Effects of β3-integrin blockade (c7E3) on the response to angioplasty and intra-arterial stenting in atherosclerotic nonhuman primates

Jonathan S. Deitch, J. Koudy Williams, Michael R. Adams, Christopher A Fly, David M. Herrington, Robert E. Jordan, Marian T. Nakada, Joseph A. Jakubowski, Randolph L. Geary

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Because the β3-antagonist abciximab (c7E3 Fab) has significantly improved late outcomes after coronary angioplasty, the β3 integrins have been implicated in the arterial response to injury. However, the mechanisms underlying this benefit are unknown. The observation that c7E3 binds β3 integrins on vascular cells (αvβ3) 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 (LD(Pre)), after angioplasty (LD(Post)), and 35 days later (LD(Day35)). 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 1918±2.5 minutes. P<0.001. Experimental angioplasty increased LD(Post) 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 (LD(Day35)-LD(Post): 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.

Original languageEnglish (US)
Pages (from-to)1730-1737
Number of pages8
JournalArteriosclerosis, thrombosis, and vascular biology
Volume18
Issue number11
DOIs
StatePublished - Jan 1 1998
Externally publishedYes

Fingerprint

Angioplasty
Integrins
Primates
Iliac Artery
Tunica Intima
Arteries
Stents
Hyperplasia
Atherosclerosis
Integrin beta3
Neointima
Platelet Glycoprotein GPIIb-IIIa Complex
Bleeding Time
Subclavian Artery
Macaca fascicularis
Platelet Aggregation
Aspirin
Blood Vessels
Heparin
Angiography

Keywords

  • Atherosclerosis
  • Cynomolgus monkeys
  • Restenosis
  • Stents
  • β3 integrins

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Effects of β3-integrin blockade (c7E3) on the response to angioplasty and intra-arterial stenting in atherosclerotic nonhuman primates. / Deitch, Jonathan S.; Williams, J. Koudy; Adams, Michael R.; Fly, Christopher A; Herrington, David M.; Jordan, Robert E.; Nakada, Marian T.; Jakubowski, Joseph A.; Geary, Randolph L.

In: Arteriosclerosis, thrombosis, and vascular biology, Vol. 18, No. 11, 01.01.1998, p. 1730-1737.

Research output: Contribution to journalArticle

Deitch, Jonathan S. ; Williams, J. Koudy ; Adams, Michael R. ; Fly, Christopher A ; Herrington, David M. ; Jordan, Robert E. ; Nakada, Marian T. ; Jakubowski, Joseph A. ; Geary, Randolph L. / Effects of β3-integrin blockade (c7E3) on the response to angioplasty and intra-arterial stenting in atherosclerotic nonhuman primates. In: Arteriosclerosis, thrombosis, and vascular biology. 1998 ; Vol. 18, No. 11. pp. 1730-1737.
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T1 - Effects of β3-integrin blockade (c7E3) on the response to angioplasty and intra-arterial stenting in atherosclerotic nonhuman primates

AU - Deitch, Jonathan S.

AU - Williams, J. Koudy

AU - Adams, Michael R.

AU - Fly, Christopher A

AU - Herrington, David M.

AU - Jordan, Robert E.

AU - Nakada, Marian T.

AU - Jakubowski, Joseph A.

AU - Geary, Randolph L.

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N2 - Because the β3-antagonist abciximab (c7E3 Fab) has significantly improved late outcomes after coronary angioplasty, the β3 integrins have been implicated in the arterial response to injury. However, the mechanisms underlying this benefit are unknown. The observation that c7E3 binds β3 integrins on vascular cells (αvβ3) 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 (LD(Pre)), after angioplasty (LD(Post)), and 35 days later (LD(Day35)). 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 1918±2.5 minutes. P<0.001. Experimental angioplasty increased LD(Post) 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 (LD(Day35)-LD(Post): 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.

AB - Because the β3-antagonist abciximab (c7E3 Fab) has significantly improved late outcomes after coronary angioplasty, the β3 integrins have been implicated in the arterial response to injury. However, the mechanisms underlying this benefit are unknown. The observation that c7E3 binds β3 integrins on vascular cells (αvβ3) 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 (LD(Pre)), after angioplasty (LD(Post)), and 35 days later (LD(Day35)). 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 1918±2.5 minutes. P<0.001. Experimental angioplasty increased LD(Post) 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 (LD(Day35)-LD(Post): 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.

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