Aim: Treatment of chronic myeloid leukemia patients with the second and third generation BCR-ABL1 tyrosine kinase inhibitors (TKIs) increases cardiovascular side effects including myocardial infarction. We investigated the effect of these TKIs on cardiovascular risk factors (plasma lipids, blood pressure, inflammation markers, endothelial dysfunction) and development of atherosclerosis, in a translational model for atherosclerosis, the APOE3*Leiden.CETP mouse. Methods: First, dose and dosage interval were determined by PK analysis to reach similar plasma concentrations as in patients. Next, mice were treated for sixteen weeks with imatinib (150 mg/kg BID), nilotinib (30 mg/ kg QD) or ponatinib (10 mg/kg QD), as representatives of the first, second and third generation TKIs. Cardiovascular risk factors were analyzed throughout, and histopathological analysis of atherosclerosis and gene expression and pathway analysis in the liver as predictor tissue were performed. Results: Imatinib and ponatinib decreased plasma cholesterol (-69%, P<0.001 and-37%, P<0.001) and atherosclerotic lesion area (-78%, P<0.001 and-48% P¼0.001), which were not affected by nilotinib. In addition, imatinib reduced inflammation markers and increased plaque stability. Ponatinib increased E-selectin levels (161%, P<0.05) and the urinary albumin:creatinin ratio (13-fold, N.S.). All three TKIs decreased pro-inflammatory Ly6Chigh monocytes, consistent with the mode of action of TKIs. Gene expression pathway analysis confirmed our findings on decreased cardiovascular risk by imatinib and increased risk by ponatinib. Conclusions: Imatinib showed a beneficial cardiovascular risk profile and nilotinib had no adverse cardiovascular effects, whereas ponatinib despite favorable effects on plasma lipids and atherosclerosis increased the cardiovascular risk through increased inflammation and endothelial activation.
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