Concomitant SK current activation and sodium current inhibition cause J wave syndrome
Mu Chen, … , James N. Weiss, Peng-Sheng Chen
Mu Chen, … , James N. Weiss, Peng-Sheng Chen
Published November 15, 2018
Citation Information: JCI Insight. 2018;3(22):e122329. https://doi.org/10.1172/jci.insight.122329.
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Research Article Cardiology

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

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.

Authors

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 IV, Zhilin Qu, James N. Weiss, Peng-Sheng Chen

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Figure 7

IKAS activation induces Osborn waves and phase 2 repolarization alternans during hypothermia.

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IKAS activation induces Osborn waves and phase 2 repolarization alterna...
Protocol IV (n = 6). (A) ECG of sinus rhythm shows Osborn waves during hypothermia, which was attenuated by apamin. (B) During hypothermia before apamin, an episode of spontaneous ventricular fibrillation was triggered by a spontaneous short-coupled premature ventricular contraction. (C) Optical maps of Cai and Vm at pacing cycle length 300 ms. Compared with baseline, hypothermia prolonged both Cai transient duration (CaiTD) and action potential duration (APD). Apamin had limited effect on CaiTD, but further prolonged APD more prominently at APD25 than at APD80. After rewarming, CaiTD and APD were shortened towards baseline. (D) During hypothermia, Cai and Vm alternans were induced by ventricular pacing at 200 ms. Before apamin, Cai and Vm were negatively coupled at distal sites (site 2 and 3) but remained positive coupling at proximal sites (site 1), leading to spatially discordant Vm alternans. The difference between 2 consecutive beats (beat 2 – beat 1) was larger at APD25 than at APD80 (phase 2 repolarization alternans). Apamin differentially prolonged APD at APD25 and APD80 and in beat 1 and beat 2. The prolongation was more prominent in beat 1, which coupled with larger Cai transient than in beat 2 coupled with smaller Cai transient, and more prominent at APD25 when Cai was more abundant than at APD80. As a result, apamin eliminated the negative Cai-Vm coupling and attenuated phase 2 repolarization alternans.