Human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) are a promising tool to study arrhythmia-related factors, but the variability of action potential (AP) recordings from these cells limits their use as an in vitro model. In this study, we use recently published, brief (10 s), dynamic voltage clamp (VC) data to provide mechanistic insights into the ionic currents contributing to AP heterogeneity - we call this approach rapid ionic current phenotyping (RICP). Features of this VC data were correlated to AP recordings from the same cells and we used computational models to generate mechanistic insights into cellular heterogeneity. This analysis uncovered several interesting links between AP morphology and ionic current density: both L-type calcium and sodium currents contribute to upstroke velocity, rapid delayed rectifier K+ current is the main determinant of the maximal diastolic potential, and an outward current in the activation range of slow delayed rectifier K+ is the main determinant of AP duration. Our analysis also identified an outward current in several cells at 6 mV that is not reproduced by iPSC-CM mathematical models but contributes to determining AP duration. RICP can be used to explain how cell-to-cell variability in ionic currents gives rise to AP heterogeneity. Due to its brief duration (10 s) and the ease of data interpretation, we recommend the use of RICP for single-cell patch-clamp experiments that include the acquisition of APs.
