Effects of cardioactive drugs on human induced pluripotent stem cell derived long QT syndrome cardiomyocytes

Abstract

Human induced pluripotent stem cells (hiPSC) have enabled a major step forward in pathophysiologic studies of inherited diseases and may also prove to be valuable in in vitro drug testing. Long QT syndrome (LQTS), characterized by prolonged cardiac repolarization and risk of sudden death, may be inherited or result from adverse drug effects. Using a microelectrode array platform, we investigated the effects of six different drugs on the electrophysiological characteristics of human embryonic stem cell-derived cardiomyocytes as well as hiPSC-derived cardiomyocytes from control subjects and from patients with type 1 (LQT1) and type 2 (LQT2) of LQTS. At baseline the repolarization time was significantly longer in LQTS cells compared to controls. Isoprenaline increased the beating rate of all cell lines by 10–73 % but did not show any arrhythmic effects in any cell type. Different QT-interval prolonging drugs caused prolongation of cardiac repolarization by 3–13 % (cisapride), 10–20 % (erythromycin), 8–23 % (sotalol), 16–42 % (quinidine) and 12–27 % (E-4031), but we did not find any systematic differences in sensitivity between the control, LQT1 and LQT2 cell lines. Sotalol, quinidine and E-4031 also caused arrhythmic beats and beating arrests in some cases. In summary, the drug effects on these patient-specific cardiomyocytes appear to recapitulate clinical observations and provide further evidence that these cells can be applied for in vitro drug testing to probe their vulnerability to arrhythmia.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-016-1889-y) contains supplementary material, which is available to authorized users.

The Effects of Pharmacological Compounds on Beat Rate Variations in Human Long QT-Syndrome Cardiomyocytes

“…Human iPSCs were generated as described earlier [42]. The LQT1-specific hiPSCs were derived from patients’ skin fibroblasts carrying G589D missense mutation in KCNQ1 [41, 43]. …”

“…Human iPS cells were cultured and differentiated as previously described [43]. All the hiPSC lines (UTA.04602.WT, UTA.00208.LQT1, UTA.00211.LQT1, UTA.00303.LQT1 and UTA.00313.LQT1) and the differentiated CMs from them have been previously characterized elsewhere [41, 43, 44].…”

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

“…demonstrated reduced beating rates in hiPSC‐CMs at lower doses of ivabradine (1‐2 μM vs 3‐9 μM) (Bedut et al , 2016). Furthermore, when drug concentrations were compared among different hPSC‐CM lines, techniques or studies, the differences appear to be significant and functionally relevant (Kuusela et al , 2016). Broader studies are still required to pinpoint the contribution of donor genetic background and subsequent epigenetic modifications on both cardiac phenotype and drug responses.…”

Short- and Long-Range Correlations in Beat Rate Variability of Human Pluripotent-Stem-Cell-Derived Cardiomyocytes

“…The LQT1-specific hiPSCs are derived from LQTS patients' skin fibroblasts carrying G589D missense mutation in KCNQ1 [7,8]. The skin biopsies are obtained from a 55-year-old female healthy individual, a symptomatic 41-year-old female LQTS patient, and an asymptomatic 28-year-old LQT-mutation carrier.…”

“…Both symptomatic and asymptomatic LQTS patients are on bisoprolol medication. The hiPSCs are cultured and differentiated into CMs as described in [8]. In this study, 30-40 days old hiPSCCMs are used.…”