title: Experimentally-Based Computational Investigation into Beat-To-Beat Variability in Ventricular Repolarization and Its Response to Ionic Current Inhibition.
abstract: Beat-to-beat variability in repolarization (BVR) has been proposed as an arrhythmic risk marker for disease and pharmacological action. The mechanisms are unclear but BVR is thought to be a cell level manifestation of ion channel stochasticity, modulated by cell-to-cell differences in ionic conductances. In this study, we describe the construction of an experimentally-calibrated set of stochastic cardiac cell models that captures both BVR and cell-to-cell differences in BVR displayed in isolated canine action potential measurements using pharmacological agents. Simulated and experimental ranges of BVR are compared in control and under pharmacological inhibition, and the key ionic currents determining BVR under physiological and pharmacological conditions are identified. Results show that the 4-aminopyridine-sensitive transient outward potassium current, Ito1, is a fundamental driver of BVR in control and upon complete inhibition of the slow delayed rectifier potassium current, IKs. In contrast, IKs and the L-type calcium current, ICaL, become the major contributors to BVR upon inhibition of the fast delayed rectifier potassium current, IKr. This highlights both IKs and Ito1 as key contributors to repolarization reserve. Partial correlation analysis identifies the distribution of Ito1 channel numbers as an important independent determinant of the magnitude of BVR and drug-induced change in BVR in control and under pharmacological inhibition of ionic currents. Distributions in the number of IKs and ICaL channels only become independent determinants of the magnitude of BVR upon complete inhibition of IKr. These findings provide quantitative insights into the ionic causes of BVR as a marker for repolarization reserve, both under control condition and pharmacological inhibition.
authors.affiliation: Biomedical Research Networking Centre on Bioengineering, Biomaterials and Nanomedicine, University of Zaragoza, Zaragoza, Spain.|Biosignal Interpretation and Computational Simulation Group, I3A, IIS, Aragón, University of Zaragoza, Zaragoza, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Pueyo
authors.affiliation: Department of Computer Science, University of Oxford, Oxford, United Kingdom.
authors.forename: C E
authors.initials: CE
authors.lastname: Dangerfield
authors.affiliation: Department of Computer Science, University of Oxford, Oxford, United Kingdom.
authors.forename: O J
authors.initials: OJ
authors.lastname: Britton
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Szeged, Hungary.|MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: L
authors.initials: L
authors.lastname: Virág
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: K
authors.initials: K
authors.lastname: Kistamás
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.|Department of Dental Physiology and Pharmacology, Faculty of Dentistry, University of Debrecen, Debrecen, Hungary.
authors.forename: N
authors.initials: N
authors.lastname: Szentandrássy
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Szeged, Hungary.|MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: N
authors.initials: N
authors.lastname: Jost
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Szeged, Hungary.|MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: A
authors.initials: A
authors.lastname: Varró
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.|Department of Dental Physiology and Pharmacology, Faculty of Dentistry, University of Debrecen, Debrecen, Hungary.
authors.forename: P P
authors.initials: PP
authors.lastname: Nánási
authors.affiliation: Department of Computer Science, University of Oxford, Oxford, United Kingdom.|School of Mathematical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia.|ARC Centre of Excellence for Mathematical and Statistical Frontiers, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: K
authors.initials: K
authors.lastname: Burrage
authors.affiliation: Department of Computer Science, University of Oxford, Oxford, United Kingdom.
authors.forename: B
authors.initials: B
authors.lastname: Rodríguez
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000465:Algorithms; D000818:Animals; D020746:Calcium Channels, L-Type / Q000502:physiology; D002478:Cells, Cultured; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D004285:Dogs; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D013269:Stochastic Processes
chemical_list: D020746:Calcium Channels, L-Type; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D015761:4-Aminopyridine