due to anatomical and technical limitations, epicardial patch type or subcutaneous type ICD have been used. Implantation of these alternative ICDs, however, was reported to be frequently associated with significant complications. We report a case of successful intrapericardial implantation of a single coil-type ICD through the transverse sinus in a 27 month-old child weighing lesser than 10 kg, and it was inferred from this experience that this alternative technique may decrease complications and morbidities after ICD implantation in children.

• Clinical and Experimental Pediatrics
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• v.60 no.11
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• pp.344-352
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• 2017

Arrhythmias in the neonatal period are not uncommon, and may occur in neonates with a normal heart or in those with structural heart disease. Neonatal arrhythmias are classified as either benign or nonbenign. Benign arrhythmias include sinus arrhythmia, premature atrial contraction, premature ventricular contraction, and junctional rhythm; these arrhythmias have no clinical significance and do not need therapy. Supraventricular tachycardia, ventricular tachycardia, atrioventricular conduction abnormalities, and genetic arrhythmia such as congenital long-QT syndrome are classified as nonbenign arrhythmias. Although most neonatal arrhythmias are asymptomatic and rarely life-threatening, the prognosis depends on the early recognition and proper management of the condition in some serious cases. Precise diagnosis with risk stratification of patients with nonbenign neonatal arrhythmia is needed to reduce morbidity and mortality. In this article, I review the current understanding of the common clinical presentation, etiology, natural history, and management of neonatal arrhythmias in the absence of an underlying congenital heart disease.

• Clinical and Experimental Pediatrics
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• v.56 no.3
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• pp.125-129
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• 2013

Purpose: The use of implantable cardioverter defibrillators (ICDs) to prevent sudden cardiac death is increasing in children and adolescents. This study investigated the use of ICDs in children with congenital heart disease. Methods: This retrospective study was conducted on the clinical characteristics and effectiveness of ICD implantation at the department of pediatrics of a single tertiary center between 2007 and 2011. Results: Fifteen patients underwent ICD implantation. Their mean age at the time of implantation was $14.5{\pm}5.4$ years (range, 2 to 22 years). The follow-up duration was $28.9{\pm}20.4$ months. The cause of ICD implantation was cardiac arrest in 7, sustained ventricular tachycardia in 6, and syncope in 2 patients. The underlying disorders were as follows: ionic channelopathy in 6 patients (long QT type 3 in 4, catecholaminergic polymorphic ventricular tachycardia [CPVT] in 1, and J wave syndrome in 1), cardiomyopathy in 5 patients, and postoperative congenital heart disease in 4 patients. ICD coils were implanted in the pericardial space in 2 children (ages 2 and 6 years). Five patients received appropriate ICD shock therapy, and 2 patients received inappropriate shocks due to supraventricular tachycardia. During follow-up, 2 patients required lead dysfunction-related revision. One patient with CPVT suffered from an ICD storm that was resolved using sympathetic denervation surgery. Conclusion: The overall ICD outcome was acceptable in most pediatric patients. Early diagnosis and timely ICD implantation are recommended for preventing sudden death in high-risk children and patients with congenital heart disease.

• The Korean Journal of Physiology and Pharmacology
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• v.14 no.3
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• pp.119-125
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• 2010

We investigated the effects of a hot-water extract of Artemisia iwayomogi, a plant belonging to family Compositae, on cardiac ventricular delayed rectifier $K^+$ current ($I_K$) using the patch clamp technique. The carbohydrate fraction AIP1 dose-dependently increased the heart rate with an apparent $EC_{50}$ value of $56.1{\pm}5.5\;{\mu}g/ml$. Application of AIP1 reduced the action potential duration (APD) in concentration-dependent fashion by activating $I_K$ without significantly altering the resting membrane potential ($IC_{50}$ value of $APD_{50}$: $54.80{\pm}2.24$, $IC_{50}$ value of $APD_{90}$: $57.45{\pm}3.47\;{\mu}g/ml$). Based on the results, all experiments were performed with $50\;{\mu}g/ml$ of AIP1. Pre-treatment with the rapidly activating delayed rectifier $K^+$ current ($I_{Kr}$) inhibitor, E-4031 prolonged APD. However, additional application of AIP1 did not reduce APD. The inhibition of slowly activating delayed rectifier $K^+$ current ($I_{Ks}$) by chromanol 293B did not change the effect of AIP1. AIP1 did not significantly affect coronary arterial tone or ion channels, even at the highest concentration of AIP1. In summary, AIP1 reduces APD by activating $I_{Kr}$ but not $I_{Ks}$. These results suggest that the natural product AIP1 may provide an adjunctive therapy of long QT syndrome.

• Biomolecules & Therapeutics
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• v.18 no.4
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• pp.448-453
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• 2010

Drug-induced long QT syndrome is known to be associated with the onset of torsades de pointes (TdP), resulting in a fatal ventricular arrhythmia. QT interval prolongation can result from blocking the human ether-a-go-go-related gene (hERG) channel, which is important for the repolarization of cardiac action potential. Nicardipine, a Ca-channel blocker and antihypertensive agent, has been reported to increase the risk of occasional serious ventricular arrhythmias. We studied the effects of nicardipine on hERG $K^+$ channels expressed in HEK293 cells and Xenopus oocytes. The cardiac electrophysiological effect of nicardipine was also investigated in this study. Our results revealed that nicardipine dose-dependently decreased the tail current of the hERG channel expressed in HEK293 cells with an $IC_{50}$ of 0.43 ${\mu}M$. On the other hand, nicardipine did not affect hERG channel trafficking. Taken together, nicardipine inhibits the hERG channel by the mechanism of short-term channel blocking. Two S6 domain mutations, Y652A and F656A, partially attenuated (Y652A) or abolished (F656A) the hERG current blockade, suggesting that nicardipine blocks the hERG channel at the pore of the channel.

• Journal of Life Science
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• v.27 no.5
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• pp.524-529
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• 2017

This study was aimed to produce a transgenic zebrafish expressing the human KCNE1 gene. Initially, the entire CDS of the human KCNE1 gene was amplified from a human genomic DNA sample by polymerase chain reaction using a primer set engineered with restriction enzyme sites (EcoRI, BamHI) at the 5' end of each primer. The resultant 402 bp KCNE1 amplicon flanked by EcoR1 and BamH1 was obtained and subsequently cloned into a plasmid vector pPB-CMVp-EF1-GreenPuro. The integrity of the cloned CDS sequence was confirmed by DNA sequencing analysis. Next, the recombinant vector containing the human KCNE1 (pPB-CMVp-hKCNE1-EF1-GreenPuro) was introduced into fertilized eggs of zebrafish by microinjection. Successful expression of the recombinant vector in the eggs was confirmed by the expression of the fluorescence protein encoded in the vector. Finally, in order to assure that the stable expression of the human KCNE1 gene occurred in the transgenic animal, RNAs were extracted from the animal and the presence of KCNE1 transcripts was confirmed by RT-PCT as well as DNA sequencing analysis. The study provides a methodology to construct a useful transgenic animal model applicable to the development of diagnostic technologies for gene therapy of LQTS (Long QT Syndrome) as well as tools for cloning of useful genes in fish.

• International Journal of Oral Biology
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• v.43 no.1
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• pp.43-51
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• 2018

$K^+$ channels are key components of the primary and secondary basolateral $Cl^-$ pump systems, which are important for secretion from the salivary glands. Paroxetine is a selective serotonin reuptake inhibitor (SSRI) for psychiatric disorders that can induce QT prolongation, which may lead to torsades de pointes. We studied the effects of paroxetine on a human $K^+$ channel, human ether-a-go-go-related gene (hERG), expressed in Xenopus oocytes and on action potential in guinea pig ventricular myocytes. The hERG encodes the pore-forming subunits of the rapidly-activating delayed rectifier $K^+$ channel ($I_{Kr}$) in the heart. Mutations in hERG reduce $I_{Kr}$ and cause type 2 long QT syndrome (LQT2), a disorder that predisposes individuals to life-threatening arrhythmias. Paroxetine induced concentration-dependent decreases in the current amplitude at the end of the voltage steps and hERG tail currents. The inhibition was concentration-dependent and time-dependent, but voltage-independent during each voltage pulse. In guinea pig ventricular myocytes held at $36^{\circ}C$, treatment with $0.4{\mu}M$ paroxetine for 5 min decreased the action potential duration at 90% of repolarization ($APD_{90}$) by 4.3%. Our results suggest that paroxetine is a blocker of the hERG channels, providing a molecular mechanism for the arrhythmogenic side effects of clinical administration of paroxetine.