Proliferation signal inhibitors and cardiac allograft vasculopathy.
OBJECTIVE
Cardiac allograft vasculopathy (CAV) is the leading cause of late morbidity and mortality in heart transplant patients and limits long-term survival. Immunosuppression following cardiac transplantation has traditionally comprised a calcineurin inhibitor in combination with mycophenolate mofetil or azathioprine and corticosteroids. This combination provides effective immunosuppression but does not prevent subsequent development of CAV. Proliferation signal inhibitors (such as sirolimus and everolimus), a new class of immunosuppressants, have recently been shown to be effective in attenuating the development of CAV following cardiac transplantation.


RESULTS
In addition to immunosuppressive properties, proliferation signal inhibitors have important antiproliferative effects outside the immune system. Several ex-vivo and preclinical studies on animal models have demonstrated control of the vascular manifestations after cardiac transplantation. In clinical trials, proliferation signal inhibitors used as secondary immunosuppressive agents in place of azathioprine or mycophenolate prevented CAV progression and reduced the incidence of clinically significant cardiac events. Proliferation signal inhibitors are also effective as primary immunosuppressants, and, after complete calcineurin inhibitor withdrawal, mitigate the progression of CAV, improve calcineurin inhibitor-induced nephropathy and hypertension.


CONCLUSIONS
Proliferation signal inhibitors are powerful immunosuppressive agents with antiproliferative properties that attenuate CAV and have the potential to improve long-term survival following cardiac transplantation.
Raichlin
Eugenia
E
Cardiovascular Division, William J. von Liebig Transplant Center, Mayo Clinic, Rochester, Minnesota 55905, USA.
Kushwaha
Sudhir S
SS
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003586:Cytomegalovirus Infections / Q000473:pathology / Q000517:prevention & control; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects*; D014184:Transplantation, Homologous; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology
D007166:Immunosuppressive Agents