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Circ Arrhythm Electrophysiol. 2020 Mar 23. doi: 10.1161/CIRCEP.119.008130. [Epub ahead of print]

Balance Between Rapid Delayed Rectifier K+ Current and Late Na+ Current on Ventricular Repolarization: An Effective Antiarrhythmic Target?

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Department of Pharmacology, University of California, Davis, CA.
Department of Pharmacology, Department of Biomedical Engineering & Department of Internal Medicine/Cardiology, University of California, Davis, CA.
Amgen, Inc., South San Francisco, CA.
InCarda Therapeutics, Inc., Newark, CA.
Department of Pharmacology, University of California, Davis, CA & Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.


Background - Rapid delayed rectifier K+ current (IKr) and late Na+ current (INaL) significantly shape the cardiac action potential (AP). Changes in their magnitudes can cause either long or short QT syndromes (LQT, SQT) associated with malignant ventricular arrhythmias and sudden cardiac death. Methods - Physiological self AP-clamp was used to measure INaL and IKr during the AP in rabbit and porcine ventricular cardiomyocytes in order to test our hypothesis that the balance between IKr and INaL affects repolarization stability in health and disease conditions. Results - We found comparable amount of net charge carried by IKr and INaL during the physiological AP suggesting that outward K+ current via IKr and inward Na+ current via INaL are in balance during physiological repolarization. Remarkably, IKr and INaL 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 IKr (mimicking LQT2) or with ATX-II to impair Na+ channel inactivation (mimicking LQT3) prolonged APD; however, using GS-967 to inhibit INaL sufficiently restored APD to control in both cases. Importantly, INaL inhibition significantly reduced the beat-to-beat and short-term variabilities of APD. Moreover, INaL inhibition also restored APD and repolarization stability in heart failure. Conversely, pretreatment with GS-967 shortened APD (mimicking SQT), and E-4031 reverted APD shortening. Furthermore, the amplitude of AP alternans occurring at high pacing frequency was decreased by INaL inhibition, increased by IKr inhibition, and restored by combined INaL and IKr inhibitions. Conclusions - Our data demonstrate that IKr and INaL are counterbalancing currents during the physiological ventricular AP and their integrals co-vary in individual myocytes. Targeting these ionic currents to normalize their balance may have significant therapeutic potential in heart diseases with repolarization abnormalities.


late sodium current; rapid delayed rectifier potassium current; repolarization stability


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