From the Department of Medicine, The University of Vermont College of
Medicine, Burlington (B.E.S., J.W.-M., D.J.S., K.M.); and Massachusetts
General Hospital, Boston (R.E.H., H.G.).
Correspondence to Dr Burton E. Sobel, Department of Medicine, FAHC-MCHV Campus, Fletcher 311, 111 Colchester Ave, Burlington, VT 05401. E-mail burton.sobel{at}vtmednet.org
Background—Inhibition of
fibrinolysis attributable to elevated concentrations of
plasminogen activator inhibitor
type 1 (PAI-1) in blood is associated with insulin resistance,
hyperinsulinemia, and type 2 diabetes mellitus.
Because we have shown that insulin can stimulate PAI-1 synthesis in
vivo and because accelerated vascular disease is common in such
patients as well, we hypothesized that increased PAI-1, potentially
predisposing to thrombosis, acute occlusion, and accelerating
atherosclerosis because of thrombus-associated
mitogens, would be present in excess in atheroma from
type 2 diabetic subjects.
Methods and Results—Samples acquired by directional
coronary atherectomy from 25 patients with type 2 diabetes and
18 patients without diabetes were characterized qualitatively
histologically for cellularity and by
immunohistochemistry visually and qualitatively and by quantitative
image analysis for assessment of urokinase-type
plasminogen activator (u-PA) and PAI-1.
Patients with and without diabetes were similar with respect to
demographic features and the distribution and severity of
coronary artery disease. Substantially more PAI-1 and
substantially less u-PA were present in the atherectomy samples
from subjects with diabetes.
Conclusions—The disproportionate elevation of PAI-1 compared with
u-PA observed in atheromatous material extracted from
vessels of diabetic subjects is consistent with increased gene
expression of PAI-1 in vessels as well as the known increase of PAI-1
in blood, presumably reflecting increased synthesis. The increased
PAI-1 detected in the atheroma may contribute in vivo to
accelerated or persistent thrombosis underlying acute occlusion and to
vasculopathy exacerbated by clot-associated mitogens in the vessel
wall. Because the changes were observed to be associated with insulin
resistance and type 2 diabetes mellitus, they may be modifiable by
reduction of insulin resistance with insulin sensitizers and stringent
control of hyperglycemia.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Increased Plasminogen Activator Inhibitor Type 1 in Coronary Artery Atherectomy Specimens From Type 2 Diabetic Compared With Nondiabetic Patients
A Potential Factor Predisposing to Thrombosis and Its Persistence
Key Words: diabetes mellitus • coronary disease • fibrinolysis • insulin • thrombosis
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|
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|
|
|
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|
|
|
|
|
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|
|
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|
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|
|
|
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|
|
|
|
|
|
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|
|
|
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|
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|
|
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|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|