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- Rapid delayed rectifier K current (I) and late Na current (I) 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.  - Physiological self AP-clamp was used to measure I and I during the AP in rabbit and porcine ventricular cardiomyocytes in order to test our hypothesis that the balance between I and I affects repolarization stability in health and disease conditions.  - We found comparable amount of net charge carried by I and I during the physiological AP suggesting that outward K current via I and inward Na current via I are in balance during physiological repolarization. Remarkably, I and I 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 (mimicking LQT2) or with ATX-II to impair Na channel inactivation (mimicking LQT3) prolonged APD; however, using GS-967 to inhibit I sufficiently restored APD to control in both cases. Importantly, I inhibition significantly reduced the beat-to-beat and short-term variabilities of APD. Moreover, I 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 I inhibition, increased by I inhibition, and restored by combined I and I inhibitions.  - Our data demonstrate that I and I 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.

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

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