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dc.contributor.author | Cano, Jordi![]() |
es_ES |
dc.contributor.author | Zorio, Esther![]() |
es_ES |
dc.contributor.author | Mazzanti, Andrea![]() |
es_ES |
dc.contributor.author | Arnau, Miguel Ángel![]() |
es_ES |
dc.contributor.author | Trenor Gomis, Beatriz Ana![]() |
es_ES |
dc.contributor.author | Priori, Silvia G.![]() |
es_ES |
dc.contributor.author | Saiz Rodríguez, Francisco Javier![]() |
es_ES |
dc.contributor.author | Romero Pérez, Lucia![]() |
es_ES |
dc.date.accessioned | 2021-06-15T03:31:31Z | |
dc.date.available | 2021-06-15T03:31:31Z | |
dc.date.issued | 2020-12-17 | es_ES |
dc.identifier.uri | http://hdl.handle.net/10251/167982 | |
dc.description.abstract | [EN] The prolongation of the QT interval represents the main feature of the long QT syndrome (LQTS), a life-threatening genetic disease. The heterozygous SCN5A V411M mutation of the human sodium channel leads to a LQTS type 3 with severe proarrhythmic effects due to an increase in the late component of the sodium current (INaL). The two sodium blockers flecainide and ranolazine are equally recommended by the current 2015 ESC guidelines to treat patients with LQTS type 3 and persistently prolonged QT intervals. However, awareness of pro-arrhythmic effects of flecainide in LQTS type 3 patients arose upon the study of the SCN5A E1784K mutation. Regarding SCN5A V411M individuals, flecainide showed good results albeit in a reduced number of patients and no evidence supporting the use of ranolazine has ever been released. Therefore, we ought to compare the effect of ranolazine and flecainide in a SCN5A V411M model using an in-silico modeling and simulation approach. We collected clinical data of four patients. Then, we fitted four Markovian models of the human sodium current (INa) to experimental and clinical data. Two of them correspond to the wild type and the heterozygous SCN5A V411M scenarios, and the other two mimic the effects of flecainide and ranolazine on INa. Next, we inserted them into three isolated cell action potential (AP) models for endocardial, midmyocardial and epicardial cells and in a one-dimensional tissue model. The SCN5A V411M mutation produced a 15.9% APD90 prolongation in the isolated endocardial cell model, which corresponded to a 14.3% of the QT interval prolongation in a one-dimensional strand model, in keeping with clinical observations. Although with different underlying mechanisms, flecainide and ranolazine partially countered this prolongation at the isolated endocardial model by reducing the APD90 by 8.7 and 4.3%, and the QT interval by 7.2 and 3.2%, respectively. While flecainide specifically targeted the mutation-induced increase in peak INaL, ranolazine reduced it during the entire AP. Our simulations also suggest that ranolazine could prevent early afterdepolarizations triggered by the SCN5A V411M mutation during bradycardia, as flecainide. We conclude that ranolazine could be used to treat SCN5A V411M patients, specifically when flecainide is contraindicated. | es_ES |
dc.description.sponsorship | This work was partially supported by Fondo Europeo de Desarrollo Regional (FEDER, "Union Europea, Una forma de hacer Europa") with the Ministerio de Economia y Competitividad (DPI2015-69125-R), Direccion General de Politica Cientifica de la Generalitat Valenciana (PROMETEO/2020/043) and Instituto de Salud Carlos III (La Fe Biobank PT17/0015/0043), as well as by Vicerrectorado de Investigacion, Innovacion y Transferencia de la Universitat Politecnica de Valencia with Ayuda a Primeros Proyectos de Investigacion (PAID-06-18), and by Memorial Nacho Barbera. | es_ES |
dc.language | Inglés | es_ES |
dc.publisher | Frontiers Media SA | es_ES |
dc.relation.ispartof | Frontiers in Pharmacology | es_ES |
dc.rights | Reconocimiento (by) | es_ES |
dc.subject | Long QT Syndrome | es_ES |
dc.subject | Flecainide | es_ES |
dc.subject | Ranolazine | es_ES |
dc.subject | In-silico model | es_ES |
dc.subject | Sodium current channelopathy | es_ES |
dc.subject | V411M | es_ES |
dc.subject.classification | TECNOLOGIA ELECTRONICA | es_ES |
dc.title | Ranolazine as an Alternative Therapy to Flecainide for SCN5A V411M Long QT Syndrome Type 3 Patients | es_ES |
dc.type | Artículo | es_ES |
dc.identifier.doi | 10.3389/fphar.2020.580481 | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/MINECO//DPI2015-69125-R/ES/SIMULACION COMPUTACIONAL PARA LA PREDICCION PERSONALIZADA DE LOS EFECTOS DE LOS FARMACOS SOBRE LA ACTIVIDAD CARDIACA/ | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/UPV//PAID-06-18/ | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/ISCIII//PT17%2F0015%2F0043/ | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/GVA//PROMETEO%2F2016%2F088/ES/MODELOS COMPUTACIONALES PERSONALIZADOS MULTI-ESCALA PARA LA OPTIMIZACION DEL DIAGNOSTICO Y TRATAMIENTO DE ARRITMIAS CARDIACAS (PERSONALISED DIGITAL HEART)/ | es_ES |
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 | Cano, J.; Zorio, E.; Mazzanti, A.; Arnau, MÁ.; Trenor Gomis, BA.; Priori, SG.; Saiz Rodríguez, FJ.... (2020). Ranolazine as an Alternative Therapy to Flecainide for SCN5A V411M Long QT Syndrome Type 3 Patients. Frontiers in Pharmacology. 11:1-19. https://doi.org/10.3389/fphar.2020.580481 | es_ES |
dc.description.accrualMethod | S | es_ES |
dc.relation.publisherversion | https://doi.org/10.3389/fphar.2020.580481 | es_ES |
dc.description.upvformatpinicio | 1 | es_ES |
dc.description.upvformatpfin | 19 | es_ES |
dc.type.version | info:eu-repo/semantics/publishedVersion | es_ES |
dc.description.volume | 11 | es_ES |
dc.identifier.eissn | 1663-9812 | es_ES |
dc.identifier.pmid | 33519442 | es_ES |
dc.identifier.pmcid | PMC7845660 | es_ES |
dc.relation.pasarela | S\434640 | es_ES |
dc.contributor.funder | Generalitat Valenciana | es_ES |
dc.contributor.funder | Instituto de Salud Carlos III | es_ES |
dc.contributor.funder | European Regional Development Fund | es_ES |
dc.contributor.funder | Universitat Politècnica de València | es_ES |
dc.contributor.funder | Ministerio de Economía y Competitividad | es_ES |
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