Rapamycin for cardiac transplant rejection and vasculopathy: one stone, two birds?

Abstract

Pour faire d’une pierre deux coups1 Heart transplantation can now be routinely performed. Acute rejection has been significantly reduced, and the limitations to the use of this procedure include the availability of organs, chronic rejection, and a late reaction that is driven by a unique vasculopathy. Post-transplant vasculopathy (PTV) shares features with the lipoprotein-driven native atherosclerosis and proliferation-driven postangioplasty restenosis, but it has been thought to be more sensitive to immune forces. These distinctions are critical, for they dictate our choice of therapy. Hypercholesterolemia dictates treatments that lower lipoproteins or their effects; thrombotic events require antiplatelet agents, antithrombotics, and even agents that interfere with the clotting cascade; proliferative and migratory events can be inhibited by directed agents; and an immune disease would suggest use of immunosuppressants. To date, statins and immunosuppressants have been the mainstay of therapy for patients with heart transplants. These drugs were intended to simultaneously reduce rejection and post-transplant vasculopathy by limiting excessive lipid accumulation and exuberant inflammation. Recent reports, including the findings by Mancini et al2 reported in this issue of Circulation , suggest that although reduction in rejection may directly follow from direct control of the immune response, the same is not true for the vasculopathy. Vascular disease in heart transplant patients is effectively controlled by an agent classified as an immunosuppressant but not because of immune modulation, rather because of antiproliferative effects.2 See p 48 PTV is an aggressive and diffuse coronary arteriopathy that occurs in heart transplant recipients. With an annual incidence rate of 5% to 10% and an unremitting course, it is the major factor limiting long-term survival after heart transplantation. Because the donor heart is denervated, PTV often presents on routine follow-up angiographies or symptomatically as congestive heart failure and/or sudden death. This vasculopathy is generally diffuse, is …