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 H. Everett, Zhilin Qu, James N. Weiss, Peng Sheng Chen

Research output: Contribution to journalArticle

5 Scopus citations

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
JournalJCI insight
Volume3
Issue number22
DOIs
StatePublished - 15 Nov 2018

Keywords

  • Arrhythmias
  • Cardiology
  • Cardiovascular disease
  • Ion channels

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    Chen, M., Xu, D. Z., Wu, A. Z., Guo, S., Wan, J., Yin, D., Lin, S-F., Chen, Z., Rubart-von der Lohe, M., Everett, T. H., Qu, Z., Weiss, J. N., & Chen, P. S. (2018). Concomitant SK current activation and sodium current inhibition cause J wave syndrome. JCI insight, 3(22). https://doi.org/10.1172/jci.insight.122329