Improving outcomes in heart transplantation: The potential of proliferation signal inhibitors

Abstract

Graft failure and mortality among heart transplant recipients remains higher than in populations receiving renal transplants. A major cause of graft loss is cardiac allograft vasculopathy (CAV), a condition characterized by diffuse thickening of coronary blood vessels. CAV often progresses silently, with major cardiac events (eg, ventricular arrhythmia) being the first presentation. Better diagnosis and monitoring of CAV is now possible with intravascular ultrasonography, a sensitive technique for measuring intimal thickness. To date, immunosuppressants have shown little efficacy for preventing CAV. However, a new class of agents, proliferation signal inhibitors (sirolimus and everolimus), have shown considerable efficacy in this regard and for preventing rejection. In an open-label trial, sirolimus therapy was associated with less intimal and medial proliferation than azathioprine. More robust evidence is available from a larger-scale, double-blind trial involving everolimus. At 12-month follow-up the incidence of CAV was significantly lower in patients receiving everolimus (35.7% and 30.4% for everolimus 1.5 and 3.0 mg/d vs 52.8% for azathioprine; P < .05). Sirolimus and everolimus were also associated with a lower rate of cytomegalovirus infection. As with other immunosuppressants, these agents are associated with adverse events (eg, hyperlipidemia), but they can be managed. Coadministration with calcineurin inhibitors (CNIs) can exacerbate CNI-related nephrotoxicity, but evidence suggests that everolimus administered with reduced-exposure cyclosporine in the maintenance phase preserves renal function without loss of immunosuppressive efficacy. Reduced CNI dosing in de novo patients is also a potential future benefit. Proliferation signal inhibitors have considerable potential for improving outcomes in heart transplantation.