Exposure to Doxorubicin Modulates the Cardiac Response to Isoproterenol in a Sex‐Dependent Manner

Abstract

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.