BCR‐ABL tyrosine kinase inhibitors promote pathological changes in dilator phenotype in the human microvasculature

Abstract

Objective Treatment with BCR‐ABL tyrosine kinase inhibitors (TKIs) is the standard of care for patients with chronic myeloid leukemia, however evidence indicates these compounds may have cardiovascular side‐effects. This study sought to determine if ex vivo exposure of human adipose arterioles to the BCR‐ABL TKIs imatinib and nilotinib causes endothelial dysfunction. Methods Human adipose arterioles were incubated overnight in cell culture media containing vehicle (PBS), imatinib (10 µmol/L) or nilotinib (100 µmol/L). Arterioles were cannulated onto glass pipettes and flow mediated dilation (FMD) was assessed via video microscopy. To determine the mechanism of vasodilation, FMD was re‐assessed in the presence of either the nitric oxide synthase inhibitor L‐NAME (100 µmol/L) or the H2O2 scavenger PEG‐Catalase (500 U/mL). Results Neither imatinib nor nilotinib affected the magnitude of FMD (max dilation = 78±17% vehicle, 80 ± 24% nilotinib, 73 ± 13% imatinib). FMD was decreased by L‐NAME in vehicle‐treated arterioles (max dilation = 47±29%). Conversely, L‐NAME had no effect on FMD in imatinib‐ or nilotinib‐treated vessels (max dilation = 79±14% and 80 ± 24%, respectively), rather FMD was inhibited by PEG‐Catalase (max dilation = 29±11% and 29 ± 14%, respectively). Conclusion Incubating human arterioles with imatinib or nilotinib switches the mediator of FMD from vasoprotective nitric oxide to pro‐inflammatory H2O2.

Predictive value of clinical examination parameters for cardiovascular adverse events during treatment of chronic myeloid leukemia with tyrosine kinase inhibitors

“…TKIs are thought to cause CAE by changing the functions of cells, including vascular endothelial cells, platelets, and immune cells (T cells, mast cells, and macrophages). Further, CAE pathogenesis also depends on the type of TKI [29][30][31][32][33][34][35], manifesting differently among patients receiving different TKI drugs [13,24]. Therefore, there may be value in developing specific monitoring and prevention methods, depending on the type of TKI used, or routine monitoring using other inspection methods to capture different types of CAE.…”