A Preclinical Study on Brugada Syndrome with a CACNB2 Variant Using Human Cardiomyocytes from Induced Pluripotent...

Area of Science:

• Cardiology
• Genetics
• Stem Cell Biology

Background:

• Brugada syndrome (BrS) is linked to sodium and calcium channel gene variants.
• The cellular phenotype and drug efficacy for BrS with calcium channel variants remain understudied.

Purpose of the Study:

• To create a cellular model of BrS using patient-derived cardiomyocytes with a CACNB2 variant.
• To investigate the functional impact of the CACNB2 variant and test potential drug treatments.

Main Methods:

• Generated human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a BrS patient with a CACNB2 variant and healthy controls.
• Utilized CRISPR/Cas9 gene editing to create isogenic controls.
• Assessed L-type calcium channel current (ICa-L), channel kinetics, and protein expression.

Main Results:

• BrS hiPSC-CMs exhibited significantly reduced ICa-L, altered inactivation curves, and accelerated recovery from inactivation.
• CACNB2 protein expression was decreased in BrS hiPSC-CMs; correction restored normal function.
• BrS hiPSC-CMs showed increased arrhythmia events, which were reduced by low-dose bisoprolol and quinidine.

Conclusions:

• The CACNB2 c.425C > T/p.S142F variant causes L-type calcium channel loss-of-function, confirming its pathogenicity in BrS.
• Low-dose bisoprolol and quinidine show potential as therapeutic agents for BrS associated with this CACNB2 variant.