Computational prediction of drug response in short QT syndrome type 1 based on measurements of compound effect in stem cell-derived cardiomyocytes

Abstract

AbstractShort QT (SQT) syndrome is a genetic cardiac disorder characterized by an abbreviated QT interval of the patient’s electrocardiogram. The syndrome is associated with increased risk of arrhythmia and sudden cardiac death and can arise from a number of ion channel mutations. Cardiomyocytes derived from induced pluripotent stem cells generated from SQT patients (SQT hiPSC-CMs) provide promising platforms for testing pharmacological treatments directly in human cardiac cells exhibiting mutations specific for the syndrome. However, a difficulty is posed by the relative immaturity of hiPSC-CMs, with the possibility that drug effects observed in SQT hiPSC-CMs could be very different from the corresponding drug effectin vivo. In this paper, we apply a multistep computational procedure for translating measured drug effects from these cells to human QT response. This process first detects drug effects on individual ion channels based on measurements of SQT hiPSC-CMs and then uses these results to estimate the drug effects on ventricular action potentials and QT intervals of adult SQT patients. We find that the procedure is able to identify IC50values in line with measured values for the four drugs quinidine, ivabradine, ajmaline and mexiletine. In addition, the predicted effect of quinidine on the adult QT interval is in good agreement with measured effects of quinidine for adult patients. Consequently, the computational procedure appears to be a useful tool for helping predicting adult drug responses from purein vitromeasurements of patient derived cell lines.Author summaryA number of cardiac disorders originate from genetic mutations affecting the function of ion channels populating the membrane of cardiomyocytes. One example is short QT syndrome, associated with increased risk of arrhythmias and sudden cardiac death. Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) provide a promising platform for testing potential pharmacological treatments for such disorders, as human cardiomyocytes exhibiting specific mutations can be generated and exposed to drugsin vitro. However, the electrophysiological properties of hiPSC-CMs differ significantly from those of adult native cardiomyocytes. Therefore, drug effects observed for hiPSC-CMs could possibly be very different from corresponding drug effects for adult cellsin vivo. In this study, we apply a computational framework for translating drug effects observed for hiPSC-CMs derived from a short QT patient to drug effects for adult short QT cardiomyocytes. For one of the considered drugs, the effect on adult QT intervals has been measured and these measurements turn out to be in good agreement with the response estimated by the computational procedure. Thus, the computational framework shows promise for being a useful tool for predicting adult drug responses from measurements of hiPSC-CMs, allowing earlier identification of compounds to accurately treat cardiac diseases.