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Mechanism of Acute Anthracycline Cardiotoxicity in Isolated Rat Hearts: Carminomycin versus Daunomycin¹

MRC-UCT Ischaemic Heart Disease Laboratory, and the Departments of Medicine [S. S., L. H. O.] and Haematology [P. J.], University of Cape Town, Cape Town, South Africa

Cardiotoxicity limits the use of anthracyclines which are potent anticancer agents. In the isolated rat heart, we investigated the mechanism of acute anthracycline cardiotoxicity and compared a new anthracycline, carminomycin, with daunomycin which is in established use. Daunomycin 1.75 x 10^-5 M produced a fall in cardiac output (36 ± 2 versus 58 ± 1 ml/min; p < 0.01), left ventricular power production (9 ± 0.7 versus 16 ± 0.3 mJ/sec/g; p < 0.01), and efficiency of heart work (3.3 ± 0.2 versus 6.3 ± 0.2 mJ/sec/ml O₂; p < 0.01; mean ± S.E. 40 min after daunomycin). Carminomycin (1.75 x 10^-5 M) produced a greater fall in cardiac output than equimolar daunomycin (26 ± 2 versus 36 ± 2 ml/min; p < 0.01). Daunomycin did not reduce coronary flow rate, heart rate, or oxygen consumption. From the preceding data, we inferred that, since afterload and preload were constant in this model, heart failure was due to a depressed inotropic state. Procedures that increased cytosolic calcium relieved heart failure namely, pretreatment with digoxin (62.4 µg), isoproterenol (10^-6 M), and increased perfusate Ca²⁺ (5 mM versus 2.5 mM) all prevented carminomycin-induced fall in cardiac output (41 ± 1, 47 ± 5, and 52 ± 1, respectively, versus 26 ± 2 ml/min; p < 0.01). Acute anthracycline contractile failure was also associated with a fall in high-energy phosphate compounds which could also have contributed to the decreased inotropic state. We conclude that carminomycin is more cardiotoxic than daunomycin in equimolar concentrations and that a lowered cytosolic calcium and decreased energy stores might cause the contractile failure. The cytosolic calcium and high-energy phosphate compounds were lowered by separate mechanisms.

¹ Supported by the Medical Research Council, University of Cape Town Research Fund, and the Chris Barnard Fund.

² Supported by the Guy Elliott Scholarship. To whom requests for reprints should be addressed.

Received 2/24/82. Accepted 12/12/83.