Contractile Failure in Chronic Doxorubicin-induced Cardiomyopathy

The mechanisms for the progression of the anthracycline-induced cardiomyopathy to contractile failure has not been defined.In vitro, doxorubicin (DOX) appears to modify calcium-mediated excitation–contraction coupling, which depresses cardiac contractility. This study characterizes the onset of contractile failure associated with the development of DOX-induced cardiomyopathy. Rabbits were treated with DOX (1 mg/kg i.v. twice weekly, 12–18 doses; DOX-treated group) and compared with a pair-fed Control group infuse with saline vehicle. The severity of the cardiomyopathy was determined by numerically-scored histopathology. Myocardial contractility was determined in thin fiber bundles from right ventricular (RV) papillary muscles and left atria that were removed and mounted on a force transducer in oxygenated Krebs-bicarbonate buffer (pH=7.4 at 30°C) to record the amplitude (DT) and maximum rate (+dT/dt) of isometric tension. Myofibrillar and calcium loading properties were determined by the calcium and caffeine-activated tension responses respectively in chemically-permeabilized fibers. With the onset of the cardiomyopathy (score <2) DT at low frequency (0.5 Hz) was depressed (0.61±0.01 mN/mg;n=14) compared to Control (0.93±0.09 mN/mg;n=15). Contractility at higher rates (1 Hz) was not different in this DOX-treated and Control groups. Maximum calcium and caffeine-activated force and the pCa to half-maximum force of permeabilized fibers were comparable in DOX-treated and Control groups. The loss of contractility of the DOX-treated group was related to reduction in sacroplasmic reticulum calcium release channel density, as determined by Bmaxfor3H-ryanodine binding in cardiac microsomal membrane fraction. Post-rest potentiation of contractility, as well as frequency-dependent (0.25–1.5 Hz) and post-extrasystolic potentiation of contractility were preserved in the DOX-treated group.In vitro, DOX depressed post-rest potentiation of contractility. Thus, the onset of contractile failure of the DOX-induced cardiomyopathy is characterized by effects consistent with disordered calcium-mediated excitation–contraction coupling and these effects are qualitatively different thanin vitroeffects of DOX.