Genetic predisposition to cardiovascular disease potentiates delayed doxorubicin cardiotoxicity during pregnancy

Doxorubicin (DOX) is an important antineoplastic agent with cardiotoxic effects that may manifest as heart failure years after therapy. Because of increased circulatory demands during gestation, pregnant women previously treated with DOX may be at increased risk for heart failure. Individuals with a genetic predisposition to cardiovascular disease may be particularly vulnerable. To test this hypothesis, peripubertal female rats predisposed to cardiovascular disease (Spontaneously Hypertensive [SHR] and Spontaneously Hypertensive Heart Failure [SHHF]), and control rats (Wistar Kyoto [WKY]) received 6 weekly injections of DOX (2 mg/kg subcutaneously) or an equal volume of saline (SAL). Four weeks later, the rats were bred with same strain males, and followed through lactation. DOX had no detectable effect on clinical health or fertility. Systolic function assessed echocardiographically as left ventricular fractional shortening (FS) did not change with either DOX or time, but WKY had higher FS (41%) than SHR/SHHF (32%). At the end of the DOX administration protocol, serum cardiac troponin-T concentration (cTnT), a biomarker of myocardial damage, was not different in SAL or DOX WKY or SHR/SHHF. However, at mid-gestation, cTnT was increased 4-fold in DOX SHR/SHHF, whereas it was unchanged in SAL and DOX WKY and SAL SHR/SHHF. These data suggest that genetic predisposition to cardiovascular disease potentiates DOX cardiotoxicity during pregnancy and may predict post-gestational DOX-induced heart failure.