title: Theoretical investigation of action potential duration dependence on extracellular Ca2+ in human cardiomyocytes.
abstract: Reduction in [Ca2+]o prolongs the AP in ventricular cardiomyocytes and the QTc interval in patients. Although this phenomenon is relevant to arrhythmogenesis in the clinical setting, its mechanisms are counterintuitive and incompletely understood. To evaluate in silico the mechanisms of APD modulation by [Ca2+]o in human cardiomyocytes. We implemented the Ten Tusscher-Noble-Noble-Panfilov model of the human ventricular myocyte and modified the formulations of the rapidly and slowly activating delayed rectifier K+ currents (IKr and IKs) and L-type Ca2+ current (ICaL) to incorporate their known sensitivity to intra- or extracellular Ca2+. Simulations were run with the original and modified models at variable [Ca2+]o in the clinically relevant 1 to 3 mM range. The original model responds with APD shortening to decrease in [Ca2+]o, i.e. opposite to the experimental observations. Incorporation of Ca2+ dependency of K+ currents cannot reproduce the inverse relation between APD and [Ca2+]o. Only when ICaL inactivation process was modified, by enhancing its dependency on Ca2+, simulations predict APD prolongation at lower [Ca2+]o. Although Ca2+-dependent ICaL inactivation is the primary mechanism, secondary changes in electrogenic Ca2+ transport (by Na+/Ca2+ exchanger and plasmalemmal Ca2+-ATPase) contribute to the reversal of APD dependency on [Ca2+]o. This theoretical investigation points to Ca2+-dependent inactivation of ICaL as a mechanism primarily responsible for the dependency of APD on [Ca2+]o. The modifications implemented here make the model more suitable to analyze repolarization mechanisms when Ca2+ levels are altered.
authors.affiliation: Biomedical Engineering Laboratory-D.E.I.S., University of Bologna, Cesena, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Grandi
authors.forename: Francesco S
authors.initials: FS
authors.lastname: Pasqualini
authors.forename: Chiara
authors.initials: C
authors.lastname: Pes
authors.forename: Cristiana
authors.initials: C
authors.lastname: Corsi
authors.forename: Antonio
authors.initials: A
authors.lastname: Zaza
authors.forename: Stefano
authors.initials: S
authors.lastname: Severi
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D017136:Ion Transport / Q000502:physiology; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism
chemical_list: D011188:Potassium; D002118:Calcium