Calvé A, Haddad R, Barama SN, Meilleur M, Sebag IA, Chalifour LE. Cardiac response to doxorubicin and dexrazoxane in intact and ovariectomized young female rats at rest and after swim training. Am J Physiol Heart Circ Physiol 302: H2048 -H2057, 2012. First published March 23, 2012; doi:10.1152/ajpheart.01069.2011The impact of cancer therapies on adult cardiac function is becoming a concern as more children survive their initial cancer. Cardiovascular disease is now a significant problem to adult survivors of childhood cancer. Specifically, doxorubicin (DOX) may be particularly harmful in young girls. The objective of this study was to characterize DOX damage and determine the ability of dexrazoxane (DEX) to reduce DOX-mediated cardiac damage in sedentary and swim-trained female rats. Female Sprague-Dawley rats were left intact or ovariectomized (OVX) at weaning then injected with DEX (60 mg/kg) before DOX (3 mg/kg), DOX alone, or PBS. Rats were separated into sedentary and swim cohorts. Body weight was reduced in DOX:DEX-but not PBSor DOX-treated rats. Echocardiographic parameters were similar in sedentary rats. Swim training revealed greater concentric remodeling in DOX-treated rats and reduced fractional shortening in DOX:DEXtreated rats. Calsequestrin 2 was reduced with DOX and increased with DOX:DEX postswim. Sarco(endo)plasmic reticulum Ca 2ϩ -ATPase 2a was reduced and calsequestrin 2 reduced further by swim training only in intact rats. OVX rats were heavier and developed eccentric remodeling post-swim with DOX and eccentric hypertrophy with DOX:DEX. Changes in SERCA2a and calsequestrin 2 expression were not observed. Ovariectomized DOX-and DOX:DEXtreated rats stopped growing during swim training. DEX coinjection did not relieve DOX-mediated cardiotoxicity in intact or hormonedeficient rats. DOX-mediated reductions in growth, cardiac function, and expression of calcium homeostasis proteins were exacerbated by swim. DEX coadministration did not substantially relieve DOXmediated cardiotoxicity in young female rats. Ovarian hormones reduce DOX-induced cardiotoxicity.echocardiography; Sprague-Dawley rat; ovariectomy; sarco(endo) plasmic reticulum Ca 2ϩ -ATPase 2a; calsequestrin 2IT IS WELL RECOGNIZED THAT increasing numbers of children now survive childhood cancer because of treatment improvements. However, almost two-thirds of childhood cancer survivors have at least one chronic illness and close to one-third had severe or life-threatening conditions when only in their midtwenties (9, 44, 61). In addition, exercise testing of childhood cancer survivors has demonstrated a below-predicted exercise capacity (22, 63). The risk for cardiovascular disease was found to be high and was attributed to anthracycline treatment years earlier (2,27,49,54,65). Anthracycline use, mostly doxorubicin (DOX), daunorubicin, and epirubicin, remains common, and it is estimated that about one-half of childhood cancer survivors will have received anthracyclines. Evidence suggests that young females may have a greater incidence of DOX...