Status epilepticus induces heart dysfunction and p-glycoprotein overexpression in cardiomyocytes: implications for sudden death syndrome in epilepsy

SALGUEIRO J; CANELLAS C; MERELLI A; LAZAROWSKY A; BUCHHOLZ B; AUZMENDI J; ZUBILLAGA M; KELLY J; RAMOS AJ; MEN P; GELPI RJ

CABA

Congreso; LXII Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2017

Sudden Unexpected Death in Epilepsy (SUDEP) is commonlyobserved cause of death after status epilepticus (SE). Refractoryepilepsywas associated with P-glycoprotein (P-gp) brain overexpressionand high risk of SUDEP by acute fatal heart failure. Wehave previously described brain/heart P-gp overexpression relatedwith fatal-SEafter repetitive penthylenetetrazole-inducedseizures(Auzmendi et al.2013).In clinical grounds, loss of the99mTc-SESTAMIBIretention is used asa biomarkerofhypoxic/ischemia(H/I) heartfailure. We here studied cardiac functional parameters and the expressionof P-gp in an experimental model of temporal lobe epilepsy(TLE). SE was induced on300 g Wistar rats by lithium chloride pluspilocarpine treatment (127 mg/kg and 30 mg/kg respectively) andstopped with 20 mg/kg diazepam after 20 min of SE. One group ofanimals received one SE (1xSE) and another group were subjectedto repeated SE (once a week; 4 weeks) (4xSE). After 72 h of SE,99mTc-SESTAMIBI (37MBq-i.v) was administrated and static imagesof whole heart were acquired in a gamma camera to evaluate tracerheart retention. By 5 days after SE, animals from the 1xSE groupalready showed in the ECG analysis both a decreased heart rateand extended QT time. On the other hand, animals from the 4xSEgroup showed after the first SE an increased expression of P-gp andHIF-1 analyzed by immunohistochemistry in cardiomyocytes, 50%reduced 99mTc-SESTAMIBI heart retention and increased mortalitywith each SE. We conclude that SE might act as H/I heart inducerwith simultaneous overexpression of HIF-1 and P-gp in cardiomyocytes,severe loss of 99mTc-SESTAMIBI heart retentions and alteredcardiac rhythms, associated with increased mortality. Under theseconditions, new stress will start acute heart failure that could to lead in death, depending on severity of stress. These results could helpto explain the mechanisms underlying in SUDEP.