|
Since its clinical introduction some 20 years ago, angioplasty (PCTA)
has increased in popularity as a clinically effective method for improving
blood flow though stenosis or occluded arteries. However, over the next
3 to 6 months, restenosis occurs in approximiately 30-40% of patients,
thereby constituting a significant limitation to the long-term success
of this procedure. A number of trials using drugs effective in animals
for reducing restinosis have produced negative clinical results. The
complexity of the restenosis process, species particularities, and sub-optimal
drug dosing may partially explain these differences. Restenosis is predominantly
due to neointimal hyperplasia and constrictive remodeling. Inadequate
compensatory enlargment of a vessel after angioplasty (inadequate vascular
remodeling) is considered an important mechanism of post-PTCA restenosis.
Constrictive remodeling can be effectively countered by the use of
stents, which may account for the decreased incidence of restenosis
observed with their use. Despite the use of stents, restenosis continued
to limit the long-term success of PTCA. Stenting may provoke an exuberant
proliferative response compared to balloon angioplasty. The favorable
effect of stents in countering constrictive remodeling is therefore
in some cases offset by the increased neointimal hyperplasis associated
with stenting, causing difficult to treat in-stent restenosis.
Few effective therapies existed at this time of neointimal proliferation.
Vascular smooth muscle cell (SMC) migration and proliferation occur
as early as 36 hours following arterial injury. The number of SMC in
the neointima peaks around 2 weeks and cell replication rate after these
first few weeks is countered by cell death. Accumulation of extracellular
matrix and connective tissue which may constitute the bulk of neointima
further increases the intimal thickness.
The doctors at the Montreal Heart Institute found that the endothelium
had important inhibitory effects on platelet aggression, monocyte adhesion
and vascular smooth-muscle cell proliferation. Endothelial injury, with
consequent endothelial dysfunction, is caused by PTCA and may play an
important role in subsequent restenosis. What was found further was
that prolonged systemically administered 17B estradiol accelerates endothelial
recovery in vivo after arterial injury.
The important conclusion was: since endothelial injury due to PCI is
a local event, the institute investigated the efficacy of a local delivery
of a single dose of 17B-E, following PCI to reduce restenosis and potentially
to enhance endothelial recovery. The hope was that reendothelialization
and recovery of nitric oxide synthase activity might influence restenosis.
Administration of L-arginine and eNOS gene therapy have been shown to
reduce intimal thickening and restenosis after balloon injury.
Top..
The preliminary studies
were meant to show:
1. the effects of local delivery of 17 B_E on late luminal loss and
restenosis after PCI (Percutaneous Coronary Intervention)
2. to investigate the improvement in endothelial function after local
delivery of 17B-E and stent implantation.
3. to understand the mechanism for the clinical benefit of local 17
B-E delivery in vascular healing
Conclusion: The
studies at the Institute found a reduction in restenosis after stenting
with 17 B-E administration in a porcine coronary artery model. Further,
there was a significant reduction in the extracellular matrix and collagen
expression after local administration of 17B-E and stenting.
Top..
 1
| 2 | 3 | 4
| 5 | HOME
| PRINT PAGE
|
