RESUMO
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.
RESUMO
Metabolic Syndrome (MetS) is increasing worldwide regardless of culture, genetic, gender, and geographic differences. While multiple individual risk factors, such as obesity, hypertension, diabetes, and hyperlipidemia, can cause cardiovascular disease (CVD), it is the intercurrence of these risk factors that defines MetS as a cluster that creates an environment for atherosclerosis and other manifestations of CVD. Despite the advances in the knowledge and management of each of the components of MetS, there are two molecular biology processes, chronic inflammation and oxidative stress, which are still underdiagnosed and undertreated. In order to assess the effect of a dietary supplement on chronic inflammation in MetS, we conducted a clinical trial with volunteers receiving a formula composed of resveratrol, piperine and alpha tocopherol (FRAMINTROL®), together with their habitual treatment, for three months. The inflammatory state was evaluated by ultrasensitive C reactive protein (US CRP) and ferritin in plasma, and oxygen consumption and chemiluminescence in neutrophils. The results showed that ferritin decreased by 10% (p < 0.05), US-CRP by 33% (p < 0.0001), oxygen consumption by 55% (p < 0.0001), and spontaneous chemiluminiscence was by 25% (p < 0.005) after treatment. As far as we know, this is the first study showing a chronic inflammation decrease in MetS patients due to the administration of a biopower Resveratrol-piperine and alpha tocopherol dietary supplement together with conventional therapy.