Abstracts

Rationale: Refractory epilepsy (RE) was associated with P-glycoprotein (P-gp) brain overexpression and high risk of Sudden Unexpected Death in Epilepsy (SUDEP) by acute fatal heart failure. We have described brain/heart P-gp overexpression related with fatal-SE after experimental repetitive penthylenetetrazole-induced seizures. Heart retention loss of the P-gp substrate 99mTc-SESTAMIBI, is clinically used as in-vivo biomarker of hypoxic/ischemia heart failure. After SE, loss of 99mTc-SESTAMIBI heart retention could be a risk factor marker for fatal heart failure Methods: SE was induced on adult male Wistar rats (300g; n=30) by lithium chloride (127 mg/kg;i.p.) plus pilocarpine (30 mg/kg; i.p.) 20hr later, and diazepam (20 mg/kg, i.p.) to stop SE after 15m. SE was induced once a week (four times; n=20); P-gp and HIF-1 heart expression were evaluate by immunohistochemistry. After each SE (24h) two rats were fixed with PFA 4% in 0.1M phosphate buffer (n=10). 99mTc-SESTAMIBI (37MBq-i.v) was administered 24h after each SE. Static acquired images were analyzed by the ROI delineation of whole heart using a Gamma Camera for little animals. 99mTc-SESTAMIBI heart retention was evaluated before (n=10) and 48h after of each SE on remaining surviving rats. In remaining rats (n=10), SE was induced once. Heart rhythm and ECG registers were obtained in before and 24h after of SE. Cardiac chemical stress was developed with dipyridamole i.p. (first: 0.56 mg/kg; second 0.28 mg/kg). Non-convulsive control group (n=10) was treated with lithium plus saline and evaluated for all parameters studied. Results: After SE, P-gp and HIF-1 overexpression in cardiomyocytes, reduced 99mTc-SESTAMIBI heart retention and increased mortality were observed. When SE-exposed animals were stressed with dipyridamole, increased bradycardia or tachycardia as well as arrhythmias were also documented Conclusions: To our knowledge, this is the first report showing that SE act as hypoxic-ischemic heart inducer with simultaneous overexpression of HIF-1 and P-gp in cardiomyocytes and severe loss of 99mTc-SESTAMIBI heart retentions in vivo, associated with increased mortality. Additionally functional alteration of cardiac rhythms and other parameters in SE animals was exacerbated by middle doses of chemical stress. Due to the known membrane depolarizing property of the P-gp, all these data suggest an active role for P-gp expressed in cardiomyocytes, in the development of acute heart failure after SE. Under these conditions, new stress will start acute heart failure that could to lead in death, depending on severity of stress, as in the repetitive convulsive or sequential SE inductions were observed.  These results could help to explain in part, the intrinsic mechanisms underlying in SUDEP.  Funding: Supported by UBACyT 20020150100003BA (to AJR and AL) AND PICT 2014-2178 (to JA)