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(Circulation. 2004;109:108-113.)
© 2004 American Heart Association, Inc.

Basic Science Reports

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; Robert O. Bonow, MD

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

Correspondence to Nirat Beohar, MD, Feinberg School of Medicine of Northwestern University, Department of Medicine, Division of Cardiology, 251 E Huron St, Feinberg Pavilion 8-526, Chicago, IL 60611. E-mail n-beohar{at}northwestern.edu

Received May 28, 2003; revision received August 25, 2003; accepted August 26, 2003.

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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