Functional analysis in three probands suffering from “true”
idiopathic ventricular fibrillation

a 2025

Functional analysis in three probands suffering from “true” idiopathic ventricular fibrillation

BÉBAROVÁ, Markéta; Martin KRÁL; Natálie JANKOVÁ; Olga ŠVECOVÁ; Štefan ZELENÁK et al.

Základní údaje

Originální název

Functional analysis in three probands suffering from “true” idiopathic ventricular fibrillation

Autoři

BÉBAROVÁ, Markéta ; Martin KRÁL ; Natálie JANKOVÁ; Olga ŠVECOVÁ ; Štefan ZELENÁK; Jiří PACHERNÍK; Tomáš BÁRTA; Michal PÁSEK; Jana ZÍDKOVÁ a Tomáš NOVOTNÝ

Vydání

Czech Cardiovascular Research and Innovation Days 2025 + 11th European Section Meeting of the International Academy of Cardiovascular Sciences, 2025

Další údaje

Jazyk

angličtina

Typ výsledku

Konferenční abstrakt

Obor

30201 Cardiac and Cardiovascular systems

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 0.900 v roce 2024

Označené pro přenos do RIV

Ano

Organizační jednotka

Lékařská fakulta

ISSN

Klíčová slova anglicky

idiopathic ventricular fibrillation; KCNH2; RYR2; SCN5A; functional analysis; multielectrode array; patch clamp; Ca2+ transient

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 24. 11. 2025 11:14, doc. MUDr. Markéta Bébarová, Ph.D.

Anotace

V originále

Variants in cardiac ion channel genes, common causes of various inherited arrhythmias, can be detected in some patients suffering from “true” idiopathic ventricular fibrillation (VF). These variants are frequently classified as variants of uncertain significance, thus, their causality is uncertain. Functional analysis is then the only way to consider their possible pathogenic character. We currently perform functional analysis on three probands suffering from idiopathic VF, the first one carrying two KCNH2 (hERG) variants (A228V and S1021Qfs*98; IKr channel), the second one a single RYR2 variant (Y4734C; RYR2 channel), and the third one a single SCN5A variant (M135V; INa channel). KCNH2 and SCN5A variants are tested using the whole-cell patch clamp technique on human ion channels with and without the specific variant transiently expressed in a cell line. The analysis revealed that S1021Qfs*98-KCNH2 is a pathogenic, dominant-negative variant with substantially decreased expression, resulting in a decrease of the repolarizing current through channels co-expressing A228V and S1021Qfs*98 variants by ~65 %. The pilot data in M135V channels show a decreased depolarizing current and several disturbances of gating, including rightward shifts of both activation and inactivation voltage dependences and faster recovery from inactivation. In the Y4734C-RYR2 variant, patient-specific hiPSC-derived cardiomyocytes of the proband, his sister with the same variant and diagnosis of catecholaminergic polymorphic ventricular tachycardia, and his healthy nephew were prepared and are being tested using the multielectrode array technique and simultaneous recording of Ca2+ transient and contraction (IonOptix). A significantly higher short-term variability of the cycle length in both control and proarrhythmic conditions (hypokalemia, fever, β-stimulation) was observed in both carriers of Y4734C-RYR2, the proband and his sister, compared to healthy cardiomyocytes of the proband´s nephew; the highest irregularity of the rhythm was identified in the proband. Analysis under application of sex-hormones is followed to explain the differences between Y4734C-RYR2 cardiomyocytes of the male proband and his sister. Functional analysis enables detailed characterization of ion channel dysfunction. In the case of idiopathic VF, it may provide essential data for understanding arrhythmogenesis and for clinical management of both probands and previously asymptomatic carriers of the same variant.

Návaznosti

MUNI/A/1641/2024, interní kód MU

Název: Od buňky k pacientovi II

Investor: Masarykova univerzita, Od buňky k pacientovi II

NU22-02-00348, projekt VaV

Název: Funkční hodnocení genetických variant u případů klinicky „skutečné“ idiopatické fibrilace komor: in vitro a in silico modelování s cílem odhalit arytmogenní mechanismus

Investor: Ministerstvo zdravotnictví ČR, Funkční hodnocení genetických variant u případů klinicky „skutečné“ idiopatické fibrilace komor: in vitro a in silico modelování s cílem odhalit arytmogenní mechanismus, Podprogram 1 - standardní

Citovat

BÉBAROVÁ, Markéta; Martin KRÁL; Natálie JANKOVÁ; Olga ŠVECOVÁ; Štefan ZELENÁK; Jiří PACHERNÍK; Tomáš BÁRTA; Michal PÁSEK; Jana ZÍDKOVÁ a Tomáš NOVOTNÝ. Functional analysis in three probands suffering from “true” idiopathic ventricular fibrillation. In Czech Cardiovascular Research and Innovation Days 2025 + 11th European Section Meeting of the International Academy of Cardiovascular Sciences. 2025. ISSN 1803-7712.

@proceedings{2535197,
   author = {Bébarová, Markéta and Král, Martin and Janková, Natálie and Švecová, Olga and Zelenák, Štefan and Pacherník, Jiří and Bárta, Tomáš and Pásek, Michal and Zídková, Jana and Novotný, Tomáš},
   booktitle = {Czech Cardiovascular Research and Innovation Days 2025 + 11th European Section Meeting of the International Academy of Cardiovascular Sciences},
   keywords = {idiopathic ventricular fibrillation; KCNH2; RYR2; SCN5A; functional analysis; multielectrode array; patch clamp; Ca2+ transient},
   language = {eng},
   title = {Functional analysis in three probands suffering from “true” idiopathic ventricular fibrillation},
   url = {https://e-coretvasa.cz/contents/cor/2025/91.pdf},
   year = {2025}
}

TY  - CONF
ID  - 2535197
AU  - Bébarová, Markéta - Král, Martin - Janková, Natálie - Švecová, Olga - Zelenák, Štefan - Pacherník, Jiří - Bárta, Tomáš - Pásek, Michal - Zídková, Jana - Novotný, Tomáš
PY  - 2025
TI  - Functional analysis in three probands suffering from “true” idiopathic ventricular fibrillation
KW  - idiopathic ventricular fibrillation
KW  - KCNH2
KW  - RYR2
KW  - SCN5A
KW  - functional analysis
KW  - multielectrode array
KW  - patch clamp
KW  - Ca2+ transient
UR  - https://e-coretvasa.cz/contents/cor/2025/91.pdf
N2  - Variants in cardiac ion channel genes, common causes of various inherited arrhythmias, can be detected in some patients suffering from “true” idiopathic ventricular fibrillation (VF). These variants are frequently classified as variants of uncertain significance, thus, their causality is uncertain. Functional analysis is then the only way to consider their possible pathogenic character. We currently perform functional analysis on three probands suffering from idiopathic VF, the first one carrying two KCNH2 (hERG) variants (A228V and S1021Qfs*98; IKr channel), the second one a single RYR2 variant (Y4734C; RYR2 channel), and the third one a single SCN5A variant (M135V; INa channel). KCNH2 and SCN5A variants are tested using the whole-cell patch clamp technique on human ion channels with and without the specific variant transiently expressed in a cell line. The analysis revealed that S1021Qfs*98-KCNH2 is a pathogenic, dominant-negative variant with substantially decreased expression, resulting in a decrease of the repolarizing current through channels co-expressing A228V and S1021Qfs*98 variants by ~65 %. The pilot data in M135V channels show a decreased depolarizing current and several disturbances of gating, including rightward shifts of both activation and inactivation voltage dependences and faster recovery from inactivation. In the Y4734C-RYR2 variant, patient-specific hiPSC-derived cardiomyocytes of the proband, his sister with the same variant and diagnosis of catecholaminergic polymorphic ventricular tachycardia, and his healthy nephew were prepared and are being tested using the multielectrode array technique and simultaneous recording of Ca2+ transient and contraction (IonOptix). A significantly higher short-term variability of the cycle length in both control and proarrhythmic conditions (hypokalemia, fever, β-stimulation) was observed in both carriers of Y4734C-RYR2, the proband and his sister, compared to healthy cardiomyocytes of the proband´s nephew; the highest irregularity of the rhythm was identified in the proband. Analysis under application of sex-hormones is followed to explain the differences between Y4734C-RYR2 cardiomyocytes of the male proband and his sister. Functional analysis enables detailed characterization of ion channel dysfunction. In the case of idiopathic VF, it may provide essential data for understanding arrhythmogenesis and for clinical management of both probands and previously asymptomatic carriers of the same variant.
ER  -

BÉBAROVÁ, Markéta; Martin KRÁL; Natálie JANKOVÁ; Olga ŠVECOVÁ; Štefan ZELENÁK; Jiří PACHERNÍK; Tomáš BÁRTA; Michal PÁSEK; Jana ZÍDKOVÁ a Tomáš NOVOTNÝ. Functional analysis in three probands suffering from “true” idiopathic ventricular fibrillation. In \textit{Czech Cardiovascular Research and Innovation Days 2025 + 11th European Section Meeting of the International Academy of Cardiovascular Sciences}. 2025. ISSN~1803-7712.

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