Cardiac-Specific Deletion of Scn8a Mitigates Dravet Syndrome-Associated Sudden Death in Adults
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F24%3A10497027" target="_blank" >RIV/00216208:11160/24:10497027 - isvavai.cz</a>
Result on the web
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=F-z2QJ4KVe" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=F-z2QJ4KVe</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.jacep.2024.01.003" target="_blank" >10.1016/j.jacep.2024.01.003</a>
Alternative languages
Result language
angličtina
Original language name
Cardiac-Specific Deletion of Scn8a Mitigates Dravet Syndrome-Associated Sudden Death in Adults
Original language description
BACKGROUND Sudden unexpected death in epilepsy (SUDEP) is a fatal complication experienced by otherwise healthy epilepsy patients. Dravet syndrome (DS) is an inherited epileptic disorder resulting from loss of function of the voltagegated sodium channel, NaV 1.1, and is associated with particularly high SUDEP risk. Evidence is mounting that NaVs abundant in the brain also occur in the heart, suggesting that the very molecular mechanisms underlying epilepsy could also precipitate cardiac arrhythmias and sudden death. Despite marked reduction of NaV 1.1 functional expression in DS, pathogenic late sodium current (I(Na,L)) is paradoxically increased in DS hearts. However, the mechanisms by which DS directly impacts the heart to promote sudden death remain unclear. OBJECTIVES In this study, the authors sought to provide evidence implicating remodeling of Na(+) - and Ca(2+) -handling machinery, including NaV 1.6 and Na(+)/Ca(2+) exchanger (NCX) within transverse (T)-tubules in DS-associated arrhythmias. METHODS The authors undertook scanning ion conductance microscopy (SICM)-guided patch clamp, super-resolution microscopy, confocal Ca(2+) imaging, and in vivo electrocardiography studies in Scn1a haploinsufficient murine model of DS. RESULTS DS promotes I(Na,L) in T-tubular nanodomains, but not in other subcellular regions. Consistent with increased NaV activity in these regions, super-resolution microscopy revealed increased NaV 1.6 density near Ca(2+) release channels, the ryanodine receptors (RyR2) and NCX in DS relative to WT hearts. The resulting I(Na,L) in these regions promoted aberrant Ca(2+) release, leading to ventricular arrhythmias in vivo. Cardiac-specific deletion of NaV 1.6 protects adult DS mice from increased T-tubular late NaV activity and the resulting arrhythmias, as well as sudden death. CONCLUSIONS These data demonstrate that NaV 1.6 undergoes remodeling within T-tubules of adult DS hearts serving as a substrate for Ca(2+) -mediated cardiac arrhythmias and may be a druggable target for the prevention of SUDEP in adult DS subjects.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30104 - Pharmacology and pharmacy
Result continuities
Project
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Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2024
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
JACC: Clinical Electrophysiology
ISSN
2405-500X
e-ISSN
2405-5018
Volume of the periodical
10
Issue of the periodical within the volume
5
Country of publishing house
US - UNITED STATES
Number of pages
14
Pages from-to
829-842
UT code for WoS article
001250252000001
EID of the result in the Scopus database
2-s2.0-85187691653