Full text of DOI:10.1007/PL00007263

Heart Vessels (2000) 15:105–111
© Springer-Verlag 2000
ORIGINAL ARTICLE
Takeshi Soeki · Yoshiyuki Tamura · Hisanori Shinohara
Hideji Tanaka · Kanji Bando · Nobuo Fukuda
Role of circulating vascular endothelial growth factor and hepatocyte
growth factor in patients with coronary artery disease
Received June 9, 2000 / Accepted September 30, 2000
Abstract Vascular endothelial growth factor (VEGF) and
Introduction
hepatocyte growth factor (HGF) are thought to stimulate
endothelial cell proliferation and induce angiogenesis in
Vascular endothelial growth factor (VEGF) is a 38- to 46-
vivo. However, the precise mechanism responsible for
kDa heparin-binding homodimeric glycoprotein, which is
VEGF and HGF release in patients with coronary artery
an important endothelial cell mitogen that can also enhance
disease is still unknown. We studied serum concentrations
vascular permeability in a number of normal tissues.1–3 The
of VEGF and HGF in 20 patients with acute myocardial
upregulation of VEGF expression in cardiac myocytes, vas-
infarction (AMI), 20 patients with stable angina pectoris
cular smooth muscle cells, and endothelial cells is induced
(AP) who had reversible perfusion defects on stress myo-
by hypoxia4–8 and myocardial ischemia.9–12 In addition,
cardial scintigraphy, and 16 patients with old myocardial
exogenous administration of VEGF in vivo has been shown
infarction (OMI) who had no reversible defects on stress
to augment collateral blood flow to the ischemic
myocardial scintigraphy. The control group consisted of 20
patients with atypical chest pain who had angiographically
normal coronary arteries. Serum VEGF and HGF concen-
myocardium.13,14
Hepatocyte growth factor (HGF) is a recently character-
ized growth factor that has a disulfide-linked heterodimer
trations were measured by enzyme-linked immunosorbent
structure and an apparent molecular weight of 80kDa.15–17
assay. Both the serum VEGF and HGF concentrations in
Its receptor has been identified as c-Met, a transmembrane
the early stage of myocardial infarction in the patients with
tyrosine kinase proto-oncogene.17 HGF has been shown
AMI were higher than those in the patients with AP and
to have numerous functions including mitogenesis,18–20
with OMI, and control patients. The VEGF concentration
motogenesis,21,22 morphogenesis,23 and angiogenesis.24,25
in the patients with AP was higher than in the patients with
Furthermore, HGF and c-Met have been implicated in cap-
OMI, whereas the HGF concentration did not differ in the
illary endothelial cell regeneration in the ischemically in-
patients with AP and OMI. The VEGF concentration in
AMI patients who had had preinfarction angina on admis-
sion was higher than that of patients who had had no
jured heart.26
Recently, circulating concentrations of VEGF and HGF
were found to have increased after acute myocardial infarc-
preinfarction angina, whereas the HGF concentration did
tion (AMI) in humans.27–32 However, no studies have com-
not differ between the two groups of patients. These results
pared the changes in these growth factors in a variety of
suggest that the serum VEGF concentration may reflect
coronary syndromes. Therefore, the present study was de-
myocardial ischemia to a greater degree than the serum
signed to determine serum VEGF and HGF concentrations
HGF concentration.
in patients with AMI, angina pectoris (AP), or old myocar-
dial infarction (OMI).
Key words Vascular endothelial growth factor · Hepato-
cyte growth factor · Coronary artery disease · Myocardial
ischemia
Subjects and methods
T. Soeki ( ) · Y. Tamura · H. Shinohara · H. Tanaka · K. Bando ·
N. Fukuda
Patients
Department of Cardiology and Clinical Research Institute, National
Zentsuji Hospital, 2-1-1 Senyu-cho, Zentsuji, Kagawa 765-8507,
Japan
Tel. ϩ81-877-62-2211; Fax ϩ81-877-63-1601
e-mail: tsoeki@jun.ncvc.go.jp
We studied 20 patients with first AMI (mean age 64 years)
who were hospitalized at our coronary care unit within 3h
after the onset of symptoms, 20 patients with AP (mean age

106
69 years) who had angiographic evidence of м90% coronary of heparin at the time of admission in patients with AMI. In
stenosis and had reversible perfusion defects on stress myo- the AP, OMI, and control groups, fasting venous blood
cardial scintigraphy, and 16 patients with OMI (mean age 64 samples were obtained at 0700h. Clotted cellular elements
years) who had angiographic evidence of м90% coronary were removed from the blood samples by centrifugation at
stenosis in one vessel and no reversible perfusion defects on room temperature (2000 ϫ g, 10min). The serum samples
stress myocardial scintigraphy. The control group consisted were stored at Ϫ70°C until the time of assay.
of 20 patients (mean age 65 years) with atypical chest pain
who had angiographically normal coronary arteries and no
evidence of myocardial ischemia.
Biochemical analysis
AMI was diagnosed based on typical chest pain lasting
Ͼ30min with Ͼ0.2mV of ST-T segment elevation in at least
two contiguous leads on a standard 12-lead electrocardio-
gram and an increase in the creatine kinase-MB activity that
was at least twice the upper normal limit. AP was defined as
typical anginal chest pain lasting between 10 and 30min
with м1mm transient ST-segment depression or elevation
0.08s after the J point, and no episodes of angina at rest or
increasing angina. The serum creating kinase and creatine
kinase-MB activities had to be less than twice the upper
limit of normal. Patients with OMI were enrolled in the
study at least 6 months after the occurrence of AMI.
Serum VEGF and HGF were concentrations measured by
enzyme-linked immunosorbent assay (VEGF, Immuno-
Biological Laboratories, Gunma, Japan; HGF, Otsuka
Assay Laboratories, Tokyo, Japan). The sensitivity of the
VEGF and HGF kits was 15.6pg/ml and 0.010ng/ml,
respectively.
Statistical analysis
All results are expressed as the mean Ϯ standard deviation.
The differences in ratios were compared using the chi-
squared test. Differences among the four groups were
evaluated by one-factor analysis of variance, and if it was
significant, Fisher’s Protected least significance difference
test was performed. Relationships were analyzed using the
Pearson correlation coefficient. A value for P Ͻ 0.05 was
considered statistically significant.
Adenosine triphosphate (ATP) stress thallium-201
myocardial scintigraphy
ATP was infused for 5 min at a rate of 0.16 mg/kg per min via
an antecubital vein. Three minutes after the start of ATP
infusion, 74 MBq of thallium-201 was injected as a bolus at
another venous site. Single photon emission computed
tomographs were obtained 5 min and 4 h after the first thal-
lium injection using a large field-of-view rotating gamma
camera equipped with a low-energy, high-resolution colli-
mator interfaced to a computer (Toshiba NEW GMS-550U,
Toshiba Medical, Tokyo, Japan). Four hours later, 37 MBq
of thallium-201 was reinjected and the imaging was repeated.
Tomographic slices were displayed in all three standard
cardiac planes to assess myocardial perfusion in each vascu-
lar territory. The presence or absence of redistribution was
determined visually from the 4-h images. Thallium-201 im-
ages were interpreted by two nuclear cardiologists who did
not know the results of the coronary angiography.
Results
Patient characteristics
Table 1 summarizes the patient characteristics in each study
group. The groups were comparable with respect to gender,
age, incidence of hypertension and diabetes mellitus, and
total cholesterol and triglyceride concentrations. The smok-
ing rate was higher in the AMI group than in the control
group. The HDL-cholesterol concentration was higher in
the control group than in the other groups, and lower in the
AMI group than in the AP group. Ejection fraction on left
ventriculography was higher in the AP and control groups
than in the AMI and OMI groups.
Coronary angiography
All patients with AP and OMI underwent coronary
angiography within 2 weeks of ATP stress thallium-201
myocardial scintigraphy. Coronary angiography was per-
formed using the standard Judkins technique. Patients with
coronary artery stenoses that were м90% of the vessel di-
ameter in one or more epicardial vessels were enrolled in
this study. The results were interpreted by two senior
angiographers who had no knowledge of the results of the
thallium imaging.
Antiplatelet drugs including aspirin, ticlopidine, and
trapidil were administered to 1 of 20 control patients, 12 of
20 AP patients, and all of OMI patients. In all AMI patients,
antiplatelet drugs were not administered on admission.
However, in patients with AP, there were no differences
between those receiving and not receiving antiplatelet
drugs with respect to the concentrations of serum VEGF
and HGF. Antihyperlipidemic drugs such as statin were
administered to 2 of 20 control patients, 5 of 20 AP patients,
3 of 16 OMI patients, and 4 of 20 patients with AMI on
admission, the ratios of which did not differ.
Blood samples
The VEGF and HGF concentrations did not differ be-
Venous blood samples for the measurement of VEGF and tween the patients with and without hypertension or diabe-
HGF were obtained immediately before the administration tes mellitus either overall or in any group.

107
Table 1. Patient demographics and clinical characteristics
Group
AMI
AP
OMI
Control
n
20
15/5
63.7 Ϯ 12.5
20
12/8
66.9 Ϯ 11.0
16
11/5
63.6 Ϯ 9.4
20
10/10
64.8 Ϯ 11.0
Male/female
Age (years)
*
Smokers (n)
10 (50.0%)
11 (55.0%)
5 (25.0%)
194.8 Ϯ 35.1
124.6 Ϯ 59.6
5 (25.0%)
11 (55.0%)
6 (30.0%)
205.0 Ϯ 37.0
151.5 Ϯ 61.5
5 (31.3%)
5 (31.3%)
4 (25.0%)
203.5 Ϯ 39.8
119.9 Ϯ 43.1
3 (15.0%)
5 (25.0%)
5 (25.0%)
201.7 Ϯ 34.6
131.4 Ϯ 53.6
Hypertension (n)
Diabetes mellitus (n)
T-Cholesterol (mg/dl)
Triglycerides (mg/dl)
**
*
**
**
HDL-Cholesterol (mg/dl)
40.5 Ϯ 9.1
46.8 Ϯ 6.1
40.9 Ϯ 12.4
52.5 Ϯ 9.2
66.3 Ϯ 8.7
*
*
**
**
LVEF (%)
55.4 Ϯ 15.2
68.6 Ϯ 7.3
55.4 Ϯ 7.4
Data are reported as the mean Ϯ standard deviation
AMI, acute myocardial infarction; AP, angina pectoris; OMI, old myocardial infarction; T-, total;
HDL-, high-density lipoprotein; LVEF, left ventricular ejection fraction
*P Ͻ 0.05; **P Ͻ 0.01
Fig. 1. Serum vascular endothelial growth factor concentrations in the
control group and patients with acute myocardial infarction (AMI),
angina pectoris (AP), and old myocardial infarction (OMI)
Fig. 2. Serum hepatocyte growth factor concentrations in the control
group and patients with acute myocardial infarction (AMI), angina
pectoris (AP), and old myocardial infarction (OMI)
Serum VEGF concentrations (Fig. 1)
control group, 0.25 Ϯ 0.06 ng/ml). The HGF concentration
did not differ between the AP, OMI, and control groups.
The serum VEGF concentration was higher at the time of
admission in patients with AMI than in the AP, OMI, and
control groups (AMI group, 89.6 Ϯ 44.0pg/ml; AP group,
74.5 Ϯ 29.0pg/ml; OMI group, 54.7 Ϯ 21.2pg/ml; control
group, 56.5 Ϯ 26.8pg/ml). The VEGF concentration was
higher in the patients with AP than in the OMI and control
groups. The VEGF concentration in the patients with OMI
did not differ from that of control patients.
Correlation between serum VEGF and HGF
concentrations (Fig. 3)
The VEGF concentration did not correlate with the HGF
concentration in the AMI (r ϭ 0.021), AP (r ϭ 0.102), OMI
(r ϭ 0.093), or control (r ϭ 0.230) groups.
Serum HGF concentrations (Fig. 2)
Correlation between serum growth factor concentrations
and the angiographic findings (Table 2)
The serum HGF concentration was higher at the time of
admission in the patients with AMI than in the AP, OMI,
and control groups (AMI group, 0.30 Ϯ 0.06 ng/ml; AP
group, 0.27 Ϯ 0.07 ng/ml; OMI group, 0.25 Ϯ 0.04 ng/ml;
Patients in the coronary artery disease subgroups (AMI, AP,
and OMI groups) were divided into four groups based on the
angiographically determined development of collaterals

108
Fig. 3. Correlation between the serum vascular endothelial growth factor (VEGF) and serum hepatocyte growth factor (HGF) concentrations.
NS, not significant
Table 2. Correlations between serum growth factor concentrations
and angiographic findings
than that of patients who had had no preinfarction angina
(12 patients) (113.2 Ϯ 59.7 vs 74.0 Ϯ 20.1pg/ml, P Ͻ 0.05),
Spearman’s r
P value whereas the HGF concentration did not differ between the
patients with and without preinfarction angina (0.310 Ϯ 0.09
AMI
Collateral score/VEGF
Collateral score/HGF
AP
Collateral score/VEGF
Collateral score/HGF
vs 0.286 Ϯ 0.04ng/ml).
0.034
0.245
0.8898
0.3029
Ϫ0.161
0.066
0.5038
0.7857
Discussion
OMI
Collateral score/VEGF
Collateral score/HGF
0.109
0.361
0.6924
0.1730
In this study, the serum VEGF and HGF concentrations
were both higher at the time of admission in the patients
with AMI than in the AP, OMI, or control patients. These
results might be due to increased expression of VEGF and
HGF induced by the myocardial ischemia.9–12,26 The degree
of myocardial ischemia might explain the differences in
serum VEGF and HGF concentrations between the AMI
and AP patients. In a model of myocardial infarction in rats,
an initial rapid rise in the mRNA expression of VEGF and
its receptors (flk-1, flt-1) was observed throughout the
entire heart.11 Furthermore, the plasma concentrations of
HGF also increases within 1h of reperfusion after 1h of
myocardial ischemia.26 In the present study, the circulating
VEGF, vascular endothelial growth factor; HGF, hepatocyte growth
factor; other abbreviations as in Table 1
using the system designed by Rentrop et al.33 (grades 0–4).
The serum VEGF and HGF concentrations did not correlate
in any group with the degree of collateral development.
Serum VEGF and HGF concentrations of AMI with or
without preinfarction angina in the AMI group
The VEGF concentration in AMI patients who had had concentrations of VEGF and HGF were elevated within 3h
preinfarction angina on admission (8 patients) was higher after the onset of AMI, suggesting that the rapid induction

109
of VEGF and HGF mRNA followed by synthesis of the radiometric assay) might have caused the difference in the
proteins might occur in response to acute myocardial is- results.
chemia in humans. Several clinical reports have demon-
HGF activator, a serum-derived serine protease, has
strated that the serum HGF concentration increases at the been identified as an activator of the single-chain form of
time of admission in patients with AMI,29–32 which is in HGF.34 The HGF activator precursor is converted to the
keeping with our results. In contrast, the changes in the active form by thrombin.35 Recent studies have shown that
serum concentration of VEGF in patients with AMI is increases in the circulating HGF concentration can be in-
controversial. Seko et al.27 demonstrated that the serum duced by arterial thrombus formation.36 Furthermore, we
VEGF concentration before reperfusion is markedly in- were able to detect an apparent thrombus by coronary an-
creased in patients with AMI. However, Tamura et al.28 and giography in 2 of 20 AMI patients, who demonstrated a
Kranz et al.29 reported that the serum VEGF concentra- higher concentration of serum HGF (0.39 and 0.32ng/ml)
tion in patients with AMI does not increase immediately than the mean value of that in AMI patients (0.30ng/ml).
after admission. In their studies, no detailed characteristics Therefore, a coronary thrombus might induce an increase in
of the subjects were presented, such as sex and mean age, the serum HGF concentration in the early stage of AMI
which makes analysis of the different results between through thrombin generation. Furthermore, the serum
their studies and ours difficult. For example, it could not be HGF concentration could reflect differences in the degree
denied that the control groups in their studies had silent of thrombus deposition between AP and AMI.
myocardial ischemia. Furthermore, the serum VEGF con-
Previous studies have also demonstrated that VEGF is
centration in the patients with AMI in the present study often extensively expressed in human coronary arteries nar-
(89.6pg/ml) comparable to that in the study by Kranz et al. rowed by atherosclerotic plaque.37 The serum HGF concen-
(105pg/ml) is less than half of those in the studies by Seko tration is increased in patients with coronary atherosclerosis
et al. (252.4pg/ml) and Tamura et al. (213pg/ml). This dis- or severe retinal arteriosclerosis,38 suggesting that VEGF
crepancy might have resulted from differences in dura- and HGF expression might be associated with the severity
tion from the onset because the patients with AMI in the of atherosclerosis. However, in the present study, no differ-
study by Tamura et al. were within 24h of the onset ences in the VEGF and HGF concentrations were found
longer than 3h in our criteria. The use of different bio- between the OMI and control groups, which suggests that
chemical analysis kits might also have contributed to this the VEGF and HGF concentrations might not directly
discrepancy.
reflect the severity of coronary atherosclerosis. Another
Previous study showed that the serum HGF concentra- previous study has demonstrated that the serum HGF con-
tion increased within 3h after the onset in patients with centration increased in hypertensive patients and decreased
AMI, which is compatible with our results. However, in diabetic patients without hypertension.39 However, in the
whether the serum VEGF concentration increases in the present study, the serum HGF concentration did not differ
very early stage in AMI is still unknown. In this study, the between the patients with and without hypertension or dia-
serum VEGF concentration also increased within 3h after betes either overall or in any one group.
the onset in AMI and was higher in the AMI patients than
VEGF and HGF also have potent angiogenic effects
in the other groups. Thus, the measurement of VEGF might in animal models; specifically, they improve the collateral
be useful for the early diagnosis of AMI if a more rapid blood flow in the ischemic myocardium13,14 and ischemic
assay for VEGF is developed.
hindlimb muscle.40–42 In the present study, neither the serum
In the present study, the serum VEGF concentration in VEGF concentration nor the HGF concentration corre-
the patients with AP was greater than in those with OMI lated with the degree of collateral development in any of
and control patients. In contrast, the HGF concentration in the groups with coronary artery disease. This result suggests
the patients with AP was comparable to that in patients that the circulating VEGF and HGF concentrations may
with OMI and control patients. These results suggest that not directly reflect the effects of the local VEGF/HGF sys-
the serum VEGF concentration reflects myocardial is- tem on collateral development. This study included a small
chemia better than the serum HGF concentration. In other number of patients, therefore the ability to generalize this
words, VEGF might be upregulated mainly by ischemia, correlation might be limited.
while HGF might be upregulated by other stimuli. This
Experimental studies have demonstrated that HGF pro-
hypothesis is supported by our finding that the VEGF con- duced by transfection with a human HGF vector can exert
centration did not correlate with the HGF concentration in stimulatory autocrine and paracrine effects on endothelial
any group. Also, the VEGF concentration in the AMI pa- cell growth.43 In a rat model, HGF and c-Met have been
tients who had had preinfarction angina on admission was implicated in capillary endothelial cell regeneration in the
higher than that of patients who had not experienced ischemically injured heart.26 Furthermore, increased local
preinfarction angina. However, Kranz et al. have shown vascular HGF production can prevent endothelial injury.44
that the serum VEGF concentration was not increased in These findings suggest that one role of increased circulating
patients with unstable angina.29 In their study, no detailed HGF in AMI might be the repair of injured endothelial
characteristics of the control group, such as angiographic cells.
findings, were presented, which makes analysis of the differ-
Our study has several limitations. First, we could not
ent results between the two studies difficult. In addition, perform serial measurements of serum VEGF and HGF
differences in biochemical analysis (they used an immuno- concentrations in the acute phase of myocardial infarction

110
because heparin administration reduces the serum VEGF28
and increases the serum HGF concentration.45 Second, we
measured only the serum concentrations of VEGF and
HGF and did not evaluate the local concentrations of
VEGF and HGF in the ischemic regions. Further studies
based on blood sampling from the coronary sinus and aorta
are needed to determine the main site of VEGF/HGF pro-
duction in patients with coronary artery disease.
17. Gherardi E, Stroker M (1991) Hepatocyte growth factor-scatter
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Cech AC, Hirschfield DW, Wong J, Miki T, Finch PW, Aaronaon
SA (1991) A broad-spectrum human lung fibroblast-derived mito-
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19. Strain AJ, Ismail T, Tsubouchi H, Arakaki N, Hishida T, Kitamura
N, Daikuhara Y, McMaster P (1991) Native and recombinat
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T, Matsumura M, Kaneko N, Terano A, Nakamura T, Omata M
(1995) Hepatocyte growth factor is the most potent endogenous
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