The immature electrophysiological phenotype of iPSC-CMs still hampers in vitro drug screening: Special focus on I_K1

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 I_f and reduced densities of the hyperpolarising current I_K1. 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 I_K1 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 I_K1 remain a major flaw in iPSC-CMs, which hampers their use for in vitro drug screening.