CARDIOPROTECTIVE EFFECTS OF DILTIAZEM DURING ACUTE REJECTION ON HETEROTOPIC HEART-TRANSPLANTS

In the presence of severe rejection, cardiac allograft perfusion has b een shown to be impaired, Since a functionally reversible vasoconstric tor component has been identified in this condition and rejection does not reverse if ischemia does not, we hypothesized that diltiazem may be beneficial in this condition, Experiments were performed on dogs wi th heterotopic heart transplants and chronic instrumentation for the a ssessment of allograft perfusion, Two groups of cardiac allograft reci pients were studied: untreated recipients and recipients treated with the calcium antagonist diltiazem (180 mg twice daily, orally), Allogra ft blood flow was monitored daily along with plasma diltiazem levels, The lymphoproliferative response to mitogens was studied at selected i ntervals until terminal rejection, Contractile function of the graft w as assessed daily by palpation, Without immunosuppression, terminal re jection was observed within 7 days, Rejection was confirmed by histolo gy; cellular infiltration and myocyte necrosis were present in all car diac allografts but to a significantly lesser degree in diltiazem-trea ted recipients, The mean blood flow of heterotopically implanted heart s was in the range of 35-50 ml/min, which decreased steadily in untrea ted recipents., In contrast, significant improvement of allograft perf usion was observed in diltiazem-treated recipients at days 4-6 after t ransplantation. Diltiazem also significantly attenuated mitogen-induce d lymphocyte proliferation at peak sensitivity (2 days after transplan tation), Diltiazem plasma concentrations were in the therapeutic range (30-60 ng/ml) before and after cardiac transplantation. Results of th e present study demonstrate beneficial effects of diltiazem in the cou rse of severe cardiac rejection, Such findings support its use during rejection when maintenance of graft blood flow and myocyte protection may be important for myocardial function and viability.