# AMPK and cardiac dysfunction in chronic epilepsy: a prognostic indicator of SUDEP risk

> **NIH NIH R21** · UNIVERSITY OF COLORADO · 2020 · $81,921

## Abstract

PROPOSAL SUMMARY
The increased risk of sudden unexplained/unexpected death in epilepsy (SUDEP) is particularly high in drug-
refractory patients. In fact, 40% of adult patients with pharmacoresistant epilepsy have one or more
abnormalities in cardiac function3. One of the main risk factors for SUDEP is frequent, convulsive seizures in
humans4-6,26. Rodents with chronic, acquired epilepsy die suddenly and unexpectedly7,8. Continuously recorded
EKG in rats with pilocarpine-induced epilepsy demonstrates that alterations in QT interval, PR interval, and T-
wave amplitude are associated with increased seizure burden. These data, combined with previous human
and animal studies, support further investigation of a shared mechanism underlying cardiac arrhythmia
development in adult acquired and genetic epilepsies that may be used as a universal prognostic biomarker of
SUDEP risk. The major goal of this proposal is to characterize the role of AMP-activated protein kinase
(AMPK) activation as a potential therapeutic target in chronic epilepsy and specifically, to evaluate the
hypothesis that spontaneous seizures impair energy metabolism in the hearts and brains of acquired and
genetic models of epilepsy contributing to increased seizure burden and SUDEP risk. Molecular methods will
be used to characterize impairment in AMPK activation and altered expression of AMPK subunits. Abnormal
cardiac function will be quantitatively measured in response to seizure-induced metabolic stress using
simultaneous video/EEG/EKG monitoring. AMPK activity will be pharmacologically modulated to determine
whether AMPK phosphorylation is preventative or pathological. We hypothesize that potential increases in
seizure frequency and severity associated with longer duration postictal depression and arrhythmogenesis
mediated by impaired AMPK phosphorylation can be prevented using clinically available AMPK activators in
both genetic and acquired epilepsies. We expect our results to unmask a shared mechanism contributing to
SUDEP risk in genetic and acquired epilepsies. Results of these studies may inspire new strategies for the
prevention of SUDEP and provide more effective treatments for chronic, pharmacoresistant epilepsy. The
proposal will provide valuable translational information about the role of impaired energy metabolism in
epileptogenesis and acquired cardiac dysfunction contributing to SUDEP risk.

## Key facts

- **NIH application ID:** 10010118
- **Project number:** 3R21NS104580-02S1
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Heidi L Grabenstatter
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $81,921
- **Award type:** 3
- **Project period:** 2019-12-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10010118

## Citation

> US National Institutes of Health, RePORTER application 10010118, AMPK and cardiac dysfunction in chronic epilepsy: a prognostic indicator of SUDEP risk (3R21NS104580-02S1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10010118. Licensed CC0.

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