Fetal Rat Hearts Do Not Display Acute Cardiotoxicity in Response to Maternal Doxorubicin Treatment

Abstract

Anthracyclines are used to treat cancers during the second and third trimester of pregnancy. The chemotherapeutic effect of anthracyclines is associated with a dose-and time-dependent cardiotoxicity that is well described for infants and adults. However, data regarding fetal anthracycline-related cardiotoxicity after administration of chemotherapeutics during pregnancy are limited. In this study, we analyzed the acute effect of doxorubicin, an anthracycline derivative, on fetal and maternal rat myocardium. We injected 10 or 20 mg/kg i.v. doxorubicin to pregnant Wistar rats at day 18 of pregnancy; age-matched pregnant rats injected with physiologic saline served as controls. Maternal echocardiography and fetal Doppler scanning were performed before the injection and before sacrifice. Cesarean operation was performed at day 19 or 20, and maternal and fetal blood samples and heart biopsies were collected to measure apoptosis, the impact on cell proliferation, and structural cardiac damage. Acute maternal cardiotoxicity is associated with loss of body weight, moderately deteriorated left ventricular function, induction of apoptosis, and a decrease in cell turnover. Despite a 30% lower fetal body weight and elevated plasma B-type natriuretic peptide concentrations after doxorubicin administration, the fetal hearts had intact microstructure, an unaltered number of apoptotic cells, and preserved cell proliferation compared with controls. Our study suggests that acute treatment using anthracyclines during pregnancy impairs maternal cardiac function, whereas fetal hearts are protected.

Regulation of Transplanted Cell Homing by FGF1 and PDGFB after Doxorubicin Myocardial Injury

“…LV wall thinning combined with a 14% reduction in LVIDd also led to significant reductions in EF, FS, SV and EDV in Dox treated mice in this study. Similar changes in cardiac geometry and hemodynamic parameters were also noted in animal models of Dox induced acute cardiotoxicity [ 52 , 53 , 54 , 55 ]. For instance, a single injection of Dox (20 mg/Kg) led to significant reductions in LVPWd dimension and fractional shortening (FS) in pregnant rats as early as 48-h time point [ 52 ].…”

“…Similar changes in cardiac geometry and hemodynamic parameters were also noted in animal models of Dox induced acute cardiotoxicity [ 52 , 53 , 54 , 55 ]. For instance, a single injection of Dox (20 mg/Kg) led to significant reductions in LVPWd dimension and fractional shortening (FS) in pregnant rats as early as 48-h time point [ 52 ]. In mice subjected to acute Dox treatment (20–25 mg/Kg), significant reductions in LVIDd, LVIDs, FS and cardiac output were noted 4–5 days after drug treatment [ 54 , 55 ].…”

Epirubicin: a new entry in the list of fetal cardiotoxic drugs? Intrauterine death of one fetus in a twin pregnancy. Case report and review of literature

“…Available data provide only limited experimental and clinical data on the transplacental transfer of these chemotherapeutics in pregnant women; in a baboon model, fetal plasma concentrations of doxorubicin, epirubicin and paclitaxel were about 7.5 %, 4.0 %, and 1.4 %, of the respective maternal concentrations [ 32 ]. Fetal blood samples from pregnant rats receiving doxorubicin showed a plasmatic concentration that was 6.2 % that of the mother; interestingly, neither Doppler analysis nor heart microstructure or cellular DNA turnover and apoptosis were influenced by doxorubicin exposure [ 33 ].…”

Exploring the safety of chemotherapy for treating breast cancer during pregnancy

“…In animal experiments, fetal rat hearts exposed to doxorubicin did not show acute cardiotoxicity in response to maternal treatment, with intact microstructure, unaltered number of apoptotic cells and preserved cell proliferation [50]. A small study in humans confirms no fetal cardiac dysfunction after anthracycline exposure during pregnancy [51].…”