CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 1, January/February 2014
12
AFRICA
associated with higher serum ACE activity. Several studies have
reported a relationship between the D allele and cardiovascular
disease,
25-28
and atherosclerosis.
29,30
Kurtoglu
et al
. reported
that concentrations of plasma endothelin-1 were increased
and NOS were decreased in patients with CSF, as a result of
microvascular vasomotor dysfunction, which may be important
in this phenomenon.
31
Pekdemir
et al
. demonstrated, with intravascular ultra-
sonography, decreasing fractional flow reserve in the coronary
arteries in patients with CSF due to diffuse atherosclerosis.
4
Tanriverdi
et al
. reported that the
ACE
I/D polymorphism
correlated with carotid intima–media thickness, which is a sign
of subclinical atherosclerosis.
11
These findings suggest that
endothelial dysfunction and diffuse atherosclerosis may play
a role in the pathogenesis of CSF. Yalcin
et al
. reported that
the frequency of the DD genotype and D allele were higher
in patients with CSF, and DD genotypes were related to a
possibility of CSF.
32
In our study we found that the D allele was
not related to the presence of CSF (Fig. 1).
PAI-1 is a key regulator of the fibrinolytic process and is
related to the PAI-1 promoter 4G/5G polymorphism, although it
is regulated by several factors, including cytokines, growth factor
and insulin.
33-35
PAI-1 activity is to reduce plasma fibrinolytic
activity, and poor fibrinolytic activity is related to cardiovascular
events.
36
The 4G/5G polymorphism in the promoter region of the
PAI-1
gene is associated and correlated with plasma levels of
PAI-1 or the response of PAI-1 to a regulator.
37
There are few and conflicting results regarding the association
of 4G allele carriers and coronary events. Some studies
suggested that PAI-1 may play a role in atherogenesis due to
increased PAI-1 expression, which has been demonstrated in
atherosclerotic plaques.
38
Lima
et al
. reported that plasma PAI-1
activity was higher in carriers of the 4G/4G genotype and this
was correlated with atherosclerotic heart disease, as determined
by coronary angiography.
39
By contrast, Onalan
et al
. reported that the
PAI-1
4G/4G
genotype was related to a lower risk of the development of stable
coronary artery disease because of the inhibitory effects of PAI
on cellular migration.
40
Likewise, some studies suggested that
higher plasma levels of PAI were associated with the 4G/4G
genotype, which could have been the cause of reduced plaque
growth.
41,42
There is no study investigating the relationship
between CSF and
PAI-1
polymorphism in the literature. Our
study, surprisingly, showed that
PAI-1
4G allele carriers had
a protective effect on CSF and the 5G allele was related to
increasing risk for CSF.
eNOS is a regulator enzyme in the cardiovascular system for
functions such as vasodilatation, inhibition of leucocyte adhesion
to the endothelium, vascular small muscle cell migration and
proliferation, and platelet aggregation. Reduced endothelial
NO concentration is an important cause of endothelial
dysfunction.
12,13,43,44
The T-786C variation of the
eNOS
gene is
associated with reduction in gene promoter activity and the
resulting reduction in NO levels, increasing the risk for coronary
spasm.
14
Some studies have shown reduced plasma NO levels in
patients with CSF.
3,45
Sezgin
et al
. reported that FMD of the brachial artery was
impaired and decreased plasma NO levels in patients with CSF.
They concluded that endothelial dysfunction might be a cause of
CSF.
46
Nurkalem
et al
. reported an association between CSF and
T-786C polymorphism of the
eNOS
gene, and a positive correlation
between TIMI frame count and the C allele.
47
In our study, T-786C
genotypes were not different between CSF patients and control
subjects. Our study population included only a small number of
patients, which could have been the cause of the different results.
Several mechanisms, including endothelial dysfunction, diffuse
atherosclerosis and small-vessel disease have been proposed as a
cause of CSF.
3,4
The relationship between endothelial dysfunction
and atherosclerosis have been reported in previous studies.
48,49
FMD
is a factor in endothelial function and is correlated with carotid
intima–media thickness and coronary flow reserve.
5
Ari
et al
.
reported impaired FMD of the brachial artery in patients with CSF
Table 2. Echocardiographic characteristics and
flow-mediated dilatation in csf patients
Clinical parameters
CSF
(
n
=
33)
Controls
(
n
=
48)
p
-value
LVEDD (mm)
48 (32–63)
47 (39–69)
0.755
LVESD (mm)
31 (23–48)
28 (20–60)
0.019
LVEF (%)
59 (27–76)
64 (28–76)
0.003
LA (mm)
38 (27–49)
36 (26–56)
0.059
E wave (cm/s)
66.3
±
16.5
72.3
±
17.5 0.127
IVRT (ms)
101.7
±
22.7
96.9
±
16.8 0.277
E/A ratio
1.06 (0.59–2.49) 1.12 (0.61–2.86) 0.973
E/E
′
ratio
7 (3.8–15.4)
8 (3.6–19.17)
0.097
Peak S (cm/s)
8 (5–11)
8 (6–13)
0.077
FMD (%)
4.9
±
6.6
7.9
±
5.6
0.029
CSF, coronary slow flow; LVDD, left ventricular end-diastolic diameter;
LVESD, left ventricular end-systolic diameter; LVEF, left ventricular ejection
fraction; LA, left atrium; IVRT, isovolumetric relaxation time, FMD, flow-
mediated dilatation.
Table 3. The polymorphic snps and genotype and allele
frequencies of
ace
i/d,
enos
and
pai-1
genes in
csf patients and control group
Gene/genotypes
CSF
(
n
=
33)
n
(%)
Controls
(
n
=
48)
n
(%)
p
-value
Odds
ratio 95% CI
ACE
I/D
Ins/Ins
7 (21.22) 8 (16.6)
Ins/Del
15 (45.45) 23 (47.9)
Del/Del
11 (33.33) 17 (35.5)
Alleles
I
0.44
0.40
–
–
–
D
0.56
0.60
0.593
0.74 0.24–2.21
eNOS
T/T
18 (54)
25 (52)
T/C
13 (40) 19 (39.5)
C/C
2 (6)
4 (8.5)
Alleles
T
0.74
0.71
–
–
–
C
0.26
0.29
0.759
0.87 0.37–2.06
PAI-1
5G/5G
10 (30.4) 11 (22.9)
5G/4G
18 (54.5) 21 (43.75)
4G/4G
5 (15.1) 16 (33.35)
Alleles
5G
0.58
0.45
0.06
2.82 0.94–8.45
4G
0.42
0.55
