Human induced pluripotent stem (iPS) cells potentially provide a unique resource 
for generating patient-specific cardiomyocytes to study cardiac disease 
mechanisms and treatments. However, existing approaches to cardiomyocyte 
production from human iPS cells are inefficient, limiting the application of iPS 
cells in basic and translational cardiac research. Furthermore, strategies to 
accurately record changes in iPS cell-derived cardiomyocyte action potential 
duration (APD) are needed to monitor APD-related cardiac disease and for rapid 
drug screening. We examined whether modulation of the bone morphogenetic protein 
4 (BMP-4) and Wnt/β-catenin signaling pathways could induce efficient cardiac 
differentiation of human iPS cells. We found that early treatment of human iPS 
cells with BMP-4 followed by late treatment with small molecule Wnt inhibitors 
led to a marked increase in production of cardiomyocytes compared to existing 
differentiation strategies. Using immunocytochemical staining and real-time 
intracellular calcium imaging, we showed that these induced cardiomyocytes 
expressed typical sarcomeric markers, exhibited normal rhythmic Ca(2+) 
transients, and responded to both β-adrenergic and electric stimulation. 
Furthermore, human iPS cell-derived cardiomyocytes demonstrated characteristic 
changes in action potential duration in response to cardioactive drugs 
procainamide and verapamil using voltage-sensitive dye-based optical recording. 
Thus, modulation of the BMP-4 and Wnt signaling pathways in human iPS cells 
leads to highly efficient production of cardiomyocytes with typical 
electrophysiological function and pharmacologic responsiveness. The use of human 
iPS cell-derived cardiomyocytes and the application of calcium- and 
voltage-sensitive dyes for the direct, rapid measurement of iPS cell-derived 
cardiomyocyte activity promise to offer attractive platforms for studying 
cardiac disease mechanisms and therapeutics.