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A computational model predicts adjunctive pharmacotherapy for cardiac safety via selective inhibition of the late cardiac Na current

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A computational model predicts adjunctive pharmacotherapy for cardiac safety via selective inhibition of the late cardiac Na current

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dc.contributor.author Yang, Pei-Chi es_ES
dc.contributor.author El-Bizri, Nesrine es_ES
dc.contributor.author Romero Pérez, Lucia es_ES
dc.contributor.author Giles, Wayne es_ES
dc.contributor.author Rajamani, Sridharan es_ES
dc.contributor.author Belardinelli, Luiz es_ES
dc.contributor.author Clancy, Colleen E es_ES
dc.date.accessioned 2018-05-13T04:24:55Z
dc.date.available 2018-05-13T04:24:55Z
dc.date.issued 2016 es_ES
dc.identifier.issn 0022-2828 es_ES
dc.identifier.uri http://hdl.handle.net/10251/101848
dc.description.abstract [EN] Background: The QT interval is a phase of the cardiac cycle that corresponds to action potential duration (APD) including cellular repolarization (T-wave). In both clinical and experimental settings, prolongation of the QT interval of the electrocardiogram (ECG) and related proarrhythmia have been so strongly associated that a prolonged QT interval is largely accepted as surrogate marker for proarrhythmia. Accordingly, drugs that prolong the QT interval are not considered for further preclinical development resulting in removal of many promising drugs from development. While reduction of drug interactions with hERG is an important goal, there are promising means to mitigate hERG block. Here, we examine one possibility and test the hypothesis that selective inhibition of the cardiac late Na current (I-NaL) by the novel compound GS-458967 can suppress proarrhythmic markers. Methods and results: New experimental data has been used to calibrate INaL in the Soltis-Saucerman computationally based model of the rabbit ventricular action potential to study effects of GS-458967 on INaL during the rabbit ventricular AP. We have also carried out systematic in silico tests to determine if targeted block of INaL would suppress proarrhythmia markers in ventricular myocytes described by TRIaD: Triangulation, Reverse use dependence, beat-to-beat Instability of action potential duration, and temporal and spatial action potential duration Dispersion. Conclusions: Our computer modeling approach based on experimental data, yields results that suggest that selective inhibition of INaL modifies all TRIaD related parameters arising from acquired Long-QT Syndrome, and thereby reduced arrhythmia risk. This study reveals the potential for adjunctive pharmacotherapy via targeted block of INaL to mitigate proarrhythmia risk for drugs with significant but unintended off-target hERG blocking effects. es_ES
dc.description.sponsorship The National Institutes of Health R01 HL128537-01 (CEC), U01 HL126273-01 (CEC) and R01HL128170-02 (CEC). es_ES
dc.language Inglés es_ES
dc.publisher Elsevier es_ES
dc.relation.ispartof Journal of Molecular and Cellular Cardiology es_ES
dc.rights Reconocimiento - No comercial - Sin obra derivada (by-nc-nd) es_ES
dc.subject Long-QT Syndrome es_ES
dc.subject GS-458967 es_ES
dc.subject Late Na current es_ES
dc.subject Proarrhythmia es_ES
dc.subject.classification TECNOLOGIA ELECTRONICA es_ES
dc.title A computational model predicts adjunctive pharmacotherapy for cardiac safety via selective inhibition of the late cardiac Na current es_ES
dc.type Artículo es_ES
dc.identifier.doi 10.1016/j.yjmcc.2016.08.011 es_ES
dc.relation.projectID info:eu-repo/grantAgreement/NIH/NATIONAL HEART, LUNG, AND BLOOD INSTITUTE/5U01HL126273-04/US/ en_EN
dc.relation.projectID info:eu-repo/grantAgreement/NIH/NATIONAL HEART, LUNG, AND BLOOD INSTITUTE/1R01HL128170-01/US/
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 Yang, P.; El-Bizri, N.; Romero Pérez, L.; Giles, W.; Rajamani, S.; Belardinelli, L.; Clancy, CE. (2016). A computational model predicts adjunctive pharmacotherapy for cardiac safety via selective inhibition of the late cardiac Na current. Journal of Molecular and Cellular Cardiology. 99:151-161. https://doi.org/10.1016/j.yjmcc.2016.08.011 es_ES
dc.description.accrualMethod S es_ES
dc.relation.publisherversion https://doi.org/10.1016/j.yjmcc.2016.08.011 es_ES
dc.description.upvformatpinicio 151 es_ES
dc.description.upvformatpfin 161 es_ES
dc.type.version info:eu-repo/semantics/publishedVersion es_ES
dc.description.volume 99 es_ES
dc.identifier.pmid 27545042 en_EN
dc.identifier.pmcid PMC5453509 en_EN
dc.relation.pasarela S\333163 es_ES


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