Nilotinib impairs relaxation and temporal electro-mechanical integrity in human iPS-derived cardiomyocyte sheets.

INTRODUCTION

Nilotinib, an anti-tumor tyrosine kinase inhibitor against BCR-ABL1, has been clinically reported to cause QT prolongation, but currently lacks evidence for a risk of torsade de pointes. Indeed, it is poorly understood why nilotinib rarely induces torsade de pointes.

METHODS AND

RESULTS

We adopted two-dimensional human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) sheets to examine effects of nilotinib on their electrophysiological and mechanical properties besides intracellular calcium (Ca2+) dynamics. Nilotinib prolonged repolarization in concentration- and reverse-frequency-dependent manners but shortened the contraction-relaxation duration (CRD), which made the electro-mechanical window negative in hiPSC-CM sheets. These effects would correspond to "trigger" of drug-induced torsade de pointes. The drug also suppressed mitochondrial maximum respiration and decreased the peak amplitude and the decay rate of Ca2+ transients, which shortened the CRD and impaired relaxation function of the cell sheets, partly explaining the onset mechanism of nilotinib-induced heart failure in patients. Additionally, nilotinib-induced early afterdepolarization (EAD) fluctuated the conduction speed and repolarization, and shifted the electro-mechanical window in a negative direction. These phenomena increased beat-to-beat variability of repolarization and electrical vulnerability of the heart. Meanwhile, nilotinib caused the conduction delay by Na channel blockade, thereby blocking "substrate" formation for the arrhythmia persistence.

CONCLUSION

Nilotinib could deteriorate relaxation ability and temporal electrical integrity of the heart through impairing Ca2+ dynamics as well as repolarization phase, which were exacerbated by nilotinib-induced EAD. However, the drug only formed "trigger", which would explain the lower occurrence of nilotinib-induced torsade de pointes.