Abstract 5024: Effects of aerobic training to improve cardiovascular function and prevent cardiac remodeling after cytotoxic therapy in early breast cancer

Abstract

Abstract Background: It is well-established that doxorubicin (DOX)-containing chemotherapy causes progressive cardiomyopathy clinically manifest as decreased left ventricular ejection fraction (LVEF). The effects of DOX on the other organ components of oxygen (O2) transport and utilization that govern global aerobic reserve capacity are poorly characterized. Methods and Results: To test our research questions, we established a mouse model of DOX in which female mice were subjected to DOX (8mg.kg.wk-1) or placebo (CON) (0.9% saline) for 4 weeks. Transthoracic echocardiography was performed to assess left ventricular wall thickness, volumes and LVEF, determined from M-mode tracings at baseline and 8 weeks. As expected, LV systolic volumes were higher and fractional shortening and LVEF were lower in the DOX group compared to CON after 8 weeks (p's <0.05). There was no change in effective arterial elastance (i.e. peripheral resistance, total lumped vascular compliance and characteristic impedance) following DOX however these mice had significantly decreased expression of proteins responsible for oxidative phosphorylation / mitochondrial biogenesis in the solelus muscle relative to CON mice (p<0.05). Injury to O2 transport organs led to significant reductions in global aerobic capacity (as measured by time to exhaustion on a motorized treadmill) in DOX compared with CON animals (p<0.05). Next, we tested whether aerobic training could prevent DOX-induced injury. Mice were subjected treadmill running, 5 d.wk-1, 18m.min-1, 45 mins/session for 8 wks during concurrent DOX (8mg.kg.wk-1) therapy (DOX+AT), DOX (8mg.kg.wk-1) only, or CON (0.9% saline). DOX-induced injury was completely abrogated by chronic aerobic training, which prevented injury in all organ components of O2 transport / utilization cumulating in preserved aerobic capacity. In patients with newly diagnosed operable breast cancer (n=20), DOX-containing chemotherapy caused a significant decline in aerobic capacity (p<0.05) despite normal LVEF and endothelial function. Supervised aerobic training completely averted this effect. Conclusions: Our findings have important implications for the identification and protection against DOX-induced acute and late-occurring injury as well as optimizing therapeutic dosing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5024. doi:10.1158/1538-7445.AM2011-5024