Heterogeneous distribution of INa-L determines interregional differences in rate adaptation of repolarization.

Abstract

The QT interval, an index of ventricular repolarization, is rate dependent. Exaggerated rate dependence of repolarization is arrhythmogenic. Whether there are differences in rate-dependent repolarization among different heart chambers is unknown. The purpose of this study was to test our hypothesis that heterogeneous distribution in late sodium current (INa-L) is responsible for interregional differences in rate adaptation of repolarization. Action potential duration (APD), QT intervals, and their rate adaptation were studied in isolated arterially perfused ventricular and atrial wedge preparations. APD and INa-L were recorded in isolated rabbit myocytes using the microelectrode and the whole-cell patch clamp technique, respectively. There were distinct interregional differences in repolarization and its rate adaptations among different cardiac chambers: the left ventricle exhibited the longest QT and APD with the greatest rate dependence, followed by the right ventricle, whereas the atria had the shortest APD without significant rate dependence. Interestingly, INa-L densities distributed heterogeneously and matched to interregional APDs and rate dependences as follows: left ventricle > right ventricle > left/right atria. Both dofetilide (an IKr blocker) and anemone toxin (a specific INa-L enhancer) amplified QT/APD rate adaptation preferentially in the left ventricle and therefore exacerbated interregional dispersion of repolarization. On the other hand, the atria exhibited blunted responses to both QT-prolonging agents. Mexiletine with an INa-L blockade effect blunted QT/APD rate adaptation preferentially in the ventricles and significantly reduced bradycardia-dependent interregional dispersion of repolarization. Our results demonstrate that heterogeneous distribution of INa-L contributes importantly to the interregional heterogeneity of repolarization in response to rate changes and APD/QT-prolonging agents.