Kv1.1 Potassium Channel Deficiency Reveals Brain-Driven Cardiac Dysfunction as a Candidate Mechanism for Sudden Unexplained Death in Epilepsy

Abstract

Mice lacking Kv1.1 Shaker-like potassium channels encoded by the Kcna1 gene exhibit severe seizures and die prematurely. The channel is widely expressed in brain but only minimally, if at all, in mouse myocardium. To test whether Kv1.1-potassium deficiency could underlie primary neurogenic cardiac dysfunction, we performed simultaneous video EEG-ECG recordings and found that Kcna1-null mice display potentially malignant interictal cardiac abnormalities, including a fivefold increase in atrioventricular (AV) conduction blocks, as well as bradycardia and premature ventricular contractions. During seizures the occurrence of AV conduction blocks increased, predisposing Kv1.1-deficient mice to sudden unexplained death in epilepsy (SUDEP), which we recorded fortuitously in one animal. To determine whether the interictal AV conduction blocks were of cardiac or neural origin, we examined their response to selective pharmacological blockade of the autonomic nervous system. Simultaneous administration of atropine and propranolol to block parasympathetic and sympathetic branches, respectively, eliminated conduction blocks. When administered separately, only atropine ameliorated AV conduction blocks, indicating that excessive parasympathetic tone contributes to the neurocardiac defect. We found no changes in Kv1.1-deficient cardiac structure, but extensive Kv1.1 expression in juxtaparanodes of the wild-type vagus nerve, the primary source of parasympathetic input to the heart, suggesting a novel site of action leading to Kv1.1-associated cardiac bradyarrhythmias. Together, our data suggest that Kv1.1 deficiency leads to impaired neural control of cardiac rhythmicity due in part to aberrant parasympathetic neurotransmission, making Kcna1 a strong candidate gene for human SUDEP.

Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death

“…The RQ mouse showed this bradycardia phenotype (Fig. 1), and other mouse SUDEP models also exhibit interictal spontaneous bradycardia and postictal death associated with bradycardia (4,5). In these models, seizure-induced death could be prevented by the parasympathetic blocker atropine, and the same treatment has also been effective for CPVT mice and human cases (52).…”

“…Despite the high mortality rate, comparable to that of sudden infant death syndrome (SIDS), the exact causes are unclear, and there is no effective prediction or intervention. Cardiorespiratory dysfunction and collapse have been observed following generalized tonicclonic seizures in a small number of monitored cases (2), "near SUDEP" cases (3), and mouse SUDEP models (4)(5)(6). Genes linked with the most common cardiac LQT syndromes including LQT1 (KCNQ1), LQT2 (KCNH2/HERG), and LQT3 (SCN5A) are expressed in both the human heart and brain, where mutations in the kinetics of these membrane ion channels prolong depolarization and produce combined seizure, cardiac arrhythmia, and sudden death phenotypes (7,8).…”

Sudden unexpected death in a mouse model of Dravet syndrome

“…Cardiac dysfunctions that may underlie SUDEP have also been investigated in K V 1.1 homozygous null mice, which exhibit temporal lobe seizures, and in K V 7.1 (KCNQ1) mutant mice that carry cardiac long QT syndrome mutations and experience brief partial seizures (33,34). Patients and mice with long QT syndrome mutations in K V 7.1 channels are thought to die of cardiac arrhythmia, not SUDEP.…”

“…Patients with mutations in K V 1.1 channels have cerebellar ataxia, continuous muscle activity, and epilepsy, but do not die of SUDEP (35,36). Homozygous K V 1.1 KO mice exhibit interictal AV blocks and bradycardia that are sensitive to atropine (33,34). These cardiac effects are associated with loss of K V 1.1 channels in juxtaparanodal regions of myelinated axons of the vagus nerve in K V 1.1 null mice.…”

Severe peri-ictal respiratory dysfunction is common in Dravet syndrome

“…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).…”