Progressive cardiorespiratory dysfunction in Kv1.1 knockout mice may provide temporal biomarkers of pending sudden unexpected death in epilepsy (SUDEP): The contribution of orexin

Abstract

Objective Immediately preceding sudden unexpected death in epilepsy (SUDEP), patients experienced a final generalized tonic‐clonic seizure (GTCS), rapid ventilation, apnea, bradycardia, terminal apnea, and asystole. Whether a progressive pathophysiology develops and increases risk of SUDEP remains unknown. Here, we determined (a) heart rate, respiratory rate, and blood oxygen saturation (SaO2) in low‐risk and high‐risk knockout (KO) mice; and (b) whether blocking receptors for orexin, a cardiorespiratory neuromodulator, influences cardiorespiratory function mice or longevity in high‐risk KO mice. Methods Heart rate and SaO2 were determined noninvasively with ECGenie and pulse oximetry. Respiration was determined with noninvasive airway mechanics technology. The role of orexin was determined within subject following acute treatment with a dual orexin receptor antagonist (DORA, 100 mg/kg). The number of orexin neurons in the lateral hypothalamus was determined with immunohistochemistry. Results Intermittent bradycardia was more prevalent in high‐risk KO mice, an effect that may be the result of increased parasympathetic drive. High‐risk KO mice had more orexin neurons in the lateral hypothalamus. Blocking of orexin receptors differentially influenced heart rate in KO, but not wild‐type (WT) mice. When DORA administration increased heart rate, it also decreased heart rate variability, breathing frequency, and/or hypopnea‐apnea. Blocking orexin receptors prevented the methacholine (MCh)–induced increase in breathing frequency in KO mice and reduced MCh‐induced seizures, via a direct or indirect mechanism. DORA improved oxygen saturation in KO mice with intermittent hypoxia. Daily administration of DORA to high‐risk KO mice increased longevity. Significance High‐risk KO mice have a unique cardiorespiratory phenotype that is characterized by progressive changes in five interdependent endpoints. Blocking of orexin receptors attenuates some of these endpoints and increases longevity, supporting the notion that windows of opportunity for intervention exist in this preclinical SUDEP model.

Proceedings of the Sleep and Epilepsy Workshop: Section 3 Mortality: Sleep, Night, and SUDEP

“…This suggests chronic sleep deficiency may contribute to a pre-SUDEP pathophysiology that increases the likelihood of death. 32 Sleep itself affects seizure occurrence in that NREM can promote and REM sleep can inhibit seizures. 33,34 Although rarer, seizures during REM sleep may confer disproportionate mortality.…”

“…This suggests chronic sleep deficiency may contribute to a pre-SUDEP pathophysiology that increases the likelihood of death. 32 …”

Tuning the Wave: Controlling Spreading Depolarization with Activation/Inactivation of Kv7.2

“…These mice are well known to display severe epilepsy with a high rate of SUDEP. 6 In contrast to Kcnq2-cKO mice, most seizures (88%) in Kv1.1-KO mice were not associated with SD, SD was seen independently from seizures in 7.4% of cases, and SD always arose unilaterally. About 5% of the seizures were associated with SD.…”

“…There were also only 2 deaths in Kv1.1-KO mice in this study. This mouse is known to have a high mortality rate 6 with progressive cardiorespiratory sequelae. 8 It would be interesting to know if more seizures would be associated with SD, SD would become more severe/widespread, and whether SD spread would be associated with cardiorespiratory sequelae as these animals age and approach death.…”

Kv1.1 potassium channel subunit deficiency alters ventricular arrhythmia susceptibility, contractility, and repolarization

“…In humans, KCNA1 mutations cause the movement disorder episodic ataxia type 1 (EA1), as well as epilepsy, which is characterized by spontaneous recurrent seizures (Paulhus et al, 2020). Mice lacking Kv1.1 due to global Kcna1 gene knockout (KO; i.e., Kcna1 –/– ) exhibit spontaneous seizures with cardiorespiratory dysfunction, brain‐driven autonomic cardiac abnormalities, and premature seizure‐related death, making them a frequently used model for exploring neuro‐cardio‐respiratory mechanisms associated with SUDEP risk (Dhaibar et al, 2019; Glasscock et al, 2010; Hutson et al, 2020; Iyer et al, 2020; Moore et al, 2014; Simeone et al, 2018). Mice with neuron‐specific conditional knockout (cKO) of Kcna1 exhibit an ameliorated premature death phenotype, living significantly longer than global knockouts (Trosclair et al, 2020).…”