Metformin Reduces Potassium Currents and Prolongs Repolarization in Non-Diabetic Heart

Autores
Malagueta Vieira, Layse; Fernandez Ruocco, Maria Julieta; Hortigón Vinagre, María P.; Zamora, Víctor; Zayas Arrabal, Julián; Echeazarra, Leyre; Smith, Godfrey L.; Vila Petroff, Martin Gerarde; Medei, Emiliano; Casis, Óscar; Gallego, Mónica
Año de publicación
2022
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Metformin is the first choice drug for the treatment of type 2 diabetes due to positive results in reducing hyperglycaemia and insulin resistance. However, diabetic patients have higher risk of ventricular arrhythmia and sudden cardiac death, and metformin failed to reduce ventricular arrhythmia in clinical trials. In order to explore the mechanisms responsible for the lack of protective effect, we investigated in vivo the effect of metformin on cardiac electrical activity in non-diabetic rats; and in vitro in isolated ventricular myocytes, HEK293 cells expressing the hERG channel and human induced pluripotent stem cells derived cardiomyocytes (hIPS-CMs). Surface electrocardiograms showed that long-term metformin treatment (7 weeks) at therapeutic doses prolonged cardiac repolarization, reflected as QT and QTc interval duration, and increased ventricular arrhythmia during the caffeine/dobutamine challenge. Patch-clamp recordings in ventricular myocytes isolated from treated animals showed that the cellular mechanism is a reduction in the cardiac transient outward potassium current (Ito). In vitro, incubation with metformin for 24 h also reduced Ito, prolonged action potential duration, and increased spontaneous contractions in ventricular myocytes isolated from control rats. Metformin incubation also reduced IhERG in HEK293 cells. Finally, metformin incubation prolonged action potential duration at 30% and 90% of repolarization in hIPS-CMs, which is compatible with the reduction of Ito and IhERG. Our results show that metformin directly modifies the electrical behavior of the normal heart. The mechanism consists in the inhibition of repolarizing currents and the subsequent decrease in repolarization capacity, which prolongs AP and QTc duration.
Fil: Malagueta Vieira, Layse. Universidad del País Vasco; España
Fil: Fernandez Ruocco, Maria Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentina
Fil: Hortigón Vinagre, María P.. University of Glasgow; Reino Unido
Fil: Zamora, Víctor. University of Glasgow; Reino Unido
Fil: Zayas Arrabal, Julián. Universidad del País Vasco; España
Fil: Echeazarra, Leyre. Universidad del País Vasco; España
Fil: Smith, Godfrey L.. University of Glasgow; Reino Unido
Fil: Vila Petroff, Martin Gerarde. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentina
Fil: Medei, Emiliano. Universidade Federal do Rio de Janeiro; Brasil
Fil: Casis, Óscar. Universidad del País Vasco; España
Fil: Gallego, Mónica. Universidad del País Vasco; España
Materia
cardiac action potential
cardiac electrophysiology
ventricular arrhythmia
diabetes
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/239337
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/239337
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Metformin Reduces Potassium Currents and Prolongs Repolarization in Non-Diabetic HeartMalagueta Vieira, LayseFernandez Ruocco, Maria JulietaHortigón Vinagre, María P.Zamora, VíctorZayas Arrabal, JuliánEcheazarra, LeyreSmith, Godfrey L.Vila Petroff, Martin GerardeMedei, EmilianoCasis, ÓscarGallego, Mónicacardiac action potentialcardiac electrophysiologyventricular arrhythmiadiabeteshttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Metformin is the first choice drug for the treatment of type 2 diabetes due to positive results in reducing hyperglycaemia and insulin resistance. However, diabetic patients have higher risk of ventricular arrhythmia and sudden cardiac death, and metformin failed to reduce ventricular arrhythmia in clinical trials. In order to explore the mechanisms responsible for the lack of protective effect, we investigated in vivo the effect of metformin on cardiac electrical activity in non-diabetic rats; and in vitro in isolated ventricular myocytes, HEK293 cells expressing the hERG channel and human induced pluripotent stem cells derived cardiomyocytes (hIPS-CMs). Surface electrocardiograms showed that long-term metformin treatment (7 weeks) at therapeutic doses prolonged cardiac repolarization, reflected as QT and QTc interval duration, and increased ventricular arrhythmia during the caffeine/dobutamine challenge. Patch-clamp recordings in ventricular myocytes isolated from treated animals showed that the cellular mechanism is a reduction in the cardiac transient outward potassium current (Ito). In vitro, incubation with metformin for 24 h also reduced Ito, prolonged action potential duration, and increased spontaneous contractions in ventricular myocytes isolated from control rats. Metformin incubation also reduced IhERG in HEK293 cells. Finally, metformin incubation prolonged action potential duration at 30% and 90% of repolarization in hIPS-CMs, which is compatible with the reduction of Ito and IhERG. Our results show that metformin directly modifies the electrical behavior of the normal heart. The mechanism consists in the inhibition of repolarizing currents and the subsequent decrease in repolarization capacity, which prolongs AP and QTc duration.Fil: Malagueta Vieira, Layse. Universidad del País Vasco; EspañaFil: Fernandez Ruocco, Maria Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; ArgentinaFil: Hortigón Vinagre, María P.. University of Glasgow; Reino UnidoFil: Zamora, Víctor. University of Glasgow; Reino UnidoFil: Zayas Arrabal, Julián. Universidad del País Vasco; EspañaFil: Echeazarra, Leyre. Universidad del País Vasco; EspañaFil: Smith, Godfrey L.. University of Glasgow; Reino UnidoFil: Vila Petroff, Martin Gerarde. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; ArgentinaFil: Medei, Emiliano. Universidade Federal do Rio de Janeiro; BrasilFil: Casis, Óscar. Universidad del País Vasco; EspañaFil: Gallego, Mónica. Universidad del País Vasco; EspañaMolecular Diversity Preservation International2022-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/239337Malagueta Vieira, Layse; Fernandez Ruocco, Maria Julieta; Hortigón Vinagre, María P.; Zamora, Víctor; Zayas Arrabal, Julián; et al.; Metformin Reduces Potassium Currents and Prolongs Repolarization in Non-Diabetic Heart; Molecular Diversity Preservation International; International Journal of Molecular Sciences; 23; 11; 5-2022; 1-141422-0067CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.mdpi.com/1422-0067/23/11/6021info:eu-repo/semantics/altIdentifier/doi/10.3390/ijms23116021info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:59:50Zoai:ri.conicet.gov.ar:11336/239337instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:59:50.565CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Metformin Reduces Potassium Currents and Prolongs Repolarization in Non-Diabetic Heart
title Metformin Reduces Potassium Currents and Prolongs Repolarization in Non-Diabetic Heart
spellingShingle Metformin Reduces Potassium Currents and Prolongs Repolarization in Non-Diabetic Heart
Malagueta Vieira, Layse
cardiac action potential
cardiac electrophysiology
ventricular arrhythmia
diabetes
title_short Metformin Reduces Potassium Currents and Prolongs Repolarization in Non-Diabetic Heart
title_full Metformin Reduces Potassium Currents and Prolongs Repolarization in Non-Diabetic Heart
title_fullStr Metformin Reduces Potassium Currents and Prolongs Repolarization in Non-Diabetic Heart
title_full_unstemmed Metformin Reduces Potassium Currents and Prolongs Repolarization in Non-Diabetic Heart
title_sort Metformin Reduces Potassium Currents and Prolongs Repolarization in Non-Diabetic Heart
dc.creator.none.fl_str_mv Malagueta Vieira, Layse
Fernandez Ruocco, Maria Julieta
Hortigón Vinagre, María P.
Zamora, Víctor
Zayas Arrabal, Julián
Echeazarra, Leyre
Smith, Godfrey L.
Vila Petroff, Martin Gerarde
Medei, Emiliano
Casis, Óscar
Gallego, Mónica
author Malagueta Vieira, Layse
author_facet Malagueta Vieira, Layse
Fernandez Ruocco, Maria Julieta
Hortigón Vinagre, María P.
Zamora, Víctor
Zayas Arrabal, Julián
Echeazarra, Leyre
Smith, Godfrey L.
Vila Petroff, Martin Gerarde
Medei, Emiliano
Casis, Óscar
Gallego, Mónica
author_role author
author2 Fernandez Ruocco, Maria Julieta
Hortigón Vinagre, María P.
Zamora, Víctor
Zayas Arrabal, Julián
Echeazarra, Leyre
Smith, Godfrey L.
Vila Petroff, Martin Gerarde
Medei, Emiliano
Casis, Óscar
Gallego, Mónica
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv cardiac action potential
cardiac electrophysiology
ventricular arrhythmia
diabetes
topic cardiac action potential
cardiac electrophysiology
ventricular arrhythmia
diabetes
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Metformin is the first choice drug for the treatment of type 2 diabetes due to positive results in reducing hyperglycaemia and insulin resistance. However, diabetic patients have higher risk of ventricular arrhythmia and sudden cardiac death, and metformin failed to reduce ventricular arrhythmia in clinical trials. In order to explore the mechanisms responsible for the lack of protective effect, we investigated in vivo the effect of metformin on cardiac electrical activity in non-diabetic rats; and in vitro in isolated ventricular myocytes, HEK293 cells expressing the hERG channel and human induced pluripotent stem cells derived cardiomyocytes (hIPS-CMs). Surface electrocardiograms showed that long-term metformin treatment (7 weeks) at therapeutic doses prolonged cardiac repolarization, reflected as QT and QTc interval duration, and increased ventricular arrhythmia during the caffeine/dobutamine challenge. Patch-clamp recordings in ventricular myocytes isolated from treated animals showed that the cellular mechanism is a reduction in the cardiac transient outward potassium current (Ito). In vitro, incubation with metformin for 24 h also reduced Ito, prolonged action potential duration, and increased spontaneous contractions in ventricular myocytes isolated from control rats. Metformin incubation also reduced IhERG in HEK293 cells. Finally, metformin incubation prolonged action potential duration at 30% and 90% of repolarization in hIPS-CMs, which is compatible with the reduction of Ito and IhERG. Our results show that metformin directly modifies the electrical behavior of the normal heart. The mechanism consists in the inhibition of repolarizing currents and the subsequent decrease in repolarization capacity, which prolongs AP and QTc duration.
Fil: Malagueta Vieira, Layse. Universidad del País Vasco; España
Fil: Fernandez Ruocco, Maria Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentina
Fil: Hortigón Vinagre, María P.. University of Glasgow; Reino Unido
Fil: Zamora, Víctor. University of Glasgow; Reino Unido
Fil: Zayas Arrabal, Julián. Universidad del País Vasco; España
Fil: Echeazarra, Leyre. Universidad del País Vasco; España
Fil: Smith, Godfrey L.. University of Glasgow; Reino Unido
Fil: Vila Petroff, Martin Gerarde. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentina
Fil: Medei, Emiliano. Universidade Federal do Rio de Janeiro; Brasil
Fil: Casis, Óscar. Universidad del País Vasco; España
Fil: Gallego, Mónica. Universidad del País Vasco; España
description Metformin is the first choice drug for the treatment of type 2 diabetes due to positive results in reducing hyperglycaemia and insulin resistance. However, diabetic patients have higher risk of ventricular arrhythmia and sudden cardiac death, and metformin failed to reduce ventricular arrhythmia in clinical trials. In order to explore the mechanisms responsible for the lack of protective effect, we investigated in vivo the effect of metformin on cardiac electrical activity in non-diabetic rats; and in vitro in isolated ventricular myocytes, HEK293 cells expressing the hERG channel and human induced pluripotent stem cells derived cardiomyocytes (hIPS-CMs). Surface electrocardiograms showed that long-term metformin treatment (7 weeks) at therapeutic doses prolonged cardiac repolarization, reflected as QT and QTc interval duration, and increased ventricular arrhythmia during the caffeine/dobutamine challenge. Patch-clamp recordings in ventricular myocytes isolated from treated animals showed that the cellular mechanism is a reduction in the cardiac transient outward potassium current (Ito). In vitro, incubation with metformin for 24 h also reduced Ito, prolonged action potential duration, and increased spontaneous contractions in ventricular myocytes isolated from control rats. Metformin incubation also reduced IhERG in HEK293 cells. Finally, metformin incubation prolonged action potential duration at 30% and 90% of repolarization in hIPS-CMs, which is compatible with the reduction of Ito and IhERG. Our results show that metformin directly modifies the electrical behavior of the normal heart. The mechanism consists in the inhibition of repolarizing currents and the subsequent decrease in repolarization capacity, which prolongs AP and QTc duration.
publishDate 2022
dc.date.none.fl_str_mv 2022-05
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/239337
Malagueta Vieira, Layse; Fernandez Ruocco, Maria Julieta; Hortigón Vinagre, María P.; Zamora, Víctor; Zayas Arrabal, Julián; et al.; Metformin Reduces Potassium Currents and Prolongs Repolarization in Non-Diabetic Heart; Molecular Diversity Preservation International; International Journal of Molecular Sciences; 23; 11; 5-2022; 1-14
1422-0067
CONICET Digital
CONICET
url http://hdl.handle.net/11336/239337
identifier_str_mv Malagueta Vieira, Layse; Fernandez Ruocco, Maria Julieta; Hortigón Vinagre, María P.; Zamora, Víctor; Zayas Arrabal, Julián; et al.; Metformin Reduces Potassium Currents and Prolongs Repolarization in Non-Diabetic Heart; Molecular Diversity Preservation International; International Journal of Molecular Sciences; 23; 11; 5-2022; 1-14
1422-0067
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.mdpi.com/1422-0067/23/11/6021
info:eu-repo/semantics/altIdentifier/doi/10.3390/ijms23116021
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Molecular Diversity Preservation International
publisher.none.fl_str_mv Molecular Diversity Preservation International
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.13397

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