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

ALBERTO LAZAROWSKI; AMALIA MERELLI; FRANCO MOSCOVICZ; JERONIMO AUZMENDI

Epilepsy Mortality: Leading Causes of Death, Co-morbidities, Cardiovascular Risk and Prevention

Frontiers

Año: 2022; p. 33 - 41

Uncontrolled repetitive generalized tonic-clonic seizures (GTCS) are the main risk factorfor sudden unexpected death in epilepsy (SUDEP). GTCS can be observed in modelssuch 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 hypoxicstress-induced by convulsions with excessive sympathetic overstimulation that triggersa neurocardiogenic injury, recently defined as ?Epileptic Heart? and characterized byheart rhythm disturbances, such as bradycardia and lengthening of the QT interval.Recently, an iron overload-dependent form of non-apoptotic cell death called ferroptosiswas 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 overloadcardiomyopathy (IOC) results from the accumulation of iron in the myocardium, with highproduction of reactive oxygen species (ROS), lipid peroxidation, and accumulation ofhemosiderin as the final biomarker related to cardiomyocyte ferroptosis. Iron overloadcardiomyopathy is the leading cause of death in patients with iron overload secondary tochronic blood transfusion therapy; it is also described in hereditary hemochromatosis.GTCS, through repeated hypoxic stress, can increase ROS production in the heartand cause cardiomyocyte ferroptosis. We hypothesized that iron accumulation in the?Epileptic Heart? could be associated with a terminal cardiac arrhythmia described in theIOC and the development of state-potentially in the development of SUDEP. Using theaforementioned PTZ-K and SE-P experimental models, after SUDEP-related repetitiveGTCS, we observed an increase in the cardiac expression of hypoxic inducible factor1α, indicating hypoxic-ischemic damage, and both necrotic cells and hemorrhagic areaswere 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 theSE-P model. These results suggest that uncontrolled recurrent seizures, as describedin 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 mechanismcontributing to the development of a terminal cardiac arrhythmia in SUDEP. Because ironaccumulation in tissues can be detected by non-invasive imaging methods, cardiac ironoverload in refractory epilepsy patients could be treated with chelation therapy to reducethe risk of SUDEP.