Mortality in acute kidney injury (AKI) remains unacceptably high, yet the cause of death is commonly related to dysfunction of extra-renal organs. We and others have observed remote organ abnormalities after renal ischemia. The term cardiorenal syndrome was first applied to the "crosstalk" between the organs by the National Heart, Lung and Blood Institute of the National Institutes of Health and the clinical importance is increasingly appreciated. Nevertheless, more information is needed to effectively address the effect of renal injury on the heart. Since AKI often occurs in patients with co-morbidities, we have investigated the effect of renal ischemia in the setting of cardiac failure. We hypothesized that the cardiac effects of renal ischemia would be significantly amplified in experimental cardiomyopathy due to doxorubicin. Male Sprague-Dawley rats with preexisting cardiac and renal injury due to low dose doxorubicin were subjected to bilateral renal artery occlusion. Cardiac structure and function were examined 48 hours after reperfusion. Loss of functional myocardial tissue with decreases in left ventricular pressure, increases in apoptotic cell death, inflammation and collagen and greater disruption in ultrastructure were seen in the doxorubicin/ischemia group as compared to those animals treated with doxorubicin alone. These results suggest that preexisting co-morbidities can result in much more severe distant organ effect of acute renal injury. The results of these studies are relevant to human AKI.