A model of J wave syndrome
Patients with J wave syndromes (JWS), such as Brugada syndrome and early repolarization syndrome are vulnerable to life-threatening ventricular arrhythmias. Factors that promote JWS are not fully understood and models of the disease are limited. In this episode, Mu Chen and Peng-Sheng Chen describe their work, which shows that activation small-conductance calcium-activated potassium (SK) current (IKAS) in conjunction with inhibition of the sodium current with CyPPA induces JWS-associated phenotypes in perfused rabbit hearts. Moreover, inhibition of IKAS in this model eliminated JWS-like manifestations. The results of this study provide important insight into the drivers of JWS and suggest that IKAS inhibition be further explored for JWS.
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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.
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
