Abstract Background - The tyrosine kinase inhibitor (TKI) nilotinib has improved treatment for patients with chronic myeloid leukaemia resistant to conventional therapy with imatinib. Unfortunately, compared to imatinib, nilotinib is linked to a higher incidence of cardiotoxic side effects, ranging from subclinical electrophysiological changes to life-threatening cardiac events. The underlying mechanisms driving these myocardial toxicities remain largely unknown. We assessed the incidence of cardiovascular toxicities and then analysed the direct impact of both drugs on three major cardiac cell types in vitro. Methods – Data from the FDA Adverse Event Reporting System (FEARS) was used to determine the incidence of nilotinib and imatinib-associated cardiovascular events. In vitro, human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs), cardiac fibroblast (CFs) and endothelial cells (ECs) were cultured and treated with 1 µM nilotinib or imatinib for 72 hours. Cell viability was assessed using the CellTiter-Glo® and gene expression analyses were performed to evaluate fibroblast-to-myofibroblast transition and (early) endothelial-to-mesenchymal transition in CFs and ECs, respectively. Results – Based upon FEARS, we determined a higher incidence (15.6%) of cardiac events in nilotinib-treated patients compared to those treated with imatinib (6.4%). In vitro, cell viability was affected in all three cell types when exposed to nilotinib compared to untreated controls: CFs (27.4%, p 0.0001; % residual cell viability, p-value), hiPSC-CMs (64.4%, p = 0.02), and ECs (60.4%, p = 0.04). Imatinib affected cell viability in neither of the three cell types. Both drugs led to increased Col3α1 (nilotinib, p = 0.02; imatinib, p = 0.02) expression in CFs, whereas Col1α1 and fibronectin expression showed a discrepancy. Notably, nilotinib significantly increased αSMA expression (p 0.0001), suggesting the transition to the myofibroblast phenotype. Both drugs did not impair EC integrity. Conclusion – A current extraction from a medication registry validated that nilotinib is more cardiotoxic than imatinib. Mechanistically, nilotinib exerts a more potent direct cytotoxic effect on cardiac cells in vitro compared to imatinib. Our data underscore the importance of investigating pro-fibrotic responses potentially impairing cardiac function in patients treated with TKIs.
Meijers et al. (Fri,) studied this question.