P400Subtle changes in cardiac function produced by anticancer-biological therapies are detected with speckle tracking echocardiography in murine models

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Purpose: Cardiotoxicity is a drawback linked to many anticancer treatments. Early identification of signs of this adversity would benefit the management of oncologic patients. New biological therapies target proteins that regulate tumor growth, but are important for cardiac homeostasis as well. The ErbB2/PI3K/Akt pathway converges on mTOR, which is a central regulator of cell growth, including cardiomyocyte growth. Here, we aim at evaluating the cardiac effects of the inhibition of this pathway at different levels, comparing the cardiac effects of the anticancer mTOR-inhibitor temsirolimus (Tem) to the prototype ErbB2-inhibitor, trastuzumab (Tras), in a mouse model in vivo.Methods: LV fractional shortening (FS) was assessed by M-mode echocardiography in sedated C57BL6 mice (2-4 mo. old) at day 0, and after 2, 7, 14, 21 days from a single i.p. injection of Tem (0.1mg/kg, a dose comparable to the one used to treat cancer in humans) or vehicle. The effects of Tras (2.25 mg/kg/day for 7 days) and Doxo (2.17 mg/kg/day for 7 days) were also evaluated. With Speckle Tracking echocardiography (ST) we also assessed radial myocardial strain (%), a very sensitive parameter which can detect subtle changes in cardiac function.Results: After 2 days, there was no change in FS with Tem or Tras, but FS was already reduced with Doxo: 52±0.2%, p=.0000001 vs sham (60±0.4%). With Tras, FS was reduced after 7 days: 49±1.5%, p=.002 vs sham (60±0.5%,), while with Tem FS was reduced only after 21 days: 50±3%, p=.009 vs sham (60±0.8%). Interestingly, with Speckle Tracking echocardiography we found that in the Tras group radial strain was already reduced at 2 days: 44±7%, p<0.05 vs sham (66±0.6%). Also in the Tem group, radial strain alterations preceded FS alterations, since they were already present at 7 days: 42±5%, p=.01 vs sham (59±1%).Conclusions: Antineoplastic blockers of the ErbB2/PI3K/Akt/mTOR pathway induce LV dysfunction in mice. Such dysfunction occurs later compared to Doxo, but speckle tracking echocardiography is more sensitive than conventional echocardiography in detecting early signs of myocardial alteration that may prelude to overt dysfunction. The clear mechanisms of cardiotoxicity of such biological drugs are to be elucidated in further studies. Interestingly, downstream inhibition of the pathway (mTOR) seems to be less cardiotoxic than upstream inhibition of the ErbB2 receptor itself. We also plan to apply speckle tracking echocardiography to clinical studies, in order to evaluate the impact of early identification of temsirolimus cardiotoxicity in the treatment of renal cell carcinoma.

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