Abstract
BackgroundAmong rare channelopathies BrS patients are at high risk of sudden cardiac death (SCD). SCN5A mutations are found in a quarter of patients. Other rare gene mutations including SCN1B have been implicated to BrS. Studying the human cellular phenotype of BrS associated with rare gene mutation remains lacking.ObjectivesWe sought to study the cellular phenotype of BrS with the SCN1B gene variants using human-induced pluripotent stem cell (hiPSCs)–derived cardiomyocytes (hiPSC-CMs).Methods and ResultsA BrS patient suffering from recurrent syncope harboring a two variants (c.629T > C and c.637C > A) in SCN1B, which encodes the function-modifying sodium channel beta1 subunit, and three independent healthy subjects were recruited and their skin biopsies were used to generate hiPSCs, which were differentiated into cardiomyocytes (hiPSC-CMs) for studying the cellular electrophysiology. A significantly reduced peak and late sodium channel current (INa) and a shift of activation curve to more positive potential as well as a shift of inactivation curve to more negative potential were detected in hiPSC-CMs of the BrS patient, indicating that the SCN1B variants impact the function of sodium channels in cardiomyocytes. The reduced INa led to a reduction of amplitude (APA) and upstroke velocity (Vmax) of action potentials. Ajmaline, a sodium channel blocker, showed a stronger effect on APA and Vmax in BrS cells as compared to cells from healthy donors. Furthermore, carbachol was able to increase arrhythmia events and the beating frequency in BrS.ConclusionOur hiPSC-CMs from a BrS-patient with two variants in SCN1B recapitulated some key phenotypic features of BrS and can provide a platform for studies on BrS with SCN1B variants.
Highlights
Sudden cardiac death (SCD) is related to ventricular tachyarrhythmias
We aimed to study the cellular phenotype of a Brugada syndrome (BrS) patient in presence of a compound mutation in the SCN1B using hiPSCCMs and provide a cellular model of BrS with SCN1B mutations for further pathophysiology and drug screening studies
We report here the first model of patient specific induced pluripotent stem cell derived cardiomyocytes from a patient carrying two variants in the SCN1B gene with BrS diagnosed by ajmaline administration
Summary
Sudden cardiac death (SCD) is related to ventricular tachyarrhythmias. A consensus statement of the ESC guideline 2015 recommended avoiding fever and/or infections as a trigger of BrS and/or arrhythmias (Casado-Arroyo et al, 2016). BrS patients and their families are at risk to develop malignant ventricular tachyarrhythmias and SCD (Morita et al, 2002). BrS patients may have other symptoms including recurrent syncope and atrial arrhythmias. In men
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