mycophenolic-acid and Myocardial-Ischemia

In this study, we examined whether cyclosporine was effective when combined with everolimus in clinical heart transplantation (HT).. From August 2004 to July 2007, 108 adult patients underwent primary HT. The main exclusion criteria were: donors > 60 years; cold ischemia times > 6 hours; recipients of multiorgan transplantation or a previous transplantation; and panel-reactive antibodies > or = 25%. The cyclosporine plus everolimus regimen (group CE, n = 32) was suggested first; upon refusal or if the recipient or donor was positive for hepatitis B surface antigen or PCR + hepatitis C infection, then patient was randomly assigned to success cyclosporine plus mycophenolate mofetil (MMF; group CM, n = 24) or tacrolimus plus MMF (group TM, n = 25). All patients underwent similar operative procedures and postoperative care with protocol endomyocardial biopsies.. No 30-day mortality was noted in any group. The efficacy failure rates were 3%, 25%, and 16% in groups CE, CM, and TM, respectively (P = .04 between groups CE and CM). The 1-year survivals were 96.7% +/- 18.1%, 89.7% +/- 29.8%, and 81.0% +/- 35.5% for groups CE, CM, and TM, respectively (P = .04 between groups CE and TM). The 3-year survival rates were 91.9% +/- 28.3%, 79.8% +/- 46.0%, and 81.0% +/- 35.5% in groups CE, CM, and TM, respectively.. The 3 immunosuppressive regimens offered good efficacy after HT. The cyclosporine plus everolimus regimen showed a significantly better result with less efficacy failure (compared with cyclosporine plus MMF: 3% vs 25%) and better 1-year survival compared with tacrolimus plus MMF: 96.7% vs 81.0%.

Topics: Adult; Cardiomyopathy, Dilated; Cyclosporine; Drug Therapy, Combination; Everolimus; Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Myocardial Ischemia; Patient Selection; Sirolimus; Survival Analysis; Survivors; Tacrolimus; Tissue Donors; Treatment Outcome

Mycophenolate mofetil (MMF) is a new immunosuppressive drug used to reduce acute rejection after heart transplantation. As with other immunosuppressive drugs, MMF therapy is associated with several adverse effects. However, the direct effects of MMF on myocardial tissue has not been yet evaluated. The aim of the work was thus to evaluate the effects of MMF on isolated cardiomyocytes (CM) in normal conditions and in an in vitro model of simulated ischemia (SI; substrate-free hypoxia) and reperfusion (R; reoxygenation). Myocyte-enriched cultures were prepared from newborn rat heart ventricles. The transmembrane potentials were recorded using conventional microelectrodes and the cell contractions were monitored with a photoelectric device. In basal conditions, MMF (10(-6) and 10(-5) M) exerted no significant effects on the survival and on the electrical and contractile activities of CM in culture, even during long-term exposure (up to 48 h). SI per se led to a gradual decrease and then an abortion of the spontaneous automaticity and electromechanical activity of CM. Pretreating CM with either 10(-6) or 10(-5) M MMF was able to reduce the SI-induced cell dysfunctions. The presence of MMF at these concentrations did not hamper the post-SI functional recovery of CM during reoxygenation. At 10(-5) M, MMF applied during reoxygenation only permitted a better recovery of CM. However, the mitochondrial function after reoxygenation, as assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl-tetrazolium bromide (MTT) test, was not significantly influenced by the addition of MMF before as well as after ischemia. Conversely, MMF was able to reduce in this model the postischemic rise in xanthine and hypoxanthine. These data from CM-enriched model show that MMF: (i) had no cytotoxic effect, (ii) displayed a cytoprotective effect during SI, and (iii) exerted its beneficial effect at least partly through the decrease in the xanthine oxidase-dependent free radical production.

Topics: Adenosine; Animals; Animals, Newborn; Cell Hypoxia; Cells, Cultured; Hypoxanthine; Immunosuppressive Agents; Membrane Potentials; Mycophenolic Acid; Myocardial Ischemia; Myocardial Reperfusion; Myocytes, Cardiac; Rats; Rats, Wistar; Xanthine