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Anthracycline-induced atrial structural and electrical remodeling characterizes early cardiotoxicity and contributes to atrial conductive instability and dysfunction.

AIMS
Cancer patients treated with anthracyclines are susceptible to atrial fibrillation (AF), while the mechanisms remain unclear. Due to sudden and unpredictable features, prediction of anthracycline-induced AF at early phase is difficult. Clinically, we tested whether anthracycline-induced early atrial remodeling in patients could be detected by echocardiography. Experimentally, we investigated mechanisms of doxorubicin-induced atrial remodeling and AF in mice, and the protective effects of dexrazoxane and antioxidants.


METHODS AND RESULTS
Post-surgery breast cancer patients with an anthracycline-containing or exclusion regimen were recruited for echocardiography at pre-chemotherapy, and 3 and 6 months post-chemotherapy. Mice were injected with doxorubicin or vehicle (5 mg/kg/week, 4 weeks), left atrial diameter, electrical transmission and AF inducibility were measured. Meanwhile, level of ROS, activity of antioxidant enzymes, cardiomyocyte size, vacuolization, inflammation and fibrosis were also measured in mouse atria. The therapeutic effect of dexrazoxane and antioxidants on doxorubicin-induced changes in the aforementioned parameters were also determined. Whilst ventricular parameters and functions were unchanged in cancer patients receiving anthracyclines at pre- and post-chemotherapy, left atrial reservoir and conduit function were decreased at 3 months post-chemotherapy vs pre-chemotherapy. Doxorubicin-induced susceptibility to AF occurred in mice prior to onset of ventricular dysfunction. Doxorubicin-induced AF was via inducing structural remodeling (cardiomyocyte death, hypotrophy and vacuolization) and electrical remodeling (reduction and redistribution of connexin 43) in atria, which was effectively prevented by dexrazoxane or antioxidants through inhibiting ROS generation or enhancing ROS elimination. Innovation and Conclusion: AF inducibility was induced after doxorubicin injection, which can be inhibited by repressing ROS level.