Abstract 174: Late INa Inhibition with Ranolazine Blunts Doxorubicin-Induced Cardiac Dysfunction and Remodeling in Mice
Background. Doxorubicin (DOX) produces a well-known cardiomyopathy through multiple mechanisms, which include, among many, Ca2+ overload due to reduced SERCA2a activity and inappropriate opening of the RyR2, and impaired myocardial energetics. DOX generate Reactive Oxygen and Nitrogen Species (ROS and RNS), posing the heart at increased demand for oxygen, setting the stage for metabolic ischemia that also activates late INa, target of ranolazine (RAN). Here, we aim at assessing whether RAN, diminishing intracellular Ca2+ through inhibition of late INa, and enhancing myocardial glucose utilization (and/or reverting impairment of glucose utilization caused by chemotherapy) blunts DOX cardiotoxicity.
Methods. We measured left ventricular (LV) end-diastolic and end-systolic diameters (LVEDD and LVESD), and evaluated LV function with fractional shortening (FS) by echocardiography in C57BL6 mice, 2-4 mo old, pretreated with RAN (370mg/kg/day, a dose comparable to the one used in humans) per os for 3 days. RAN was then administered for additional 7 days, alone and together with DOX (2.17mg/kg/day ip), according to our well established protocol. Hearts were then excised, mRNA expression was analyzed by RT PCR.
Results. After 7 days with DOX, hearts were dilated with depressed function: LVEDD and LVESD increased from 2.8±.03 and 1.1±.03mm to 3.04±.06 and to 1.55±.08mm, respectively (both p<.005 vs sham). FS decreased to 50±2%, p=.002 vs 60±1% (sham). RAN alone did not change LV dimensions nor function. Interestingly, mice treated with RAN and DOX had smaller LVEDD and LVESD (2.85±.05 and 1.22±.03mm, respectively, both p<.05 vs DOX alone), with a better cardiac function: FS was 57±1%, p=.01 vs DOX alone. DOX-cardiotoxicity was accompanied by significant elevation in CTGF and MMP2 genes, showing alterations in extracellular matrix remodeling. Cardiac function improvement with RAN was paralleled by significantly lower levels of these same genes compared to DOX alone.
Conclusions. RAN blunts DOX cardiotoxic effects in mice, improving remodeling and function. We plan to test RAN as a cardioprotective agent with other antineoplastic cardiotoxic drugs in mice, and to better characterize the cardioprotective mechanisms of RAN in all these settings.
- © 2012 by American Heart Association, Inc.