Prevention Of Neointimal Hyperplasia - Taxol, Rapamycin, And Radiation

Alexander Clowes, MD

The animal and clinical studies of intimal hyperplasia during the last two decades have documented over and over again that it is a response to injury and a complication of all forms of arterial reconstruction.

Although pathological remodeling (a decrease in overall arterial cross-sectional area) is a more important mechanism for luminal narrowing in vessels treated by balloon angioplasty, intimal hyperplasia followed by stenosis or restenosis is the principal cause for failure in vein and synthetic grafts and in stented atherosclerotic arteries. Restenosis affects ca 20-30% of coronary and other small arterial reconstructions, and the treatment of restenosis is further vascular reconstruction.

The arterial wall thickens and the lumen narrows because vascular smooth muscle cells (SMCs) accumulate in the intima and secrete matrix proteins. We know from animal studies that SMCs are derived from adventitial cells and blood borne stem cells as well as populations of SMCs in and around the zone of injury.

The migration of these cells from one tissue compartment to another followed by proliferation in the intima are required for intimal thickening and are regulated by factors released from thrombus (thrombin, PDGF), inflammatory cells (TNF, IL1b), or the vascular wall cells themselves (basic FGF, TGFb, etc.).

The growth and migratory factors as well as critical intracellular signaling pathways represent logical targets for pharmacological blockade and the prevention of intimal hyperplasia.

Approaches to prevention including adjuvant pharmacology (taxol and rapamycin) and radiation are just now being tested and are the subject of this brief review.

Taxol	Taxol (Paclitaxel) and related drugs are used as cancer chemotherapeutic agents; their principal mechanism of action depends on microtubule stabilization. Recently investigators have found that taxol inhibits SMC proliferation and migration in vitro and in vivo in balloon injured rat arteries. The drug prevents intimal hyperplasia in stented pig coronary and rabbit iliac arteries, and in very small clinical trials it appears to prevent restenosis in stented human coronary arteries (de la Fuente et al. Catheter Cardiovasc Interv 2001; 53:480). However, late coronary occlusion possibly related to sudden thrombosis (Liistro et al. Heart 2001; 86:262) has been reported and might be the consequence of incomplete intimal healing; this disasterous complication plagues stented arteries treated with radiation and appears to be caused by failure of endothelial repair.
Rapamycin	Rapamycin (Sirolimus) is a macrolide antibiotic that possesses immunosuppressant activity. It also is an inhibitor of SMC proliferation and migration. Its effect on SMCs depends on binding to its receptor, the FK506 binding protein (FKBP12), and it thereby blocks cell cycle progression by preventing the downregulation of the CDK inhibitor p27kip1. Deletion of p27kip1 makes the cells resistant to rapamycin while overexpression of p27kip1 using gene transfer techniques inhibits intimal hyperplasia. It is of note that the related immunosuppressant drug FK506 (Tacrolimus) also binds to FKBP12 but does not inhibit SMC proliferation and migration. Two small coronary trials have reported a beneficial effect of rapamycin released from stents; in these studies no patient developed >50 % narrowing (Marx et al. Circulation 2001:104:852). No complications have been reported.
Radiation Therapy	The inhibitory effects of radiation on SMC growth have been known for some time. This finding became clinically important when Teirstein et al reported that locally delivered radiation prevents further narrowing in human coronary arteries treated with stents for restenosis after balloon angioplasty (Teirstein et al. N. Engl. J. Med 1997; 336:1697). Enthusiasm for this form of adjuvant therapy has diminished as longer term studies have revealed two important and serious limitations. It appears that the stented and irradiated arteries are at risk for sudden thrombosis, because the luminal endothelial layer is not reestablished. In addition, although the radiation effectively suppresses intimal hyperplasia and lumenal narrowing in the stented zone, the neighboring artery at the margin of the radiation field appears to develop exuberant intimal hyperplastic ("candy wrapper ") lesions (Albiero et al. Circulation 2000; 101:18).

Conclusions
Until very recently, symptomatic restenosis of a stented artery or stenosis of a bypass graft could not be prevented and usually required further vascular reconstruction. A number of drugs have been tried including antithrombotic agents, anticoagulants, ACE inhibitors, and cytotoxic agent, and they have all failed.

Taxol, rapamycin, and radiation have achieved some success in preliminary trials in suppressing intimal hyperplasia, in part because the drugs and radiation are particularly effective when they are delivered or released into the injured artery. This form of delivery targets the vascular bed at risk and prevents systemic toxicity.

It is unfortunate that none of them is specific for the SMC, the cell responsible for the intimal lesion, and it is possible that failure of endothelial regeneration may leave the reconstructed vessel vulnerable to late thrombosis as has been shown in irradiated and stented coronary arteries. Adjuvant therapy currently under development and targeted specifically at the SMCs (e.g. PDGF blockade) would be expected to circumvent this problem.

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