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.

临床前药物筛查并非基于人体生理学，可能会使心脏毒性的预测复杂化。药物筛选可以使用人诱导的多能干细胞衍生的心肌细胞（iPSC-CM）通过体外测定进行人源化。然而，与成年的心室心肌细胞相反，iPSC-CM由于起搏电流I _f的存在和超极化电流I _K1的密度降低而自发搏动。在成人的心肌细胞，我_K1通过稳定的静息膜电位，同时也保持兴奋定型复极化。降低的I _K1密度有助于iPSC-CMs的心律失常特征，从而导致电生理表型，可能使药物反应偏倚。可以通过平衡增加I _K1来抑制心律失常性状。我们系统地评估了所有报告成熟iPSC-CM策略的研究，发现只有极少数研究报告了I _K1当前密度。此外，这些研究未成功建立足够的I _K1水平，因为它们添加的I _K1太少或太多。我们得出的结论是，降低的I _K1密度仍然是iPSC-CM的主要缺陷，这阻碍了它们在体外药物筛选中的应用。