Effects of ischaemia-reperfusion and cyclosporin-A on cardiac muscle ultrastructure


  • Julia Buján
  • F. Jurado
  • J. M. Bellón
  • J. A. Pareja
  • A. Golitsin
  • L. Millán
  • G. Pascual


heart transplant, ischaemialreperfusion, cyclosporin-A, myocardium, mitochondria


The present study investigates the effects on the cardiac muscle cell of two of the determining factors for the success of organ transplant; ischaemia-perfusion and immunosuppressive treatment with cyclosporin-A (CsA). To this end an abdominal, heterotopic heart transplant model in singenic Sprague-Dawley rats was employed.

Three study groups were established: Group I (control, n=15) animals undergoing heart transplant without treatment; Group I1 (n=15) animals undergoing heart transplant and subjected to a daily dose of CsA in a cremophor vehicle (sandimunB) (5 mg/kg/sc); Group I11 (n=15): animals undergoing heart transplant and administered a daily dose of pure CsA (5 mg/kg/sc). Recipient animals were sacrificed 7, 14, 21, 30 and 50 days after transplant. During the post-operative period, heart function was assessed by daily abdominal palpation. Graft specimens obtained at each follow-up period were subjected to light and transmission electron microscopy. Immunohistochemical analysis of specimens was performed using the rat macrophagespecific monoclonal antibody MCA-341.

The ischaemia/reperfusion process induced considerable alteration to cardiac muscle cells of control animals. Effects, apparent after the first week of transplant, included mitochondrial swelling and loss of cristae, hypertrophy of the sarcoplasmic reticulum and structural changes to sarcomeres. Two weeks after transplant, the myocardium was infiltrated by inflammatory cells. These effects diminished 30 days post-transplant. Cardiac tissues of treated animals (groups I1 and 111) showed similar behaviour although, in the latter group, mitochondrial damage was greater and intense myocardial fibrosis took place. Infiltration of cardiac muscle by white blood cells did not take place until 3 weeks post-implant.

These results indicate: a) The ultrastructural changes detected in cardiac fibres of animals of the three study groups were attributable to the ischaemialreperfusion process rather than to treatment with CsA; b) CsA appears to augment mitochondrial damage and myocardial fibrosis; c) the inflammatory response was delayed and reduced by the immunosupressant; and d) the cremophor administration vehicle did not seem to exert an independent toxic effect on the myocardium.