Authors:

Areeb Fatima

Date Created:

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About Paper:

Over 33 million people worldwide suffer with atrial fibrillation (AF), which can dramatically raise the risk of morbidity and death if treatment is not received. AF disproportionately affects minority groups, who frequently have more severe clinical effects. African Americans are more likely to have the common ancestry-specific mutation SCN5A-S1103Y, which has been linked to an increased risk of AF, sudden cardiac death, and sudden infant death syndrome. While previous research has demonstrated that SCN5A-S1103Y modifies sodium channel activity, little is known about how exactly it contributes to the pathophysiology of AF. We hypothesize that the SCN5A-S1103Y variant increases AF risk by creating an altered electrophysiological (EP) substrate. The SCN5A-S1103Y+/- iPSC was generated from an AF patient. Electrophysiological (EP) assessments included: Whole-cell patch clamp recordings to assess sodium current (INa) current. Contractility was recorded with lonOptix system. Optical voltage mapping was employed to measure Action Potential with the lonOptix system. Bulk RNA sequencing (RNA-seq) was performed on iPSC-acMs to identify transcriptomic changes. Downstream bioinformatic analysis included Ingenuity Pathway Analysis (IPA) to identify altered molecular pathways associated with the SCN5A-S1103Y variant. SCN5A-S1103Y*" iPSC-aCMs exhibited significantly increased beating frequency and late sodium current compared to wild-type (WT). Action potential duration was also significantly increased in SCN5A-S1103Y*" in iPSC-aCMs, indicating heightened cellular excitability. RNA-seq analysis reveal Estrogen-Related Receptor Alpha (ESRRA) as central regulator atrial and ion channel remodeling. The SCN5A-S1103Y variant predisposes to AF through increased late sodium current and enhanced sarcomeric contractility. Transcriptomic analysis using RNA-seq and Ingenuity Pathway Analysis (IPA) revealed ESRRA reveal ESRRA as a central regulator of SCNS5A variant-linked AF. This study offers insight into AF mechanisms and may help identify novel therapeutic targets to improve outcomes.

Source:

University of Chicago

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Co-authors:

Areeb Fatima