Altered Cardiac Electrophysiology and SUDEP in a Model of Dravet Syndrome

Abstract

ObjectiveDravet syndrome is a severe form of intractable pediatric epilepsy with a high incidence of SUDEP: Sudden Unexpected Death in epilepsy. Cardiac arrhythmias are a proposed cause for some cases of SUDEP, yet the susceptibility and potential mechanism of arrhythmogenesis in Dravet syndrome remain unknown. The majority of Dravet syndrome patients have de novo mutations in SCN1A, resulting in haploinsufficiency. We propose that, in addition to neuronal hyperexcitability, SCN1A haploinsufficiency alters cardiac electrical function and produces arrhythmias, providing a potential mechanism for SUDEP.MethodsPostnatal day 15-21 heterozygous SCN1A-R1407X knock-in mice, expressing a human Dravet syndrome mutation, were used to investigate a possible cardiac phenotype. A combination of single cell electrophysiology and in vivo electrocardiogram (ECG) recordings were performed.ResultsWe observed a 2-fold increase in both transient and persistent Na+ current density in isolated Dravet syndrome ventricular myocytes that resulted from increased activity of a tetrodotoxin-resistant Na+ current, likely Nav1.5. Dravet syndrome myocytes exhibited increased excitability, action potential duration prolongation, and triggered activity. Continuous radiotelemetric ECG recordings showed QT prolongation, ventricular ectopic foci, idioventricular rhythms, beat-to-beat variability, ventricular fibrillation, and focal bradycardia. Spontaneous deaths were recorded in 2 DS mice, and a third became moribund and required euthanasia.InterpretationThese data from single cell and whole animal experiments suggest that altered cardiac electrical function in Dravet syndrome may contribute to the susceptibility for arrhythmogenesis and SUDEP. These mechanistic insights may lead to critical risk assessment and intervention in human patients.

Severe peri-ictal respiratory dysfunction is common in Dravet syndrome

“…Auerbach et al (7) reported spontaneous death preceded by bradycardia in 3 Scn1a R1407X/+ mice, and in that study, death was attributed to abnormal intrinsic electrophysiological properties of cardiac myocytes (7). However, breathing was not measured in either the study by Auerbach et al (7) or the study by Kalume et al (40). Here we report postictal bradycardia in Scn1a R1407X/+ mice with a similar time course to that previously reported (7,40), but found that central apnea occurred prior to bradycardia.…”

“…However, breathing was not measured in either the study by Auerbach et al (7) or the study by Kalume et al (40). Here we report postictal bradycardia in Scn1a R1407X/+ mice with a similar time course to that previously reported (7,40), but found that central apnea occurred prior to bradycardia. Apnea rapidly causes hypoxemia in mice and rats within seconds (67,68).…”

“…The phenotype of the Scn1a R1407X/+ mutation and the Scn1a knockout are similar and recapitulate the phenotype of DS in humans (31), including seizures that occur spontaneously and in response to hyperthermia (7,39,40). Heat-induced seizures in DS mice are often followed by death (7,40). In addition to the brain, Nav1.1 is expressed in the heart, including the sinoatrial node (41) and cardiac T tubules (42).…”

“…In addition to the brain, Nav1.1 is expressed in the heart, including the sinoatrial node (41) and cardiac T tubules (42). Mice with an Scn1a R1407X/+ mutation have cardiac myocyte dysfunction and die spontaneously at a young age after severe bradycardia, which has been interpreted as indicating that these mice die from intrinsic cardiac dysfunction (7). However, selective knockout of Scn1a only in brain interneurons results in seizures and spontaneous death (43).…”

“…A variety of mechanisms have been proposed for SUDEP (1,2,(4)(5)(6), including cardiac arrhythmias (7)(8)(9)(10), dysfunction of autonomic control (11)(12)(13)(14)(15), apnea/hypoventilation (3,(16)(17)(18)(19)(20)(21), airway obstruction (22), pulmonary edema (23), brain stem spreading depolarization (BSD) (24), and postictal generalized EEG suppression (PGES) (25). Many investigators have focused on cardiac tachyarrhythmias as the cause of death, in part because of an association between SUDEP and mutations of genes expressed in the heart, such as those that underlie long QT syndrome (10,(26)(27)(28).…”