Published Online
on December 8, 2003

A more recent version of this article appeared on January 6, 2004

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Submitted on May 28, 2003
Revised on August 25, 2003
Accepted on August 26, 2003

Antirestenotic Effects of a Locally Delivered Caspase Inhibitor in a Balloon Injury Model

Nirat Beohar MD^*, James D. Flaherty MD, Charles J. Davidson MD, Robert C. Maynard MD, Joel D. Robbins MD, Atman P. Shah MD, James W. Choi MD, Lee A. MacDonald MD, Jesse P. Jorgensen MD, Jack V. Pinto MD, Sonal Chandra MD, Heather M. Klaus MD, Norman C. Wang MD, Kathleen R. Harris BS, Robert Decker PhD, and Robert O. Bonow MD

From Feinberg School of Medicine, Northwestern University, Chicago, Ill.

^* To whom correspondence should be addressed. E-mail: n-beohar{at}northwestern.edu.

Background--The precise role of arterial barotrauma-mediated apoptosis in causing restenosis is unclear. The purpose of this study was to determine if a link exists between angioplasty-mediated medial smooth muscle cell apoptosis and subsequent neointimal hyperplasia.

Methods and Results--Bilateral iliac artery angioplasty was performed in 25 male New Zealand White rabbits. Simultaneous with balloon injury, each artery was treated locally with either the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp(Ome)-fluoromethylketone (ZVAD-fmk) or control. In the acute cohort that was survived to 4 hours (n=10, 7 high dose and 3 low dose), an apoptotic index was calculated using the terminal deoxynucleotidyl TUNEL method. In the intermediate cohort that was survived to 2 weeks (n=5), luminal reendothelialization was measured via CD-31 staining. In the chronic cohort that was survived to 4 weeks (n=10), neointimal area was measured. In the acute cohort, there was a 40% reduction in the apoptotic index with high-dose ZVAD-fmk (P=0.008) and a 33% reduction with low-dose ZVAD-fmk (P=0.08). At 2 weeks, there was no significant difference in the degree of luminal reendothelialization. However, at 4 weeks, there was a 33% (0.33±0.23 versus 0.22±0.20 mm²) (P<0.005) reduction in neointimal area in ZVAD-fmk-treated arteries.

Conclusions--The local delivery of ZVAD-fmk during balloon injury inhibits smooth muscle cell apoptosis. This corresponds to a significant reduction in neointimal proliferation seen at 4 weeks without a significant change in the degree of reendothelialization at 2 weeks.

Key words: angioplasty • apoptosis • restenosis

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