title: EAD and DAD mechanisms analyzed by developing a new human ventricular cell model.
abstract: It has long been suggested that the Ca(2+)-mechanisms are largely involved in generating the early afterdepolarization (EAD) as well as the delayed afterdepolarization (DAD). This view was examined in a quantitative manner by applying the lead potential analysis to a new human ventricular cell model. In this ventricular cell model, the tight coupled LCC-RyR model (CaRU) based on local control theory (Hinch et al. 2004) and ion channel models mostly based on human electrophysiological data were included to reproduce realistic Ca(2+) dynamics as well as the membrane excitation. Simultaneously, the Ca(2+) accumulation near the Ca(2+) releasing site was incorporated as observed in real cardiac myocytes. The maximum rate of ventricular repolarization (-1.02 mV/ms) is due to IK1 (-0.55 mV/ms) and the rest is provided nearly equally by INCX (-0.20 mV/ms), INaL (-0.16 mV/ms) and INaT (-0.13 mV/ms). These INaL and INaT components are due to closure of the voltage gate, which remains partially open during the plateau potential. DADs could be evoked by applying high-frequency stimulations supplemented by a partial Na(+)/K(+) pump inhibition, or by a microinjection of Ca(2+). EADs was evoked by retarding the inactivation of INaL. The lead potential (VL) analysis revealed that IK1 and IKr played the primary role to reverse the AP repolarization to depolarizing limb of EAD. ICaL and INCX amplified EAD, while the remaining currents partially antagonized dVL/dt. The maximum rate of rise of EAD was attributable to the rapid activation of both ICaL (45.5%) and INCX (54.5%).
authors.affiliation: Nippon Shinyaku, Co., Ltd., Kyoto, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Asakura
authors.affiliation: Biosimulation Project, College of Life Sciences, Ritsumeikan University, Japan.
authors.forename: C Y
authors.initials: CY
authors.lastname: Cha
authors.affiliation: Biosimulation Project, College of Life Sciences, Ritsumeikan University, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yamaoka
authors.affiliation: Biosimulation Project, College of Life Sciences, Ritsumeikan University, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Horikawa
authors.affiliation: Biosimulation Project, College of Life Sciences, Ritsumeikan University, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Memida
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK.
authors.forename: T
authors.initials: T
authors.lastname: Powell
authors.affiliation: Biosimulation Project, College of Life Sciences, Ritsumeikan University, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Amano
authors.affiliation: Biosimulation Project, College of Life Sciences, Ritsumeikan University, Japan. Electronic address: noma@sk.ritsumei.ac.jp.
authors.forename: A
authors.initials: A
authors.lastname: Noma
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D003198:Computer Simulation; D006352:Heart Ventricles / Q000166:cytology; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology*; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D016276:Ventricular Function / Q000502:physiology*
chemical_list: D015220:Calcium Channels; D002118:Calcium
keywords: Delayed afterdepolarization; Early afterdepolarization; Human ventricular myocyte; Late Na(+) current; Lead potential analysis; Mathematical model