Claudia Altomare1, Chiara Bartolucci1, Luca Sala1, Joyce Bernardi1, Gaspare Mostacciuolo1, Marcella Rocchetti1, Stefano Severi1, Antonio Zaza2. 1. 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.). 2. 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.
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. METHODS AND 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.
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. METHODS AND 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: Bence Hegyi; Ye Chen-Izu; Leighton T Izu; Sridharan Rajamani; Luiz Belardinelli; Donald M Bers; Tamás Bányász Journal: Circ Arrhythm Electrophysiol Date: 2020-03-23
Authors: E Pueyo; C E Dangerfield; O J Britton; L Virág; K Kistamás; N Szentandrássy; N Jost; A Varró; P P Nánási; K Burrage; B Rodríguez Journal: PLoS One Date: 2016-03-28 Impact factor: 3.240
Authors: Chon Lok Lei; Michael Clerx; Dominic G Whittaker; David J Gavaghan; Teun P de Boer; Gary R Mirams Journal: Philos Trans A Math Phys Eng Sci Date: 2020-05-25 Impact factor: 4.226