Infusion of an antialpha4 integrin antibody is associated with less neoadventitial formation after balloon injury of porcine coronary arteries.
BACKGROUND
The alpha4beta1 (or very late antigen-4 [VLA-4]) integrin is thought to play a role in inflammatory processes, mediating mononuclear leukocyte infiltration. The adventitial response to balloon injury is an important determinant of neointimal formation and arterial remodelling.


OBJECTIVE
To determine whether the monoclonal antibody hHP1/2 directed against the human alpha4-integrin subunit decreases neoadventitial formation and subsequent luminal narrowing following balloon injury.


METHODS
Randomized, double-blind, placebo controlled study.


METHODS
Tertiary care, Canadian university hospital vascular biology laboratory.


METHODS
In 16 pigs, two coronary arteries were injured with an oversized balloon, while a third coronary artery was designated as an uninjured control vessel. One hour before balloon injury, 5 mg/kg of hHP1/2 was administered to eight animals, while another eight animals received an infusion of a saline placebo. Animals were killed three and 14 days following balloon injury.


RESULTS
Administration of hHP1/2 resulted in an immediate decrease in circulating monocyte and lymphocyte counts. These parameters returned to normal within three days. There was a decrease in neoadventitial formation 14 days after arterial injury in pigs treated with hHP1/2 compared with controls (2.26+/-0.77 versus 3.42+/-1.01 mm, respectively, P=0.04). There was a loss of lumen area between days 3 (4.33+/-1.09 mm2) and 14 (3.09+/-0.38 mm2, P=0.02) after balloon injury in pigs treated with saline, but not in the pigs treated with hHP1/2.


CONCLUSIONS
Administration of an antibody to the alpha4-integrin subunit is associated with less neoadventitial formation and less lumenal narrowing after balloon injury. This novel therapy may play an important role in modulating arterial remodelling and thereby may reduce restenosis following percutaneous coronary interventions in humans.
Labinaz
M
M
University of Ottawa Heart Institute, Ottawa, Canada. mlabinaz@ottawaheart.ca
Hoffert
C
C
Pels
K
K
Aggarwal
S
S
Pepinsky
R B
RB
Leone
D
D
Koteliansky
V
V
Lobb
R R
RR
O'Brien
E R
ER
D015906:Angioplasty, Balloon, Coronary; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D003331:Coronary Vessels / Q000276:immunology / Q000293:injuries* / Q000473:pathology; D005352:Fibromuscular Dysplasia / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000276:immunology* / Q000502:physiology; D018655:Lymphocyte Count; D016201:Receptors, Lymphocyte Homing / Q000276:immunology* / Q000502:physiology; D013552:Swine; D017539:Tunica Intima / Q000276:immunology / Q000293:injuries* / Q000473:pathology
D000911:Antibodies, Monoclonal; D039041:Integrin alpha4beta1; D016023:Integrins; D016201:Receptors, Lymphocyte Homing