Use of Proliferation Signal Inhibitors in Cardiac Transplantation

Abstract

Cardiac transplantation remains the definitive and most highly successful therapy for patients with advanced heart failure who have failed all other therapies. Long-term survival is limited by cardiac allograft vasculopathy, the transplant coronary artery disease, and malignancy. Standard, traditional immunosuppressive agents such as calcineurin inhibitors, anti-proliferative agents, and corticosteroids do little to attenuate cardiac allograft vasculopathy, which, because of its diffuse nature, is usually not amenable to percutaneous or surgical revascularization approaches, and may potentiate the developments of malignancies after cardiac transplantation. Proliferation signal inhibitors block the mammalian target of rapamycin, a critical protein involved in cell proliferation, and inhibit lymphocyte and smooth muscle cell proliferation. This results in inhibition of the alloimmune response and acute cellular rejection, even in the setting of low calcineurin levels. More significantly, they have been shown in several clinical trials to attenuate the progression of cardiac allograft vasculopathy when compared to mycophenolate or azathioprine regimens.