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Early cardiac electrographic and molecular remodeling in a model of status epilepticus and acquired epilepsy.

ABSTRACT: OBJECTIVES:A myriad of acute and chronic cardiac alterations are associated with status epilepticus (SE) including increased sympathetic tone, rhythm and ventricular repolarization disturbances. Despite these observations, the molecular processes underlying SE-associated myocardial remodeling remain to be identified. Here we determined early SE-associated myocardial electrical and molecular alterations using a model of SE and acquired epilepsy. METHODS:We performed electrocardiography (ECG) assessments in rats beginning at 2 weeks following kainate-induced SE, and calculated short-term variability (STV) of the corrected QT intervals (QTc) as a marker of ventricular stability. Using western blotting, we quantified myocardial ?1-adrenergic receptors (?1-AR) and ventricular gap junction protein connexin 43 (Cx43) levels as makers of increased sympathetic tone. We determined the activation status of three kinases associated with sympathetic stimulation and their downstream ion channel targets: extracellular signal-regulated kinase (ERK), protein kinase A (PKA), Ca2+ /calmodulin-dependent protein kinase II (CamKII), hyperpolarization-activated cyclic nucleotide-gated channel subunit 2 (HCN2), and voltage-gated potassium channels 4.2 (Kv4.2 ). We investigated whether SE was associated with altered Ca2+ homeostasis by determining select Ca2+ -handling protein levels using western blotting. RESULTS:Compared with the sham group, SE animals exhibited higher heart rate, longer QTc interval, and higher STV beginning at 2 weeks following SE. Concurrently, the myocardium of SE rats showed lower ?1-AR and higher Cx43 protein levels, higher levels of phosphorylated ERK, PKA, and CamKII along with decreased HCN2 and Kv4.2 channel levels. In addition, the SE rats had altered proteins levels of Ca2+ -handling proteins, with decreased Na+ /Ca2+ exchanger-1 and increased calreticulin. SIGNIFICANCE:SE triggers early molecular alterations in the myocardium consistent with increased sympathetic tone and altered Ca2+ homeostasis. These changes, coupled with early and persistent ECG abnormalities, suggest that the observed molecular alterations may contribute to SE-associated cardiac remodeling. Additional mechanistic studies are needed to determine potential causal roles.

SUBMITTER: Brewster AL

PROVIDER: S-EPMC5545890 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Early cardiac electrographic and molecular remodeling in a model of status epilepticus and acquired epilepsy.

Brewster Amy L AL Marzec Kyle K Hairston Alexandria A Ho Marvin M Anderson Anne E AE Lai Yi-Chen YC

Epilepsia 20160824 11

<h4>Objectives</h4>A myriad of acute and chronic cardiac alterations are associated with status epilepticus (SE) including increased sympathetic tone, rhythm and ventricular repolarization disturbances. Despite these observations, the molecular processes underlying SE-associated myocardial remodeling remain to be identified. Here we determined early SE-associated myocardial electrical and molecular alterations using a model of SE and acquired epilepsy.<h4>Methods</h4>We performed electrocardiogr ...[more]

PMID: 27555091

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Project description:PurposeElectrographic seizures (ESs) and electrographic status epilepticus (ESE) are common in children with acute neurologic conditions in pediatric intensive care units (PICUs), and ESE is associated with worse functional and quality-of-life outcomes. As an exploratory study, we aimed to determine if ESE was associated with worse outcomes using more detailed neurobehavioral measures.MethodsThree hundred children with an acute neurologic condition and altered mental status underwent clinically indicated EEG monitoring and were enrolled in a prospective observational study. We obtained follow-up data from subjects who were neurodevelopmentally normal prior to PICU admission. We evaluated for associations between ESE and adaptive behavior (Adaptive Behavior Assessment System-II, ABAS-II), behavioral and emotional problems (Child Behavior Checklist, CBCL), and executive function (Behavior Rating Inventory of Executive Function, BRIEF) using linear regression analyses. A p-value of <0.05 was considered significant.ResultsOne hundred thirty-seven of 300 subjects were neurodevelopmentally normal prior to PICU admission. We obtained follow-up data from 36 subjects for the CBCL, 32 subjects for the ABAS-II, and 20 subjects for the BRIEF. The median duration from admission to follow-up was 2.6 years (IQR: 1.2-3.8). There were no differences in the acute care variables (age, sex, mental status category, intubation status, paralysis status, acute neurologic diagnosis category, seizure category, EEG background category, or short-term outcome) between subjects with and without follow-up data for any of the outcome measures. On univariate analysis, significant differences were not identified for CBCL total problem (ES coefficient: -4.1, p = 0.48; ESE coefficient: 8.9, p = 0.13) or BRIEF global executive function (ES coefficient: 2.1, p = 0.78; ESE coefficient: 14.1, p = 0.06) scores, although there were trends toward worse scores in subjects with ESE. On univariate analysis, ESs were not associated with worse scores (coefficient: -21.5, p = 0.051), while ESE (coefficient: -29.7, p = 0.013) was associated with worse ABAS-II adaptive behavioral global composite scores. On multivariate analysis, when compared to subjects with no seizures, both ESs (coefficient: -28, p=0.014) and ESE (coefficient: -36, p = 0.003) were associated with worse adaptive behavioral global composite scores.DiscussionAmong previously neurodevelopmentally normal children with acute neurologic disorders, ESs and ESE were associated with worse adaptive behavior and trends toward worse behavioral-emotional and executive function problems. This was a small exploratory study, and the impact of ESs and ESE on these neurobehavioral measures may be clarified by subsequent larger studies. This article is part of a Special Issue entitled "Status Epilepticus".

Project description:Intravenous third-line anaesthetic agents are typically titrated in refractory status epilepticus to achieve either seizure suppression or burst suppression on continuous EEG. However, the optimum treatment paradigm is unknown and little data exist to guide the withdrawal of anaesthetics in refractory status epilepticus. Premature withdrawal of anaesthetics risks the recurrence of seizures, whereas the prolonged use of anaesthetics increases the risk of treatment-associated adverse effects. This study sought to measure the accuracy of features of EEG activity during anaesthetic weaning in refractory status epilepticus as predictors of successful weaning from intravenous anaesthetics. We prespecified a successful anaesthetic wean as the discontinuation of intravenous anaesthesia without developing recurrent status epilepticus, and a wean failure as either recurrent status epilepticus or the resumption of anaesthesia for the purpose of treating an EEG pattern concerning for incipient status epilepticus. We evaluated two types of features as predictors of successful weaning: spectral components of the EEG signal, and spatial-correlation-based measures of functional connectivity. The results of these analyses were used to train a classifier to predict wean outcome. Forty-seven consecutive anaesthetic weans (23 successes, 24 failures) were identified from a single-centre cohort of patients admitted with refractory status epilepticus from 2016 to 2019. Spectral components of the EEG revealed no significant differences between successful and unsuccessful weans. Analysis of functional connectivity measures revealed that successful anaesthetic weans were characterized by the emergence of larger, more densely connected, and more highly clustered spatial functional networks, yielding 75.5% (95% confidence interval: 73.1-77.8%) testing accuracy in a bootstrap analysis using a hold-out sample of 20% of data for testing and 74.6% (95% confidence interval 73.2-75.9%) testing accuracy in a secondary external validation cohort, with an area under the curve of 83.3%. Distinct signatures in the spatial networks of functional connectivity emerge during successful anaesthetic liberation in status epilepticus; these findings are absent in patients with anaesthetic wean failure. Identifying features that emerge during successful anaesthetic weaning may allow faster and more successful anaesthetic liberation after refractory status epilepticus.

Project description:ObjectiveConvulsive status epilepticus can exert profound cardiovascular effects in adults including ventricular depolarization-repolarization abnormalities. Whether status epilepticus adversely affects ventricular electrical properties in children is less understood. Therefore, we sought to characterize ventricular alterations and the associated clinical factors in children following convulsive status epilepticus.MethodsWe conducted a 2-year retrospective, case-control study. Children between 1 month and 21 years of age were included if they were admitted to the pediatric intensive care unit with primary diagnosis of convulsive status epilepticus and had 12-lead electrocardiogram (ECG) within 24 hours of admission. Children with heart disease, ion channelopathy, or on vasoactive medications were excluded. Age-matched control subjects had no history of seizures or epilepsy. The primary outcome was ventricular abnormalities represented by ST segment changes, abnormal T wave, QRS axis deviation, and corrected QT (QTc) interval prolongation. The secondary outcomes included QT/RR relationship, beat-to-beat QTc interval variability, ECG interval measurement between groups, and clinical factors associated with ECG abnormalities.ResultsOf 317 eligible children, 59 met the inclusion criteria. History of epilepsy was present in 31 children (epileptic) and absent in 28 children (non-epileptic). Compared with the control subjects (n = 31), the status epilepticus groups were more likely to have an abnormal ECG with overall odds ratio of 3.8 and 7.0 for the non-epileptic and the epileptic groups respectively. Simple linear regression analysis demonstrated that children with epilepsy exhibited impaired dependence and adaptation of the QT interval on heart rate. Beat-to-beat QTc interval variability, a marker of ventricular repolarization instability, was increased in children with epilepsy.SignificanceConvulsive status epilepticus can adversely affect ventricular electrical properties and stability in children, especially those with epilepsy. These findings suggest that children with epilepsy may be particularly vulnerable to seizure-induced arrhythmias. Therefore postictal cardiac surveillance may be warranted in this population.

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Early cardiac electrographic and molecular remodeling in a model of status epilepticus and acquired epilepsy.

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Early cardiac electrographic and molecular remodeling in a model of status epilepticus and acquired epilepsy.

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