Pronounced Shortening of QT Interval With Mexiletine Infusion Test in Patients With Type 3 Congenital Long QT Syndrome

Funasako, Moritoshi; Aiba, Takeshi; Ishibashi, Keiichiro; Nakajima, Ikutaro; Miyamoto, Koji; Inoue, Yuko; Okamura, Hideo; Noda, Takashi; Kamakura, Shiro; Anzai, Toshihisa; Noguchi, Teruo; Yasuda, Satoshi; Miyamoto, Yoshihiro; Kusano, Kengo; Ogawa, Hisao; Shimizu, Wataru

doi:10.1253/circj.cj-15-0984

Cited by 35 publications

(37 citation statements)

References 28 publications

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“…Preliminary experimental and clinical evidences claim that mexiletine, a sodium channel blocker targeted in the inactivated state [26], could preferentially reduce the elevated late I Na [27] and shorten the APD in a cellular model of LQT3 [28,29] and the QT interval in LQT3 patients [30,31]. Liu et al reported that mexiletine produces more significant QRS widening when APD prolongation is induced by late I Na enhancer than I Kr blocker in the rabbit ventricular wedges, which indicates that the enhanced late I Na may be the consequence due to the failure of fast Na channel inactivation [32].…”

Section: Discussionmentioning

confidence: 99%

Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5A mutation, N406K, found in LQT3 patients

Tester

et al. 2018

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Introduction: Individual mutations in the SCN5A-encoding cardiac sodium channel α-subunit usually cause a single cardiac arrhythmia disorder, some cause mixed biophysical or clinical phenotypes. Here we report an infant, female patient harboring a N406K mutation in SCN5A with a marked and mixed biophysical phenotype and assess pathogenic mechanisms. Methods and Results: A patient suffered from recurrent seizures during sleep and torsades de pointes with a QTc of 530 ms. Mutational analysis identified a N406K mutation in SCN5A. The mutation was engineered by site-directed mutagenesis and heterologously expressed in HEK293 cells. After 48 hours incubation with and without mexiletine, macroscopic voltage-gated sodium current (INa) was measured with standard whole-cell patch clamp techniques. SCN5A-N406K elicited both a significantly decreased peak INa and a significantly increased late INa compared to wide-type (WT) channels. Furthermore, mexiletine both restored the decreased peak INa of the mutant channel and inhibited the increased late INa of the mutant channel. Conclusion: SCN5A-N406K channel displays both “gain-of-function” in late INa and “loss-of-function” in peak INa density contributing to a mixed biophysical phenotype. Moreover, our finding may provide the first example that mexiletine exerts a dual rescue of both “gain-of-function” and “loss-of-function” of the mutant sodium channel.

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Section: Discussionmentioning

confidence: 99%

Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5A mutation, N406K, found in LQT3 patients

Tester

et al. 2018

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“…Since an oral mexiletine administration is generally chosen as the maintenance therapy for LQT3, a mexiletine infusion challenge test for a diagnosis and the prediction of the efficacy would be reasonable. Although there have been reports of mexiletine challenge tests in older children and adults, to the best of our knowledge, this case is the first report of an intravenous mexiletine challenge test in a neonate. According to Schwarts, half of the daily dose of oral mexiletine should be administered and the ECG should be followed for 2 hours.…”

Section: Discussionmentioning

confidence: 80%

“…Because mexiletine has minimal side effects involving prolongation of the QT interval, and also has the effect of reducing the dispersion of the repolarization and prevents TdP, the mexiletine challenge test can be performed safely with a low risk of pro‐arrhythmic events in LQTS patients . Mexiletine has the potential of shortening the QT interval in any type of LQTS by inhibiting the late sodium current.…”

Section: Discussionmentioning

confidence: 99%

Mexiletine infusion challenge test for neonatal long QT syndrome with 2:1 atrioventricular block

Okuwaki

Kato

Lin

et al. 2019

Journal of Arrhythmia

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For applying a genotype‐based treatment in neonatal long QT syndrome (LQTS), early detection of the genotype becomes an important issue. We report a case of a neonate with LQTS type 3 that presented with 2:1 atrioventricular block and underwent a mexiletine infusion challenge test, and achieved shortening of the QTc and 1:1 atrioventricular conduction. The mexiletine infusion challenge test was helpful to make an early detection of the genotype of the LQTS and predicted the drug efficacy in a neonatal patient.

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“…9) A small sample size clinical study observed QTc interval shortened and no proarrhythmic complication after mexiletine infusion in 16 LQT1/LQT2 patients. 10) Recently, mexiletine was demonstrated to significantly reduce the occurrence of polymorphic VT in pharmacological models of LQT2 in isolated rabbit hearts. 11) Our experience of VT suppression by oral mexiletine in an old LQT2 patient on regular hemodialysis strengthened the evidence.…”

Section: Discussionmentioning

confidence: 99%

Mexiletine Suppressed Recurrent Ventricular Tachycardia Triggered by Hemodialysis in an Old Patient with LQT2

Kang

Wei

2019

Int. Heart J.

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The first onset of cardiac event of long QT syndrome (LQTS) was at young age and caused by emotional or physical triggers. We presented a 64-year-old woman who experienced recurrent ventricular arrhythmia after hemodialysis initiation because of end-stage renal disease. Persistent prolonged QTc interval and diagnosis of inherited LQT2 were missed at her first 3 years of hemodialysis. The patient was beta-blocker nonresponder for ventricular arrhythmias suppression and experienced multiple ICD discharge. We reported an inherited LQT2 case with uncommon clinical manifestations and the successful experience of mexiletine use in such a patient.

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Pronounced Shortening of QT Interval With Mexiletine Infusion Test in Patients With Type 3 Congenital Long QT Syndrome

Cited by 35 publications

References 28 publications

Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5A mutation, N406K, found in LQT3 patients

Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5A mutation, N406K, found in LQT3 patients

Mexiletine infusion challenge test for neonatal long QT syndrome with 2:1 atrioventricular block

Mexiletine Suppressed Recurrent Ventricular Tachycardia Triggered by Hemodialysis in an Old Patient with LQT2

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