AbstractHuman induced pluripotent stem cells–derived cardiomyocytes have revolutionized the field of regenerative medicine, offering unparalleled potential forin–vitromodeling of normal and pathological human cardiomyocytes. The ability to produce stem cardiac myocytes in abundance has opened new avenues for drug efficacy and safety testing, as well as the study of conditions such as atrial fibrillation, a familial cardiac disorder. The development of atrial fibrillation is influenced by ion channel mutations, genetic variants, and other risk factors. Stem cells derived cardiomyocytes hold promise in personalized medicine, as they share the genetic heritage of the donor. While mathematical models have focused on immature stem cardiomyocytes phenotypes, they have primarily relied on a system of stiff ordinary differential equations. Computational modeling of diseased tissue presents an opportunity to evaluate drugs in a patient-specific manner, thereby improving therapeutic targets and ablation techniques. Previous studies categorized cell phenotypes based on action potential morphology, yet classification criteria remains ambiguous.This work introduces the first atrial-specificin–silicomodel of stem cells ionic currents, leveraging experimental data provided by Altomare et al. It begins by summarizing the baseline electrophysiological model and mathematical descriptions of atrial–specific additional currents. Model parameter tuning was performed through automatic optimization techniques to ensure realistic action potential shape and expedite the parameter adjustment process. The resulting model was validated against rate dependence and atrial–specific ion current blocking data. In summary, the development of an atrial-specificin–silicomodel represents a significant step forward in understanding cardiac electrophysiology and the potential for personalized medicine in treating conditions like atrial fibrillation. This model offers new tools for drug evaluation, therapeutic improvement, and a deeper comprehension of cardiac phenotypes.Author summaryHuman induced pluripotent stem cells have revolutionized regenerative medicine since their discovery in 2006, leading to a Nobel Prize in 2012. This kind of pluripotent cells can give rise to different types of specific tissue cells, such as derived cardiomyocytes. Differentiated cardiac cells offer an unlimited supply for studying human heart cells in normal and disease conditions, aiding a patient–specific drug testing and helping to explore pathogenic mechanisms behind different cardiomyopathies, including atrial fibrillation. Atrial fibrillation is a common heart condition, and stem cells with the same genetic heritage as the donor, are ideal for patient-specific treatments.Recent advances have produced mathematical models for the ionic currents in cardiomyocytes derived from stem cells, focusing on immature forms and enabling virtual drug testing. However, previous models did not capture the atrial–specific characteristics. We decided to create and introduce by this study the first atrial–likein–silicomodel for these cells, using novel experimental data. Thus, we describe the baseline model and additional atrial–specific currents, we tune the model parameters using automatic optimization technique, and we validate the model’s accuracy in simulating atrial action potentials and ion current blockage. This research paves the way for better understanding and treating atrial fibrillation and other heart conditions.

This work introduces the first atrial-specific in-silico human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) model, based on a set of phenotype-specific IKur,IKCa and IK1 membrane currents. This model is built on novel in-vitro experimental data recently published by some of the co-authors to simulate the paced action potential of matured atrial-like hiPSC-CMs. The model consists of a system of stiff ordinary differential equations depending on several parameters, which have been tuned by automatic optimization techniques to closely match selected experimental biomarkers. The new model effectively simulates the electronic in-vitro hiPSC-CMs maturation process, transitioning from an unstable depolarized membrane diastolic potential to a stable hyperpolarized resting potential, and exhibits spontaneous firing activity in unpaced conditions. Moreover, our model accurately reflects the experimental rate dependence data at different cycle length and demonstrates the expected response to a specific current blocker. This atrial-specific in-silico model provides a novel computational tool for electrophysiological studies of cardiac stem cells and their applications to drug evaluation and atrial fibrillation treatment.

Regenerative cardiology recently advanced in patient–specific medicine by employing somatic cells to derive pluripotent stem cells and differentiate them into cardiomyocytes. Resulting populations present an immature phenotype; the Dynamic Clamp technique is a popular experimental manipulation to induce electronic maturation towards an adult phenotype. In this work, we present a fully virtual framework to study this Dynamic Clamp technique, based on the injection of the inward-rectifier potassium current into the myocyte, taking into account six different current formulations. We investigate the effects of the current injection on the action potential morphology and on three specific biomarkers for different current percentages, and we compare resulting morphologies with the standard transmembrane potential profile of a human adult cardiomyocyte. The results of this quantitative analysis suggest that atrial–like potassium current formulations allow the cell to reach action potential features comparable with the ones of mature cells, preventing the cell to show a non physiological morphology.

Regenerative cardiology recently advanced in patient-specific medicine by employing somatic cells to derive pluripotent stem cells and differentiate them into cardiomyocytes.In this work, the cardiac Monodomain model is coupled with stem cell ionic models to simulate the action potential propagation in the engineered ventricle. The cardiac model is then discretized by means of Isogeometric Analysis, carrying out numerical experiments to assess the accuracy of the approach. Finally, the presented framework is used to investigate the propagation of an action potential on the calibrated model of the engineered ventricle.

Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) are a virtually endless source of human cardiomyocytes, considerably used in vitro models to test drug toxicity.These cells express the major cardiac markers and ion channels, but they also result in a mix of incompletely mature cardiac cells that can be classified as atrial-like and ventricular-like cardiomyocytes.One of the most popular manipulations used to push towards more adult cardiac phenotypes is the dynamic clamp technique, based on virtual inward -rectifier potassium current (I K1 ) injection.In this exploratory in silico study, six different I K1 expressions have been virtually analyzed to classify hiPSC-CM phenotypes.Starting from the resulting action potential morphologies, we defined a mathematical criterion to estimate the efficacy of the injected I K1 current in terms of the threshold percentage of the current density required to obtain an hiPSC-CM physiological response.It was found that atrial I K1 formulations are more reliable than ventricular ones, with the Koivumäki I K1 formulation being the most appropriate since it requires the minimal current density to be injected.