Imatinib Mesylate Induced Cardiotoxicity: a Cardiac Progenitor Cell Disease?.

Abstract 2200

Poster Board II-177

Cardiotoxicity is a limiting factor of successful anthracycline-based anticancer regimens. Recently, cardiac side effects have been also reported for Tyrosine Kinase Inhibitors, among which Imatinib Mesylate (IM) has been able to change the natural history of Chronic Myeloid Leukemia (CML) and Gastrointestinal Stromal Tumors. The mechanism of IM-related cardiac dysfunction has not been fully elucidated. Since we have demonstrated the presence of resident cardiac stem cells controlling homeostasis of the human and murine heart, we advanced the hypothesis that IM-induced cardiotoxicity involves myocardial cell turnover resulting in an impairment of the adaptive response of the heart to the toxic insult. To this purpose, we studied the in vitro genotoxic effect of 5mM, 25mM and 50 mM concentrations of IM on human and rat Cardiac Progenitor Cells (CPCs). Freshly isolated human BM CML cells carrying Bcr/Abl translocation served as control. In addition, to ascertain whether IM affects cardiac structure and function, young rats were treated by three weekly i.p. injections of 50, 100 and 200 mg/kg IM for 4 weeks when hemodynamic parameters and LV remodelling were analyzed. A dose and time dependent DNA damage was observed in both CPCs and CML after in vitro exposure to IM. As early as 6 hours after 50 mM IM, DNA double strand breaks formation (dSBs), as shown by immunostaining of Histone A2X, involved 50% and 70% of CPCs and CML, respectively. At later time points more than 80% of both cells died. However, low concentrations (5mM), corresponding to therapeutic doses, exerted a permissive reparative response on CPCs that persisted with time. As a result of this divergent effect, CPCs proliferation and survival increased from 12 to 24 h in spite of the presence of IM. In vivo studies showed that, following 200 mg/kg IM, all animals died within the first 2 weeks. In the presence of moderate anemia, diastolic dysfunction was present even at 50 mg/kg IM and a dose dependent impairment in Left Ventricular End Diastolic Pressure (LVEDP) and +/- dP/dT was observed. Anatomical parameters indicated that only higher doses IM resulted in a smaller LV with a concentric type of remodelling. In the absence of diffuse myocardial fibrosis and/or high levels of apoptosis, small foci of myocardial damage were observed only with 200 mg/kg IM. Preliminary data on myocardial cell turnover indicate that high doses of IM blunted the proliferative response.of cardiomyocytes to the cytotoxic injury. Conversely, in agreement with in vitro data, low IM doses were associated with a reparative response. In conclusion, IM, by inhibiting the multiple pathways modulated by tyrosine kinases, affects in a dose dependent manner CPCs and cardiac function suggesting possible alternative mechanisms of its effects on the cardiovascular system.