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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/156771
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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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13.070432 |