Altered Cardiac Excitability and Arrhythmia in Models of SCN1B-Linked Developmental and Epileptic Encephalopathy
Identifikátory výsledku
Kód výsledku v IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064203%3A_____%2F25%3A10500145" target="_blank" >RIV/00064203:_____/25:10500145 - isvavai.cz</a>
Nalezeny alternativní kódy
RIV/00216208:11130/25:10500145
Výsledek na webu
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=bAg9NP4sEN" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=bAg9NP4sEN</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1172/jci.insight.190918" target="_blank" >10.1172/jci.insight.190918</a>
Alternativní jazyky
Jazyk výsledku
angličtina
Název v původním jazyce
Altered Cardiac Excitability and Arrhythmia in Models of SCN1B-Linked Developmental and Epileptic Encephalopathy
Popis výsledku v původním jazyce
Biallelic variants in SCN1B, encoding the voltage-gated sodium channel β1/β1B subunits, are linked to DEE52, a developmental and epileptic encephalopathy with a high risk of Sudden Unexpected Death in Epilepsy (SUDEP). DEE52 patients present clinically with Dravet syndrome or the more severe early infantile DEE. SCN1B is expressed in brain and heart in humans and in mice. Thus, we have proposed that, in addition to generalized seizures, cardiac arrhythmia may play a role in SUDEP. Mice with homozygous expression of the DEE52 variant Scn1b-c.265C>T, predicting p.R89C, have spontaneous and hyperthermia-induced generalized seizures and SUDEP. Here we conducted cardiac characterization of Scn1b-c.265C>T mice and studied induced pluripotent stem cell cardiomyocytes (iPSC-CMs) derived from two SCN1B-c.265C>T DEE52 patients. Scn1bC89/C89 mouse CMs showed increased transient outward potassium current (Ito) density and heart sections revealed ventricular fibrosis. Scn1bC89/C89 mice were susceptible to pacing-induced cardiac arrhythmias. Patient-derived iPSC-CMs with biallelic SCN1B-c.265C>T variant expression showed increased sodium current (INa), late INaL, and Ito current densities. We conclude that, while mouse and human cardiac AP waveforms have critical differences, increased Ito is common to both models of DEE52. Overall, our data suggest that electrical and structural substrates may lead to arrhythmias and contribute to SUDEP in DEE52.
Název v anglickém jazyce
Altered Cardiac Excitability and Arrhythmia in Models of SCN1B-Linked Developmental and Epileptic Encephalopathy
Popis výsledku anglicky
Biallelic variants in SCN1B, encoding the voltage-gated sodium channel β1/β1B subunits, are linked to DEE52, a developmental and epileptic encephalopathy with a high risk of Sudden Unexpected Death in Epilepsy (SUDEP). DEE52 patients present clinically with Dravet syndrome or the more severe early infantile DEE. SCN1B is expressed in brain and heart in humans and in mice. Thus, we have proposed that, in addition to generalized seizures, cardiac arrhythmia may play a role in SUDEP. Mice with homozygous expression of the DEE52 variant Scn1b-c.265C>T, predicting p.R89C, have spontaneous and hyperthermia-induced generalized seizures and SUDEP. Here we conducted cardiac characterization of Scn1b-c.265C>T mice and studied induced pluripotent stem cell cardiomyocytes (iPSC-CMs) derived from two SCN1B-c.265C>T DEE52 patients. Scn1bC89/C89 mouse CMs showed increased transient outward potassium current (Ito) density and heart sections revealed ventricular fibrosis. Scn1bC89/C89 mice were susceptible to pacing-induced cardiac arrhythmias. Patient-derived iPSC-CMs with biallelic SCN1B-c.265C>T variant expression showed increased sodium current (INa), late INaL, and Ito current densities. We conclude that, while mouse and human cardiac AP waveforms have critical differences, increased Ito is common to both models of DEE52. Overall, our data suggest that electrical and structural substrates may lead to arrhythmias and contribute to SUDEP in DEE52.
Klasifikace
Druh
J<sub>imp</sub> - Článek v periodiku v databázi Web of Science
CEP obor
—
OECD FORD obor
30103 - Neurosciences (including psychophysiology)
Návaznosti výsledku
Projekt
—
Návaznosti
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Ostatní
Rok uplatnění
2025
Kód důvěrnosti údajů
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Údaje specifické pro druh výsledku
Název periodika
JCI Insight
ISSN
2379-3708
e-ISSN
2379-3708
Svazek periodika
10
Číslo periodika v rámci svazku
17
Stát vydavatele periodika
US - Spojené státy americké
Počet stran výsledku
18
Strana od-do
e190918
Kód UT WoS článku
001568992500001
EID výsledku v databázi Scopus
2-s2.0-105015727183