Improvement of doxorubicin induced cardiomyopathy in rats treated with insulin-like growth factor I

Abstract

This study was designed to assess the effects of treatment with insulin-like growth factor-I (IGF-I) on cardiac function and structure in rats with an established cardiomyopathy. Adult male Wistar rats were injected with doxorubicin (2 mg.kg-1 subcutaneously) weekly for 12 weeks and either rhIGF-I (0.8 mg.kg-1.day-1; n = 16, D-I group) or saline (n = 25, D-S group) subcutaneously via an osmotic pump from weeks 9 to 12. A non-doxorubicin injected control group was also studied. After 12 weeks survivors were anaesthetised and cardiac output determined with radiolabelled microspheres. At postmortem pleural effusion and ascitic volumes were measured and the heart was removed for histological examination by light and transmission electron microscopy. Doxorubicin treated animals showed less mean weight gain from week 2 than the untreated control group. Animals treated with IGF-I from week 9 showed a significant (p < 0.05) but non-sustained increase in weight. Survival to 12 weeks was 56% in the D-I group and 44% in the D-S group (p = 0.2). Evidence of cardiac failure was seen in the D-I and the D-S groups, but there was a tendency (p = 0.06) for less ascites in the D-I group (21 (SEM 8) ml) than in the D-S group (46 (10) ml). Cardiac output was significantly higher in the D-I than in the D-S group (132 (7.2) v 91.4 (6.4) ml.min-1, p < 0.01), as was stroke volume (0.323 (0.03) v 0.226 (0.02) ml, p < 0.01). There was focal cardiac damage in both D-I and D-S animals. Scattered groups of myocytes showed prominent vacuolation of the nuclear envelope, sarcoplasmic reticulum, and t tubular system, mild to severe mitochondrial swelling, and loss of orientation and definition of myofibrils. No clear morphological differences were evident between the two groups. Administration of IGF-I may improve the function of damaged myocardium, although the mechanisms are unclear. Further studies with earlier coadministration of IGF-I, quantitative histological analysis, and with other models of cardiac injury are indicated.