CLINICAL STUDY
Arterial repair after stenting and the effects of gm6001, a matrix metalloproteinase inhibitor
Chris Li, MD*,
Warren J. Cantor, MD, FACC*,
Nafiseh Nili, PhD*,
Ranga Robinson, PhD*,
Louis Fenkell, BSc*,
Yen L. e Tran, BSc*,
Heather A. Whittingham, MSc*,
Winston Tsui, MD*,
Asim N. Cheema, MD*,
John D. Sparkes, MSc*,
Kenneth Pritzker, MD ,
Daniel E. Levy, PhD and
Bradley H. Strauss, MD, PhD, FACC*,*
* Roy and Ann Foss Interventional Cardiology Research Program, Terrence Donnelly Heart Center, St. Michael’s Hospital, Toronto, Canada
Department of Laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Canada
Glycomed, Incorporated, Alameda, California, USA
Manuscript received September 18, 2001;
revised manuscript received February 20, 2002,
accepted March 6, 2002.
* Reprint requests and correspondence: Dr. Bradley H. Strauss, St. Michael’s Hospital, 30 Bond Street, Toronto, Ontario, Canada M5B 1W8.
straussb{at}smh.toronto.on.ca
OBJECTIVES: This study compared the extracellular matrix (ECM) and cellular responses after stenting to balloon angioplasty (BA) and to determine the late effects of matrix metalloproteinase (MMP) inhibition on arterial repair after stenting.
BACKGROUND: Although stenting is the predominant form of coronary intervention, there is limited understanding of the early and late arterial response.
METHODS: In a double-injury rabbit model, adjacent iliac arteries in 87 animals received BA (3.0 mm diameter) or stenting (3.0 mm NIR). Rabbits were treated for 1 week postprocedure with either GM6001 (100 mg/kg per day), an MMP inhibitor or placebo and sacrificed at 1 week or at 10 weeks’ postprocedure. Arteries were analyzed for morphometry, collagen content, gelatinase activity, cell proliferation and DNA content.
RESULTS: Stented arteries had significant increases in collagen content (2-fold) at 10 weeks compared to BA-treated arteries. At one week, overall gelatinase activity was increased >2-fold in stented arteries, with both 72 kD and 92 kD gelatinase activity. Stented arteries also had increases in both intimal DNA content (1.5-fold) and absolute cell proliferation (4-fold). Compared to placebo, GM6001 significantly inhibited intimal hyperplasia and intimal collagen content, and it increased lumen area in stented arteries without effects on proliferation rates.
CONCLUSIONS: Stenting causes a more vigorous ECM and MMP response than BA, which involves all layers of the vessel wall. Inhibition by MMP blocks in-stent intimal hyperplasia and offers a novel approach to prevent in-stent restenosis.
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Abbreviations and Acronyms
| | ANOVA | | analysis of variance | | BA | | balloon angioplasty | | BrdU | | bromodeoxyuridine | | CSA | | cross-sectional area | | ECM | | extracellular matrix | | HPF | | high power field | | IVUS | | intravascular ultrasound | | MMP | | matrix metalloproteinase | | MMPI | | matrix metalloproteinase inhibitor | | SMC | | smooth muscle cell |
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