Action potential characteristics in derived cardiomyocytes of a patient carrying RYR2 variant

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14110%2F22%3A00129702" target="_blank" >RIV/00216224:14110/22:00129702 - isvavai.cz</a>

Result on the web

—

DOI - Digital Object Identifier

—

Result language

angličtina

Original language name

Action potential characteristics in derived cardiomyocytes of a patient carrying RYR2 variant

Original language description

Ventricular fibrillation (VF) is a common cause of death in young adults. It can originate from a dysfunction of a cardiac ionic channel which may be caused by a variant in the encoding gene. We have found a potentially proarrhythmic variant in the RyR2 gene, p.Y4734C-RYR2, in a patient with VF, but structurally and functionally healthy heart (no signs of heart impairment on magnetic resonance, echocardiography, and electrocardiography both at rest and after exercise; i.e. idiopathic VF). This variant has not been functionally tested yet. RYR2 channel variants are usually associated with an inherited arrhythmogenic syndrome called catecholaminergic polymorphic ventricular tachycardia (CPVT). It might also apply to this variant because a sister of the proband suffers from this disease as has been recently revealed. However, no signs of CPVT could be identified in the proband. Hence, the dysfunction might be masked by other electrophysiological changes in his heart. To reveal the mechanism and specific conditions that may lead to VF in the proband, we have recently started a functional analysis of the Y4734C-RYR2 variant using cardiomyocytes derived from patient-specific human-induced pluripotent stem cells (hiPSC). It is a clinically relevant, up-to-date model that enables fast transmission of the experimentally acquired data to clinical practice. Here we bring pilot data showing basic characteristics of spontaneous action potential waveforms in Y4734C-RYR2 cardiomyocytes in comparison with the characteristics in hiPSC-derived cardiomyocytes of an unrelated healthy control (WT-RYR2; methods: whole-cell patch-clamp technique, at 37C, 5 and 6 samples in Y4734C-RYR2 and WT-RYR2 cardiomyocytes, respectively). No significant differences have been identified. We just observed a tendency to an increased beating rate and decreased action potential duration in Y4734C-RYR2 cardiomyocytes; the latter remained even after correction of the action potential duration to the respective beating rate using both Bazett´s and Fridericia´s formulas. For a better understanding of the influence of this variant, we will have to perform more measurements and analyse changes in action potential configuration at specific conditions. It will help us to better understand the mechanism of VF generation in the proband which might be essential for his treatment and prevention of life-threatening VF episodes in the future.

Czech name

—

Czech description

—

Type

O - Miscellaneous

CEP classification

—

OECD FORD branch

30201 - Cardiac and Cardiovascular systems

Project

<a href="/en/project/NU22-02-00348" target="_blank" >NU22-02-00348: Functional assessment of genetic variants in clinically “true” cases of idiopathic ventricular fibrillation: in vitro and in silico modelling to reveal the arrhythmogenic mechanism</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2022

Confidentiality

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