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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. Disclosures: No relevant conflicts of interest to declare.

Abstract 1482 Poster Board I-505 Alterations in cell trafficking and chemoattractive properties may represent basic mechanisms responsible for organ pathology in diabetes mellitus (DM). These functional events involving both inflammatory and progenitor cells may be translated in the proneness to major septic events and effaced reparative response characterizing the clinical course of the disease. To determine whether DM affects BM progenitor cell number and function, tissue resident and GSF mobilized disease-free BM CD34pos cells were evaluated in 19 DM and 38 non-diabetic control (CTR) biopsies and in 18 DM and 48 CTR patients undergoing autologous BM transplantation. DM was documented by the presence of glucose intolerance, HbA1C > 6 g% and need of high dose insulin treatment. CTR were selected on the basis of normal glucose tolerance and the absence of neoplastic infiltration and/or morphologic changes in cellular hematopoietic compartments compatible with hematologic disorders. Reduction in trabecular bone, fat accumulation, rearrangement of microvascular structures and marked DNA oxidative damage characterized BM structural and cellular remodelling in DM. Immunohistochemical and FACS analysis documented that DM produced a 50% reduction in the number of both BM resident and mobilized CD34pos Linneg cells. In addition only 16% of diabetic patients were able to mobilize >10 × 106 CD34pos cells/kg compared to 62% of CTR. After infusion of mobilized CD34pos progenitors, BM engraftment was partially prolonged in diabetic patients. Severe impairment of SC engraftment by DM was striking by the comparative analysis of the infusion of similar number of mononuclear cells (nearly 180 ×106/Kg) directly harvested from the bone marrow of DM and CTR patients. In this setting, PMN and Plts recovery was delayed by nearly 2 and 4 weeks, respectively. Thus, DM severely affects human progenitor cell function and BM microenvronment in vivo inevitably impairing the outcome of BM transplantation. Whether all these changes are due to specific perturbation of the GSF-dependent SDF-1/CXCR4 axis and whether drugs interfering with ROS mediated damage may reverse this phenomenon is under intense investigation. Disclosures: No relevant conflicts of interest to declare.