ABSTRACT
In-stent restenosis, mainly caused by an abundant neointimal hyperplasia, remains the major limitation of coronary stent implantation. Mural thrombi, inflammatory response, smooth muscle cell (SMC) dedifferentiation, migration and proliferation, and furthermore extracellular matrix formation, all participate in the pathogenesis of neointimal hyperplasia. Changing any of these factors could have an impact on neointimal hyperplasia. Systemic delivery of drugs has been unsuccessful in reducing restenosis. Indeed, local drug delivery via infusion devices has introduced additional complexity to the procedure and may not deliver sufficient medication to the injury site. Drug eluting stents, however, can deliver an adequate amount of medication to the injury site for a sufficient period of time, and have been proposed as an alternative approach to decrease neointimal hyperplasia. Some preliminary studies have shown very promising results.1,2
MODE OF ACTION OF DEXAMETHASONE
The role of inflammation in atherosclerosis and restenosis has been widely discussed in recent literature.3-6 Inflammation is an inevitable consequence of angioplasty, as injury to the vessel wall and the introduction of a foreign object (stent) both elicit an adverse host response. Whilst the injury is somewhat dictated by the procedure used or the type of stent selected, the subsequent host response can be controlled by use of antiinflammatory compounds. The corticosteroids, including dexamethasone, methylprednisolone, and hydrocortisone, are a well-documented group of steroidal drugs. Indeed, dexamethasone itself has been approved by the Federal Drug Administration (FDA) since 1958 and is extensively used in inflammation management. In animal models, local delivery of such corticosteroids has been shown to reduce inflammation markers caused by percutaneous transluminal coronary angioplasty (PTCA) and stenting procedures (Figure 53.1).7,8
The inflammatory response consists of both innate (non-specific) and acute (specific) reactions. The innate reactions are induced by release of plasma and cell-derived mediators. Increased vessel permeability results in the exudation of fluid into the injured tissue, which contains components from the complement, coagulation, fibrinolytic, and kinin cascades, that stimulate the release of a host of chemical inflammatory mediators; cellular events are induced by endothelial, mast, and macrophage cells present in the tissue, and platelets and leukocytes from the blood. The acute reactions are a consequence of more specific activation of B-and T-lymphocytes by antigens that migrate to the lymph nodes.
