Abstract 18766: Trastuzumab Cardiomyopathy is Prevented by the Administration of Ranolazine at the End of Antineoplastic Treatment in Model Mouse
Introduction: Trastuzumab (TRAS), an anti-ErbB2 inhibitor, is the foundation of care for patients with HER2-positive breast cancer. Cardiovascular complications due to TRAS are a growing problem in clinical practice that may frustrate modern oncological outcome of therapy (asymptomatic left ventricular dysfunction and heart failure). The mechanisms of cardiotoxicity of TRAS have not been fully elucidated and can include changes in Ca2+ regulation related to blockade of ErbB2 and PI3K-Akt and MAPK pathways.
Hypothesis: Here, we aim at assessing whether Ranolazine (RAN), administered after TRAS treatment, blunts TRAS cardiotoxicity in vivo.
Methods: To evaluate cardiac function in vivo, fractional shortening (FS) and ejection fraction (EF) were measured by M/B mode echocardiography and radial and longitudinal strain (RS and LS) were measured using 2D speckle-tracking echocardiography, in C57/BL6 mice, 2-4 mo old, at day 0, and after 2 and 7 days of daily administration of TRAS (2.25 mg/kg/day, ip). These measurements were repeated after 5 days of RAN treatment (305 mg/Kg/day, gavage, dose comparable with that used in humans of 750 mg twice) initiated at the end of TRAS treatment.
Results: In our in vivo studies, after 7 days with TRAS, FS decreased to 48.7±4.1%, p<0.01 vs 62.3±0.8% (sham), EF to 81.8±3.5%, p<0.01 vs 91.7±0.5% (sham), RS to 21±8.1%, p<0.01 vs 43.2±4% (sham), and LS to -11±3.7%, p<0.01 vs -38.8±6% (sham). In mice treated with RAN for 5 days after TRAS treatment, the indices of cardiac function recovered: FS was 61±1.2%, EF was 91±0.7%, p<0.01; RS was 21±8.1%, p<0.05 vs TRAS+RAN. However the alteration of LS persists after treatment with RAN (-15.4±5.1%, p=0.3 vs TRAS+RAN).
Conclusions: RAN post-treatment blunts cardiotoxic effects due to TRAS, as demonstrated by the normalization of the values of FS, EF and RS. The explanation for the persistent abnormalities of LS could be that the subendocardial fibers, responsible for the alteration of LS, are the first to impair and may be the last to recover.
Author Disclosures: C. Coppola: None. G. Piscopo: None. F. Galletta: None. C. Maurea: None. D. Rea: None. C. Arra: None. N. Maurea: None.
- © 2014 by American Heart Association, Inc.