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Plasminogen Activator Inhibitor Type 1 in Adults
With Down Syndrome and Protection Against
Macrovascular Disease
William E. Hopkins, MD, Naomi K. Fukagawa, MD, PhD, Burton E. Sobel, MD, and
David J. Schneider, MD
A
lthough most subjects with Down syndrome now
live well into adulthood, the incidence of sys-
temic hypertension and atherosclerotic vascular dis-
ease appears to be low.
1–5
In fact, in 1977 Murdoch et
al
3
suggested that Down syndrome may represent “an
atheroma-free model.” The reason for the apparent
lack of macroangiopathy is unknown. Obesity is com-
mon, premature aging is evident in other organ sys-
tems, and lipid levels are unfavorable compared with
those in unaffected siblings.
6–8
Conversely, mentally
retarded subjects without Down syndrome are not
spared from either systemic hypertension or athero-
sclerosis.
3–5
Some have suggested that a genetic “tri-
ple-dose effect” is responsible for the apparent pro-
tection because the genes for cystathionine beta syn-
thase and superoxide dismutase are located on
chromosome 21.
4,9
Plasminogen activator inhibitor type-1 (PAI-1), the
primary physiologic inhibitor of plasminogen activa-
tion, has been associated with myocardial infarction in
epidemiologic studies and appears to be a marker or
determinant for recurrent myocardial infarction.
10,11
We have recently implicated increased PAI-1 in vessel
walls as a potential determinant of accelerated athero-
sclerosis and particularly the development of lipid-
laden plaques vulnerable to rupture.
12
The relative
protection against atherosclerosis in Down syndrome
may imply that the expression of 1 determinant, in-
cluding PAI-1, is less prominent than in age, gender, and
body habit-matched unaffected subjects. If such a poten-
tial determinant were to be identified, the likelihood that
the factor would indeed be a causally connected contrib-
utor to atherogenesis would be increased.
•••
The study groups consisted of 24 adults with Down
syndrome and 26 control subjects. Body mass index
was measured in each subject and expressed as kg/m
2
.
No subject with Down syndrome and no control sub-
ject was known to have diabetes mellitus, systemic
hypertension, overt atherosclerotic vascular disease,
or a history of smoking.
Venous blood was sampled from the antecubital
vein with as brief a period of tourniquet time as
possible. The times of day at which samples were
drawn in controls and in subjects with Down syn-
drome were comparable; an important consideration
in view of the well known diurnal variation of con-
centrations of PAI-1 in blood. All blood samples were
random rather than fasting samples. Samples were
placed immediately on ice, and plasma was separated
by centrifugation at 2,000 g for 10 minutes and stored
at -70°C until assayed for PAI-1, PAI-1 activity,
tissue plasminogen activator (tPA), and homocysteine.
Total PAI-1 and tPA were assayed by enzyme-
linked immunosorbent assay (Tint Elise, Biopool,
Umea, Sweden, and American Diagnostica, Green-
wich, Connecticut, respectively) with results ex-
pressed as pM. Functional activity of PAI-1 was de-
termined with a kinetic, chromogenic substrate assay
that quantifies inhibition of activation of plasminogen
by exogenous tPA with results expressed as AU/ml.
13
Total homocysteine in plasma (M) was measured by
high-perfromance liquid chromatography with the use
of a method described by Araki and Sako.
14
From the Department of Medicine, University of Vermont College of
Medicine, Burlington, Vermont. Dr. Hopkins’ address is: University of
Vermont College of Medicine, McClure 1, MCHV Campus, 111
Colchester Avenue, Burlington, Vermont 05401. E-mail: william.
hopkins@vtmednet.org. Manuscript received August 23, 1999; re-
vised manuscript received and accepted October 28, 1999.
784 ©2000 by Excerpta Medica, Inc. All rights reserved. 0002-9149/00/$–see front matter
The American Journal of Cardiology Vol. 85 March 15, 2000 PII S0002-9149(99)00864-4