TY - JOUR
T1 - HiPSC-derived cardiomyocyte to model Brugada syndrome
T2 - both asymptomatic and symptomatic mutation carriers reveal increased arrhythmogenicity
AU - Penttinen, Kirsi
AU - Prajapati, Chandra
AU - Shah, Disheet
AU - Rajan, Dhanesh Kattipparambil
AU - Cherian, Reeja Maria
AU - Swan, Heikki
AU - Aalto-Setälä, Katriina
N1 - © 2023. The Author(s).
PY - 2023/4/25
Y1 - 2023/4/25
N2 - Brugada syndrome is an inherited cardiac arrhythmia disorder that is mainly associated with mutations of the cardiac voltage-gated sodium channel alpha subunit 5 (SCN5A) gene. The clinical symptoms include ventricular fibrillation and an increased risk of sudden cardiac death. Human-induced pluripotent stem cell (hiPSC) lines were derived from symptomatic and asymptomatic individuals carrying the R1913C mutation in the SCN5A gene. The present work aimed to observe the phenotype-specific differences in hiPSC-derived cardiomyocytes (CMs) obtained from symptomatic and asymptomatic mutation carriers. In this study, CM electrophysiological properties, beating abilities and calcium parameters were measured. Mutant CMs exhibited higher average sodium current densities than healthy CMs, but the differences were not statistically significant. Action potential durations were significantly shorter in CMs from the symptomatic individual, and a spike-and-dome morphology of action potential was exclusively observed in CMs from the symptomatic individual. More arrhythmias occurred in mutant CMs at single cell and cell aggregate levels compared with those observed in wild-type CMs. Moreover, there were no major differences in ionic currents or intracellular calcium dynamics between the CMs of asymptomatic and symptomatic individuals after the administration of adrenaline and flecainide.In conclusion, mutant CMs were more prone to arrhythmia than healthy CMs but did not explain why only one of the mutation carriers was symptomatic.
AB - Brugada syndrome is an inherited cardiac arrhythmia disorder that is mainly associated with mutations of the cardiac voltage-gated sodium channel alpha subunit 5 (SCN5A) gene. The clinical symptoms include ventricular fibrillation and an increased risk of sudden cardiac death. Human-induced pluripotent stem cell (hiPSC) lines were derived from symptomatic and asymptomatic individuals carrying the R1913C mutation in the SCN5A gene. The present work aimed to observe the phenotype-specific differences in hiPSC-derived cardiomyocytes (CMs) obtained from symptomatic and asymptomatic mutation carriers. In this study, CM electrophysiological properties, beating abilities and calcium parameters were measured. Mutant CMs exhibited higher average sodium current densities than healthy CMs, but the differences were not statistically significant. Action potential durations were significantly shorter in CMs from the symptomatic individual, and a spike-and-dome morphology of action potential was exclusively observed in CMs from the symptomatic individual. More arrhythmias occurred in mutant CMs at single cell and cell aggregate levels compared with those observed in wild-type CMs. Moreover, there were no major differences in ionic currents or intracellular calcium dynamics between the CMs of asymptomatic and symptomatic individuals after the administration of adrenaline and flecainide.In conclusion, mutant CMs were more prone to arrhythmia than healthy CMs but did not explain why only one of the mutation carriers was symptomatic.
KW - Humans
KW - Brugada Syndrome/diagnosis
KW - Induced Pluripotent Stem Cells/metabolism
KW - Myocytes, Cardiac/metabolism
KW - Calcium/metabolism
KW - Arrhythmias, Cardiac/diagnosis
KW - Action Potentials
KW - Mutation
U2 - 10.1186/s12872-023-03234-7
DO - 10.1186/s12872-023-03234-7
M3 - Article
C2 - 37098502
SN - 1471-2261
VL - 23
JO - BMC Cardiovascular Disorders
JF - BMC Cardiovascular Disorders
M1 - 208
ER -