Arrhythmogenicity Test Based on a Human-Induced Pluripotent Stem Cell (iPSC)-Derived Cardiomyocyte Layer

In vitro screening for potential side effects of drugs on human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs) is a cutting-edge technology in pharmaceutical industry. International groups are currently considering using iPSC-CM as a part of comprehensive battery for an accurate and complex mechanistic-based assessment of the proarrhythmic potential of drugs. Despite iPSC-CMs expression and phenotype differences from mature adult CMs screening for drug-induced prolonged QT interval is now routinely carried and also recommended by ICH. The revelation of the mechanism of how the elongation of the QT interval is associated with the occurrence of an arrhythmia should extend the prospects of screening. To address this problem, a comprehensive tissue-based test for arrhythmogenicity is needed. Induced pluripotent stem (iPS) cells from a healthy individual were differentiated into a CM monolayer that was identified by immunocytochemistry and the patch-clamp technique also considering of the potential impact of the developing phenotype of the iPSC-CMs. To study the occurrence of reentry as a precursor to arrhythmias, a standard obstacle was created in the cell layer. With the aid of optical mapping, the measure of arrhythmogenicity was determined, as defined by the probability of a reentry occurrence for the particular frequency of stimulation. A change in the potassium current corresponding to LQTS type 2 at frequencies matching high heart rates was demonstrated visually and quantitatively. Also, the efficiency of this method for quantifying both the effectiveness and ineffectiveness of drugs for a particular donor and for determining the donor's cardiovascular disease risk zone was tested.