Restenosis process

See color plate.) The phases and their timing in the restenosis process. 

One of the most dramatic examples of a biomimetic coating in clinical use is the stent marketed by the Johnson and Johnson Corporation. The stent had a polymer-based coating containing a drug that inhibited the restenosis process. The dnig was released from the polymer at a slow pace over time while the polymer remained on the stent permanently. Results were rather dramatic, with a reduction in the restenosis rate from 40% to 10%. In spite of its success, we should consider that the polymer coat used in this stent might not have been the optimal for the process in consideration. 

Figure 21.1. Stents are used to open arteries of the heart blocked by atherosclerotic plaques (A) a balloon and stent are placed across the plaque (B) the balloon is expanded, leaving the stent to prop open the artery (C) restenosis is the process wherein scar tissue builds up around the stent, again causing a flow restriction. A balloon is required for stainless steel, whereas a nitinol stent will expand on its own, due to the shape memory property of nitinol. (From Ref. 11, with permission.)...

The restenosis benefit is also intriguing, but, in all likelihood, has nothing to do with the antiplatelet actions of cilostazol, and may relate more to its effects on cytokine release from endothelial cells and smooth muscle cells, There is also preliminary evidence suggesting that cilostazol may speed the process of endothelialization (53). Again, with DES and their well-documented difficulties with endothelialization (54,55), this is a potentially very important future application that will require prospective testing in clinical trials. 

Acute vessel recoil, chronic remodeling, and intimal hyperplasia were the mechanisms involved in this process (1-4). However, after the introduction of stents in the daily practice during interventional procedures, intimal hyperplasia became the mechanism associated in the pathophysiology of in-stent restenosis (5-9). Therefore, its prevention should be related with therapies that inhibit smooth muscle cell proliferation. 

In contrast, in the current stent era, experimental studies indicated that a marked activation of inflammatory cells at the site of stent struts play a key role in the process of neointimal proliferation and restenosis (37-40), Indeed, interleukins I and 6 secreted by activated macrophages are powerful stimuli for smooth muscle cell proliferation and restenosis (41,42),... 

Restenosis is caused by an exaggerated healing response involving smooth-muscle migration, neointimal hyperplasia, and a lack of compensatory vessel wall dilation, which result in a reduced vessel luminal diameter at the site of previous endothelial trauma or injury (12-14). Therefore, ICB attempts to attenuate this process and reduce target-vessel restenosis and repeat revascularization. 

This chapter focuses on percutaneous transluminal coronary angioplasty (PTCA), provides a summary of the underlying immune activities of the diseased vasculature, and focuses in part on the role of immune and inflammatory mediators in the restenotic process. In addition, the mechanism of action of sirolimus, the drug used in the first successful DES for reduction of restenosis will be highlighted. Finally, the potential role for immune mediators on the overall processes of atherosclerosis will be explored. 

Sirolimus has pleotropic effects on a wide variety of cell types with relevance to restenosis. The underlying mechanism of action of the compound is as an inhibitor of the cell cycle, with its principal effect on the G I to S transition (40), Importantly, sirolimus affects the numerous cell types thought to be involved in the restenotic process including cells typically resident to the vascular wall, such as SMCs, as well as those recruited from the circulation at times of injury such as immune constituents, As the complete delineation of the steps and mechanisms of restenosis remain to be determined, the benefit of sirolimus may be due to its ability to affect the multiple cell types involved. 

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