CHARACTERIZATION OF A CELLULAR-MODEL OF CARDIOMYOPATHY, IN THE RABBIT, PRODUCED BY CHRONIC ADMINISTRATION OF THE ANTHRACYCLINE, EPIRUBICIN

The objective of this study was to assess the structural, mechanical a nd electrophysiological changes associated with chronic administration of epirubicin (Pharmorubicin), which is a cardiotoxic anthracycline a ntibiotic used in conventional cancer chemotherapy, New Zealand white rabbits (8 weeks) were treated with twice-weekly infusions of epirubic in (2 mg/kg) or saline for a period of 6 weeks, followed by a wash-out period of 2 weeks. Myocardial damage consistent with cardiomyopathy w as observed in the epirubicin-treated animals; electron micrographs in dicated myofibril loss together with separation of the intercalated di sc and dilation of the sarcotubular system. Contractile function, as m easured by mechanical shortening, action potentials and L-type Ca2+ cu rrents were examined in ventricular cardiomyocytes, which were isolate d by means of enzymatic dissociation using collagenase. There was an a ttenuation in the contractile response to isoprenaline in cardiomyocyt es isolated from the hearts of epirubicin-treated rabbits compared to control rabbits. Cardiomyocytes isolated from epirubicin-treated rabbi ts had greater basal contractile amplitude (11.0 +/- 0.3 %dL, n=8) tha n control myocytes (8.2 +/- 0.3 %dL, n=9), but had similar maximum res ponses of 19.1 +/- 0.6 %dL, and 17.3 +/- 0.5 %dL, respectively, when s timulated with 1 mu M isoprenaline. No differences were noted in the p eak L-type Ca2+ current of myocytes isolated from the hearts of contro l and epirubicin-treated rabbits; however, in the latter, there was a prolongation of the action potential duration (396 +/- 25 ms) compared to that in controls (321 +/- 26 ms). These results demonstrate struct ural and mechanical alterations in ventricular cardiomyocytes which ar e compatable with a mild cardiomyopathy following chronic treatment wi th the anthracycline, epirubicin. The increase in basal contraction is likely to be due to more efficient coupling of electrical stimulation , and the depressed inotropic responsiveness following stimulation wit h isoprenaline indicates that there may be changes in cell membrane pr operties. Compared to control cardiomyocytes, cells isolated from the hearts of epirubicin-treated rabbits were more heterogeneous, with res pect to cell dimensions, and had significantly different electromechan ical properties. (C) 1997 Academic Press Limited.