Abstract P3111: Can ACE Inhibitors Provide Similar Long-lasting Cardioprotection Against Chronic Anthracycline Cardiotoxicity As An Approved Drug Dexrazoxane On A Well-established Animal Model?

Abstract

Background: ACE inhibitors (ACEi) have been reported cardioprotective in a secondary prevention of anthracycline (ANT) cardiotoxicity in high-risk patients. However, it remains to be determined whether they can also prevent the onset of ANT-induced cardiac damage and provide long-lasting cardioprotection in primary settings similarly as approved drug dexrazoxane (DEX). Objectives: The aim of this study was to assess whether ACEis can prevent TOP2B-mediated DNA damage induced by ANTs in the heart as a very upstream event, and thus provide long-lasting cardioprotection against chronic ANT cardiotoxicity. Methods: Chronic cardiotoxicity was induced in rabbits by daunorubicin (DAU, 3 mg/kg weekly for 10 weeks). Perindopril (PER) in two clinically relevant doses (0.05 and 0.1 mg/kg/day) was administered before and throughout the chronic DAU treatment. The cardioprotection was evaluated at the end of treatment period and after 3- and 10-week drug-free post-treatment follow-up (FU). TOP2B-depedent DNA damage signaling in the heart was determined 6 h after single dose of DAU, while TOPB interaction was studied in vitro ; the results were compared to DEX. Results: A week after completion of the chronic DAU administration, PER-co-treatment completely overcame or markedly reduced DAU-induced mortality, blood congestion and systolic dysfunction (LVFS 41.5% vs. 34.3% in the DAU group, p<0.05), increase of troponin T in plasma and histopathological changes in the heart. However, most of these parameters were significantly deteriorated during 3-week drug-free FU. Further worsening of the left ventricular systolic function and cardiac morphological damage occurred in the 10-week FU which led to a heart failure-related mortality in the PER co-treated group. DEX showed very effective protection against DAU cardiotoxicity both at the end of chronic treatment and after the 10-week FU. In contrast to DEX, the PER co-treatment did not affect TOP2B activity in vitro and did not prevent DAU-induced acute p53-mediated DNA damage signaling in the heart. Conclusions: Unlike approved drug DEX, the ACEi treatment provided only temporary control of ANT cardiotoxicity development which may be associated with the lack of the effects on ANT-induced and TOP2B-mediated DNA damage response in the heart.