The immature electrophysiological phenotype of iPSC-CMs still hampers in vitro drug screening: Special focus on IK1

Preclinical drug screens are not based on human physiology, possibly complicating predictions on cardiotoxicity. Drug screening can be humanised with in vitro assays using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). However, in contrast to adult ventricular cardiomyocytes, iPSC-CMs beat spontaneously due to presence of the pacemaking current If and reduced densities of the hyperpolarising current In. In adult cardiomyocytes, I-K1 finalises repolarisation by stabilising the resting membrane potential while also maintaining excitability. The reduced I-K1 density contributes to proarrhythmic traits in iPSC-CMs, which leads to an electrophysiological phenotype that might bias drug responses. The proarrhythmic traits can be suppressed by increasing La in a balanced manner. We systematically evaluated all studies that report strategies to mature iPSC-CMs and found that only few studies report I-K1 current densities. Furthermore, these studies did not succeed in establishing sufficient I-K1 levels as they either added too little or too much I-K1. We conclude that reduced densities of In remain a major flaw in iPSC-CMs, which hampers their use for in vitro drug screening.