Isogenic sets of hiPSC-CMs harboring distinct KCNH2 mutations differ functionally and in susceptibility to drug-induced arrhythmias

Brandao K, van den Brink L, Miller DC, Grandela C, van Meer BJ, Mol MPH, de Korte T, Tertoolen LGJ, Mummery CL, Sala L, Verkerk AO, and P. Davis R

Stem Cell Reports, 2020


Type 2 congenital long QT syndrome (LQT2) is a genetic disease characterized by a mutations in the cardiac potassium channel, KCNH2. The location of the mutation within this ion channel plays a crucial role in determining the risk of the development of arrhythmias for LQT2 patients. In this study, the authors characterized the phenotypic differences between a set of isogenic human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) genetically altered to include different types of KCNH2 mutations.  A multiwell microelectrode array (MEA) system was used to confirm that prolonged repolarization of the action potential duration (APD) and the field potential duration (FPD) was dependent on the location of the gene mutation. These results highlight how to the introduction of mutations into well-defined patient derived hiPSC lines can help identify subtle phenotypic and functional changes, providing a means to evaluate the arrhythmic risk for individual patients.