Abstract P3112: Pharmacological Inhibition Of ATM Sensitizes Rabbit Hearts For Development Of Chronic Anthracycline Cardiotoxicity And Heart Failure

Introduction: Anthracycline (ANT) cardiotoxicity is still a serious complication of cancer chemotherapy. While it has been originally explained by direct oxidative damage to the heart, recently topoisomerase II beta (TOP2B)-dependent DNA damage to cardiomyocytes has been implicated. However, the specific role of DNA damage response (DDR) signaling downstream of TOP2B in the development of chronic ANT cardiotoxicity remains unclear. Hypothesis: Pharmacological inhibition of ATM will confirm the involvement of the ATM pathway in DDR signaling in the heart after ANT exposure and determine whether this signaling leads to the development of ANT cardiotoxicity or the opposite is true. Methods: A well-established rabbit model of chronic ANT cardiotoxicity (daunorubicin/DAU/3 mg/kg, weekly for ten weeks) was employed. The highly selective ATM inhibitor AZD0156, which is currently in clinical evaluation elsewhere, was administered at 0.5 mg/kg before each DAU dose. The results were compared with the group receiving AZD0156 alone and the controls receiving saline or vehicle for AZD0156. In another set of animals, the acute DDR in the heart was studied 6 hours after a single administration of the same drugs. Results: AZD0156 effectively prevented acute DAU-induced increase of p53 levels and up-regulation of p53 target genes (p21 and many others) in the left ventricular myocardium. Chronic co-treatment of AZD0156 with DAU markedly increased the incidence of DAU-induced blood congestion (hydrothorax 80 % vs. 40 % in the DAU-alone group), end-stage heart failure, and heart failure-related mortality (60 % vs. 20 % in the DAU-alone group). Before the observed deaths, plasma levels of cardiac troponin T increased steeply, while left ventricular fractional shortening (LVFS) determined by echocardiography declined. The last measured LVFS values in the AZD0156+DAU group were significantly lower than in the DAU-alone group. AZD0156 alone was well tolerated and had no significant impact on any studied parameter. Conclusion: ANT-induced DDR signaling in the heart appears to be ATM-dependent, and pharmacological inhibition of ATM sensitizes rabbit hearts to ANT-induced chronic cardiotoxicity and heart failure.