Abstract
Background: Atrial fibrillation (AF), the most common arrhythmia, is associated with significant morbidity and increased mortality. Although antiarrhythmic drugs are still commonly used to treat symptomatic AF, membrane-active drugs are incompletely and unpredictably effective, failing to target the underlying mechanisms of AF. Our pilot data shows atrial iPSC-CMs generated from a familial AF kindred recapitulated the electrophysiologic (EP) phenotype of an AF-linked SCN5A mutation, serving as a novel platform to target underlying cellular AF mechanisms. However, structural, molecular, and EP immaturity as compared to adult atrial CMs has hindered successful mechanistic evaluation. Objective: We aim to determine optimal condition(s) to enhance the maturity of atrial iPSC-CMs, establishing them as a novel platform to model AF, elucidate the cellular mechanisms, and identify/assess novel, mechanism based therapies. Methods: Maturity of atrial iPSC-CMs was enhanced using TID (T3, IGF-1, dexamethasone), fatty acids (FA), acute electrical stimulation (ES), and extracellular matrix (ECM) modulation. We examined for improvements in structural maturity (immunofluorescence, transmission electron microscopy), molecular (qPCR, RNA seq) and EP (patch clamping, multi-electrode array, high-throughput automated patch clamping). The maturity of atrial iPSC-CMs was compared with adult atrial CMs obtained from the same patient during cardiac surgery. Results and Conclusion: Fig. 1 demonstrates that acute ES, combined with TID and FA supplementation, significantly improves structural and in part EP maturity of atrial iPSC-CMs.
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