CHRONIC CARDIOTOXICITY OF ADRIAMYCIN STUDIED IN A RAT MODEL BY P-31 NMR

Adriamycin induced cardiotoxicity is, among other factors, characterized by an impairment of mitochondrial function and altered energy metabolism. The possible merits of 31P NMR in timely detection of this cardiotoxicity were studied in perfused hearts of chronically treated rats after cumulative doses of 6,8,10,12 and 13 mg adriamycin/kg body wt and compared to histological evaluation. After high cumulative doses the Phosphocreatine (PCr)/ATP ratio was significantly decreased in the hearts of treated animals, compared to the control animals (1.65±0.13 vs. 2.47±0.36 (p < 0.001) at 12 mg/kg and 1.92 ± 0.22 vs. 2.37±0.15 (p < 0.01) at 13 mg/kg adriamycin, respectively). This decrease coincides with a sudden increase in the histological score from 2.0 at 10 mg/kg to 8.0 at 12 mg/kg adriamycin on a scale of 10.0. The Pi/PCr ratio, coronary flow and rate pressure product (RPP) of the isolated hearts of treated animals were not significantly different from controls. When heart rates were increased, parallel changes in PCr/ATP ratio, Pi/PCr ratio, RPP and coronary flow were observed in both control and treated groups, except for the 12 mg/kg adriamycin group in which pacing failed to increase RPP. In addition, in this group the Pi/PCr ratio at higher heart rates was significantly increased (p < 0.001) compared to controls. At 13 mg/kg similar effects were observed but less pronounced. The decreased PCr/ATP ratio may indicate an increased ADP concentration and altered regulation of energy metabolism. Differences between control and treated groups in RPP and Pi/PCr ratio during pacing may also be related to cardiotoxicity. The results of this study show that changes in energy metabolism in the heart during chronic adriamycin treatment may well be observed by 31P NMR. Furthermore, they indicate that clinical 31P NMR may be a suitable tool for monitoring the development of adriamycin induced cardiotoxicity, thereby avoiding the disadvantages of invasive procedures. Copyright © 1991 John Wiley & Sons, Ltd.