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

Abstract

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.

Keywords: Arrhythmia; Cardiac electrophysiology; CiPA; I(K1); Safety pharmacology; iPSC-CMs.