Catheter Ablation -> Atrial Fibrillation & Atrial Flutter: -> Experimental methods D-PO01 - Featured Poster Session (ID 11) Poster

D-PO01-139 - Modeling Atrial Fibrillation In A Dish Using Human Atrial Ipsc-cardiomyocytes Carrying A Heritable Scn5a Mutation (ID 935)


Background: Mutations in cardiac ion channel genes have been linked with familial atrial fibrillation (AF) but the underlying pathophysiologic mechanisms and implications for therapy remain unclear.
Objective: To characterize the electrophysiologic (EP) phenotype of AF-linked SCN5A mutations and assess mechanism-based therapies using patient-specific atrial induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).
Methods: We generated iPSC-CMs from two kindreds carrying SCN5A mutations (E428K and N470K), controls and isogenic controls using CRISPR using an atrial differentiation protocol. Whole-cell patch clamp recordings of single cell and multi-electrode array (MEA) to assess the electrophysiological (EP) phenotypes of atrial iPSC-CMs.
Results: The SCN5A mutation cell lines displayed abnormal EP properties including increased beating frequency and irregularity with triggered beats characteristic of AF (Fig. A-F). MEA recordings of mutant atrial iPSC-CMs showed spontaneous arrhythmogenic activity with beat-to-beat irregularity (Fig. G-H). Ranolazine inhibited INa,L and normalized the aberrant EP phenotype in the SCN5A-E428K atrial iPSC-CMs (Fig. I-L).
Conclusion: Patient-specific atrial iPSC-CMs recapitulated the EP phenotype of an SCN5A gain-of-function mutation linked with familial AF. Our study illustrates the potential use of atrial iPSC-CMs for modeling AF in a dish, elucidating the underlying cellular mechanisms, and identifying novel mechanism-based therapies custom-tailored for individual patients.