Possible proarrhythmic stimuli in Y4734C-RYR2 variant associated with idiopathic ventricular fibrillation

BÉBAROVÁ, Markéta, Olga ŠVECOVÁ, Martin KRÁL, Štefan ZELENÁK, Jiří PACHERNÍK, Tomáš BÁRTA, Samuel LIETAVA, Iva SYNKOVÁ, Jana ZÍDKOVÁ and Tomáš NOVOTNÝ. Possible proarrhythmic stimuli in Y4734C-RYR2 variant associated with idiopathic ventricular fibrillation. In 47th Meeting of the European Working Group on Cardiac Cellular Electrophysiology. 2023.

Basic information

• Original name: Possible proarrhythmic stimuli in Y4734C-RYR2 variant associated with idiopathic ventricular fibrillation
• Authors: BÉBAROVÁ, Markéta (203 Czech Republic, guarantor, belonging to the institution), Olga ŠVECOVÁ (203 Czech Republic, belonging to the institution), Martin KRÁL (203 Czech Republic, belonging to the institution), Štefan ZELENÁK (703 Slovakia, belonging to the institution), Jiří PACHERNÍK (203 Czech Republic), Tomáš BÁRTA (203 Czech Republic, belonging to the institution), Samuel LIETAVA (703 Slovakia, belonging to the institution), Iva SYNKOVÁ (203 Czech Republic), Jana ZÍDKOVÁ (203 Czech Republic, belonging to the institution) and Tomáš NOVOTNÝ (203 Czech Republic).
• Edition: 47th Meeting of the European Working Group on Cardiac Cellular Electrophysiology, 2023.

Other information

• Original language: English
• Type of outcome: Conference abstract
• Field of Study: 30201 Cardiac and Cardiovascular systems
• Country of publisher: Denmark
• Confidentiality degree: is not subject to a state or trade secret
• RIV identification code: RIV/00216224:14110/23:00134665
• Organization unit: Faculty of Medicine
• Keywords in English: proarrhythmic stimuli; Y4734C-RYR2; idiopathic ventricular fibrillation
• Tags: International impact, Reviewed

Abstract

Background: The RYR2 variant Y4734C was identified in a patient suffering from idiopathic ventricular fibrillation. To investigate its pathogenic character, functional analysis has been started. Here, we present the pilot data on potential proarrhythmic stimuli in this variant. Material and Methods: The recordings of the spontaneous electrical activity of Y4734C-RYR2 (Y4734C) and unrelated healthy control (WT) hiPSC-CM (5 and 3 measured samples, respectively) were performed using the multielectrode array (MEA) technique at 37°C. Besides the evaluation of the cycle length (CL), the short-term variability of CL (STVCL) was calculated. Since some data were not normally distributed, the median ± interquartile range (IQR) and non-parametric statistical tests were used. Results: In the control Tyrode solution (5 mM K+ Tyr), CL significantly differed in WT and Y4734C (1.36±0.22 and 0.53±0.14 s, respectively; P  0.05), but STVCL was the same (8.0 ms). Subsequently, the possible proarrhythmic impact of additively applied hypokalaemia (3 mM K+), β-adrenergic stimulation (1 µM isoprenaline), and high temperature (40°C) was tested. In Y4734C, STVCL slightly decreased in 3 mM K+ and then gradually increased when 1 µM isoprenaline was added, first alone and later in combination with 40°C (4.1, 22.4, and 39.3 ms, respectively; P  0.05). In contrast, STVCL in WT was considerably higher only in the concurrent presence of 3 mM K+ and 1 µM isoprenaline (30.7 ms vs. 13.3 ms in 3 mM K+ and 9.3 ms in the presence of all the stimuli; P  0.05). Conclusions: The pilot data showed non-significant differences between the effect of three selected proarrhythmic stimuli, namely hypokalaemia, β-adrenergic stimulation, and high temperature, on the spontaneous electrical activity of WT- and Y4734C-RYR2 hiPSC-CM.

Links

• MUNI/A/1343/2022, interní kód MU: Name: Zátěže kardiovaskulárního systému od A po Z

Investor: Masaryk University, Loads on the cardiovascular system from A to Z

• NU22-02-00348, research and development project: Name: Funkční hodnocení genetických variant u případů klinicky „skutečné“ idiopatické fibrilace komor: in vitro a in silico modelování s cílem odhalit arytmogenní mechanismus

Investor: Ministry of Health of the CR, Subprogram 1 - standard