title: In Vivo and In Silico Investigation Into Mechanisms of Frequency Dependence of Repolarization Alternans in Human Ventricular Cardiomyocytes.
abstract: BACKGROUND
  Repolarization alternans (RA) are associated with arrhythmogenesis. Animal studies have revealed potential mechanisms, but human-focused studies are needed. RA generation and frequency dependence may be determined by cell-to-cell variability in protein expression, which is regulated by genetic and external factors.
  
  
  OBJECTIVE
  To characterize in vivo RA in human and to investigate in silico using human models, the ionic mechanisms underlying the frequency-dependent differences in RA behavior identified in vivo.
  
  
  RESULTS
  In vivo electrograms were acquired at 240 sites covering the epicardium of 41 patients at 6 cycle lengths (600-350 ms). In silico investigations were conducted using a population of biophysically detailed human models incorporating variability in protein expression and calibrated using in vivo recordings. Both in silico and in vivo, 2 types of RA were identified, with Fork- and Eye-type restitution curves, based on RA persistence or disappearance, respectively, at fast pacing rates. In silico simulations show that RA are strongly correlated with fluctuations in sarcoplasmic reticulum calcium, because of strong release and weak reuptake. Large L-type calcium current conductance is responsible for RA disappearance at fast frequencies in Eye-type (30% larger in Eye-type versus Fork-type; P<0.01), because of sarcoplasmic reticulum Ca(2+) ATPase pump potentiation caused by frequency-induced increase in intracellular calcium. Large Na(+)/Ca(2+) exchanger current is the main driver in translating Ca(2+) fluctuations into RA.
  
  
  CONCLUSIONS
  In human in vivo and in silico, 2 types of RA are identified, with RA persistence/disappearance as frequency increases. In silico, L-type calcium current and Na(+)/Ca(2+) exchanger current determine RA human cell-to-cell differences through intracellular and sarcoplasmic reticulum calcium regulation.
authors.affiliation: From the Department of Computer Science, BHF Centre of Research Excellence, University of Oxford, Oxford, United Kingdom (X.Z., A.B.-O., K.B., B.R.); Institute of Cardiovascular Science, University College London, London, United Kingdom (M.O., P.T., P.D.L.); Mechanical Engineering Department, University College London, London, United Kingdom (B.H.); The Heart Hospital, University College London Hospital, London, United Kingdom (M.O., M.H., P.T., P.D.L.); and ACEMS ARC Centre of Excellence and School of Mathematical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia (K.B.).
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.affiliation: From the Department of Computer Science, BHF Centre of Research Excellence, University of Oxford, Oxford, United Kingdom (X.Z., A.B.-O., K.B., B.R.); Institute of Cardiovascular Science, University College London, London, United Kingdom (M.O., P.T., P.D.L.); Mechanical Engineering Department, University College London, London, United Kingdom (B.H.); The Heart Hospital, University College London Hospital, London, United Kingdom (M.O., M.H., P.T., P.D.L.); and ACEMS ARC Centre of Excellence and School of Mathematical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia (K.B.).
authors.forename: Alfonso
authors.initials: A
authors.lastname: Bueno-Orovio
authors.affiliation: From the Department of Computer Science, BHF Centre of Research Excellence, University of Oxford, Oxford, United Kingdom (X.Z., A.B.-O., K.B., B.R.); Institute of Cardiovascular Science, University College London, London, United Kingdom (M.O., P.T., P.D.L.); Mechanical Engineering Department, University College London, London, United Kingdom (B.H.); The Heart Hospital, University College London Hospital, London, United Kingdom (M.O., M.H., P.T., P.D.L.); and ACEMS ARC Centre of Excellence and School of Mathematical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia (K.B.).
authors.forename: Michele
authors.initials: M
authors.lastname: Orini
authors.affiliation: From the Department of Computer Science, BHF Centre of Research Excellence, University of Oxford, Oxford, United Kingdom (X.Z., A.B.-O., K.B., B.R.); Institute of Cardiovascular Science, University College London, London, United Kingdom (M.O., P.T., P.D.L.); Mechanical Engineering Department, University College London, London, United Kingdom (B.H.); The Heart Hospital, University College London Hospital, London, United Kingdom (M.O., M.H., P.T., P.D.L.); and ACEMS ARC Centre of Excellence and School of Mathematical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia (K.B.).
authors.forename: Ben
authors.initials: B
authors.lastname: Hanson
authors.affiliation: From the Department of Computer Science, BHF Centre of Research Excellence, University of Oxford, Oxford, United Kingdom (X.Z., A.B.-O., K.B., B.R.); Institute of Cardiovascular Science, University College London, London, United Kingdom (M.O., P.T., P.D.L.); Mechanical Engineering Department, University College London, London, United Kingdom (B.H.); The Heart Hospital, University College London Hospital, London, United Kingdom (M.O., M.H., P.T., P.D.L.); and ACEMS ARC Centre of Excellence and School of Mathematical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia (K.B.).
authors.forename: Martin
authors.initials: M
authors.lastname: Hayward
authors.affiliation: From the Department of Computer Science, BHF Centre of Research Excellence, University of Oxford, Oxford, United Kingdom (X.Z., A.B.-O., K.B., B.R.); Institute of Cardiovascular Science, University College London, London, United Kingdom (M.O., P.T., P.D.L.); Mechanical Engineering Department, University College London, London, United Kingdom (B.H.); The Heart Hospital, University College London Hospital, London, United Kingdom (M.O., M.H., P.T., P.D.L.); and ACEMS ARC Centre of Excellence and School of Mathematical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia (K.B.).
authors.forename: Peter
authors.initials: P
authors.lastname: Taggart
authors.affiliation: From the Department of Computer Science, BHF Centre of Research Excellence, University of Oxford, Oxford, United Kingdom (X.Z., A.B.-O., K.B., B.R.); Institute of Cardiovascular Science, University College London, London, United Kingdom (M.O., P.T., P.D.L.); Mechanical Engineering Department, University College London, London, United Kingdom (B.H.); The Heart Hospital, University College London Hospital, London, United Kingdom (M.O., M.H., P.T., P.D.L.); and ACEMS ARC Centre of Excellence and School of Mathematical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia (K.B.).
authors.forename: Pier D
authors.initials: PD
authors.lastname: Lambiase
authors.affiliation: From the Department of Computer Science, BHF Centre of Research Excellence, University of Oxford, Oxford, United Kingdom (X.Z., A.B.-O., K.B., B.R.); Institute of Cardiovascular Science, University College London, London, United Kingdom (M.O., P.T., P.D.L.); Mechanical Engineering Department, University College London, London, United Kingdom (B.H.); The Heart Hospital, University College London Hospital, London, United Kingdom (M.O., M.H., P.T., P.D.L.); and ACEMS ARC Centre of Excellence and School of Mathematical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia (K.B.).
authors.forename: Kevin
authors.initials: K
authors.lastname: Burrage
authors.affiliation: From the Department of Computer Science, BHF Centre of Research Excellence, University of Oxford, Oxford, United Kingdom (X.Z., A.B.-O., K.B., B.R.); Institute of Cardiovascular Science, University College London, London, United Kingdom (M.O., P.T., P.D.L.); Mechanical Engineering Department, University College London, London, United Kingdom (B.H.); The Heart Hospital, University College London Hospital, London, United Kingdom (M.O., M.H., P.T., P.D.L.); and ACEMS ARC Centre of Excellence and School of Mathematical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia (K.B.). blanca.rodriguez@cs.ox.ac.uk.
authors.forename: Blanca
authors.initials: B
authors.lastname: Rodriguez
mesh_terms: D000200:Action Potentials; D000368:Aged; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D020013:Calcium Signaling; D003198:Computer Simulation; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D006339:Heart Rate; D006352:Heart Ventricles / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011237:Predictive Value of Tests; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D012815:Signal Processing, Computer-Assisted; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*
chemical_list: D020746:Calcium Channels, L-Type; D019831:Sodium-Calcium Exchanger; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
keywords: calcium; calibration; electrophysiology; pericardium; sarcoplasmic reticulum