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Computational assessment of drug-induced effects on the electrocardiogram: from ion channel to body surface potentials

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Computational assessment of drug-induced effects on the electrocardiogram: from ion channel to body surface potentials

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dc.contributor.author Zemzemi, Nejib es_ES
dc.contributor.author Bernabeu, Miguel O. es_ES
dc.contributor.author Saiz Rodríguez, Francisco Javier es_ES
dc.contributor.author Cooper, Jonathan es_ES
dc.contributor.author Pathmanathan, Pras es_ES
dc.contributor.author Mirams, Gary R. es_ES
dc.contributor.author Pitt-Francis, Joe es_ES
dc.contributor.author Rodríguez, Blanca es_ES
dc.date.accessioned 2013-12-26T11:41:55Z
dc.date.issued 2013-01
dc.identifier.issn 0007-1188
dc.identifier.uri http://hdl.handle.net/10251/34675
dc.description.abstract BACKGROUND AND PURPOSE Understanding drug effects on the heart is key to safety pharmacology assessment and anti-arrhythmic therapy development. Here our goal is to demonstrate the ability of computational models to simulate the effect of drug action on the electrical activity of the heart, at the level of the ion-channel, cell, heart and ECG body surface potential. EXPERIMENTAL APPROACH We use the state-of-the-art mathematical models governing the electrical activity of the heart. A drug model is introduced using an ion channel conductance block for the hERG and fast sodium channels, depending on the IC50 value and the drug dose. We simulate the ECG measurements at the body surface and compare biomarkers under different drug actions. KEY RESULTS Introducing a 50% hERG-channel current block results in 8% prolongation of the APD90 and 6% QT interval prolongation, hERG block does not affect the QRS interval. Introducing 50% fast sodium current block prolongs the QRS and the QT intervals by 12% and 5% respectively, and delays activation times, whereas APD90 is not affected. CONCLUSIONS AND IMPLICATIONS Both potassium and sodium blocks prolong the QT interval, but the underlying mechanism is different: for potassium it is due to APD prolongation; while for sodium it is due to a reduction of electrical wave velocity. This study shows the applicability of in silico models for the investigation of drug effects on the heart, from the ion channel to the ECG-based biomarkers. es_ES
dc.description.sponsorship The authors would like to thank Drs Philippe Moireau, Miguel Fernandez and Elsie Phe from INRIA Paris-Rocquencourt for their work on the anatomical models and meshes. We are also grateful to Professors Dominique Chapelle and Jean-Frederic Gerbeau heads of MACS and REO teams respectively, in INRIA Paris-Rocquencourt for providing us with the meshes. This study was supported financially by the European Commission preDiCT grant (DG-INFSO224381). BR holds a Medical Research Council Career Development Award. en_EN
dc.language Inglés es_ES
dc.publisher Wiley-Blackwell es_ES
dc.relation European Commission preDiCT grant [DG-INFSO224381] es_ES
dc.relation Medical Research Council Career Development Award es_ES
dc.relation.ispartof British Journal of Pharmacology es_ES
dc.rights Reserva de todos los derechos es_ES
dc.subject ECG modelling es_ES
dc.subject Computer simulation es_ES
dc.subject Drug es_ES
dc.subject HERG es_ES
dc.subject Sodium blockers es_ES
dc.subject QT prolongation es_ES
dc.subject QRS widening es_ES
dc.subject.classification TECNOLOGIA ELECTRONICA es_ES
dc.title Computational assessment of drug-induced effects on the electrocardiogram: from ion channel to body surface potentials es_ES
dc.type Artículo es_ES
dc.identifier.doi 10.1111/j.1476-5381.2012.02200.x
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/224381/EU en_EN
dc.rights.accessRights Abierto es_ES
dc.contributor.affiliation Universitat Politècnica de València. Departamento de Ingeniería Electrónica - Departament d'Enginyeria Electrònica es_ES
dc.description.bibliographicCitation Zemzemi, N.; Bernabeu, MO.; Saiz Rodríguez, FJ.; Cooper, J.; Pathmanathan, P.; Mirams, GR.; Pitt-Francis, J.... (2013). Computational assessment of drug-induced effects on the electrocardiogram: from ion channel to body surface potentials. British Journal of Pharmacology. 168(3):718-733. doi:10.1111/j.1476-5381.2012.02200.x es_ES
dc.description.accrualMethod Senia es_ES
dc.relation.publisherversion http://onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2012.02200.x/pdf es_ES
dc.description.upvformatpinicio 718 es_ES
dc.description.upvformatpfin 733 es_ES
dc.type.version info:eu-repo/semantics/publishedVersion es_ES
dc.description.volume 168 es_ES
dc.description.issue 3 es_ES
dc.relation.senia 243033
dc.identifier.pmid 22946617 en_EN
dc.identifier.pmcid PMC3579290


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