Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
JCI Insight. 2018 Nov 15;3(22):122329. doi: 10.1172/jci.insight.122329.
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.
J 波综合征（JWS）的机制尚未完全阐明。在这里，我们表明，小电导钙激活钾电流（IKAS）的同时激活和环己基-[2-（3,5-二甲基-吡唑-1-基）-6-甲基-嘧啶-4-基]-甲脒（CyPPA）对钠电流的抑制作用，可再现 Langendorff 灌注兔心 JWS 的表型。CyPPA 诱导明显的 J 波抬高和频繁自发室性颤动（SVF），以及窦性心动过缓、房室传导阻滞和室内传导延迟。CyPPA 通过激活 IKAS 导致动作电位（AP）时程（APD）和复极化交替的不均匀缩短。CyPPA 抑制心脏钠电流（INa）并减慢 AP 上升和细胞内钙瞬变。SVF 通常由短耦联的室性早搏触发，由 2 相折返引发，起源于右心室的频率高于左心室。随后的 Apamin 阻断 IKAS 降低了 J 波抬高并消除了 SVF。β-肾上腺素能刺激在 CyPPA 诱导的电风暴中具有抗心律失常作用。与 CyPPA 一样，低温（32.0°C）也可引起 J 波抬高和 SVF。它促进了负钙电压偶联和 2 相复极交替，具有空间和机电不同步，Apamin 可改善这种情况。这些发现表明，IKAS 的激活有助于兔心室 JWS 的发展。
