Abstract P352: the Anticancer Mtor-Inhibitor Temsirolimus Produces Left Ventricular Dysfunction in Murine Hearts

Background: Cardiotoxicity is a major drawback and social problem linked to many anticancer treatments. Early identification of signs of this adversity would certainly benefit the management of oncologic patients. The mTOR-inhibitor temsirolimus is currently being evaluated for anticancer efficacy in hundreds of clinical trials and is approved for treatment of advanced renal cell carcinoma. However, the 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 anticancer mTOR-inhibitor temsirolimus in a mouse model in vivo. Methods: Left Ventricular (LV) fractional shortening (FS) was assessed by M-mode echocardiography in sedated C57BL/6 mice (2–4 mo. old) at day 0, and after 2, 7, 14, 21 days from a single i.p. injection of temsirolimus (0.1mg/kg, a dose comparable to the one used to treat cancer in humans) or vehicle. Doxorubicin (Doxo, 2.17 mg/kg/day for 7 days) was used as a positive control. With Speckle Tracking echocardiography (ST) we also evaluated 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 temsirolimus, but FS was already reduced with Doxo: 52±0.2%, p=.0000001 vs sham (60±0.4%). With temsirolimus, FS was reduced only after 21 days: 50±3%, p=.009 vs sham. Interestingly, with Speckle Tracking echocardiography we found that in the temsirolimus group radial strain was already decreased at 7 days: 42±5%, p=.01 vs sham (59±1%). Conclusions: The antineoplastic mTOR-inhibitor temsirolimus induces LV dysfunction in mice. Such dysfunction occurs later than the one observed with Doxo, but speckle tracking echocardiography is more sensitive than conventional echocardiography and can detect early signs of myocardial alteration that may prelude to overt LV dysfunction. The clear mechanisms of temsirolimus cardiotoxicity are to be elucidated in further experimental studies. 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.