Local Delivery of Ceramide for Restenosis

Despite the clinical advantage of percutaneous transluminal coronary angioplasty (PTCA) in treating severely narrowed blood vessels, long-term success is often compromised by restenosis. It is unclear what mechanisms cause vessels to renarrow, despite numerous studies involving patients and experimental animal models of arterial injury. Although neointimal thickening was initially considered the major cause, recent evidence suggests that arterial constriction, adventitial thickening, or both may be critical in the restenosis process. The geometric changes of vessel expansion and contraction constitute the definition of remodeling. The present emphasis on remodeling and restenosis has been driven by studies failing to show a direct correlation between neointimal thickening and lumen size, suggesting that intimal mass alone is insufficient to explain narrowing.1 Analyses of human coronary angioplasty sites at autopsy by our laboratory support the thesis that constrictive remodeling and the initial plaque burden, rather than neointimal formation, are responsible for the failure of angioplasty.2 Other potential contributors to the pathophysiology of restenosis include arterial spasm, vessel recoil, platelet aggregation, and thrombus formation.Arterial injury evokes a sequence of events, consisting of medial smooth muscle cell activation, migration and proliferation, and matrix secretion culminating in a thickened neointima.3 This series of events is linked to complex interactions between cells within the vessel wall as well as circulating blood cells and cytokines. At least in theory, restenosis should be a treatable process with adjunctive pharmacotherapy. Several agents, such as vascular endothelial growth factor,4 heparin,5 paclitaxel,6 7 urokinase,8 recombinant hirudin,9 colchicine,10 11 rapamycin sirolimus,12 13 cytochalasin B,14 IIb and IIIa inhibitors,15 and antisense oligomers,16 17 18 19 have been tested in animal models or patients. Most of these agents have failed to solve the restenosis problem in humans, but two recent promising agents, paclitaxel …