A simulation study of the impact of drug-IKr binding mechanisms on biomarkers of proarrhythmic risk reveals a crucial role in reverse use-dependence of action potential duration and a marked influence on the vulnerable window

[EN] Background and objective In silico human models are being used more and more to predict the potential proarrhythmic risk of compounds. It has been shown that incorporation of the dynamics of drug-hERG channel interactions can have an important impact on the action potential duration (APD) at no...

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Autores: Gomis-Tena Dolz, Julio|||0000-0002-1309-2368, Escobar-Ropero, Fernando|||0000-0001-7602-447X, Romero Pérez, Lucia|||0000-0003-4605-8630
Tipo de recurso: artículo
Fecha de publicación:2025
País:España
Institución:Universitat Politècnica de València (UPV)
Repositorio:RiuNet. Repositorio Institucional de la Universitat Politécnica de Valéncia
Idioma:inglés
OAI Identifier:oai:riunet.upv.es:10251/214551
Acceso en línea:https://riunet.upv.es/handle/10251/214551
Access Level:acceso abierto
Palabra clave:Action potential triangulation
Instability
Transmural dispersion of repolarization
Computer modelling
HERG blockers
Class III drugs
Proarrhythmic risk
Drug safety
TECNOLOGIA ELECTRONICA
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network_acronym_str ES
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repository_id_str
dc.title.none.fl_str_mv A simulation study of the impact of drug-IKr binding mechanisms on biomarkers of proarrhythmic risk reveals a crucial role in reverse use-dependence of action potential duration and a marked influence on the vulnerable window
title A simulation study of the impact of drug-IKr binding mechanisms on biomarkers of proarrhythmic risk reveals a crucial role in reverse use-dependence of action potential duration and a marked influence on the vulnerable window
spellingShingle A simulation study of the impact of drug-IKr binding mechanisms on biomarkers of proarrhythmic risk reveals a crucial role in reverse use-dependence of action potential duration and a marked influence on the vulnerable window
Gomis-Tena Dolz, Julio|||0000-0002-1309-2368
Action potential triangulation
Instability
Transmural dispersion of repolarization
Computer modelling
HERG blockers
Class III drugs
Proarrhythmic risk
Drug safety
TECNOLOGIA ELECTRONICA
title_short A simulation study of the impact of drug-IKr binding mechanisms on biomarkers of proarrhythmic risk reveals a crucial role in reverse use-dependence of action potential duration and a marked influence on the vulnerable window
title_full A simulation study of the impact of drug-IKr binding mechanisms on biomarkers of proarrhythmic risk reveals a crucial role in reverse use-dependence of action potential duration and a marked influence on the vulnerable window
title_fullStr A simulation study of the impact of drug-IKr binding mechanisms on biomarkers of proarrhythmic risk reveals a crucial role in reverse use-dependence of action potential duration and a marked influence on the vulnerable window
title_full_unstemmed A simulation study of the impact of drug-IKr binding mechanisms on biomarkers of proarrhythmic risk reveals a crucial role in reverse use-dependence of action potential duration and a marked influence on the vulnerable window
title_sort A simulation study of the impact of drug-IKr binding mechanisms on biomarkers of proarrhythmic risk reveals a crucial role in reverse use-dependence of action potential duration and a marked influence on the vulnerable window
dc.creator.none.fl_str_mv Gomis-Tena Dolz, Julio|||0000-0002-1309-2368
Escobar-Ropero, Fernando|||0000-0001-7602-447X
Romero Pérez, Lucia|||0000-0003-4605-8630
author Gomis-Tena Dolz, Julio|||0000-0002-1309-2368
author_facet Gomis-Tena Dolz, Julio|||0000-0002-1309-2368
Escobar-Ropero, Fernando|||0000-0001-7602-447X
Romero Pérez, Lucia|||0000-0003-4605-8630
author_role author
author2 Escobar-Ropero, Fernando|||0000-0001-7602-447X
Romero Pérez, Lucia|||0000-0003-4605-8630
author2_role author
author
dc.contributor.none.fl_str_mv Departamento de Ingeniería Electrónica
Escuela Técnica Superior de Ingeniería Aeroespacial y Diseño Industrial
Escuela Técnica Superior de Ingeniería Industrial
Centro de Investigación e Innovación en Bioingeniería
AGENCIA ESTATAL DE INVESTIGACION
COMISION DE LAS COMUNIDADES EUROPEA
Agència Valenciana de la Innovació
MINISTERIO DE UNIVERSIDADES E INVESTIGACION
Repositorio Institucional de la Universitat Politècnica de València Riunet
dc.subject.none.fl_str_mv Action potential triangulation
Instability
Transmural dispersion of repolarization
Computer modelling
HERG blockers
Class III drugs
Proarrhythmic risk
Drug safety
TECNOLOGIA ELECTRONICA
topic Action potential triangulation
Instability
Transmural dispersion of repolarization
Computer modelling
HERG blockers
Class III drugs
Proarrhythmic risk
Drug safety
TECNOLOGIA ELECTRONICA
description [EN] Background and objective In silico human models are being used more and more to predict the potential proarrhythmic risk of compounds. It has been shown that incorporation of the dynamics of drug-hERG channel interactions can have an important impact on the action potential duration (APD) at normal heart rates. Our aim is to investigate the relevance of drug dynamics on other important biomarkers of proarrhythmic risk. Methods We use the state-of-the-art mathematical models of the cardiac electrophysiological activity to simulate TRIaD biomarkers, namely Triangulation, Reverse use-dependency, electrical Instability of the action potential and Dispersion, together with the vulnerable window to unidirectional block. They were simulated in control conditions and in the presence of an extensive set of 114 in silico IKr blockers with different kinetics and affinities to conformational states of the channel and 10 well-known real IKr blockers at the concentration leading to a 25 % prolongation of the APD. Results Our results show that drug binding dynamics to hERG are crucial for the reverse use-dependence of APD, the slope of the APD restitution curve as a function of the root square of the cycle length ranging from 0 to 5.6 ms/ms (2.1 ms/ms in control conditions). The vulnerable window for unidirectional block and the transmural action potential duration dispersion markedly depended on the drug binding mechanisms and kinetics, although to a lesser extent. Virtual drugs led to increments of these two biomarkers from 25 % to 200 %. On the contrary, temporal instability and, beat-to-beat instability, are less dependent on the dynamics of drug binding. The results obtained with the models of real IKr blockers are in line with those obtained with the virtual drugs. Conclusions Our study highlights the importance of considering the drug binding mechanism, as well as the kinetics, to assess the effects of IKr blockers. Moreover, adoption of in silico models mimicking these characteristics would contribute to the improvement of the prediction of the proarrhythmic risk of new compounds.
publishDate 2025
dc.date.none.fl_str_mv 2025
2025-03-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://riunet.upv.es/handle/10251/214551
url https://riunet.upv.es/handle/10251/214551
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Ministerio de Ciencia, Innovación y Universidades https://doi.org/10.13039/100014440 FPU19%2F02200 MODELOS IN SILICO PARA EL ESTUDIO DEL EFECTO DE FÁRMACOS EN EL CORAZÓN. BIOMARCADORES PARA LA PREDICCIÓN DE LA EFICACIA Y SEGURIDAD DE NUEVOS FÁRMACOS
Agencia Estatal de Investigación http://dx.doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023 PID2022-140553OB-C41 MODELADO Y SIMULACION DE LA MEDICINA DE PRECISION EN CARDIOLOGIA
European Commission https://doi.org/10.13039/501100000780 H2020 101016496 Simulation of Cardiac Devices & Drugs for in-silico Testing and Certification
Agència Valenciana de la Innovació https://doi.org/10.13039/501100016028 INNVA1%2F2024%2F60
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Reconocimiento - No comercial - Sin obra derivada (by-nc-nd)
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Reconocimiento - No comercial - Sin obra derivada (by-nc-nd)
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:RiuNet. Repositorio Institucional de la Universitat Politécnica de Valéncia
instname:Universitat Politècnica de València (UPV)
instname_str Universitat Politècnica de València (UPV)
reponame_str RiuNet. Repositorio Institucional de la Universitat Politécnica de Valéncia
collection RiuNet. Repositorio Institucional de la Universitat Politécnica de Valéncia
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling A simulation study of the impact of drug-IKr binding mechanisms on biomarkers of proarrhythmic risk reveals a crucial role in reverse use-dependence of action potential duration and a marked influence on the vulnerable windowGomis-Tena Dolz, Julio|||0000-0002-1309-2368Escobar-Ropero, Fernando|||0000-0001-7602-447XRomero Pérez, Lucia|||0000-0003-4605-8630Action potential triangulationInstabilityTransmural dispersion of repolarizationComputer modellingHERG blockersClass III drugsProarrhythmic riskDrug safetyTECNOLOGIA ELECTRONICA[EN] Background and objective In silico human models are being used more and more to predict the potential proarrhythmic risk of compounds. It has been shown that incorporation of the dynamics of drug-hERG channel interactions can have an important impact on the action potential duration (APD) at normal heart rates. Our aim is to investigate the relevance of drug dynamics on other important biomarkers of proarrhythmic risk. Methods We use the state-of-the-art mathematical models of the cardiac electrophysiological activity to simulate TRIaD biomarkers, namely Triangulation, Reverse use-dependency, electrical Instability of the action potential and Dispersion, together with the vulnerable window to unidirectional block. They were simulated in control conditions and in the presence of an extensive set of 114 in silico IKr blockers with different kinetics and affinities to conformational states of the channel and 10 well-known real IKr blockers at the concentration leading to a 25 % prolongation of the APD. Results Our results show that drug binding dynamics to hERG are crucial for the reverse use-dependence of APD, the slope of the APD restitution curve as a function of the root square of the cycle length ranging from 0 to 5.6 ms/ms (2.1 ms/ms in control conditions). The vulnerable window for unidirectional block and the transmural action potential duration dispersion markedly depended on the drug binding mechanisms and kinetics, although to a lesser extent. Virtual drugs led to increments of these two biomarkers from 25 % to 200 %. On the contrary, temporal instability and, beat-to-beat instability, are less dependent on the dynamics of drug binding. The results obtained with the models of real IKr blockers are in line with those obtained with the virtual drugs. Conclusions Our study highlights the importance of considering the drug binding mechanism, as well as the kinetics, to assess the effects of IKr blockers. Moreover, adoption of in silico models mimicking these characteristics would contribute to the improvement of the prediction of the proarrhythmic risk of new compounds.This work was funded by the Spanish Ministerio de Ciencia, Innovacion y Universidades [grant "Formacion de Profesorado Universitario" FPU19/02200; grant PID2022-140553OB-C41 funded by MICIU/AEI/10.13039/501100011033 and by ERDF/EU] ; the European Union's Horizon 2020 research and innovation program [grant agreement No 101016496 (SimCardioTest) ] ; and the Agencia Valenciana de la Innovacio and by ERDF/EU (INNVA1/2024/60) .ElsevierDepartamento de Ingeniería ElectrónicaEscuela Técnica Superior de Ingeniería Aeroespacial y Diseño IndustrialEscuela Técnica Superior de Ingeniería IndustrialCentro de Investigación e Innovación en BioingenieríaAGENCIA ESTATAL DE INVESTIGACIONCOMISION DE LAS COMUNIDADES EUROPEAAgència Valenciana de la InnovacióMINISTERIO DE UNIVERSIDADES E INVESTIGACIONRepositorio Institucional de la Universitat Politècnica de València Riunet20252025-03-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://riunet.upv.es/handle/10251/214551reponame:RiuNet. Repositorio Institucional de la Universitat Politécnica de Valénciainstname:Universitat Politècnica de València (UPV)InglésengMinisterio de Ciencia, Innovación y Universidades https://doi.org/10.13039/100014440 FPU19%2F02200 MODELOS IN SILICO PARA EL ESTUDIO DEL EFECTO DE FÁRMACOS EN EL CORAZÓN. BIOMARCADORES PARA LA PREDICCIÓN DE LA EFICACIA Y SEGURIDAD DE NUEVOS FÁRMACOSAgencia Estatal de Investigación http://dx.doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023 PID2022-140553OB-C41 MODELADO Y SIMULACION DE LA MEDICINA DE PRECISION EN CARDIOLOGIAEuropean Commission https://doi.org/10.13039/501100000780 H2020 101016496 Simulation of Cardiac Devices & Drugs for in-silico Testing and CertificationAgència Valenciana de la Innovació https://doi.org/10.13039/501100016028 INNVA1%2F2024%2F60open accesshttp://purl.org/coar/access_right/c_abf2Reconocimiento - No comercial - Sin obra derivada (by-nc-nd) http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:riunet.upv.es:10251/2145512026-06-13T07:49:27Z
score 15,81155

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