Cardiac-Specific Deletion of Scn8a Mitigates Dravet Syndrome-Associated Sudden Death in Adults

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

Cardiac-Specific Deletion of Scn8a Mitigates Dravet Syndrome-Associated Sudden Death in Adults

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

Cardiac-Specific Deletion of Scn8a Mitigates Dravet Syndrome-Associated Sudden Death in Adults

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

JACC: Clinical Electrophysiology

ISSN

2405-500X

e-ISSN

2405-5018

Svazek periodika

10

Číslo periodika v rámci svazku

5

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

14

Strana od-do

829-842

Kód UT WoS článku

001250252000001

EID výsledku v databázi Scopus

2-s2.0-85187691653