Kv1.1 potassium channel deficiency reveals brain-driven cardiac dysfunction as a candidate mechanism for sudden unexplained death in epilepsy.
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.
Glasscock
Edward
E
Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA.
Yoo
Jong W
JW
Chen
Tim T
TT
Klassen
Tara L
TL
Noebels
Jeffrey L
JL
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000503:physiopathology*; D054537:Atrioventricular Block / Q000188:drug therapy / Q000503:physiopathology; D001285:Atropine / Q000494:pharmacology; D001919:Bradycardia / Q000188:drug therapy / Q000503:physiopathology; D001921:Brain / Q000503:physiopathology*; D004562:Electrocardiography / Q000379:methods; D004569:Electroencephalography / Q000379:methods; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D051662:Kv1.1 Potassium Channel / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010276:Parasympatholytics / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D012640:Seizures / Q000503:physiopathology*; D014630:Vagus Nerve / Q000378:metabolism; D018879:Ventricular Premature Complexes / Q000188:drug therapy / Q000503:physiopathology; D014741:Video Recording / Q000379:methods
D000889:Anti-Arrhythmia Agents; C496947:Kcna1 protein, mouse; D010276:Parasympatholytics; D051662:Kv1.1 Potassium Channel; D001285:Atropine; D011433:Propranolol
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