Proliferation signal inhibitors in cardiac transplantation.
OBJECTIVE
Standard immunosuppression after cardiac transplantation includes a calcineurin inhibitor in combination with mycophenolate mofetil or azathioprine and corticosteroids. These agents have led to excellent outcomes but have shortcomings in terms of efficacy and toxicity. A new class of immunosuppressants, proliferation signal inhibitors, may meet some of these shortcomings.


RESULTS
The efficacy of the available proliferation signal inhibitors - sirolimus and its derivative everolimus - has been compared with azathioprine in three randomized clinical trials. Sirolimus or everolimus use was associated with lower rates of acute rejection and reduced development of chronic allograft vasculopathy. Sirolimus was not found to be superior to mycophenolate mofetil in a randomized trial. Proliferation signal inhibitors have been reported to be effective in refractory recurrent acute rejection. Nonrandomized studies have demonstrated that proliferation signal inhibitor-based immunosuppression enables recovery from renal dysfunction secondary to calcineurin inhibitor treatment. Proliferation signal inhibitor-based treatment is associated with a lower risk of malignancy than calcineurin inhibitor-based regimens. Proliferation signal inhibitors have significant adverse effects that may limit widespread use.


CONCLUSIONS
Proliferation signal inhibitors are important new immunosuppressive agents that have added considerably to the armamentarium allowing further tailored immunosuppression to individualize patient care after heart transplantation.
Gustafsson
Finn
F
Division of Cardiology and Transplant, Toronto General Hospital, Toronto, Ontario, Canada. finng@dadlnet.dk
Ross
Heather J
HJ
D001379:Azathioprine / Q000627:therapeutic use; D019703:Calcineurin / Q000009:adverse effects; D065095:Calcineurin Inhibitors; D049109:Cell Proliferation / Q000187:drug effects*; D003324:Coronary Artery Disease / Q000209:etiology / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus; D006084:Graft Rejection / Q000150:complications / Q000517:prevention & control; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology*; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D000068338:Everolimus; D019703:Calcineurin; D009173:Mycophenolic Acid; D001379:Azathioprine; D020123:Sirolimus