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This Article Full Text Full Text (PDF) All Versions of this Article: 297/4/H1398    most recent 00411.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Maleckar, M. M. Articles by Trayanova, N. A. PubMed PubMed Citation Articles by Maleckar, M. M. Articles by Trayanova, N. A.

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

¹Department of Biomedical Engineering and Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland; ²Center for Biomedical Computing, Simula Research Laboratory, Oslo, Norway; and ³Faculty of Kinesiology, University of Calgary, Calgary, Alberta, Canada

Submitted May 4, 2009 ; accepted in final form July 20, 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.

ionic model; repolarization; potassium current

Abbreviations: a_ur, Activation gating variable for I_Kur • AP, Action potential • APD, AP duration • APD₂₀, APD at 20% repolariation • APD₃₀, APD at 30% repolarization • APD₉₀, APD at 90% repolarization • [Ca²⁺]_c, Ca²⁺ concentration in the extracellular cleft space • [Ca²⁺]_d, Ca²⁺ concentration in the restricted subsarcolemmal space • [Ca²⁺]_i, Intracellular Ca²⁺ concentration • [Ca²⁺]_rel, Ca²⁺ concentration in the sarcoplasmic reticulum release compartment • [Ca²⁺]_up, Ca²⁺ concentration in the sarcoplasmic reticulum uptake compartment • C_m, Cell capacitance • d_L, Activation gating variable for I_Ca,L • dV/dt_max, Maximum upstroke velocity • E_K, Equilibrium (Nernst) potential for K⁺ • f_L1, Fast inactivation gating variable for I_Ca,L • f_L2, Slow inactivation gating variable for I_Ca,L • F, Faraday's constant • F₁, Relative amount of "inactive precursor" in the I_rel formulation • F₂, Relative amount of "activator" in the I_rel formulation • g_Kur, Maximum conductance for I_Kur • g_t, Maximum conductance for I_t • g_K1, Maximum conductance for I_K1 • h₁, Fast inactivation variable for I_Na • h₂, Slow inactivation variable for I_Na • hAMr model, Human atrial myocyte with new repolarization model • i_ur, Inactivation gating variable for I_Kur • I_BCa, Background Ca²⁺ current • I_BNa, Background Na⁺ current • I_Ca,L, L-type Ca²⁺ current • I_CaP, Ca²⁺ pump current, sarcolemmal • I_K1, Inwardly rectifying K⁺ current • I_K(ACh), ACh-sensitive K⁺ current • I_Kr, Rapid delayed rectifier K⁺ current (human ether-a-go-go-related gene) • I_Ks, Slow delayed rectifier K⁺ current • I_Kur, Ultrarapid delayed rectifier K⁺ current • I_Na, Na⁺ current • I_NaCa, Na⁺/Ca²⁺ exchange current • I_NaK, Na⁺-K⁺ pump current, sarcolemmal • I_NaK,max, Maximum Na⁺-K⁺ pump current • I_stim, Stimulus current • I_t, Transient outward K⁺ current • k_Ca, Half-maximum Ca²⁺ binding concentration for f_Ca • [K⁺]_c, K⁺ concentration in the extracellular cleft space • [K⁺]_i, Intracellular K⁺ concentration • m, Activation gating variable for I_Na • n, Activation gating variable for I_Ks • [Na⁺]_c, Na⁺ concentration in the extracellular cleft space • [Na⁺]_i, Intracellular Na⁺ concentration • O_C, Fractional occupancy of the calmodulin-Ca²⁺ buffer by Ca²⁺ • O_Calse, Fractional occupancy of the calsequestrin-Ca²⁺ buffer by Ca²⁺ • O_TC, Fractional occupancy of the troponin-Ca²⁺ buffer by Ca²⁺ • O_TMgC, Fractional occupancy of the troponin-Mg²⁺ buffer by Ca²⁺ • O_TMgMg, Fractional occupancy of the troponin-Mg²⁺ buffer by Mg²⁺ • p_a, Activation gating variable for I_Kr • P_Na, Permeability for I_Na • r, Activation gating variable for I_t • R, Universal gas constant • RMP, Resting membrane potential • s, Inactivation gating variable for I_t • T, Absolute temperature • V, Membrane voltage • Vol_i, Total myocyte volume • _Na,en, Electroneutral Na⁺ influx • _aur, Activation time constant for I_Kur • _iur, Inactivation time constant for I_Kur • _r, Activation time constant for I_t • _s, Inactivation time constant for I_t