Concomitant SK current activation and sodium current inhibition cause J wave syndrome

Mu Chen, Dong Zhu Xu, Adonis Z. Wu, Shuai Guo, Juyi Wan, Dechun Yin, Shien-Fong Lin, Zhenhui Chen, Michael Rubart-von der Lohe, Thomas Everett, Zhilin Qu, James N. Weiss, Peng-Sheng Chen

Research output: Contribution to journalArticle

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Abstract

The mechanisms of J wave syndrome (JWS) are incompletely understood. Here, we showed that the concomitant activation of small-conductance calcium-activated potassium (SK) current (IKAS) and inhibition of sodium current by cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA) recapitulate the phenotypes of JWS in Langendorff-perfused rabbit hearts. CyPPA induced significant J wave elevation and frequent spontaneous ventricular fibrillation (SVF), as well as sinus bradycardia, atrioventricular block, and intraventricular conduction delay. IKAS activation by CyPPA resulted in heterogeneous shortening of action potential (AP) duration (APD) and repolarization alternans. CyPPA inhibited cardiac sodium current (INa) and decelerated AP upstroke and intracellular calcium transient. SVFs were typically triggered by short-coupled premature ventricular contractions, initiated with phase 2 reentry and originated more frequently from the right than the left ventricles. Subsequent IKAS blockade by apamin reduced J wave elevation and eliminated SVF. β-Adrenergic stimulation was antiarrhythmic in CyPPA-induced electrical storm. Like CyPPA, hypothermia (32.0°C) also induced J wave elevation and SVF. It facilitated negative calcium-voltage coupling and phase 2 repolarization alternans with spatial and electromechanical discordance, which were ameliorated by apamin. These findings suggest that IKAS activation contributes to the development of JWS in rabbit ventricles.

Original languageEnglish (US)
JournalJCI insight
Volume3
Issue number22
DOIs
StatePublished - Nov 15 2018

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Ventricular Fibrillation
Apamin
Sodium
Calcium
Action Potentials
Heart Ventricles
Rabbits
Ventricular Premature Complexes
Atrioventricular Block
Bradycardia
Hypothermia
Adrenergic Agents
Amines
Potassium
Phenotype

Keywords

  • Arrhythmias
  • Cardiology
  • Cardiovascular disease
  • Ion channels

Cite this

Concomitant SK current activation and sodium current inhibition cause J wave syndrome. / Chen, Mu; Xu, Dong Zhu; Wu, Adonis Z.; Guo, Shuai; Wan, Juyi; Yin, Dechun; Lin, Shien-Fong; Chen, Zhenhui; Rubart-von der Lohe, Michael; Everett, Thomas; Qu, Zhilin; Weiss, James N.; Chen, Peng-Sheng.

In: JCI insight, Vol. 3, No. 22, 15.11.2018.

Research output: Contribution to journalArticle

Chen, Mu ; Xu, Dong Zhu ; Wu, Adonis Z. ; Guo, Shuai ; Wan, Juyi ; Yin, Dechun ; Lin, Shien-Fong ; Chen, Zhenhui ; Rubart-von der Lohe, Michael ; Everett, Thomas ; Qu, Zhilin ; Weiss, James N. ; Chen, Peng-Sheng. / Concomitant SK current activation and sodium current inhibition cause J wave syndrome. In: JCI insight. 2018 ; Vol. 3, No. 22.
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AU - Xu, Dong Zhu

AU - Wu, Adonis Z.

AU - Guo, Shuai

AU - Wan, Juyi

AU - Yin, Dechun

AU - Lin, Shien-Fong

AU - Chen, Zhenhui

AU - Rubart-von der Lohe, Michael

AU - Everett, Thomas

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AU - Weiss, James N.

AU - Chen, Peng-Sheng

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AB - The mechanisms of J wave syndrome (JWS) are incompletely understood. Here, we showed that the concomitant activation of small-conductance calcium-activated potassium (SK) current (IKAS) and inhibition of sodium current by cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA) recapitulate the phenotypes of JWS in Langendorff-perfused rabbit hearts. CyPPA induced significant J wave elevation and frequent spontaneous ventricular fibrillation (SVF), as well as sinus bradycardia, atrioventricular block, and intraventricular conduction delay. IKAS activation by CyPPA resulted in heterogeneous shortening of action potential (AP) duration (APD) and repolarization alternans. CyPPA inhibited cardiac sodium current (INa) and decelerated AP upstroke and intracellular calcium transient. SVFs were typically triggered by short-coupled premature ventricular contractions, initiated with phase 2 reentry and originated more frequently from the right than the left ventricles. Subsequent IKAS blockade by apamin reduced J wave elevation and eliminated SVF. β-Adrenergic stimulation was antiarrhythmic in CyPPA-induced electrical storm. Like CyPPA, hypothermia (32.0°C) also induced J wave elevation and SVF. It facilitated negative calcium-voltage coupling and phase 2 repolarization alternans with spatial and electromechanical discordance, which were ameliorated by apamin. These findings suggest that IKAS activation contributes to the development of JWS in rabbit ventricles.

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