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.
View: Text | PDF
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

×

Figure 6

Isoproterenol is antiarrhythmic in CyPPA-induced J wave syndrome.

Options: View larger image (or click on image) Download as PowerPoint
Isoproterenol is antiarrhythmic in CyPPA-induced J wave syndrome. Protoc...
Protocol III (n = 6). (A) pECG after CyPPA (upper panel) shows J wave elevation during sinus rhythm and an episode of spontaneous ventricular fibrillation (SVF). The SVF was shock resistant (shocks 1–7), which was defibrillated by the eighth attempt of shock (shock 8). After isoproterenol infusion (lower panel), J wave was slightly attenuated and no SVF was generated. Ventricular pacing induced 2 episodes of VF. The first episode was defibrillated by the first attempt (shock 9). The second episode was self-terminated. (B) Optical maps during sinus rhythm. During CyPPA, action potential duration (APD25) and APD80 maps exhibited heterogeneous APD distribution and large APD gradient, especially in the right ventricle. The activation (AT) map shows slow intraventricular conduction. Subsequent isoproterenol markedly shortened APD25 and APD80, diminished APD heterogeneities, and accelerated conduction velocity. (C) Simultaneous optical traces of Cai and Vm at the time of defibrillation. During CyPPA, the shock-resistant VF on ECG was actually successfully defibrillated by shock 1. However, phase 2 reentry was immediately reinitiated after 1 sinus beat, such that VF appeared to sustain on pECG. After isoproterenol, the pacing-induced VF was successfully defibrillated by the first attempt (shock 9) without reinitiation.