Remote Ischemic Pre-Conditioning Attenuates Adverse Cardiac Remodeling and Mortality Following Doxorubicin Administration in Mice

Objectives Because of its multifaceted cardioprotective effects, remote ischemic pre-conditioning (RIPC) was examined as a strategy to attenuate doxorubicin (DOX) cardiotoxicity. Background The use of DOX is limited by dose-dependent cardiotoxicity and heart failure. Oxidative stress, mitochondrial dysfunction, inflammation, and autophagy modulation have been proposed as mediators of DOX cardiotoxicity. Methods After baseline echocardiography, adult male CD1 mice were randomized to either sham or RIPC protocol (3 cycles of 5 min femoral artery occlusion followed by 5 min reperfusion) 1 h before receiving DOX (20 mg/kg, intraperitoneal). The mice were observed primarily for survival over 85 days (86 mice). An additional cohort of 50 mice was randomized to either sham or RIPC 1 h before DOX treatment and was followed for 25 days, at which time cardiac fibrosis, apoptosis, and mitochondrial oxidative phosphorylation were assessed, as well as the expression profiles of apoptosis and autophagy markers. Results Survival was significantly improved in the RIPC cohort compared with the sham cohort (p = 0.007). DOX-induced cardiac fibrosis and apoptosis were significantly attenuated with RIPC compared with sham (p \u3c 0.05 and p \u3c 0.001, respectively). Although no mitochondrial dysfunction was detected at 25 days, there was a significant increase in autophagy markers with DOX that was attenuated with RIPC. Moreover, DOX caused a 49% decline in cardiac BCL2/BAX expression, which was restored with RIPC (p \u3c 0.05 vs. DOX). DOX also resulted in a 17% reduction in left ventricular mass at 25 days, which was prevented with RIPC (p \u3c 0.01), despite the lack of significant changes in left ventricular ejection fraction. Conclusions Our preclinical results suggested that RIPC before DOX administration might be a promising approach for attenuating DOX cardiotoxicity

Prevention of Anthracycline-Induced Cardiotoxicity Challenges and Opportunities

AbstractAnthracycline compounds are major culprits in chemotherapy-induced cardiotoxicity, which is the chief limiting factor in delivering optimal chemotherapy to cancer patients. Although extensive efforts have been devoted to identifying strategies to prevent anthracycline-induced cardiotoxicity, there is little consensus regarding the best approach. Recent advances in basic mechanisms of anthracycline-induced cardiotoxicity provided a unified theory to explain the old reactive-oxygen species hypothesis and identified topoisomerase 2β as the primary molecular target for cardioprotection. This review outlines current strategies for primary and secondary prevention of anthracycline-induced cardiotoxicity resulting from newly recognized molecular mechanisms and identifies knowledge gaps requiring further investigation