Efficient inhibition of in-stent restenosis by controlled stent-based inhibition of elastase: a pilot study.
OBJECTIVE
It is proposed that local elastase inhibition could suppress the extracellular matrix (ECM) degradation and subsequent smooth muscle cell migration and limit subsequent in-stent restenosis. This study evaluated the effect of stent-based controlled elastase inhibition on restenosis after stent implantation in a rabbit model.


METHODS
Biodegradable microspheres containing the potent elastase inhibitor alpha-1-antitrypsin (AAT) were prepared. Daily release of AAT from the microspheres was confirmed in vitro. The microspheres were loaded into stents with an abluminal polymer reservoir. Implantation of the stent with AAT microspheres and blank microspheres (control) was performed in the abdominal aortae of six rabbits in each group. After stent deployment, all stents were overdilated to 125% diameter. Stent-implanted arteries were harvested after 7 days (n = 3 each) or 28 days (n = 3 each). To assess the effect of local delivery of AAT, elastase activity and elastin content of the stent-implanted aortae were analyzed. As an endpoint, intima-to-media (I/M) ratio was determined in the 7-day and 28-day specimens.


RESULTS
Significant inhibition of elastase was confirmed in treated vessels versus controls at 7 days after stent implantation (P < .05). This reduction in elastase activity was sufficient to afford early and late reduction of in-stent neointima. Plaque progression in the 28-day specimens decreased to 67% with elastase inhibition relative to controls (P < .05).


CONCLUSIONS
Stent-based controlled release of elastase inhibitor may significantly reduce ECM degradation and might limit in-stent restenosis.
Ganaha
Fumikiyo
F
Department of Cardiovascular and Interventional Radiology, Program in Human Gene Therapy, Stanford University School of Medicine, 300 Pasteur Drive, H3648, Stanford, California 94305, USA.
Ohashi
Kazuo
K
Do
Young So
YS
Lee
Jane
J
Sugimoto
Koji
K
Minamiguchi
Hiroki
H
Elkins
Christopher J
CJ
Sameni
Diba
D
Modanlou
Shoreh
S
Ali
Mir
M
Kao
Edward Y
EY
Kay
Mark A
MA
Waugh
Jacob M
JM
Dake
Michael D
MD
D000704:Analysis of Variance; D000818:Animals; D004549:Elastin / Q000187:drug effects; D005263:Femoral Artery / Q000601:surgery; D006083:Graft Occlusion, Vascular / Q000517:prevention & control*; D066298:In Vitro Techniques; D008297:Male; D008488:Medical Illustration; D008863:Microspheres; D023421:Models, Animal; D010196:Pancreatic Elastase / Q000187:drug effects*; D010865:Pilot Projects; D011817:Rabbits; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D015607:Stents; D013997:Time Factors; D000515:alpha 1-Antitrypsin / Q000008:administration & dosage / Q000494:pharmacology*
D015842:Serine Proteinase Inhibitors; D000515:alpha 1-Antitrypsin; D004549:Elastin; D010196:Pancreatic Elastase