Balance Between Rapid Delayed Rectifier K + Current and Late Na + Current on Ventricular Repolarization

作者：Bence Hegyi, Ye Chen‐Izu, Leighton T. Izu, Sridharan Rajamani, Luiz Belardinelli, Donald M. Bers, Tamás Bányász · 发表于：Circulation Arrhythmia and Electrophysiology · 年份：2020 · DOI：10.1161/circep.119.008130 · 被引用次数：24 · 研究领域：Cardiac electrophysiology and arrhythmias、Ion channel regulation and function、ECG Monitoring and Analysis

Background: Rapid delayed rectifier K + current (I Kr ) and late Na + current (I NaL ) significantly shape the cardiac action potential (AP). Changes in their magnitudes can cause either long or short QT syndromes associated with malignant ventricular arrhythmias and sudden cardiac death. Methods: Physiological self AP-clamp was used to measure I NaL and I Kr during the AP in rabbit and porcine ventricular cardiomyocytes to test our hypothesis that the balance between I Kr and I NaL affects repolarization stability in health and disease conditions. Results: We found comparable amount of net charge carried by I Kr and I NaL during the physiological AP, suggesting that outward K + current via I Kr and inward Na + current via I NaL are in balance during physiological repolarization. Remarkably, I Kr and I NaL integrals in each control myocyte were highly correlated in both healthy rabbit and pig myocytes, despite high overall cell-to-cell variability. This close correlation was lost in heart failure myocytes from both species. Pretreatment with E-4031 to block I Kr (mimicking long QT syndrome 2) or with sea anemone toxin II to impair Na + channel inactivation (mimicking long QT syndrome 3) prolonged AP duration (APD); however, using GS-967 to inhibit I NaL sufficiently restored APD to control in both cases. Importantly, I NaL inhibition significantly reduced the beat-to-beat and short-term variabilities of APD. Moreover, I NaL inhibition also restored APD and repolarization stab...