Ultrastructural alterations in adriamycin-induced cardiomyopathy

18 ULTRASTRUCTURAL ALTERATIONS IN ADRIAMYCIN-INDUCED CARDIOMYOPATHY. K.Tominaga$ T.Suzuki*$ H.Kanda*$ T.Shinkai*$ and K.Murata*+ *National Cancer Center Hospital, Tokyo, Japan. **De artment of Internal Medicine, Gunma University School o !i Medicine, Maebashi, Japan. Adriamycin ADR), an anthracycline antibiotic is an effective drug rI or treatment of neoplasms.However, recent studies have indicated thatthedrugisoflimited clinical value,becauseofthe development ofadose-dependent cardiomyopathy in man. In order to study pathogenesis of this undesirable side effect, ultrastructural examination and measurement of the electrol te contentsinthe left ventricular myocardium from ra z bits treated with ADR were carried out. A group of 31 male albino rabbits received intravenous injectionof aqueous solutionof ADR at a dose of 2.5mg/kg.weekly. Five of 31 rabbits died of cardiac failure after 7 weeks or later. Five or6treated and two control rabbits were sacrificed at l, 3, 5, 8, and 11 weeks after initial in'ection. The earliest ultrastructural alteration was t ii e progressive dilatation of the sarcoplasmic reticulum and transverse tubular system, leadin occasionally to extensive vacuolization and ballooning o f myocytes.Accompanying sarcotubular dilatation, myofibrils freauentlv formed contraction bands. Further alteration of myofibrilswas characterizedbythe pro ressive disruption accompaniedbylysis of myofilaments. 8 ccasionally,myocardial cells revealed almost complete disappearance of myofibrils.The mitochondria showed various stages of degeneration as the total doseof ADR increased, including the swelling, loss of cristae, increase in density and formation of m elin figures.Insomeareas exhibiting remarkable mvofibril 31ar disorganization. afewmitochondria contained amorphous dense boaiesorring-shaped inclusions composed of small dense particles in the matrix. At later stages, sarcoplasm of some myocardial cells was occupied by-a lar e amount of degenerating mitochondria and laminated which appeared to have been derived from mye Fin figures, sarcoplasmic reticulum. Nuclear changewas apparently not SO remarkable. However,some nuclei had multi le, kz;;;:; vacua 7 es. arranged nucleolior small intranuclear of ventricular myocardial electrolyte determinations showed marked elevation of Ca concentration in rabbits, which received ADRover ZZOmg/sqm. Mean myocardial Na was also elevated in this group, but not significantly, as From the results obtained, compared with control values. there appeartobe two possible mechanisms concerning the pathogenesis of ADR-induced cardiomyopathy. ADR-treated rabbits showed remarkable alterationsof contractile eledisruption and lysis of myofilaments. These ments, i.e., changes may result from inhibition of protein synthesis with ADR, through interfering DNA-dependent RNAsynthesis. However marked cytoplasmic vacuolation due to dilatation findof the Aarcotubular s stem was another conspicuous which has never 45een seen in other types of cardiot$%;athy. This finding and than esofmyocardial electroof lyte contents, presumably attri 3 uted to disturbance selective permeability of cell membranes, su gest that t fi 1s context, ADR may injure the membranous component.In lipid peroxidation may play a role in the pathogenesis of ADK-induced cardiomyopathy.