000048673 001__ 48673
000048673 005__ 20200221144347.0
000048673 0247_ $$2doi$$a10.1371/journal.pone.0151461
000048673 0248_ $$2sideral$$a94725
000048673 037__ $$aART-2016-94725
000048673 041__ $$aeng
000048673 100__ $$0(orcid)0000-0002-1960-407X$$aPueyo, E.$$uUniversidad de Zaragoza
000048673 245__ $$aExperimentally-based computational investigation into beat-to-beat variability in ventricular repolarization and its response to ionic current inhibition
000048673 260__ $$c2016
000048673 5060_ $$aAccess copy available to the general public$$fUnrestricted
000048673 5203_ $$aBeat-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.
000048673 536__ $$9info:eu-repo/grantAgreement/ES/MINECO/TIN2013-41998-R
000048673 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000048673 590__ $$a2.806$$b2016
000048673 591__ $$aMULTIDISCIPLINARY SCIENCES$$b15 / 63 = 0.238$$c2016$$dQ1$$eT1
000048673 592__ $$a1.236$$b2016
000048673 593__ $$aAgricultural and Biological Sciences (miscellaneous)$$c2016$$dQ1
000048673 593__ $$aMedicine (miscellaneous)$$c2016$$dQ1
000048673 593__ $$aBiochemistry, Genetics and Molecular Biology (miscellaneous)$$c2016$$dQ1
000048673 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000048673 700__ $$aDangerfield, C.E.
000048673 700__ $$aBritton, O.J.
000048673 700__ $$aVirág, L.
000048673 700__ $$aKistamás, K.
000048673 700__ $$aSzentandrássy, N.
000048673 700__ $$aJost, N.
000048673 700__ $$aVarró, A.
000048673 700__ $$aNánási, P.P.
000048673 700__ $$aBurrage, K.
000048673 700__ $$aRodríguez, B.
000048673 7102_ $$15008$$2800$$aUniversidad de Zaragoza$$bDpto. Ingeniería Electrón.Com.$$cÁrea Teoría Señal y Comunicac.
000048673 773__ $$g11, 3 (2016), 151461 [20 pp]$$pPLoS One$$tPloS one$$x1932-6203
000048673 8564_ $$s747176$$uhttps://zaguan.unizar.es/record/48673/files/texto_completo.pdf$$yVersión publicada
000048673 8564_ $$s114571$$uhttps://zaguan.unizar.es/record/48673/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000048673 909CO $$ooai:zaguan.unizar.es:48673$$particulos$$pdriver
000048673 951__ $$a2020-02-21-13:53:13
000048673 980__ $$aARTICLE