Effects of beta3-integrin blockade (c7E3) on the response to angioplasty and intra-arterial stenting in atherosclerotic nonhuman primates.
Because the beta3-antagonist abciximab (c7E3 Fab) has significantly improved late outcomes after coronary angioplasty, the beta3 integrins have been implicated in the arterial response to injury. However, the mechanisms underlying this benefit are unknown. The observation that c7E3 binds beta3 integrins on vascular cells (alphavbeta3) 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 microg. 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.
Deitch
J S
JS
Departments of Surgery and Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Williams
J K
JK
Adams
M R
MR
Fly
C A
CA
Herrington
D M
DM
Jordan
R E
RE
Nakada
M T
MT
Jakubowski
J A
JA
Geary
R L
RL
D000077284:Abciximab; D015906:Angioplasty, Balloon, Coronary; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001158:Arteries; D001161:Arteriosclerosis / Q000628:therapy*; D001777:Blood Coagulation / Q000187:drug effects; D003131:Combined Modality Therapy; D004353:Drug Evaluation, Preclinical; D006403:Hematologic Tests; D006965:Hyperplasia / Q000188:drug therapy; D007140:Immunoglobulin Fab Fragments / Q000627:therapeutic use*; D016023:Integrins / Q000037:antagonists & inhibitors*; D008055:Lipids / Q000097:blood; D008252:Macaca fascicularis; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D015607:Stents; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D016023:Integrins; D008055:Lipids; D010975:Platelet Aggregation Inhibitors; D000077284:Abciximab