In terms of ROS production, DNA damage, and cardiomyocyte apoptosis in cardiomyocyte cell culture in vitro as well as in the mouse in vivo. We found a reduction in LVEF that was significantly less with epirubicin and non-pegylated liposomal-doxorubicin as compared to standard doxorubicin. Furthermore, we found that epirubicin reduces the heart rate to a similar degree as doxorubicin while liposomal doxorubicin did not depress the heart rate. In animal models of anthracyclines toxicity, doxorubicin was proven to consistently induce a reduction in resting heart rate, reflective of damage of the sinoatrial node. While all three drugs reduced LVEF, treatment with liposomal doxorubicin led to a modest reduction in LVEF and a modest increase in heart rate, thereby maintaining a normal cardiac output, a measure dependent on stroke volume x heart rate]. While this work analyzed different markers of cardiac toxicity using both in vitro cultures of adult murine cardiomyocytes and the in vivo mouse model, we cannot exclude the possibility that the differences observed between the liposomal formulation of doxorubicin and standard doxorubicin and epirubicin will prove to be less dramatic in the clinical setting. Prior studies have shown that preclinical models, in which significant benefits were observed with treatments designed to counteract ROS production following anthracycline therapy failed to translate to the patient population, leading to a reappraisal of the clinical importance of the oxidative stress paradigm. One other limitation of our study was to evaluate the myocardial damage based on echocardiographic parameters only. The use of markers of myocardial damage as the serum levels of cardiac troponin T or cardiac troponin I may be an alternative technique to assess cardiac damage. Another possible limitation in our study is the use of a stable cell line of murine cardiomyocytes. The use of immortalized cell lines presents both advantages and limitations. Replicating cardiac myocytes are often used to study the cardiotoxic effects of anthracyclines as these models generally express the majority of cardiac specific genes and have a beating phenotype. In this study we decided to use mouse-derived adult cardiomyocytes over other cell lines since they origin from the same species used in the in-vivo experiments. However, cardiomyocytes represent only one component of cardiac function and future studies using fibroblasts, endothelial cells may help to collect additional data on different cardiotoxic profiles of these three anthracyclines of the heart function. Furthermore, the choice of the correct animal species or strain is a challenging step since each animal species or strains may present advantages and limitations. We choose CF-1 mice over other strains due to their extensive use in studies on anthracyclines cardiotoxicity and because they have a slightly bigger size compared to other mice, making it easier to assess heart function and dimensions. The use of both in vivo and in vitro models helps to overcome some of the limitations of each model. The in vitro assays were planned to determine the acute effects of the anthracyclines on the cardiomyocytes and to assess whether they could corroborate the chronic in vivo effects. Although there is no evidence of delayed effects of the non-pegylated liposomal-doxorubicin compared to the other anthracyclines in vitro.
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