Long QT syndrome (LQTS) is caused by functional alterations of cardiac ion channels and is associated with prolonged cardiac repolarization time and increased risk for ventricular arrhythmias. Both inherited type 2 LQTS (LQT2) and drug-induced LQTS result from altered function of the hERG channel. We investigated whether the electrophysiological characteristics of LQT2 can be recapitulated in vitro using induced pluripotent stem cell (iPSC) technology. Spontaneously beating cardiomyocytes were differentiated from two iPSC lines derived from a LQT2-patient carrying the R176W mutation of KCNH2 (HERG) gene. The patient had been asymptomatic except for occasional palpitations, but his sister and father had died suddenly at early age. Electrophysiological properties of LQT2-specific cardiomyocytes were studied using microelectrode array and patch-clamp and compared to those of cardiomyocytes derived from control cells. The action potential duration of LQT2-specific cardiomyocytes was significantly longer than that of control cardiomyocytes, and the rapid delayed potassium channel (IKr) density of the LQT2-cardiomyocytes was significantly reduced. Additionally, LQT2-derived cardiac cells were more sensitive than controls to potentially arrhythmogenic drugs, including sotalol, and demonstrated arrhythmogenic electrical activity. Consistent with clinical observations, the LQT2-cardiomyocytes demonstrated a more pronounced inverse correlation between the beating rate and repolarization time compared to control cells. Prolonged action potential is present in LQT2-specific cardiomyocytes derived from a mutation carrier and arrhythmias can be triggered by a commonly used drug. Thus, the iPSC-derived, disease-specific cardiomyocytes could serve as an important platform to study pathophysiological mechanisms and drug sensitivity of LQT2.
- Received June 30, 2011.
- Accepted October 20, 2011.
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