K+ current changes account for the rate dependence of the action potential in the human atrial myocyte

Maleckar MM, Greenstein JL, Giles WR, Trayanova NA. K+ current changes account for the rate dependence of the action potential in the human atrial myocyte. Am J Physiol Heart Circ Physiol 297: H1398-H1410, 2009. First published July 24, 2009; doi: 10.1152/ajpheart.00411.2009.-Ongoing investigation of the electrophysiology and pathophysiology of the human atria requires an accurate representation of the membrane dynamics of the human atrial myocyte. However, existing models of the human atrial myocyte action potential do not accurately reproduce experimental observations with respect to the kinetics of key repolarizing currents or rate dependence of the action potential and fail to properly enforce charge conservation, an essential characteristic in any model of the cardiac membrane. In addition, recent advances in experimental methods have resulted in new data regarding the kinetics of repolarizing currents in the human atria. The goal of this study was to develop a new model of the human atrial action potential, based on the Nygren et al. model of the human atrial myocyte and newly available experimental data, that ensures an accurate representation of repolarization processes and reproduction of action potential rate dependence and enforces charge conservation. Specifically, the transient outward K+ current (I-t) and ultrarapid rectifier K+ current (I-Kur) were newly formulated. The inwardly recitifying K+ current (I-K1) was also reanalyzed and implemented appropriately. Simulations of the human atrial myocyte action potential with this new model demonstrated that early repolarization is dependent on the relative conductances of I-t and I-Kur, whereas densities of both I-Kur and I-K1 underlie later repolarization. In addition, this model reproduces experimental measurements of rate dependence of I-t, I-Kur, and action potential duration. This new model constitutes an improved representation of excitability and repolarization reserve in the human atrial myocyte and, therefore, provides a useful computational tool for future studies involving the human atrium in both health and disease.