Acute adriamycin cardiotoxicity: morphologic alterations in isolated perfused rabbit heart

Adriamycin is an antitumor agent whose use is limited by cardiac toxicity resulting in a late congestive cardiomyopathy. The time course of the cardiac changes and whether they are due to direct effect of the drug on the myocyte is unknown. The purpose of this study was to determine the very early changes in subcellular structure caused by adriamycin in an isolated, perfused, working heart. Eighteen rabbit hearts were perfused with oxygenated Krebs-Ringer-bicarbonate buffer at 39 degrees C. containing either 1, 2, 4, or 8 mg. per liter of adriamycin for periods of 30 to 150 minutes; 10 controls were perfused with buffer only. Light microscopic study of sections through both ventricles revealed no differences between treated and control hearts. Electron microscopy showed a striking and distinctive central clumping of nuclear chromatin in all 18 hearts exposed to adriamycin, but in no controls; this nuclear change was more marked with increasing dose of drug, but not with longer durations of perfusion. In 15 of 18 hearts sarcomeres and mitochondria were normal, and in 15 of 18 mild cytoplasmic vacuolization was present. In contrast, of 10 control hearts nuclei in seven were normal, and three showed some focal peripheral clumping of chromatin; seven had normal sarcomeres and mitochondria, and three showed mild cytoplasmic vacuolization. Thus, exposure of the isolated rabbit heart to adriamycin results in acute and distinctive nuclear alterations, with associated mild cytoplasmic changes. To what extent these nuclear effects mediate subsequent myocyte degeneration or dysfunction remains to be determined.