The role of late sodium current in the inherited and acquired cardiac arrhythmias: from the biophysics properties to new therapeutic targets

Abstract

The control of cardiac rhythm is dictated by the shape of the action potential (AP), which relays on the distinct class of ion currents, among them sodium current (INa), whichever has two components, a fast and a slow inactivating current. The latter is known as late sodium current (INaL). INaL has an important role in the repolarization phase of the AP in cardiac cells and under pathophysiological conditions it may be augmented, which is an important arrhythmogenic substrate. INaL may be up-regulated by means of: (1) point mutations in the SCN5A gene, the one responsible for most of the INa in cardiac cells. Sometimes the point mutation leads to Long QT type 3 syndrome; (2) intracellular signaling triggered by heart remodeling, precipitating changes in the biophysical properties of the gene product of the SCN5A gene. It is postulated that the heart remodeling observed in the Chagas' disease (CD) may conduct to an increased INaL. Depend upon the trigger to increased INaL, the pharmacological responsiveness to class I antiarrhythmic drugs, such as Lidocaine (1b) and Flecainide (Ic) are changed. Thus, it is necessary to understand the relationship between etiology x pharmacology of INaL and its pharmacological implication. Along these lines, the present project has two main objectives: (1) study the point mutation linked to SCN5A and long QT type 3 syndrome and its impact on the biophysical and pharmacological properties of INaL; (2) to understand whether INaL triggers arrhythmias during CD and if class I anti-arrhythmic drugs are therapeutics agents to treat arrhythmias in CD. The proposed project intents to be the corner stone to initiate a laboratory to study inherited and acquired cardiac arrhythmias due to changes in the biophysical properties of ion channels. (AU)