title: IKr Impact on Repolarization and Its Variability Assessed by Dynamic Clamp.
abstract: BACKGROUND
  Repolarization and its stability are exquisitely sensitive to IKr features. Information on the relative importance of specific IKr abnormalities is missing and would assist in the evaluation of arrhythmogenic risk.
  
  
  RESULTS
  In single guinea-pig myocytes, endogenous IKr was replaced by modeled IKr (mIKr) by dynamic clamp (DC) at a cycle length of 1 s. mIKr parameters were systematically modified, and the resulting changes in action potential duration (APD) and its short term variability (SD1) were measured. We observed that (1) IKr blockade increased SD1 more than expected by its dependency on APD; (2) mIKr completely reversed APD and SD1 changes caused by IKr blockade; (3) repolarization was most sensitive to inactivation shifts, which affected APD and SD1 concordantly; (4) activation shifts of the same magnitude had marginal impact on APD, but only when reducing mIKr, they significantly increased SD1; (5) changes in maximal conductance resulted in a pattern similar to that of activation shifts.
  
  
  CONCLUSIONS
  The largest effect on repolarization and its stability are expected from changes in IKr inactivation. APD is less sensitive to changes in other IKr gating parameters, which are better revealed by SD1 changes. SD1 may be more sensitive than APD in detecting IKr-dependent repolarization abnormalities.
authors.affiliation: From the Department of Biotechnologies & Biosciences, University of Milano-Bicocca, Milano (C.A., L.S., J.B., G.M., M.R., A.Z.); and Department of Electrical, Electronic and Information Engineering "Guglielmo Marconi", University of Bologna, Cesena, Italy (C.B., S.S.).
authors.forename: Claudia
authors.initials: C
authors.lastname: Altomare
authors.affiliation: From the Department of Biotechnologies & Biosciences, University of Milano-Bicocca, Milano (C.A., L.S., J.B., G.M., M.R., A.Z.); and Department of Electrical, Electronic and Information Engineering "Guglielmo Marconi", University of Bologna, Cesena, Italy (C.B., S.S.).
authors.forename: Chiara
authors.initials: C
authors.lastname: Bartolucci
authors.affiliation: From the Department of Biotechnologies & Biosciences, University of Milano-Bicocca, Milano (C.A., L.S., J.B., G.M., M.R., A.Z.); and Department of Electrical, Electronic and Information Engineering "Guglielmo Marconi", University of Bologna, Cesena, Italy (C.B., S.S.).
authors.forename: Luca
authors.initials: L
authors.lastname: Sala
authors.affiliation: From the Department of Biotechnologies & Biosciences, University of Milano-Bicocca, Milano (C.A., L.S., J.B., G.M., M.R., A.Z.); and Department of Electrical, Electronic and Information Engineering "Guglielmo Marconi", University of Bologna, Cesena, Italy (C.B., S.S.).
authors.forename: Joyce
authors.initials: J
authors.lastname: Bernardi
authors.affiliation: From the Department of Biotechnologies & Biosciences, University of Milano-Bicocca, Milano (C.A., L.S., J.B., G.M., M.R., A.Z.); and Department of Electrical, Electronic and Information Engineering "Guglielmo Marconi", University of Bologna, Cesena, Italy (C.B., S.S.).
authors.forename: Gaspare
authors.initials: G
authors.lastname: Mostacciuolo
authors.affiliation: From the Department of Biotechnologies & Biosciences, University of Milano-Bicocca, Milano (C.A., L.S., J.B., G.M., M.R., A.Z.); and Department of Electrical, Electronic and Information Engineering "Guglielmo Marconi", University of Bologna, Cesena, Italy (C.B., S.S.).
authors.forename: Marcella
authors.initials: M
authors.lastname: Rocchetti
authors.affiliation: From the Department of Biotechnologies & Biosciences, University of Milano-Bicocca, Milano (C.A., L.S., J.B., G.M., M.R., A.Z.); and Department of Electrical, Electronic and Information Engineering "Guglielmo Marconi", University of Bologna, Cesena, Italy (C.B., S.S.).
authors.forename: Stefano
authors.initials: S
authors.lastname: Severi
authors.affiliation: From the Department of Biotechnologies & Biosciences, University of Milano-Bicocca, Milano (C.A., L.S., J.B., G.M., M.R., A.Z.); and Department of Electrical, Electronic and Information Engineering "Guglielmo Marconi", University of Bologna, Cesena, Italy (C.B., S.S.). antonio.zaza@unimib.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Zaza
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D015220:Calcium Channels / Q000502:physiology; D006168:Guinea Pigs; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000502:physiology*
chemical_list: D015220:Calcium Channels; D015221:Potassium Channels
keywords: HERG arrhythmia; IKr; dynamic clamp; electrophysiology; modeling; repolarization