Toxicology and applied pharmacology · 2025
Nilotinib impairs relaxation and temporal electro-mechanical integrity in human iPS-derived cardiomyocyte sheets.
СтатьяНазвание и аннотация: Перевод в очереди
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Izumi-Nakaseko Hiroko, Sekino Yuko, Kambayashi Ryuichi, Goto Ai, Takei Yoshinori, Himeno Yukiko, Okado-Matsumoto Ayako, Nagasawa Yoshinobu, Naito Atsuhiko T, Kanda Yasunari, Sugiyama Atsushi
Аннотация
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.
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.