Measuring in vivo effects of chemotherapy treatment on cardiac capillary permeability

Background: Cardiotoxicity is a life-threatening side effect of chemotherapy that is multi-factorial in nature. Increased capillary permeability due to endothelial damage after anthracycline administration could be an important contributor to cardiac dysfunction. Methods: We investigated the cardiotoxic effects of the anthracycline doxorubicin (DOX) in rats using intraperitoneal injections of saline (n=10) or DOX (n=10) over 12 days for a cumulative dose of 18 mg/kg. We studied cardiotoxicity by serial echocardiography and with an isolated heart setup. We monitored perfusion and left ventricle pressures and measured permeability using a fluorescent indicator dilution method developed by our group. Results: There were significant differences (p=0.029) in permeability surface area product between control (0.047±0.009 cm³/s) and DOX animals (0.068±0.025 cm³/s). This is consistent with our hypothesis that chemotherapy-induced changes in the coronary capillary endothelium lead to increased permeability. We also observed changes in cardiac function consistent with chemotherapy-induced cardiotoxicity. Contractility (+dP/dt) and LVDP were significantly reduced (p = 0.030) in the DOX group. Average +dP/dt was 2465±183 mm Hg/s for controls vs. 1817±177 mm Hg/s for DOX-treated rats, and average LVDP was 92.4 mm Hg for controls vs. 78.7 mm Hg for DOX-treated rats. Fractional shortening (FS) echocardiographic measurements decreased significantly over the course of treatment for the DOX group (p = 0.028, end FS = 32.8%, n=5), but not for the control group (p = 0.209, end FS = 50.7%, n=5). Conclusion: Changes in permeability after chemotherapy treatment can be detected using a fluorescent indicator dilution method. These changes are consistent with other measures of cardiac function observed in the chemotherapy group. Efforts toward the development of chemotherapy drugs with reduced cardiotoxicity should consider the effect on the endothelial layer, and our method to measure permeability in an isolated heart setup could be useful during testing of new drug alternatives.