Cellular Biology Cardiomyocytes Obtained From Induced Pluripotent Stem Cells With Long-QT Syndrome 3 Recapitulate Typical Disease-Specific Features In Vitro

Rationale: Current approaches for the investigation of long-QT syndromes (LQTS) are mainly focused on identification of the mutation and its characterization in heterologous expression systems. However, it would be extremely helpful to be able to characterize the pathophysiological effects of mutations and to screen drugs in cardiomyocytes. Objective: The aim of this study was to establish as a proof of principle the disease-specific cardiomyocytes from a mouse model with LQTS 3 by use of induced pluripotent stem (iPS) cells and to demonstrate that the mutant cardiomyocytes display the characteristic pathophysiological features in vitro. Methods and Results: We generated disease-specific iPS cells from a mouse model with a human mutation of the cardiac Na channel that causes LQTS 3. The control and LQTS 3–specific iPS cell lines were pluripotent and could be differentiated into spontaneously beating cardiomyocytes. Patch-clamp measurements of LQTS 3–specific cardiomyocytes showed the biophysical effects of the mutation on the Na current, with faster recovery from inactivation and larger late currents than observed in controls. Moreover, LQTS 3–specific cardiomyocytes had prolonged action potential durations and early afterdepolarizations at low pacing rates, both of which are classic features of the LQTS 3 mutation. Conclusions: We demonstrate that disease-specific iPS cell–derived cardiomyocytes from an LQTS 3 mouse model with a human mutation recapitulate the typical pathophysiological phenotype in vitro. Thus, this method is a powerful tool to investigate disease mechanisms in vitro and to perform patient-specific drug screening. (Circ Res. 2011;109:841-847.)