CONTRACTILE FAILURE IN CHRONIC DOXORUBICIN-INDUCED CARDIOMYOPATHY

The mechanisms for the progression of the anthracycline-induced cardio myopathy to contractile failure has not been defined. In vitro, doxoru bicin (DOX) appears to modify calcium-mediated excitation-contraction coupling, which depresses cardiac contractility. This study characteri zes the onset of contractile failure associated with the development o f 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. M yocardial contractility was determined in thin fiber bundles from righ t ventricular (RV) papillary muscles and left atria that were removed and mounted on a force transducer in oxygenated Krebs-bicarbonate buff er (pH = 7.4 at 30 degrees 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 tensi on responses respectively in chemically-permeabilized fibers. With the onset of the cardiomyopathy (score <2) DT at low frequency (0.5 Hz) w as 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 diffe rent in this DOX-treated and Control groups. Maximum calcium and caffe ine-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 sa croplasmic reticulum calcium release channel density, as determined by B-max for H-3-ryanodine binding in cardiac microsomal membrane fracti on. Post-rest potentiation of contractility, as well as frequency-depe ndent (0.25-1.5 Hz) and post-extrasystolic potentiation of contractili ty were preserved in the DOX-treated group. In vitro, DOX depressed po st-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 cou pling and these effects are qualitatively different than in vitro effe cts of DOX. (C) 1997 Academic Press Limited.