Early detection of cardiac dysfunction induced by the mTOR inhibitor temsirolimus.

Abstract

e13612 Background: The mTOR inhibitor temsirolimus is being evaluated for anticancer efficacy in hundreds of clinical trials and is approved for treatment of advanced renal cell carcinoma. The PI3K/Akt pathway converges on mTOR, which is a central regulator of cell growth, including cardiomyocyte growth. Hence, we assess whether the anticancer mTOR inhibitor temsirolimus affects cardiac function. Methods: In vivo cardiac function was measured with left ventricular (LV) fractional shortening (FS) 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. administration of temsirolimus (0.1μg/g, a dose comparable to the one used to treat cancer in humans) or vehicle. Doxorubicin (Doxo, 2.17 μg/g/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 predict LV dysfunction. 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%). FS was reduced only after 21 days in the temsirolimus group: 50±3%, p=.009 vs sham. Interestingly, with speckle tracking echocardiography we found that radial strain was already decreased at 7 days: 42±5%, p=.01 vs sham (59±1%). Conclusions: The mTOR inhibitor temsirolimus induces LV dysfunction in mice. Such dysfunction occurs later than the one observed with Doxo, but can be identified with speckle tracking echocardiography (reduction in myocardial strain) before a decrease in FS is observed with conventional echocardiography. 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.