Caffeine enhances doxorubicin cardiac toxicity in an animal model

Based on in vitro data suggesting an interaction between methylxanthines and doxorubicin in regulating Ca²⁺ across muscle sarcoplasmic reticulum, this study was designed to test the hypothesis that a commonly used methylxanthine, caffeine, might influence the cardiac toxicity of doxorubicin. Three days following doxorubicin treatment, in vivo intracardiac pressures, cardiac outputs, in vitro cardiac weights, and cardiac electron microscopy were performed. Guinea pigs were treated with doxorubicin alone, doxorubicin plus caffeine, caffeine alone, and sterile saline as a control measure. Animals treated with doxorubicin had no significant differences in in vivo hemodynamics compared to the control animals. The average histology score was slightly but not statistically greater than the control animals, score (1.19 ± 0.36 vs 1.60 ± 0.34, respectively, P = NS). Animals receiving both doxorubicin and caffeine compared to the control animals had important differences in left ventricular systolic pressure (67 ± 10 vs 92 ± 7 mmHg; P = .003), cardiac output (154 ± 35 vs 217 ± 41 mL/min; P = .0174), stroke volume (.59 ± 12 vs .79 ± .07 mL; P = .0045), and histology score (2.36 ± 0.21 vs 1.19 ± 0.36; P = .028). There were no differences in left or right heart filling pressures between treatment groups. As an independent confirmation, there was a weak but statistically significant negative correlation between the biopsy score and cardiac output or stroke volume for all four groups of animals (r = .44, P = .031 and r = -.42, P = .040, respectively). These data are consistent with caffeine and doxorubicin having additive or potentiating effects on cardiac toxicity in this animal model.