Remodeling of cardiac repolarization: mechanisms and implications of memory

Memory is a well established property of biological organisms, allowing them to adapt to their environment and respond to novel stimuli. Sensitization occurs in response to a noxious stimulus, and increases the behavioral response to subsequent stimuli. In contrast, habituation occurs in response to an innocuous stimulus, and decreases the behavioral response to subsequent stimuli. Therefore, the response of an organism to a stimulus does not simply depend on the stimulus, but also on previous stimuli that the organism has received. Similarly, the response of the heart to a stimulus does not simply depend on the stimulus, but also on previous patterns of depolarization and repolarization, due to electrical remodeling. Electrical remodeling, the persistent change in electrophysiological properties of myocardium in response to a change in rate or activation sequence, has been well described in atria. It can be induced by rapid pacing or atrial fibrillation (AF), and results in shortened atrial refractory period and increased susceptibility to atrial arrhythmias. These changes have been associated with alterations of potassium and calcium currents. However, the fundamental mechanisms responsible for triggering changes in channel expression in response to alterations in rate and activation sequence in AF are poorly understood. Even less is known about electrical remodeling in ventricle. Rapid ventricular pacing or an alteration of ventricular activation sequence produces persistent changes in heterogeneity of repolarization and, in contrast to atria, a prolongation of action potential duration. Ventricular electrical remodeling is responsible for "T-wave memory," which is observed commonly in patients after periods of altered activation sequence (e.g., chronic pacing). These changes have been associated with alterations of potassium currents, specifically I(to), implying that electrical remodeling is heterogeneously expressed in the different cell types across the transmural wall. Finally, remodeling of gap junctions may also play a prominent role in action potential changes during remodeling. The signal transduction pathways through which a change in rate or activation sequence triggers changes in the expression of ionic currents are being actively investigated.