Remote ischemic preconditioning ameliorates anthracycline-induced cardiotoxicity and preserves mitochondrial integrity

Autores
Galán Arriola, Carlos; Villena Gutiérrez, Rocio; Higuero Verdejo, María I.; Díaz Rengifo, Iván A.; Pizarro, Gonzalo; López, Gonzalo J.; de Molina Iracheta, Antonio; Pérez Martínez, Claudia; García, Rodrigo Damián; González Calle, David; Lobo, Manuel; Sánchez, Pedro L.; Oliver, Eduardo; Córdoba, Raúl; Fuster, Valentin; Sánchez González, Javier; Ibanez, Borja
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Aims: Anthracycline-induced cardiotoxicity (AIC) is a serious adverse effect among cancer patients. A central mechanism of AIC is irreversible mitochondrial damage. Despite major efforts, there are currently no effective therapies able to prevent AIC. Methods and results: Forty Large-White pigs were included. In Study 1, 20 pigs were randomized 1:1 to remote ischaemic preconditioning (RIPC, 3 cycles of 5 min leg ischaemia followed by 5 min reperfusion) or no pretreatment. RIPC was performed immediately before each intracoronary doxorubicin injections (0.45 mg/kg) given at Weeks 0, 2, 4, 6, and 8. A group of 10 pigs with no exposure to doxorubicin served as healthy controls. Pigs underwent serial cardiac magnetic resonance (CMR) exams at baseline and at Weeks 6, 8, 12, and 16, being sacrifice after that. In Study 2, 10 new pigs received 3 doxorubicin injections (with/out preceding RIPC) and were sacrificed at week 6. In Study 1, left ventricular ejection fraction (LVEF) depression was blunted animals receiving RIPC before doxorubicin (RIPC-Doxo), which had a significantly higher LVEF at Week 16 than doxorubicin treated pigs that received no pretreatment (Untreated-Doxo) (41.5 ± 9.1% vs. 32.5 ± 8.7%, P = 0.04). It was mainly due to conserved regional contractile function. In Study 2, transmission electron microscopy (TEM) at Week 6 showed fragmented mitochondria with severe morphological abnormalities in Untreated-Doxo pigs, together with upregulation of fission and autophagy proteins. At the end of the 16-week Study 1 protocol, TEM revealed overt mitochondrial fragmentation with structural fragmentation in Untreated-Doxo pigs, whereas interstitial fibrosis was less severe in RIPC+Doxo pigs. Conclusion: In a translatable large-animal model of AIC, RIPC applied immediately before each doxorubicin injection resulted in preserved cardiac contractility with significantly higher long-term LVEF and less cardiac fibrosis. RIPC prevented mitochondrial fragmentation and dysregulated autophagy from AIC early stages. RIPC is a promising intervention for testing in clinical trials in AIC.
Fil: Galán Arriola, Carlos. Centro de Investigacion Biomedica En Red.; España
Fil: Villena Gutiérrez, Rocio. Centro de Investigacion Biomedica En Red.; España
Fil: Higuero Verdejo, María I.. Centro Nacional de Investigaciones Cardiovasculares; España
Fil: Díaz Rengifo, Iván A.. Centro Nacional de Investigaciones Cardiovasculares; España
Fil: Pizarro, Gonzalo. Centro de Investigacion Biomedica En Red.; España
Fil: López, Gonzalo J.. Centro Nacional de Investigaciones Cardiovasculares; España
Fil: de Molina Iracheta, Antonio. Centro Nacional de Investigaciones Cardiovasculares; España
Fil: Pérez Martínez, Claudia. Universidad de Leon. Facultad de Veterinaria; Argentina
Fil: García, Rodrigo Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
Fil: González Calle, David. Centro de Investigacion Biomedica En Red.; España
Fil: Lobo, Manuel. Centro de Investigacion Biomedica En Red.; España
Fil: Sánchez, Pedro L.. Centro de Investigacion Biomedica En Red.; España
Fil: Oliver, Eduardo. Centro de Investigacion Biomedica En Red.; España
Fil: Córdoba, Raúl. Hospital Fundacion Jimenez Diaz; España
Fil: Fuster, Valentin. Centro Nacional de Investigaciones Cardiovasculares; España
Fil: Sánchez González, Javier. No especifíca;
Fil: Ibanez, Borja. Centro de Investigacion Biomedica En Red.; España
Materia
ANTHRACYCLINES
CARDIO-ONCOLOGY
CARDIOTOXICITY
MAGNETIC RESONANCE IMAGING
MITOCHONDRIA
REMOTE CONDITIONING
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/138528
Acceder
id CONICETDig_03d8c63f383b3e851854d6b75a304856
oai_identifier_str oai:ri.conicet.gov.ar:11336/138528
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Remote ischemic preconditioning ameliorates anthracycline-induced cardiotoxicity and preserves mitochondrial integrityGalán Arriola, CarlosVillena Gutiérrez, RocioHiguero Verdejo, María I.Díaz Rengifo, Iván A.Pizarro, GonzaloLópez, Gonzalo J.de Molina Iracheta, AntonioPérez Martínez, ClaudiaGarcía, Rodrigo DamiánGonzález Calle, DavidLobo, ManuelSánchez, Pedro L.Oliver, EduardoCórdoba, RaúlFuster, ValentinSánchez González, JavierIbanez, BorjaANTHRACYCLINESCARDIO-ONCOLOGYCARDIOTOXICITYMAGNETIC RESONANCE IMAGINGMITOCHONDRIAREMOTE CONDITIONINGhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Aims: Anthracycline-induced cardiotoxicity (AIC) is a serious adverse effect among cancer patients. A central mechanism of AIC is irreversible mitochondrial damage. Despite major efforts, there are currently no effective therapies able to prevent AIC. Methods and results: Forty Large-White pigs were included. In Study 1, 20 pigs were randomized 1:1 to remote ischaemic preconditioning (RIPC, 3 cycles of 5 min leg ischaemia followed by 5 min reperfusion) or no pretreatment. RIPC was performed immediately before each intracoronary doxorubicin injections (0.45 mg/kg) given at Weeks 0, 2, 4, 6, and 8. A group of 10 pigs with no exposure to doxorubicin served as healthy controls. Pigs underwent serial cardiac magnetic resonance (CMR) exams at baseline and at Weeks 6, 8, 12, and 16, being sacrifice after that. In Study 2, 10 new pigs received 3 doxorubicin injections (with/out preceding RIPC) and were sacrificed at week 6. In Study 1, left ventricular ejection fraction (LVEF) depression was blunted animals receiving RIPC before doxorubicin (RIPC-Doxo), which had a significantly higher LVEF at Week 16 than doxorubicin treated pigs that received no pretreatment (Untreated-Doxo) (41.5 ± 9.1% vs. 32.5 ± 8.7%, P = 0.04). It was mainly due to conserved regional contractile function. In Study 2, transmission electron microscopy (TEM) at Week 6 showed fragmented mitochondria with severe morphological abnormalities in Untreated-Doxo pigs, together with upregulation of fission and autophagy proteins. At the end of the 16-week Study 1 protocol, TEM revealed overt mitochondrial fragmentation with structural fragmentation in Untreated-Doxo pigs, whereas interstitial fibrosis was less severe in RIPC+Doxo pigs. Conclusion: In a translatable large-animal model of AIC, RIPC applied immediately before each doxorubicin injection resulted in preserved cardiac contractility with significantly higher long-term LVEF and less cardiac fibrosis. RIPC prevented mitochondrial fragmentation and dysregulated autophagy from AIC early stages. RIPC is a promising intervention for testing in clinical trials in AIC.Fil: Galán Arriola, Carlos. Centro de Investigacion Biomedica En Red.; EspañaFil: Villena Gutiérrez, Rocio. Centro de Investigacion Biomedica En Red.; EspañaFil: Higuero Verdejo, María I.. Centro Nacional de Investigaciones Cardiovasculares; EspañaFil: Díaz Rengifo, Iván A.. Centro Nacional de Investigaciones Cardiovasculares; EspañaFil: Pizarro, Gonzalo. Centro de Investigacion Biomedica En Red.; EspañaFil: López, Gonzalo J.. Centro Nacional de Investigaciones Cardiovasculares; EspañaFil: de Molina Iracheta, Antonio. Centro Nacional de Investigaciones Cardiovasculares; EspañaFil: Pérez Martínez, Claudia. Universidad de Leon. Facultad de Veterinaria; ArgentinaFil: García, Rodrigo Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: González Calle, David. Centro de Investigacion Biomedica En Red.; EspañaFil: Lobo, Manuel. Centro de Investigacion Biomedica En Red.; EspañaFil: Sánchez, Pedro L.. Centro de Investigacion Biomedica En Red.; EspañaFil: Oliver, Eduardo. Centro de Investigacion Biomedica En Red.; EspañaFil: Córdoba, Raúl. Hospital Fundacion Jimenez Diaz; EspañaFil: Fuster, Valentin. Centro Nacional de Investigaciones Cardiovasculares; EspañaFil: Sánchez González, Javier. No especifíca;Fil: Ibanez, Borja. Centro de Investigacion Biomedica En Red.; EspañaOxford University Press2021-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/138528Galán Arriola, Carlos; Villena Gutiérrez, Rocio; Higuero Verdejo, María I.; Díaz Rengifo, Iván A.; Pizarro, Gonzalo; et al.; Remote ischemic preconditioning ameliorates anthracycline-induced cardiotoxicity and preserves mitochondrial integrity; Oxford University Press; Cardiovascular Research; 117; 4; 4-2021; 1132-11430008-6363CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/cardiovascres/advance-article/doi/10.1093/cvr/cvaa181/5864719info:eu-repo/semantics/altIdentifier/doi/10.1093/cvr/cvaa181info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:00:16Zoai:ri.conicet.gov.ar:11336/138528instacron: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 10:00:16.356CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Remote ischemic preconditioning ameliorates anthracycline-induced cardiotoxicity and preserves mitochondrial integrity
title Remote ischemic preconditioning ameliorates anthracycline-induced cardiotoxicity and preserves mitochondrial integrity
spellingShingle Remote ischemic preconditioning ameliorates anthracycline-induced cardiotoxicity and preserves mitochondrial integrity
Galán Arriola, Carlos
ANTHRACYCLINES
CARDIO-ONCOLOGY
CARDIOTOXICITY
MAGNETIC RESONANCE IMAGING
MITOCHONDRIA
REMOTE CONDITIONING
title_short Remote ischemic preconditioning ameliorates anthracycline-induced cardiotoxicity and preserves mitochondrial integrity
title_full Remote ischemic preconditioning ameliorates anthracycline-induced cardiotoxicity and preserves mitochondrial integrity
title_fullStr Remote ischemic preconditioning ameliorates anthracycline-induced cardiotoxicity and preserves mitochondrial integrity
title_full_unstemmed Remote ischemic preconditioning ameliorates anthracycline-induced cardiotoxicity and preserves mitochondrial integrity
title_sort Remote ischemic preconditioning ameliorates anthracycline-induced cardiotoxicity and preserves mitochondrial integrity
dc.creator.none.fl_str_mv Galán Arriola, Carlos
Villena Gutiérrez, Rocio
Higuero Verdejo, María I.
Díaz Rengifo, Iván A.
Pizarro, Gonzalo
López, Gonzalo J.
de Molina Iracheta, Antonio
Pérez Martínez, Claudia
García, Rodrigo Damián
González Calle, David
Lobo, Manuel
Sánchez, Pedro L.
Oliver, Eduardo
Córdoba, Raúl
Fuster, Valentin
Sánchez González, Javier
Ibanez, Borja
author Galán Arriola, Carlos
author_facet Galán Arriola, Carlos
Villena Gutiérrez, Rocio
Higuero Verdejo, María I.
Díaz Rengifo, Iván A.
Pizarro, Gonzalo
López, Gonzalo J.
de Molina Iracheta, Antonio
Pérez Martínez, Claudia
García, Rodrigo Damián
González Calle, David
Lobo, Manuel
Sánchez, Pedro L.
Oliver, Eduardo
Córdoba, Raúl
Fuster, Valentin
Sánchez González, Javier
Ibanez, Borja
author_role author
author2 Villena Gutiérrez, Rocio
Higuero Verdejo, María I.
Díaz Rengifo, Iván A.
Pizarro, Gonzalo
López, Gonzalo J.
de Molina Iracheta, Antonio
Pérez Martínez, Claudia
García, Rodrigo Damián
González Calle, David
Lobo, Manuel
Sánchez, Pedro L.
Oliver, Eduardo
Córdoba, Raúl
Fuster, Valentin
Sánchez González, Javier
Ibanez, Borja
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ANTHRACYCLINES
CARDIO-ONCOLOGY
CARDIOTOXICITY
MAGNETIC RESONANCE IMAGING
MITOCHONDRIA
REMOTE CONDITIONING
topic ANTHRACYCLINES
CARDIO-ONCOLOGY
CARDIOTOXICITY
MAGNETIC RESONANCE IMAGING
MITOCHONDRIA
REMOTE CONDITIONING
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Aims: Anthracycline-induced cardiotoxicity (AIC) is a serious adverse effect among cancer patients. A central mechanism of AIC is irreversible mitochondrial damage. Despite major efforts, there are currently no effective therapies able to prevent AIC. Methods and results: Forty Large-White pigs were included. In Study 1, 20 pigs were randomized 1:1 to remote ischaemic preconditioning (RIPC, 3 cycles of 5 min leg ischaemia followed by 5 min reperfusion) or no pretreatment. RIPC was performed immediately before each intracoronary doxorubicin injections (0.45 mg/kg) given at Weeks 0, 2, 4, 6, and 8. A group of 10 pigs with no exposure to doxorubicin served as healthy controls. Pigs underwent serial cardiac magnetic resonance (CMR) exams at baseline and at Weeks 6, 8, 12, and 16, being sacrifice after that. In Study 2, 10 new pigs received 3 doxorubicin injections (with/out preceding RIPC) and were sacrificed at week 6. In Study 1, left ventricular ejection fraction (LVEF) depression was blunted animals receiving RIPC before doxorubicin (RIPC-Doxo), which had a significantly higher LVEF at Week 16 than doxorubicin treated pigs that received no pretreatment (Untreated-Doxo) (41.5 ± 9.1% vs. 32.5 ± 8.7%, P = 0.04). It was mainly due to conserved regional contractile function. In Study 2, transmission electron microscopy (TEM) at Week 6 showed fragmented mitochondria with severe morphological abnormalities in Untreated-Doxo pigs, together with upregulation of fission and autophagy proteins. At the end of the 16-week Study 1 protocol, TEM revealed overt mitochondrial fragmentation with structural fragmentation in Untreated-Doxo pigs, whereas interstitial fibrosis was less severe in RIPC+Doxo pigs. Conclusion: In a translatable large-animal model of AIC, RIPC applied immediately before each doxorubicin injection resulted in preserved cardiac contractility with significantly higher long-term LVEF and less cardiac fibrosis. RIPC prevented mitochondrial fragmentation and dysregulated autophagy from AIC early stages. RIPC is a promising intervention for testing in clinical trials in AIC.
Fil: Galán Arriola, Carlos. Centro de Investigacion Biomedica En Red.; España
Fil: Villena Gutiérrez, Rocio. Centro de Investigacion Biomedica En Red.; España
Fil: Higuero Verdejo, María I.. Centro Nacional de Investigaciones Cardiovasculares; España
Fil: Díaz Rengifo, Iván A.. Centro Nacional de Investigaciones Cardiovasculares; España
Fil: Pizarro, Gonzalo. Centro de Investigacion Biomedica En Red.; España
Fil: López, Gonzalo J.. Centro Nacional de Investigaciones Cardiovasculares; España
Fil: de Molina Iracheta, Antonio. Centro Nacional de Investigaciones Cardiovasculares; España
Fil: Pérez Martínez, Claudia. Universidad de Leon. Facultad de Veterinaria; Argentina
Fil: García, Rodrigo Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
Fil: González Calle, David. Centro de Investigacion Biomedica En Red.; España
Fil: Lobo, Manuel. Centro de Investigacion Biomedica En Red.; España
Fil: Sánchez, Pedro L.. Centro de Investigacion Biomedica En Red.; España
Fil: Oliver, Eduardo. Centro de Investigacion Biomedica En Red.; España
Fil: Córdoba, Raúl. Hospital Fundacion Jimenez Diaz; España
Fil: Fuster, Valentin. Centro Nacional de Investigaciones Cardiovasculares; España
Fil: Sánchez González, Javier. No especifíca;
Fil: Ibanez, Borja. Centro de Investigacion Biomedica En Red.; España
description Aims: Anthracycline-induced cardiotoxicity (AIC) is a serious adverse effect among cancer patients. A central mechanism of AIC is irreversible mitochondrial damage. Despite major efforts, there are currently no effective therapies able to prevent AIC. Methods and results: Forty Large-White pigs were included. In Study 1, 20 pigs were randomized 1:1 to remote ischaemic preconditioning (RIPC, 3 cycles of 5 min leg ischaemia followed by 5 min reperfusion) or no pretreatment. RIPC was performed immediately before each intracoronary doxorubicin injections (0.45 mg/kg) given at Weeks 0, 2, 4, 6, and 8. A group of 10 pigs with no exposure to doxorubicin served as healthy controls. Pigs underwent serial cardiac magnetic resonance (CMR) exams at baseline and at Weeks 6, 8, 12, and 16, being sacrifice after that. In Study 2, 10 new pigs received 3 doxorubicin injections (with/out preceding RIPC) and were sacrificed at week 6. In Study 1, left ventricular ejection fraction (LVEF) depression was blunted animals receiving RIPC before doxorubicin (RIPC-Doxo), which had a significantly higher LVEF at Week 16 than doxorubicin treated pigs that received no pretreatment (Untreated-Doxo) (41.5 ± 9.1% vs. 32.5 ± 8.7%, P = 0.04). It was mainly due to conserved regional contractile function. In Study 2, transmission electron microscopy (TEM) at Week 6 showed fragmented mitochondria with severe morphological abnormalities in Untreated-Doxo pigs, together with upregulation of fission and autophagy proteins. At the end of the 16-week Study 1 protocol, TEM revealed overt mitochondrial fragmentation with structural fragmentation in Untreated-Doxo pigs, whereas interstitial fibrosis was less severe in RIPC+Doxo pigs. Conclusion: In a translatable large-animal model of AIC, RIPC applied immediately before each doxorubicin injection resulted in preserved cardiac contractility with significantly higher long-term LVEF and less cardiac fibrosis. RIPC prevented mitochondrial fragmentation and dysregulated autophagy from AIC early stages. RIPC is a promising intervention for testing in clinical trials in AIC.
publishDate 2021
dc.date.none.fl_str_mv 2021-04
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/11336/138528
Galán Arriola, Carlos; Villena Gutiérrez, Rocio; Higuero Verdejo, María I.; Díaz Rengifo, Iván A.; Pizarro, Gonzalo; et al.; Remote ischemic preconditioning ameliorates anthracycline-induced cardiotoxicity and preserves mitochondrial integrity; Oxford University Press; Cardiovascular Research; 117; 4; 4-2021; 1132-1143
0008-6363
CONICET Digital
CONICET
url http://hdl.handle.net/11336/138528
identifier_str_mv Galán Arriola, Carlos; Villena Gutiérrez, Rocio; Higuero Verdejo, María I.; Díaz Rengifo, Iván A.; Pizarro, Gonzalo; et al.; Remote ischemic preconditioning ameliorates anthracycline-induced cardiotoxicity and preserves mitochondrial integrity; Oxford University Press; Cardiovascular Research; 117; 4; 4-2021; 1132-1143
0008-6363
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://academic.oup.com/cardiovascres/advance-article/doi/10.1093/cvr/cvaa181/5864719
info:eu-repo/semantics/altIdentifier/doi/10.1093/cvr/cvaa181
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
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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