A phase II, open, nonrandomized trial was carried out in a group of epirubicin-treated patients with cancer at different sites with the aim of detecting early preclinical changes that are predictive of the risk for heart failure. All patients underwent conventional echocardiography, as well as tissue Doppler imaging (TDI) with strain (sigma) and strain rate (SR), a very accurate technique for detecting minimal changes in cardiac left ventricular (LV) function. Moreover, echocardiographic changes identified during epirubicin treatment were compared with those of a series of biochemical markers of both myocardial damage and inflammation/oxidative stress. Sixteen patients (male-to-female ratio, 3:13; mean age +/- standard deviation, 56 +/-3 years; range, 27-75 years) with histologically confirmed tumors at different sites, scheduled to be treated with an epirubicin-based chemotherapy regimen, were enrolled in the study. A significant impairment in systolic LV function was observed after 200 mg/m2 of epirubicin; this was shown by a lower SR peak compared with baseline (1.82 +/- 0.57/second versus 1.45 +/- 0.44/second), whereas sigma remained unchanged. The following significant changes in LV diastolic function occurred only after 300 mg/m2 of epirubicin: a decrease in conventional early/late diastolic (E/A) velocities (1.16 +/- 0.31 versus 0.93 +/- 0.24) and a reduction in both the E(m) wave in the basal portion of the interventricular septum (8.86 +/- 1.73 cm/second versus 7.51 +/- 2.30 cm/second) and in the E(m)/A(m) ratio (1.09 +/- 0.51 versus 0.83 +/- 0.51), as measured using the TDI technique. No significant changes in LV ejection fraction were observed. Baseline values of brain natriuretic peptide, troponin I, myoglobin, and creatine kinase-myocardial subfraction were within the normal range and no significant changes were observed throughout the study. Levels of interleukin (IL)-6 and its soluble receptor (sIL-6R) and reactive oxygen species increased significantly, whereas glutathione peroxidase (GPx) levels decreased significantly, after 200 mg/m2 of epirubicin. Significant correlations between the reduction in the SR peak (deltaSR) after 200 mg/m2 of epirubicin and the increase in IL-6 and ROS and decrease in GPx were observed. The multiple regression analysis showed that the only independent predictive variable for deltaSR was ROS level. Our data show that: (a) subtle cardiac abnormalities may occur at epirubicin doses significantly below those known to be potentially clinically harmful and (b) the earliest myocardial impairment affects LV systolic rather than diastolic function. Early contractility impairment during epirubicin treatment was associated with high levels of ROS and markers of inflammation. The clinical meaningfulness of our findings warrants further investigations in a larger number of patients for a longer period of follow-up.