Effect of glutamine on doxorubicin-induced cardiotoxicity: an echocardiographic assessment.

Abstract

Abstract Abstract #6143 Background: Doxorubicin (DOX) is a widely used chemotherapeutic agent with a dose-dependent cardiotoxicity. Previous studies showed that dietary glutamine (GLN) reduced cardiac oxidative damages in rats treated with DOX through the increase of cardiac and blood glutathione, reduction of cardiac lipid peroxidation and reducing cardiac apoptosis. The present study aimed to examine further the effect of GLN on DOX-induced cardiac injury and to gain insight into the physiological aspects of this process by using high-resolution micro-ultrasound imaging and Doppler echocardiography.
 Materials and Methods: Female Fisher 344 rats (n=12) were randomized into 2 groups: (i) GLN-supplemented (n=6) and ii) controls (n=6). GLN-supplemented rats received 1g/kg/day GLN via gavage starting 1 week before DOX administration. DOX (12 mg/kg) was injected i.p. in all animals. Each animal was examined before DOX administration, 3 days, 7 days, and 10 days after DOX administration using ultrasound imaging system Vevo 770 (VisualSonics, Toronto, ON, Canada). RMVTM 716 "high frame" scan head, designed for real-time small animal imaging applications, was used. The short-axis imaging was taken in B-mode to view the left ventricle (LV) movement during diastole and systole. Anatomical M-mode was used to obtain LV measurements including LV end-diastolic and systolic inner diameters, LV posterior wall, LV ejection fraction (%EF) and LV fraction shortening (%FS). The LV filling was evaluated by pulsed-Doppler sampling of the mitral valve (MV) inflow. The peak E-wave velocity (E), peak A-wave velocity (A) and the MV E/A ratio were obtained. All data and images were saved and analyzed by Vevo 770 Analytic Software (VisualSonics, Toronto, ON, Canada).
 Results: Ten days after DOX treatment the control animals had: i) increased LV posterior wall end-diastolic thickness of an average from 1.7 mm before DOX administration to 1.8 mm and end-systolic from 2.9 mm to 3.7 mm; ii) reduction of the %EF by 10% and %FS by 14%; and iii) increased MVE by 30% with a resulting MVE/A ratio >2.0; all these suggestive of the development of restrictive cardiomyopathy (RCM). RCM, characterized by thickening and increased rigidity of the endocardium due to infiltration and fibrosis, restrictive ventricular filling with MVE/A >2.0 and in some cases reduction of the EF, has been reported in several clinical studies of patients treated with DOX. In GLN-supplemented rats of this study there was no statistically significant difference between posterior wall thickness before and after DOX administration, MVE/A ratio was maintained between 1.4 and 1.8; and EF was reduced by 2% only.
 Conclusions: The results from this study are in agreement with our previous data showing that GLN is able to reduce cardiac oxidative damages caused by DOX. This data further confirmed the safety of GLN supplementation and its cardioprotective effects during chemotherapeutic treatment with DOX.
 Acknowledgements: This work was supported by a grant from Susan G. Komen to VKT. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6143.