Abstract

Aging is associated with alterations in the electrical properties of the heart resulting in an increased incidence of arrhythmic events and perturbation of cardiac performance. The aim of the present study was to determine whether the late sodium current (I NaL ), which presents slow inactivation kinetics, is upregulated in myocytes from old hearts contributing to the electrical remodeling of the senescent myocardium. For this purpose, the electrical profile of young (3-5 months) and old (24-30 months) C57BL6 mice was established at the organ and cellular levels. In comparison to young mice, old animals presented enlarged left ventricles and declined systolic and diastolic functions. The QRS complex and QT interval of the ECG were significantly prolonged in old animals, indicating that aging delays the electrical activation and recovery of the myocardium. The latter property was confirmed by slower repolarization phases of epicardial monophasic action potentials (AP) in old hearts, using perfused Langendorff preparations. Moreover, old hearts were more prone to develop arrhythmia by programmed electrical stimulation. By patch-clamp technique, myocytes from old mice showed a 2- and 1.7-fold increase in the time to 50% and 90% repolarization of the AP, respectively, than cells from young animals. In voltage-clamp mode, I NaL , which is operative during the repolarization phase of the AP, was 1.7-fold larger in cells obtained from old hearts with respect to young. Activation, steady state inactivation and time constants for I NaL were comparable in young and old myocytes, indicating that the enhanced late current was mediated by an increased maximal conductance. In old myocytes, blockade of I NaL with low doses of tetrodotoxin or mexiletine reduced by 24-48% the intermediate and late repolarization phases of the AP, whereas in young cells this intervention affected to a lesser extent only the late repolarization phase. Finally, administration of mexiletine in old mice shortened the QT interval by 25%, restoring ventricular electrical recovery. In conclusion, the late sodium current I NaL is upregulated with aging and contributes to the slower repolarization of the senescent myocardium.