Exploring the role of ATP1A3 mutations in sudden unexplained death in epilepsy - PROJECT SUMMARY/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.
