Compound Testing of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes Using Multi-Well Microelectrode Arrays

The cardiac action potential is a highly orchestrated process that depends on the precise timing of activation and inactivation of various ion channel subtypes. Any deviation from this carefully regulated sequence, such as the blockage of specific voltage-gated potassium channels, can disrupt the electrical balance and lead to life-threatening arrhythmias. Standard cellular assays, which typically rely on cells engineered to express only a single ion channel subtype, have significant limitations in accurately predicting a compound's effects on the heart. These limitations often result in prematurely rejecting many potentially promising compounds during the early stages of drug development.To address this, there is an increasing demand for more physiologically relevant and predictive functional assays. The emergence of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) has revolutionized this field by offering assays that are more representative of human cardiac physiology. These cells not only provide a more accurate model for assessing drug effects but also support the development of patient-derived disease models, offering personalized insights into cardiac health.Microelectrode array (MEA) systems have become a crucial tool in this context, enabling the non-invasive recording and analysis of cardiac field action potentials from cultured hiPSC-CMs. These systems provide a platform to monitor the electrical activity of cardiomyocytes in real time, offering valuable data on the electrophysiological properties of cardiac cells under various conditions. This chapter presents a comprehensive protocol for cultivating hiPSC-CMs on two parallelized MEA systems. We also outline a strategic approach for conducting compound testing, designed to maximize the predictive power of these assays and enhance their application in safety pharmacology.