Anthracycline-induced atrial structural and electrical remodeling
characterizes early cardiotoxicity and contributes to atrial
fibrillation
Abstract
Background and Purpose: Cancer patients treated with anthracyclines are
susceptible to atrial fibrillation (AF) with unknown mechanisms. Due to
sudden and unpredictable features of AF, detection or prediction of
anthracycline-induced AF at early phase is difficult. Experimental
Approach: Breast cancer patients (post-surgery) with an
anthracycline-containing regimen were recruited for echocardiography at
pre-, and 3 and 6 months post-chemotherapy. Mice were injected with
doxorubicin or vehicle and the following parameters were determined:
left atrial diameter, electrical transmission, AF inducibility.
Meanwhile, oxidative stress, cardiomyocyte size, vacuolization,
inflammation and fibrosis were measured in mouse atria. The therapeutic
effect of dexrazoxane on doxorubicin-induced changes in the
aforementioned parameters were also determined. Key Results: Whilst
ventricular parameters and functions were unchanged in cancer patients
pre- and post-chemotherapy, strain and strain rate of left atrial
reservoir function and conduit function were decreased at 3 months
post-chemotherapy vs pre-chemotherapy. Doxorubicin-induced atrial
dilatation and susceptibility to AF occurred in mice prior to onset of
ventricular dysfunction. Doxorubicin-induced AF was via inducing
structural remodeling (i.e. cardiomyocyte death, hypotrophy and
vacuolization) and electrical remodeling (i.e. reduction and
redistribution of connexin 43) in the atrium, which was effectively
prevented by dexrazoxane. Atrial remodeling and AF inducibility were
induced after doxorubicin injection, which can be inhibited by
dexrazoxane. Conclusions and Implications: Clinically, we tested whether
anthracycline-induced early atrial remodeling in patients could be
detected by echocardiography. Experimentally, we investigated the
mechanisms of doxorubicin-induced atrial remodeling and AF in mice, and
the protective effect of the free radical scavenger dexrazoxane.