BPS2026 – Development and validation of an isogenic iPSC-CM model to recapitulate sex differences in cardiac electrophysiology

Sex differences in ventricular cardiac pharmacology are well known but remain poorly predicted and understood. Women have a prolonged QT interval when compared to males, resulting in disproportionately higher rates (2-4X) of drug-induced long-QT and torsades de pointes. This sex-dependent response is often credited to increased function of potassium channels in males and increased calcium handling ability in females. Previous research into each of these causes is conflicting, often confounded by model-to-model variability and genetic heterogeneity. Additionally, differential sex hormone expression, such as estrogen and testosterone, has been tied to these responses, making the roles of chromosomal sex versus the role of sex hormones difficult to isolate in current pre-clinical model systems. Our project uses recently derived isogenic hiPSC-CMs from a patient with mosaic Klinefelter syndrome (XXY) to systematically investigate sex-based differences in myocyte electrophysiological response to drugs. Preliminary data on XX/XY-CM recapitulate the prolonged AP phenotype in XX-CM seen in previous research, both at baseline and under drug perturbation when compared to their male counterparts. This project aims to quantify this relationship utilizing patch clamping and optical assays in conjunction with hormonal supplementation to further understand the role of sex as a complex variable in cardiac pharmacology. By establishing this platform, we aim to predict whether novel reagents have a sex dependent likelihood to become proarrhythmic, informing de novo drug development. The long-term goal is that the introduction of this model system in both cardiac and eventually other tissue types to provide a model of study for sex differential responses.