000063328 001__ 63328
000063328 005__ 20171129112117.0
000063328 0247_ $$2doi$$a10.1371/journal.pone.0056359
000063328 0248_ $$2sideral$$a80281
000063328 037__ $$aART-2013-80281
000063328 041__ $$aeng
000063328 100__ $$aWalmsley, John
000063328 245__ $$amRNA Expression Levels in Failing Human Hearts Predict Cellular Electrophysiological Remodeling: A Population- Based Simulation Study
000063328 260__ $$c2013
000063328 5060_ $$aAccess copy available to the general public$$fUnrestricted
000063328 5203_ $$aDifferences in mRNA expression levels have been observed in failing versus non-failing human hearts for several membrane channel proteins and accessory subunits. These differences may play a causal role in electrophysiological changes observed in human heart failure and atrial fibrillation, such as action potential (AP) prolongation, increased AP triangulation, decreased intracellular calcium transient (CaT) magnitude and decreased CaT triangulation. Our goal is to investigate whether the information contained in mRNA measurements can be used to predict cardiac electrophysiological remodeling in heart failure using computational modeling. Using mRNA data recently obtained from failing and non-failing human hearts, we construct failing and non-failing cell populations incorporating natural variability and up/down regulation of channel conductivities. Six biomarkers are calculated for each cell in each population, at cycle lengths between 1500 ms and 300 ms. Regression analysis is performed to determine which ion channels drive biomarker variability in failing versus non-failing cardiomyocytes. Our models suggest that reported mRNA expression changes are consistent with AP prolongation, increased AP triangulation, increased CaT duration, decreased CaT triangulation and amplitude, and increased delay between AP and CaT upstrokes in the failing population. Regression analysis reveals that changes in AP biomarkers are driven primarily by reduction in I, and changes in CaT biomarkers are driven predominantly by reduction in I and SERCA. In particular, the role of I is pacing rate dependent. Additionally, alternans developed at fast pacing rates for both failing and non-failing cardiomyocytes, but the underlying mechanisms are different in control and heart failure.
000063328 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000063328 590__ $$a3.534$$b2013
000063328 591__ $$aMULTIDISCIPLINARY SCIENCES$$b8 / 56 = 0.143$$c2013$$dQ1$$eT1
000063328 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000063328 700__ $$0(orcid)0000-0001-7612-266X$$aRodriguez, Jose F$$uUniversidad de Zaragoza
000063328 700__ $$aMirams, Gary R
000063328 700__ $$aBurrage, Kevin
000063328 700__ $$aEfimov, Igor R
000063328 700__ $$aRodriguez, Blanca
000063328 7102_ $$15004$$2605$$aUniversidad de Zaragoza$$bDepartamento de Ingeniería Mecánica$$cMec. de Medios Contínuos y Teor. de Estructuras
000063328 773__ $$g8, 2 (2013), e56359 [11 pp]$$pPLoS One$$tPLoS One$$x1932-6203
000063328 8564_ $$s988075$$uhttp://zaguan.unizar.es/record/63328/files/texto_completo.pdf$$yVersión publicada
000063328 8564_ $$s130627$$uhttp://zaguan.unizar.es/record/63328/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000063328 909CO $$ooai:zaguan.unizar.es:63328$$particulos$$pdriver
000063328 951__ $$a2017-11-28-13:51:37
000063328 980__ $$aARTICLE