Exploring the role of ATP1A3 mutations in sudden unexplained death in epilepsy

Ended Project Grant Awarded Last action

Award ID
R01HL160654
Recipient
Awarding agency
Obligated
$4,172,187

Award facts

Assistance listing
93.837 Cardiovascular Diseases Research
Completion date
Place of performance
Durham, NC 27710, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Sudden unexplained death in epilepsy (sudep) is the sudden and unexplained death of a patient with a history of seizures and epilepsy who is in a reasonable state of health. IT is a major cause of death in patients with epilepsy and a common cause of neurologic death overall. Believed to be caused by a culmination of cardiac and neurologic factors, epilepsy induced bradycardia is a risk factor for sudep and may trigger lethal ventricular arrhythmias in susceptible myocardium. Development of a robust experimental model which recapitulates this would open the door for foundational studies to develop critical pharmacotherapies. Sudep is a tragic outcome in patients with alternating hemiplegia of childhood (AHC) which is characterized by epilepsy, dystonia, paralysis, and, notably, sudden death in the setting of bradycardia. Among AHC patients, 90% harbor underlying pathologic genetic variants in the ATP1A3-encoded alpha-3 catalytic subunit of the NA/k atpase pump (ATP1A3). We have identified a strong correlation between the most common AHC-associated ATP1A3 variant (D801N) and short QT on ECG and ventricular fibrillation during bradycardia. Human induced pluripotent stem cell-derived cardiac myocytes from an ATP1A3-D801N-positive child (hipsc-CMD801N) demonstrate shortened repolarization time, disrupted calcium homeostasis, and delayed-after depolarizations, which are triggers for arrhythmias. Knock-in mice hosting the D801N variant (ATP1A3D801N) have seizures, bradycardia, and sudden death. Further, ATP1A3D801N mice have a predisposition to ventricular arrhythmias, particularly at lower heart rates, compared to controls. Collectively, these findings raise the possibility that disruption of ATP1A3 in the heart underlies sudep in AHC patients through bradycardia-triggered arrhythmias. We hypothesize that D801N reduces pump function leading to shortened repolarization time and predisposes to lethal ventricular arrhythmias. Our goal is to use AHC as a model to establish the role ATP1A3 in the heart, determine the mechanism of sudep, and explore the proarrhythmic effect of bradycardia. To approach this in an innovative and rigorous way, we will utilize patient-derived HIPSCD801N- and murine ATP1A3D801N-based models for in vitro, EX vivo, and in vivo studies to determine the mechanism of arrhythmia predisposition in the heart. Specifically, we propose to determine 1) the mechanism of action potential duration shortening induced by D801N in cardiac myocytes, 2) the mechanism of cardiac arrhythmogenesis induced by D801N in 3D tissue models and EX vivo analysis, and 3) whether bradycardia due to seizures is an arrhythmogenic trigger for a "vulnerable" myocardium in ATP1A3D801N mice. In accomplishing these aims and overall goal, we will determine the function of ATP1A3 in cardiovascular physiology and its role in cardiac repolarization, calcium signaling, and ventricular arrhythmias, thus identifying molecular targets for pharmacotherapy. Finally, this will develop robust and rigorous models to determine the mechanisms of sudden death in AHC and will provide insights into mechanisms of sudep more broadly.

Transactions

Action Obligated Date
Amendment $0
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Amendment $687,279
Amendment $670,378
Amendment $689,380
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Amendment $717,885
Original award $717,885

Subawards

Subrecipient Amount Awarded
Duke University The scope of work for the next funding period will build on our ongoing collaborative efforts to evaluate autonomic modulators as candidate rescue strategies… $220,243
University Of California, Davis Dr.Donald Bers (UC Davis) will participate as an expert advisor and collaborator for the isolated cardiac myocyte studies proposed. He will help in developing… $64,575

Quick answers

Who received award R01HL160654?

R01HL160654 was awarded to Duke University by National Heart Lung and Blood Institute (National Institutes of Health) on August 22, 2022.

How much is award R01HL160654 worth?

$4,172,187 has been obligated on R01HL160654.

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