Proliferation signal inhibitors and cardiac allograft vasculopathy

Abstract

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. 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. 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.