Myocardial iron overload in an experimental model of sudden unexpected death in epilepsy

Autores
Akyuz, Enes; Doganyigit, Zuleyha; Eroglu, Ece; Moscovicz, Franco; Merelli, Amalia Margarita; Lazarowski, Alberto Jorge; Auzmendi, Jerónimo Andrés
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Uncontrolled repetitive generalized tonic-clonic seizures (GTCS) are the main risk factor for sudden unexpected death in epilepsy (SUDEP). GTCS can be observed in models such as Pentylenetetrazole kindling (PTZ-K) or pilocarpine-induced Status Epilepticus (SE-P), which share similar alterations in cardiac function, with a high risk of SUDEP. Terminal cardiac arrhythmia in SUDEP can develop as a result of a high rate of hypoxic stress-induced by convulsions with excessive sympathetic overstimulation that triggers a neurocardiogenic injury, recently defined as ?Epileptic Heart? and characterized by heart rhythm disturbances, such as bradycardia and lengthening of the QT interval. Recently, an iron overload-dependent form of non-apoptotic cell death called ferroptosis was described at the brain level in both the PTZ-K and SE-P experimental models. However, seizure-related cardiac ferroptosis has not yet been reported. Iron overload cardiomyopathy (IOC) results from the accumulation of iron in the myocardium, with high production of reactive oxygen species (ROS), lipid peroxidation, and accumulation of hemosiderin as the final biomarker related to cardiomyocyte ferroptosis. Iron overload cardiomyopathy is the leading cause of death in patients with iron overload secondary to chronic blood transfusion therapy; it is also described in hereditary hemochromatosis. GTCS, through repeated hypoxic stress, can increase ROS production in the heart and cause cardiomyocyte ferroptosis. We hypothesized that iron accumulation in the ?Epileptic Heart? could be associated with a terminal cardiac arrhythmia described in the IOC and the development of state-potentially in the development of SUDEP. Using the aforementioned PTZ-K and SE-P experimental models, after SUDEP-related repetitive GTCS, we observed an increase in the cardiac expression of hypoxic inducible factor 1α, indicating hypoxic-ischemic damage, and both necrotic cells and hemorrhagic areas were related to the possible hemosiderin production in the PTZ-K model. Furthermore, we demonstrated for the first time an accumulation of hemosiderin in the heart in the SE-P model. These results suggest that uncontrolled recurrent seizures, as described in refractory epilepsy, can give rise to high hypoxic stress in the heart, thus inducing hemosiderin accumulation as in IOC, and can act as an underlying hidden mechanism contributing to the development of a terminal cardiac arrhythmia in SUDEP. Because iron accumulation in tissues can be detected by non-invasive imaging methods, cardiac iron overload in refractory epilepsy patients could be treated with chelation therapy to reduce the risk of SUDEP.
Fil: Akyuz, Enes. Yozgat Bozok University; Turquía
Fil: Doganyigit, Zuleyha. Yozgat Bozok University; Turquía
Fil: Eroglu, Ece. Yozgat Bozok University; Turquía
Fil: Moscovicz, Franco. Universidad de Buenos Aires; Argentina
Fil: Merelli, Amalia Margarita. Universidad de Buenos Aires; Argentina
Fil: Lazarowski, Alberto Jorge. Universidad de Buenos Aires; Argentina
Fil: Auzmendi, Jerónimo Andrés. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Fisiopatología y Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina
Materia
EPILEPSY
FERROPTOSIS
HEART FAILURE
IRON OVERLOAD CARDIOMYOPATHY
SUDEP
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:11336/156771

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network_name_str CONICET Digital (CONICET)
spelling Myocardial iron overload in an experimental model of sudden unexpected death in epilepsyAkyuz, EnesDoganyigit, ZuleyhaEroglu, EceMoscovicz, FrancoMerelli, Amalia MargaritaLazarowski, Alberto JorgeAuzmendi, Jerónimo AndrésEPILEPSYFERROPTOSISHEART FAILUREIRON OVERLOAD CARDIOMYOPATHYSUDEPhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1https://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Uncontrolled repetitive generalized tonic-clonic seizures (GTCS) are the main risk factor for sudden unexpected death in epilepsy (SUDEP). GTCS can be observed in models such as Pentylenetetrazole kindling (PTZ-K) or pilocarpine-induced Status Epilepticus (SE-P), which share similar alterations in cardiac function, with a high risk of SUDEP. Terminal cardiac arrhythmia in SUDEP can develop as a result of a high rate of hypoxic stress-induced by convulsions with excessive sympathetic overstimulation that triggers a neurocardiogenic injury, recently defined as ?Epileptic Heart? and characterized by heart rhythm disturbances, such as bradycardia and lengthening of the QT interval. Recently, an iron overload-dependent form of non-apoptotic cell death called ferroptosis was described at the brain level in both the PTZ-K and SE-P experimental models. However, seizure-related cardiac ferroptosis has not yet been reported. Iron overload cardiomyopathy (IOC) results from the accumulation of iron in the myocardium, with high production of reactive oxygen species (ROS), lipid peroxidation, and accumulation of hemosiderin as the final biomarker related to cardiomyocyte ferroptosis. Iron overload cardiomyopathy is the leading cause of death in patients with iron overload secondary to chronic blood transfusion therapy; it is also described in hereditary hemochromatosis. GTCS, through repeated hypoxic stress, can increase ROS production in the heart and cause cardiomyocyte ferroptosis. We hypothesized that iron accumulation in the ?Epileptic Heart? could be associated with a terminal cardiac arrhythmia described in the IOC and the development of state-potentially in the development of SUDEP. Using the aforementioned PTZ-K and SE-P experimental models, after SUDEP-related repetitive GTCS, we observed an increase in the cardiac expression of hypoxic inducible factor 1α, indicating hypoxic-ischemic damage, and both necrotic cells and hemorrhagic areas were related to the possible hemosiderin production in the PTZ-K model. Furthermore, we demonstrated for the first time an accumulation of hemosiderin in the heart in the SE-P model. These results suggest that uncontrolled recurrent seizures, as described in refractory epilepsy, can give rise to high hypoxic stress in the heart, thus inducing hemosiderin accumulation as in IOC, and can act as an underlying hidden mechanism contributing to the development of a terminal cardiac arrhythmia in SUDEP. Because iron accumulation in tissues can be detected by non-invasive imaging methods, cardiac iron overload in refractory epilepsy patients could be treated with chelation therapy to reduce the risk of SUDEP.Fil: Akyuz, Enes. Yozgat Bozok University; TurquíaFil: Doganyigit, Zuleyha. Yozgat Bozok University; TurquíaFil: Eroglu, Ece. Yozgat Bozok University; TurquíaFil: Moscovicz, Franco. Universidad de Buenos Aires; ArgentinaFil: Merelli, Amalia Margarita. Universidad de Buenos Aires; ArgentinaFil: Lazarowski, Alberto Jorge. Universidad de Buenos Aires; ArgentinaFil: Auzmendi, Jerónimo Andrés. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Fisiopatología y Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFrontiers Media2021-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/156771Akyuz, Enes; Doganyigit, Zuleyha; Eroglu, Ece; Moscovicz, Franco; Merelli, Amalia Margarita; et al.; Myocardial iron overload in an experimental model of sudden unexpected death in epilepsy; Frontiers Media; Frontiers in Neurology; 12; 2-2021; 1-91664-2295CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/articles/10.3389/fneur.2021.609236/fullinfo:eu-repo/semantics/altIdentifier/doi/10.3389/fneur.2021.609236info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:08:25Zoai:ri.conicet.gov.ar:11336/156771instacron: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:34982025-09-29 10:08:26.098CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Myocardial iron overload in an experimental model of sudden unexpected death in epilepsy
title Myocardial iron overload in an experimental model of sudden unexpected death in epilepsy
spellingShingle Myocardial iron overload in an experimental model of sudden unexpected death in epilepsy
Akyuz, Enes
EPILEPSY
FERROPTOSIS
HEART FAILURE
IRON OVERLOAD CARDIOMYOPATHY
SUDEP
title_short Myocardial iron overload in an experimental model of sudden unexpected death in epilepsy
title_full Myocardial iron overload in an experimental model of sudden unexpected death in epilepsy
title_fullStr Myocardial iron overload in an experimental model of sudden unexpected death in epilepsy
title_full_unstemmed Myocardial iron overload in an experimental model of sudden unexpected death in epilepsy
title_sort Myocardial iron overload in an experimental model of sudden unexpected death in epilepsy
dc.creator.none.fl_str_mv Akyuz, Enes
Doganyigit, Zuleyha
Eroglu, Ece
Moscovicz, Franco
Merelli, Amalia Margarita
Lazarowski, Alberto Jorge
Auzmendi, Jerónimo Andrés
author Akyuz, Enes
author_facet Akyuz, Enes
Doganyigit, Zuleyha
Eroglu, Ece
Moscovicz, Franco
Merelli, Amalia Margarita
Lazarowski, Alberto Jorge
Auzmendi, Jerónimo Andrés
author_role author
author2 Doganyigit, Zuleyha
Eroglu, Ece
Moscovicz, Franco
Merelli, Amalia Margarita
Lazarowski, Alberto Jorge
Auzmendi, Jerónimo Andrés
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv EPILEPSY
FERROPTOSIS
HEART FAILURE
IRON OVERLOAD CARDIOMYOPATHY
SUDEP
topic EPILEPSY
FERROPTOSIS
HEART FAILURE
IRON OVERLOAD CARDIOMYOPATHY
SUDEP
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Uncontrolled repetitive generalized tonic-clonic seizures (GTCS) are the main risk factor for sudden unexpected death in epilepsy (SUDEP). GTCS can be observed in models such as Pentylenetetrazole kindling (PTZ-K) or pilocarpine-induced Status Epilepticus (SE-P), which share similar alterations in cardiac function, with a high risk of SUDEP. Terminal cardiac arrhythmia in SUDEP can develop as a result of a high rate of hypoxic stress-induced by convulsions with excessive sympathetic overstimulation that triggers a neurocardiogenic injury, recently defined as ?Epileptic Heart? and characterized by heart rhythm disturbances, such as bradycardia and lengthening of the QT interval. Recently, an iron overload-dependent form of non-apoptotic cell death called ferroptosis was described at the brain level in both the PTZ-K and SE-P experimental models. However, seizure-related cardiac ferroptosis has not yet been reported. Iron overload cardiomyopathy (IOC) results from the accumulation of iron in the myocardium, with high production of reactive oxygen species (ROS), lipid peroxidation, and accumulation of hemosiderin as the final biomarker related to cardiomyocyte ferroptosis. Iron overload cardiomyopathy is the leading cause of death in patients with iron overload secondary to chronic blood transfusion therapy; it is also described in hereditary hemochromatosis. GTCS, through repeated hypoxic stress, can increase ROS production in the heart and cause cardiomyocyte ferroptosis. We hypothesized that iron accumulation in the ?Epileptic Heart? could be associated with a terminal cardiac arrhythmia described in the IOC and the development of state-potentially in the development of SUDEP. Using the aforementioned PTZ-K and SE-P experimental models, after SUDEP-related repetitive GTCS, we observed an increase in the cardiac expression of hypoxic inducible factor 1α, indicating hypoxic-ischemic damage, and both necrotic cells and hemorrhagic areas were related to the possible hemosiderin production in the PTZ-K model. Furthermore, we demonstrated for the first time an accumulation of hemosiderin in the heart in the SE-P model. These results suggest that uncontrolled recurrent seizures, as described in refractory epilepsy, can give rise to high hypoxic stress in the heart, thus inducing hemosiderin accumulation as in IOC, and can act as an underlying hidden mechanism contributing to the development of a terminal cardiac arrhythmia in SUDEP. Because iron accumulation in tissues can be detected by non-invasive imaging methods, cardiac iron overload in refractory epilepsy patients could be treated with chelation therapy to reduce the risk of SUDEP.
Fil: Akyuz, Enes. Yozgat Bozok University; Turquía
Fil: Doganyigit, Zuleyha. Yozgat Bozok University; Turquía
Fil: Eroglu, Ece. Yozgat Bozok University; Turquía
Fil: Moscovicz, Franco. Universidad de Buenos Aires; Argentina
Fil: Merelli, Amalia Margarita. Universidad de Buenos Aires; Argentina
Fil: Lazarowski, Alberto Jorge. Universidad de Buenos Aires; Argentina
Fil: Auzmendi, Jerónimo Andrés. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Fisiopatología y Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina
description Uncontrolled repetitive generalized tonic-clonic seizures (GTCS) are the main risk factor for sudden unexpected death in epilepsy (SUDEP). GTCS can be observed in models such as Pentylenetetrazole kindling (PTZ-K) or pilocarpine-induced Status Epilepticus (SE-P), which share similar alterations in cardiac function, with a high risk of SUDEP. Terminal cardiac arrhythmia in SUDEP can develop as a result of a high rate of hypoxic stress-induced by convulsions with excessive sympathetic overstimulation that triggers a neurocardiogenic injury, recently defined as ?Epileptic Heart? and characterized by heart rhythm disturbances, such as bradycardia and lengthening of the QT interval. Recently, an iron overload-dependent form of non-apoptotic cell death called ferroptosis was described at the brain level in both the PTZ-K and SE-P experimental models. However, seizure-related cardiac ferroptosis has not yet been reported. Iron overload cardiomyopathy (IOC) results from the accumulation of iron in the myocardium, with high production of reactive oxygen species (ROS), lipid peroxidation, and accumulation of hemosiderin as the final biomarker related to cardiomyocyte ferroptosis. Iron overload cardiomyopathy is the leading cause of death in patients with iron overload secondary to chronic blood transfusion therapy; it is also described in hereditary hemochromatosis. GTCS, through repeated hypoxic stress, can increase ROS production in the heart and cause cardiomyocyte ferroptosis. We hypothesized that iron accumulation in the ?Epileptic Heart? could be associated with a terminal cardiac arrhythmia described in the IOC and the development of state-potentially in the development of SUDEP. Using the aforementioned PTZ-K and SE-P experimental models, after SUDEP-related repetitive GTCS, we observed an increase in the cardiac expression of hypoxic inducible factor 1α, indicating hypoxic-ischemic damage, and both necrotic cells and hemorrhagic areas were related to the possible hemosiderin production in the PTZ-K model. Furthermore, we demonstrated for the first time an accumulation of hemosiderin in the heart in the SE-P model. These results suggest that uncontrolled recurrent seizures, as described in refractory epilepsy, can give rise to high hypoxic stress in the heart, thus inducing hemosiderin accumulation as in IOC, and can act as an underlying hidden mechanism contributing to the development of a terminal cardiac arrhythmia in SUDEP. Because iron accumulation in tissues can be detected by non-invasive imaging methods, cardiac iron overload in refractory epilepsy patients could be treated with chelation therapy to reduce the risk of SUDEP.
publishDate 2021
dc.date.none.fl_str_mv 2021-02
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/11336/156771
Akyuz, Enes; Doganyigit, Zuleyha; Eroglu, Ece; Moscovicz, Franco; Merelli, Amalia Margarita; et al.; Myocardial iron overload in an experimental model of sudden unexpected death in epilepsy; Frontiers Media; Frontiers in Neurology; 12; 2-2021; 1-9
1664-2295
CONICET Digital
CONICET
url http://hdl.handle.net/11336/156771
identifier_str_mv Akyuz, Enes; Doganyigit, Zuleyha; Eroglu, Ece; Moscovicz, Franco; Merelli, Amalia Margarita; et al.; Myocardial iron overload in an experimental model of sudden unexpected death in epilepsy; Frontiers Media; Frontiers in Neurology; 12; 2-2021; 1-9
1664-2295
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.frontiersin.org/articles/10.3389/fneur.2021.609236/full
info:eu-repo/semantics/altIdentifier/doi/10.3389/fneur.2021.609236
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 Frontiers Media
publisher.none.fl_str_mv Frontiers Media
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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