Hemosiderin, a possible biomarker for sudep?

Epilepsy is one of the neurological diseases of complex etiology that affects around 50 million people worldwide and is characterized by abnormal electrical activity and recurrent seizures. Uncontrolled generalized repetitive tonic-clonic seizures (GTCS) are the main causes of unexpected sudden death in epilepsy (SUDEP). Hypoxic stress induced by seizure results in neurocardiogenic dysfunctions, including iron overload and cardiomyopathy (IOC) which is related to severe lipid peroxidation caused by the production of reactive oxygen species (ROS). ROS induces recurrent seizure activity, favoring the overexpression of P glycoprotein (P-gp) in the heart. P-gp plays a depolarizing role in cardiomyocyte membranes and potassium (Kir) channels control cellular excitability regarding the repolarization of the cardiac action potential. All these events result in a possible appearance of severe bradycardia and fatal arrhythmia. Several studies have sought evidence for different possible biomarkers for potential prediction of the risk of SUDEP avoiding its fatal outcome.


INTRODUCTION
Epilepsy is a chronic neurological disorder characterized by abnormal electrical activity of the brain with a permanent predisposition to generate epileptic seizures 1  The risk of SUDEP is known to increase with the severity and frequency of uncontrolled epileptic seizures, which is also common in patients with ER, so the risk is greater in this population. More than one mechanism appears to play a role in the development of SUDEP, but its specific mechanical cause has not yet been identified 5 .
Several studies in the literature suggest that SUDEP may be related to cardiogenic origin and that they occur in the ictal and interictal periods. ECG and ECG tests performed during episodes of seizures identified an increase in heart rate that preceded the clinical and electrographic onset of the episodes. On the other hand, involvement of the parasympathetic system identified by sinus bradycardia was also observed, possibly due to apnea during crises 6,7 . that produces them and, therefore, it is not possible to use them for an effectively preventive approach 5 .

Ferroptosis and iron metabolism in epilepsy
Much has been said about the various forms of cell death that are involved in the pathogenesis of diseases 8 . The physiological process of cell death is related to the development, aging and homeostasis of tissues, which is sometimes deregulated in various pathological conditions 9 .
There are some types of programmed cell death that are apoptosis, necrosis, autophagy, and necrotic apoptosis, each with its specific physiological and biological characteristics.
Currently, a new mode of cell death known as ferroptosis has been identified 10 .

Epileptic heart
Adequate energy supply is essential for the functioning of the brain and heart. The literature illustrates that the "epileptic heart" is a heart with damaged coronary

SUDEP Biomarkers
As previously seen, the cause of SUDEP is still unknown, however, several possible causes and relationships have been studied and investigated, among them cardiovascular changes are suggested as the most common mechanisms.
Convulsive stress leads the heart muscle cells to hypoxic conditions, activating the HIF-1α factor and overexpression of P-gp and erythropoietin (EPO) 5 .
Despite the diversity of studies, there is still no reliable biomarker and, therefore, prevention strategies are basically based on clinical findings and on imaging, electrocardiogram, and electroencephalogram exams.
Among the possible biomarkers studied for risk stratification, microRNAs (miRNAs) stand out. One study identified that among a miRNA panel only miR-301a-3p was regulated positively in both the hippocampus and the plasma 8 . Another study reported the detection of 22miRNAs, including miR-301a-3p, in the plasma of patients with heart failure, which corroborates the bets on miRNAs as a possible biomarker for SUDEP 5,26 .
Other studies have also proposed that the accumulation of iron in the heart could be associated with terminal cardiac arrhythmia and the development of SUDEP status, indicating hypoxic-ischemic damage, thus inducing hemosiderin accumulation as in the IOC 6 .
Since the accumulation of iron in tissues can be detected by non-invasive imaging methods, iron overload in the heart can assist in the identification of cardiac injury as a risk biomarker for SUDEP.
Finally, a last study pointed out that the cardiac fatty acid-binding protein (H-FABP) that is released from cardiomyocytes after an ischemic episode 27 , can also be a sensitive and early biomarker for myocardial infarction, since it is twenty times more specific to the heart muscle than myoglobin. Therefore, H-FABP could be used as an early diagnosis tool for myocardial infarction 16 .