Bench to bedside: the development of rapamycin and its application to stent restenosis.

Abstract

In response to physiological stimuli (eg, wound healing), normally quiescent smooth muscle cells (SMCs) within the vessel wall can be activated to migrate and proliferate to produce new blood vessels. In addition to this physiological response, pathological migration and proliferation within the vessel wall can occur in disease states. Examples of such disease states include tumor growth and metastasis, diabetic retinopathy, arthritis, accelerated arteriopathy after cardiac transplantation, and neointimal proliferation after balloon angioplasty (PTCA) and stent placement. An important limitation of PTCA is restenosis, which is due in large part to luminal narrowing; restenosis occurs in 20% to 40% of patients within the first few months after a successful intervention.1,2 The percentage of patients that develop early restenosis after PTCA can be reduced by stent implantation. However, stents actually increase the amount of late luminal narrowing due to intimal hyperplasia,3 and the overall rate of stent restenosis remains unacceptably high (≈30%). Numerous pharmacological agents, including antiplatelet agents, anticoagulants, ACE inhibitors, and cytotoxic agents, have failed to adequately reduce restenosis after PTCA and stenting. Novel therapeutic approaches based on understanding the molecular mechanisms that cause intimal hyperplasia are needed to reduce the high incidence of stent restenosis. Arterial injury is associated with SMC activation and re-entry into the cell cycle. Multiple approaches to inhibiting SMC proliferation have been and are being evaluated. Gene delivery systems aimed at blocking SMC proliferation after PTCA have been tested4,5; however, the low efficiency and/or potential hazards of this approach may limit its usefulness. Radiation therapy has been evaluated in numerous studies and has shown considerable promise as a nonpharmacological, antiproliferative approach for the reduction of restenosis. However, significant side effects, including late stent thrombosis, may also limit its usefulness.6–8 The unusually late stent thrombosis seen in the patients treated with …