Modeling Short QT Syndrome Using Human‐Induced Pluripotent Stem Cell–Derived Cardiomyocytes

Abstract

BackgroundShort QT syndrome (SQTS), a disorder associated with characteristic ECG QT‐segment abbreviation, predisposes affected patients to sudden cardiac death. Despite some progress in assessing the organ‐level pathophysiology and genetic changes of the disorder, the understanding of the human cellular phenotype and discovering of an optimal therapy has lagged because of a lack of appropriate human cellular models of the disorder. The objective of this study was to establish a cellular model of SQTS using human‐induced pluripotent stem cell–derived cardiomyocytes (hiPSC‐CMs).Methods and ResultsThis study recruited 1 patient with short QT syndrome type 1 carrying a mutation (N588K) in KCNH2 as well as 2 healthy control subjects. We generated hiPSCs from their skin fibroblasts, and differentiated hiPSCs into cardiomyocytes (hiPSC‐CMs) for physiological and pharmacological studies. The hiPSC‐CMs from the patient showed increased rapidly activating delayed rectifier potassium channel current (IK r) density and shortened action potential duration compared with healthy control hiPSC‐CMs. Furthermore, they demonstrated abnormal calcium transients and rhythmic activities. Carbachol increased the arrhythmic events in SQTS but not in control cells. Gene and protein expression profiling showed increased KCNH2 expression in SQTS cells. Quinidine but not sotalol or metoprolol prolonged the action potential duration and abolished arrhythmic activity induced by carbachol.ConclusionsPatient‐specific hiPSC‐CMs are able to recapitulate single‐cell phenotype features of SQTS and provide novel opportunities to further elucidate the cellular disease mechanism and test drug effects.

Drug Testing in Human‐Induced Pluripotent Stem Cell–Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1

“…Our recent study demonstrated that SQTS1 hiPSC-CMs displayed shortened APD and increased the number of arrhythmic events and that quinidine but not sotalol prolonged APD and reduced the number of arrhythmic episodes. 27 These results indicate that hiPSC-CMs from SQTS1 patients can recapitulate the disease feature and respond to drugs in a way similar to that of cardiomyocytes in patients. Furthermore, we observed that SQTS1 hiPSC-CMs lost adaptation of APD to increasing stimulation frequencies, similar to the reduction of adaptation of QT interval to increasing heart rate reported in patients with SQTS1.…”

“…The fibroblasts for induced pluripotent stem cell generation were from a 29‐year‐old male patient with familial SQTS1 due to identified missense mutation (C to G substitution at nucleotide 1764), resulting in substitution of an amino acid at the position of 588 from asparagine to lysine (N588K) in the KCNH2 (also called HERG or I Kr ) channel. The clinical data of the patient are described in our recent report …”

“…The hiPSC line was generated in feeder‐free culture conditions using the integration‐free CytoTune‐iPS 2.0 Sendai Reprogramming Kit (Thermo Fisher Scientific, Karlsruhe, Germany, number A16517) with the reprogramming factors octamer‐binding transcription factor 4, Kruppel‐like factor 4, sex determining region Y‐box 2, and cellular myelocytomatosis proto‐oncogene according to manufacturer's instructions, with modifications. The generated hiPSCs were characterized for their pluripotency and their in vitro differentiation potential …”

“…Quinidine (here used as a control) displayed a strong effect on I Kr ( Figure 5), consistent with its APD-prolonging effect in SQTS1 hiPSC-CMs shown in our previous study. 27 Ivabradine, ajmaline, and mexiletine reduce arrhythmic events in SQTS1 hiPSC-CMs Because ivabradine, ajmaline, and mexiletine prolonged APD90 in SQTS1 hiPSC-CMs, their effects on the occurrence of arrhythmias were further examined in cells exhibiting arrhythmic events (triggered beats) induced by a high concentration (300 μM) of epinephrine. In single-cell contraction measurements in spontaneously beating cells, 300 μM epinephrine increased the beating frequency of cells significantly (Figure 6e-h).…”

“…Our group has successfully used human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to model some key features of different diseases, including SQTS1. [22][23][24][25][26][27][28] We have demonstrated that the hiPSC-CMs from an SQTS1 patient (SQTS1 hiPSC-CMs) are able to recapitulate the single-cell phenotypic features of SQTS (APDshortening and arrhythmic calcium transients) and provide novel opportunities to further elucidate the disease mechanism and test drug effects. 27 Therefore, we designed the current study to examine the APDprolonging and antiarrhythmic effects of some drugs using our well-defined and characterized model of SQTS1.…”