[Eur Heart J] Development of a reentrant arrhythmia model in human pluripotent stem cell-derived cardiac cell sheets

1 December 2012

[European Heart Journal] Development of a human cell-derived reentrant arrhythmia model is needed for studying the mechanisms of disease and accurate drug response.

The Norio Nakatsuji and Konstantin Agladze labs and their colleagues at Kyoto University iCeMS have differentiated human pluripotent stem cells (hPSCs) into cardiomyocytes, and then re-plated them into cell sheets that proved capable of forming electrically coupled assemblies. The labs monitored the function of these re-plated sheets optically with the Ca2+ sensitive dye Fluo-4, and found that they generated characteristic waves of activity whose velocity and patterns of propagation depended upon the concentration of sodium channel blockers; lidocaine and tetrodotoxin, and also the time after re-plating, as well as the applied stimulation frequency. Importantly, reentrant spiral-wave propagation could be generated in these sheets by applying high-frequency stimulation, particularly when cell-density in the sheets was relatively low. This was because cardiac troponin T-positive cells were more non-homogeneously distributed at low cell densities. Especially in such sheets, the labs could terminate spiral waves by administering the anti-arrhythmic drugs; nifekalant, E-4031, sotalol, and quinidine. The labs also found that in these sheets, nifekalant showed a clear dose-dependent increase in the size of the unexcitable 'cores' of these induced spiral waves, an important parallel with the treatment for ventricular tachycardia in the clinical situation, which was not shown properly in cardiac-cell sheets derived from dissociated rodent hearts.

The labs have succeeded in creating from hPSCs a valuable type of cardiomyocyte sheet that is capable of generating reentrant arrhythmias, and thus is demonstrably useful for screening and testing all sorts of drugs with anti-arrhythmic potential. [Extenal LinkRead more]

These findings have received nationwide media coverage in Japan.

Publication information

Development of a reentrant arrhythmia model in human pluripotent stem cell-derived cardiac cell sheets
Shin Kadota, Itsunari Minami, Nobuhiro Morone, John E Heuser, Konstantin Agladze*, Norio Nakatsuji*
European Heart Journal | Published online 30 November 2012 | DOI: 10.1093/eurheartj/ehs418