Introduction Subclinical cardiotoxicity occurs in cancer patients who receive low doses of anthracyclines such as doxorubicin (DOX), which can develop into overt cardiomyopathy when triggered by other cardiovascular stressors. Female rodents are protected from DOX‐induced cardiac dysfunction in experimental studies. However, the sex‐related differences in DOX‐induced increased susceptibility to later‐onset cardiovascular stressors are yet to be determined. Therefore, in the present study, we determined the effects of a low dose of DOX on the cardiac response to catecholamine stress induced by isoproterenol (ISO) in male and female mice. Since sex hormones are believed to mediate the sexually dimorphic response to DOX, we determined whether gonadectomy is able to reverse the observed response. Methods Five‐week old intact and gonadectomized male and female C57Bl/6 mice were administered saline or DOX (4 mg/kg/week for 5 weeks by intraperitoneal injections). After a 5‐week recovery period, mice were administered daily subcutaneous injections of ISO (10 mg/kg) or saline for 14 days. Cardiac function was measured by echocardiography before, immediately after the first dose of ISO (stress echo), and following 14 days of daily ISO injections. Hearts were harvested and weighed at the end of the experiment. Results Stress echo shows that the positive chronotropic effect of ISO was blunted in DOX‐treated male and female mice, while the positive inotropic effect is maintained. Following 14 days of daily ISO injections, saline‐treated male mice exhibited a hypertrophic response to ISO, indicated by an increase in the heart weight‐to‐tibia length, while DOX‐treated male mice did not. In addition, ISO caused more reduction of cardiac output in DOX‐treated male mice than that in saline‐treated male mice. On the other hand, both saline‐treated and DOX‐treated female groups exhibited a hypertrophic response to ISO. ISO treatment for 14 days did not cause significant reduction in cardiac output in either saline‐treated or DOX‐treated female mice. Similar experiments were performed in a cohort of gonadectomized male and female mice. Intriguingly, sexually dimorphic responses are observed in gonadectomized mice similar to those observed in intact mice. Conclusion Exposure to DOX modulates the cardiac response to isoproterenol in a sex‐dependent manner. DOX treatment abrogates the adaptive hypertrophic response to ISO in male mice, making them more susceptible to declining cardiac output. Deprivation of sex hormones by gonadectomy did not reverse this sexual dimorphism, suggesting that other mechanisms are implicated. Further research is warranted to determine the mechanisms of this sexual dimorphism.

Sex is a salient risk factor in the development of doxorubicin-induced cardiotoxicity. Sex differences in the heart’s ability to respond to hypertrophic stimuli in doxorubicin-exposed animals have not been reported. We identified the sexual dimorphic effects of isoproterenol in mice pre-exposed to doxorubicin. Male and female intact or gonadectomized C57BL/6N mice underwent five weekly intraperitoneal injections of 4 mg/kg doxorubicin followed by a five-week recovery period. Fourteen days of subcutaneous isoproterenol injections (10 mg/kg/day) were administered after the recovery period. Echocardiography was used to assess heart function one and five weeks after the last doxorubicin injection and on the fourteenth day of isoproterenol treatment. Thereafter, mice were euthanized, and the hearts were weighed and processed for histopathology and gene expression analysis. Doxorubicin did not produce overt cardiac dysfunction in male or female mice before starting isoproterenol treatment. The chronotropic response to a single isoproterenol injection was blunted by doxorubicin, but the inotropic response was maintained in both males and females. Pre-exposure to doxorubicin caused cardiac atrophy in both control and isoproterenol-treated male mice but not in female mice. Counterintuitively, pre-exposure to doxorubicin abrogated isoproterenol-induced cardiac fibrosis. However, there were no sex differences in the expression of markers of pathological hypertrophy, fibrosis, or inflammation. Gonadectomy did not reverse the sexually dimorphic effects of doxorubicin. Additionally, pre-exposure to doxorubicin abrogated the hypertrophic response to isoproterenol in castrated male mice but not in ovariectomized female mice. Therefore, pre-exposure to doxorubicin caused male-specific cardiac atrophy that persisted after isoproterenol treatment, which could not be prevented by gonadectomy.