Successful treatment of electrical storm in a child with early repolarization syndrome by orciprenaline and radiofrequency ablation

Abstract Aims The early repolarization syndrome (ERS) can cause ventricular fibrillation (VF) and sudden death in young, otherwise healthy individuals. There are limited data suggesting that ERS might be heritable. The aim of this study was to characterize the clinical phenotype and to identify a causal variant in an affected family using an exome-sequencing approach. Methods and results Early repolarization syndrome was diagnosed according to the recently proposed Shanghai ERS Score. After sequencing of known ERS candidate genes, whole-exome sequencing (WES) was performed. The index patient (23 years, female) showed a dynamic inferolateral early repolarization (ER) pattern and electrical storm with intractable VF. Isoproterenol enabled successful termination of electrical storm with no recurrence on hydroquinidine therapy during 33 months of follow-up. The index patient’s brother (25 years) had a persistent inferior ER pattern with malignant features and a history of syncope. Both parents were asymptomatic and showed no ER pattern. While there was no pathogenic variant in candidate genes, WES detected a novel missense variant affecting a highly conserved residue (p. H2245R) in the ANK3 gene encoding Ankyrin-G in the two siblings and the father. Conclusion We identified two siblings with a malignant ERS phenotype sharing a novel ANK3 variant. A potentially pathogenic role of the novel ANK3 variant is suggested by the direct interaction of Ankyrin-G with the cardiac sodium channel, however, more patients with ANK3 variants and ERS would be required to establish ANK3 as novel ERS susceptibility gene. Our study provides additional evidence that ERS might be a heritable condition.

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Epicardial Substrate as a Target for Radiofrequency Ablation in an Experimental Model of Early Repolarization Syndrome

Circulation Arrhythmia and Electrophysiology ◽

10.1161/circep.118.006511 ◽

2018 ◽

Vol 11 (9) ◽

Cited By ~ 4

Author(s):

Namsik Yoon ◽

Bence Patocskai ◽

Charles Antzelevitch

Keyword(s):

Radiofrequency Ablation ◽

Experimental Model ◽

Early Repolarization ◽

Early Repolarization Syndrome

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Successful Treatment of Electrical Storm with Isoproterenol in a Patient of Myocarditis with Early Repolarization in Hypothermia

Chonnam Medical Journal ◽

10.4068/cmj.2021.57.3.223 ◽

2021 ◽

Vol 57 (3) ◽

pp. 223

Author(s):

Hyung Ki Jeong

Keyword(s):

Successful Treatment ◽

Electrical Storm ◽

Early Repolarization

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P3827Low dose of quinidine is effective to normalize the slow inactivation in mutant Kv4.3 channel identified in an early repolarization syndrome patient

European Heart Journal ◽

10.1093/eurheartj/ehz745.0669 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

K Takayama ◽

W G Ding ◽

H Matsuura ◽

M Horie ◽

S Ohno

Keyword(s):

Ion Channels ◽

Serum Concentration ◽

Time Course ◽

Electrical Storm ◽

Slow Inactivation ◽

Loading Test ◽

Gain Of Function ◽

Early Repolarization ◽

Electrophysiological Analysis ◽

Early Repolarization Syndrome

Abstract Background Early repolarization syndrome (ERS) is characterized by J-point elevation in the ECG and ventricular fibrillation (VF). Several mutations in genes encoding cardiac ion channels have been reported as the causes for ERS. For the treatment of ERS, clinical studies have shown that quinidine is effective for the suppression of electrical storm. However, the mechanism or the optimal concentration for quinidine to suppress the electrical storm has not been elucidated yet. Purpose The aim of the present study is to clarify pharmacological effect of quinidine on mutant Kv4.3 channel by electrophysiological analysis and to establish theoretically effective treatment for ERS. Methods A KCND3 mutation, p.G306A, identified heterozygously in a 12-year-old boy was examined by whole-cell patch-clamp methods using CHO cells. We performed functional analysis of the Kv4.3 channels encoded by KCND3 of wild-type (WT), heterozygous (WT/G306A), or homozygous (G306A) mutants. Pharmacological normalizing effects of quinidine to the WT and mutant channels were investigated by loading test in various concentration. The sensitivity of quinidine was evaluated in terms of the concentration of the clinical course and the loading test. Results The patient suffered VF while sleeping or under sedation. Significant J-point elevations in multiple leads were recorded and he was diagnosed as ERS. Quinidine administration in the serum concentration of 1.2 to 3.1 μM was effective to stop his VF storm. Mutant Kv4.3 currents showed significantly slow inactivation time course (Fig 1), which meant that the mutation caused the gain-of-function channel. Quinidine loading to the mutant Kv4.3 normalized the inactivation time course in concentration-dependent manner (Fig 2, 3). In the loading concentration of 1 μM, the peak currents were not changed regardless of the voltage (Fig 4). The optimal serum concentration of quinidine in clinical use as multi-ion-channels blocker is 6 to 15 μM and the concentration was higher than that of the patient to stop the VF storm. The electrophysiological analysis showed that the low dose loading of quinidine was effective to prevent the gain-of function change of mutant Kv4.3 channels. Electrophysiological analysis Conclusions We showed the pharmacological mechanism of quinidine against the mutant Kv4.3 channels identified in an ERS patient. Even the low concentration of quinidine was effective to normalize the slow inactivation, gain-of-function, in mutant Kv4.3 channels. Our data would be helpful to confirm the optimal concentration of quinidine for ERS patients to avoid adverse effect.

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