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Myocardial Iron Overload in an Experimental Model of Sudden Unexpected Death in Epilepsy

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 c...

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Autores principales: Akyuz, Enes, Doganyigit, Zuleyha, Eroglu, Ece, Moscovicz, Franco, Merelli, Amalia, Lazarowski, Alberto, Auzmendi, Jerónimo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905080/
https://www.ncbi.nlm.nih.gov/pubmed/33643194
http://dx.doi.org/10.3389/fneur.2021.609236
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author Akyuz, Enes
Doganyigit, Zuleyha
Eroglu, Ece
Moscovicz, Franco
Merelli, Amalia
Lazarowski, Alberto
Auzmendi, Jerónimo
author_facet Akyuz, Enes
Doganyigit, Zuleyha
Eroglu, Ece
Moscovicz, Franco
Merelli, Amalia
Lazarowski, Alberto
Auzmendi, Jerónimo
author_sort Akyuz, Enes
collection PubMed
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.
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spelling pubmed-79050802021-02-26 Myocardial Iron Overload in an Experimental Model of Sudden Unexpected Death in Epilepsy Akyuz, Enes Doganyigit, Zuleyha Eroglu, Ece Moscovicz, Franco Merelli, Amalia Lazarowski, Alberto Auzmendi, Jerónimo Front Neurol Neurology 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. Frontiers Media S.A. 2021-02-11 /pmc/articles/PMC7905080/ /pubmed/33643194 http://dx.doi.org/10.3389/fneur.2021.609236 Text en Copyright © 2021 Akyuz, Doganyigit, Eroglu, Moscovicz, Merelli, Lazarowski and Auzmendi. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neurology
Akyuz, Enes
Doganyigit, Zuleyha
Eroglu, Ece
Moscovicz, Franco
Merelli, Amalia
Lazarowski, Alberto
Auzmendi, Jerónimo
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
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_short 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
topic Neurology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905080/
https://www.ncbi.nlm.nih.gov/pubmed/33643194
http://dx.doi.org/10.3389/fneur.2021.609236
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