© 1998 American Heart Association, Inc.
Original Contributions |
Effects of ß3-Integrin Blockade (c7E3) on the Response to Angioplasty and Intra-Arterial Stenting in Atherosclerotic Nonhuman Primates
From the Departments of Surgery (J.S.D., C.A.F., R.L.G.) and Comparative Medicine (J.K.W., M.R.A.) and the Section of Cardiology (D.M.H.) of Wake Forest University School of Medicine, Winston-Salem, NC; Centocor Corp (R.E.J., M.T.N.), Malvern, Pa; and Eli Lilly Corp (J.A.J.), Indianapolis, Ind.
Correspondence to Randolph L. Geary, MD, Division of Surgical Sciences, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157. E-mail rgeary{at}bgsm.edu
Abstract—Because the
ß3-antagonist abciximab (c7E3 Fab) has significantly
improved late outcomes after coronary angioplasty, the ß3
integrins have been implicated in the arterial response to
injury. However, the mechanisms underlying this benefit are unknown.
The observation that c7E3 binds ß3 integrins on vascular cells
(
vß3) with affinity equal to that for the platelet
glycoprotein IIb/IIIa integrin has led to the hypothesis
that c7E3 may act directly on the artery wall to prevent
restenosis after angioplasty. To test this hypothesis, we
studied the effects of c7E3 on structural changes within the artery
wall after angioplasty or stent angioplasty in 23 male cynomolgus
monkeys with established atherosclerosis. Animals were
randomly assigned to receive either a bolus of c7E3 (0.4 mg/kg IV,
n=11) followed by a 48-hour infusion (0.2 µg ·
kg-1 · min-1) or an equal volume of
vehicle (n=12). Animals received weight-adjusted aspirin and heparin
and then underwent unilateral iliac artery experimental angioplasty and
subclavian artery stent angioplasty (Palmaz). Iliac artery lumen
diameter (LD) was determined by angiography at baseline
(LDPre), after angioplasty (LDPost), and 35
days later (LDDay35). Arteries were then fixed by perfusion
and removed for analysis. Lumen, intima, media, and external
elastic lamina (EEL) areas were measured in iliac artery cross
sections. Values from each injured iliac artery were normalized to the
contralateral uninjured iliac artery to control for interanimal
variability in baseline artery size and atherosclerosis
extent. Intimal area was also measured in subclavian stent cross
sections. c7E3 blocked platelet aggregation and prolonged the
bleeding time from 2.8±1.1 to 19.8±2.5 minutes,
P<0.001. Experimental angioplasty increased
LDPost an average of 28%, and the initial gain was similar
in both groups (P=NS). Despite an anti-platelet
effect, c7E3 did not inhibit iliac lumen narrowing
(LDDay35-LDPost: c7E3, -0.69±0.17 versus
vehicle, -0.99±.17 mm, P=0.35); intimal
hyperplasia (neointima area: c7E3, 1.12±.28 versus
vehicle, 1.22±.20 mm2, P=0.77); or
decrease in artery wall size (EEL area [percent of uninjured
control]: c7E3, 101±7% versus vehicle, 121±7%). Stent intimal
hyperplasia was also unaltered by c7E3 treatment
(neointimal area: c7E3, 1.09±0.16 versus vehicle,
1.28±0.11 mm2, P=0.36). These results
suggest that the benefits of c7E3 treatment in coronary
angioplasty were not from inhibition of intimal hyperplasia or improved
artery wall remodeling. Alternative mechanisms should be explored to
explain improved late outcomes after angioplasty in patients treated
with c7E3.
Key Words: ß3 integrins • atherosclerosis • restenosis • stents • cynomolgus monkeys
This article has been cited by other articles:
 |
|
 |
|
  S. V. Dee and H. Samady Evolving Strategies for the Prevention and Treatment of Coronary Restenosis Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2003; 7(3): 281 - 293. [Abstract] [PDF]
|
|
|
|
 |
|
 C. Horvath, F. G.P. Welt, M. Nedelman, P. Rao, and C. Rogers Targeting CCR2 or CD18 Inhibits Experimental In-Stent Restenosis in Primates: Inhibitory Potential Depends on Type of Injury and Leukocytes Targeted Circ. Res., March 8, 2002; 90(4): 488 - 494. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. S. Cherr, S. J. Motew, J. A. Travis, J. Fingerle, L. Fisher, M. Brandl, J. K. Williams, and R. L. Geary Metalloproteinase Inhibition and the Response to Angioplasty and Stenting in Atherosclerotic Primates Arterioscler. Thromb. Vasc. Biol., January 1, 2002; 22(1): 161 - 166. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P. Bendeck, C. Irvin, M. Reidy, L. Smith, D. Mulholland, M. Horton, and C. M. Giachelli Smooth Muscle Cell Matrix Metalloproteinase Production Is Stimulated via {alpha}v{beta}3 Integrin Arterioscler. Thromb. Vasc. Biol., June 1, 2000; 20(6): 1467 - 1472. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Chandrasekar and J.-F. Tanguay Platelets and restenosis J. Am. Coll. Cardiol., March 1, 2000; 35(3): 555 - 562. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Overhaus, J. Heckenkamp, S. Kossodo, D. Leszczynski, and G. M. LaMuraglia Photodynamic Therapy Generates a Matrix Barrier to Invasive Vascular Cell Migration Circ. Res., February 18, 2000; 86(3): 334 - 340. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Scarborough, N. S. Kleiman, and D. R. Phillips Platelet Glycoprotein IIb/IIIa Antagonists : What Are the Relevant Issues Concerning Their Pharmacology and Clinical Use? Circulation, July 27, 1999; 100(4): 437 - 444. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. R. Coleman, G. A. Braden, M. C. Willingham, and D. C. Sane Vitaxin, a Humanized Monoclonal Antibody to the Vitronectin Receptor ({alpha}vß3), Reduces Neointimal Hyperplasia and Total Vessel Area After Balloon Injury in Hypercholesterolemic Rabbits Circ. Res., June 11, 1999; 84(11): 1268 - 1276. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Horvath, F. G.P. Welt, M. Nedelman, P. Rao, and C. Rogers Targeting CCR2 or CD18 Inhibits Experimental In-Stent Restenosis in Primates: Inhibitory Potential Depends on Type of Injury and Leukocytes Targeted Circ. Res., March 8, 2002; 90(4): 488 - 494. [Abstract] [Full Text] [PDF]
|
|