From the Klinik für Thorax-, Herz und Gefäßchirurgie,
Klinikum Fulda, Germany, and Chirurgische Forschung (B.U.v.S.),
Universitätsklinik Freiburg, Germany.
Correspondence to B. Schumacher, MD, Klinik für Thorax-, Herz und Gefäßchirurgie, Klinikum Fulda, Pacelliallee 4, D-36043 Fulda, Germany.
Methods and Results—FGF-I was obtained from strains
of Escherichia coli by genetic engineering, then
isolated and highly purified. Several series of animal experiments
demonstrated the apathogenic action and neoangiogenic potency of this
factor. After successful conclusion of the animal experiments, it was
used clinically for the first time. FGF-I (0.01 mg/kg body weight) was
injected close to the vessels after the completion of internal mammary
artery (IMA)/left anterior descending coronary artery (LAD)
anastomosis in 20 patients with three-vessel coronary disease.
All the patients had additional peripheral stenoses
of the LAD or one of its diagonal branches. Twelve weeks later, the IMA
bypasses were selectively imaged by intra-arterial digital
subtraction angiography and quantitatively evaluated. In all the animal
experiments, the development of new vessels in the ischemic
myocardium could be demonstrated angiographically. The
formation of capillaries could also be demonstrated in humans and was
found in all cases around the site of injection. A capillary network
sprouting from the proximal part of the coronary artery could
be shown to have bypassed the stenoses and rejoined the distal
parts of the vessel.
Conclusions—We believe that the use of FGF-I for
myocardial revascularization is in principle a new
concept and that it may be particularly suitable for patients with
additional peripheral stenoses that cannot be
revascularized surgically.
In the search for alternative and/or additional treatment
for improving the long-term prognosis, especially in diffuse CHD,
attention has recently been directed toward natural
angiogenesis.3 4 5 6 7 8 9 Growth factors, especially
FGF-I, have recently become of major importance because they can induce
angiogenesis.8 10 11 12
Gimenez-Gallego et al13 succeeded in
elucidating the biochemical structure of FGF-I in 1985. Jaye et
al14 isolated human FGF-I from brain tissue in
1986. In 1991, Forough and coworkers15
successfully used the technique of gene transfer to introduce the
information for expressing human FGF-I into apathogenic
Escherichia coli.
Our aim was to evaluate the information currently available on the
biological effect of angiogenetic growth factors in animals and, if
appropriate, to use human growth factor for the treatment of CHD. This
involved (1) the production of human growth factor by genetic
engineering, followed by its isolation, characterization, and
purification; (2) using animal experiments to establish its
angiogenetic potency and to exclude any possible pathogenic effect; and
(3) using FGF-I clinically as an adjunct to coronary surgery
and to demonstrate neoangiogenesis in the ischemic human
myocardium.
Genetic engineering was used to produce human FGF-I from apathogenic
strains of E coli, a plasmid containing the genetic
information being introduced into the
microorganisms.15 These were kindly provided by
Prof T. Maciag (Laboratory of Molecular Biology, American Red Cross,
Rockville, Md). After production, FGF-I was eluted by heparin
sepharose column chromatography, and several elution
fractions were collected and purified by dialysis. Positive protein
elution fractions were identified in the BIO-RAD
assay7 by SDS-PAGE,16 and
the biochemical isolation of FGF-I was confirmed by the Western blot
method.17 Further purification was obtained by
HPLC.18 The factors were lyophilized and stored
at -32°C and diluted to 1 mL with NaCl solution containing 500 IU of
heparin.
Chorioallantoic Membrane Assay
Exclusion of the Pyrogenicity of FGF-I
Confirmation of the Angiogenetic Potency of FGF-I in Animal
Experiments
Clinical Use of FGF-I in Patients With CHD
The details, nature, and aims of this procedure were explained
beforehand to every patient who underwent the operation. In all cases,
we received their fully informed consent. Both groups of patients were
closely comparable with regard to clinical symptoms, accompanying
disorders, cardiovascular risk factors,
ventricular function, sex, and age. A comparable
coronary morphology was found in both groups.
All patients had a further stenosis in the distal third of the
LAD or at the origin of one of its branches in addition to a severe
proximal stenosis. The mean ejection fraction of the left
ventricle for all patients was 50%. The operative procedure for
coronary revascularization with autologous
grafts (an average per patient of 2 to 3 venous bypasses and 1 from the
left IMA) was routinely performed. FGF-I (mean concentration, 0.01
mg/kg body weight) was injected into the myocardium, distal
to the IMA/LAD anastomosis and close to the LAD, during the
maintenance of the extracorporeal circulation and after
completion of the distal anastomoses (Fig 1
Angiograms obtained in this way were evaluated by means of EDP-assisted
digital gray-value analysis, a universally recognized and
well-established technique for demonstrating capillary
neoangiogenesis.21 22 23 24 25 26 Sites of interest both
with and without FGF-I (meaning heat-denatured FGF-I) were selected in
the vessels filled with contrast medium and in regions of the
myocardium distal to the IMA/LAD anastomosis. One hundred
pixels were selected from each site of interest and analyzed
digitally. Complete blackening of the x-ray films was rated with a gray
value of 150, and areas without blackening of the film were allotted a
zero value. During the first 5 postoperative days, separate laboratory
checks in addition to the routine postoperative follow-up procedures
were made twice daily, and the temperature checked three times a
day.
In the chorioallantoic membrane assay, the angiogenetic potency
of FGF-I could be demonstrated in vivo. As early as 4 days after
application of the factor, the vascular structure of the membrane was
completely altered. Emanating radially from the site of application, an
unequivocal growth of new vessels from the original host vessels had
grown out into the periphery (Fig 4A
Pyrogenic effects of the human growth factor produced in this way
could be definitively ruled out in the animal model. There was no
significant rise of body temperature when checked at short intervals
and no trace of an inflammatory reaction in comparison with the control
group (n=13) in any of the 27 test animals during the period of
observation. This result was independent of the concentration and the
route of administration (intravenous, subcutaneous, or
intramuscular) of the factor.
Earlier investigations into the application of FGF-I to the
nonischemic rat heart made it possible to demonstrate
neoangiogenesis both histologically and
angiographically after 9 weeks in 11 of 12 test animals after the
implantation of a tissue bridge pretreated with growth factor between
the heart and thoracic aorta. In the control group without FGF-I (n=6),
no signs of induced neoangiogenesis could be
found.4 7
Unequivocal proof of induced neoangiogenesis was also found in
the ischemic rat heart. In the test animals, in which
myocardial ischemia had previously been induced with titanium
clips and growth factor had subsequently been injected into the
myocardium, a manifest accumulation of contrast medium was
shown by aortic angiography at the site of the FGF-I injection 12 weeks
later (Fig 5A
When the growth factor FGF-I was used clinically for the first
time on the human heart, neoangiogenesis together with the development
of a normal vascular appearance could be demonstrated angiographically,
exactly as in the earlier animal experiments.4 7
Selective imaging of the IMA bypasses by intra-arterial
digital subtraction angiography confirmed the following result in all
20 patients: at the site of injection and in the distal areas supplied
by the LAD, a pronounced accumulation of contrast medium extended
peripherally around the artery for
At the site of injection of the FGF-I, a capillary network could be
seen sprouting out from the coronary artery into the
myocardium. This enabled retrograde imaging of a stenosed
diagonal branch to be performed (Fig 7A
The results of EDP-assisted digital gray value analysis for
quantification of the neoangiogenesis (Fig 8
During the last few years, several working groups have been able
to establish indications for the effective use of growth factors to
improve blood flow in the presence of tissue ischemia in animal
experiments.3 9 27 Yanagisawa-Miwa et
al9 succeeded in demonstrating a significant
collateralization together with reduction in the size of the infarct
after intracoronary administration of growth factor in rabbits.
Baffour et al3 also observed a significant
formation of collaterals in ischemic extremities after growth
factor administration in animals. Albes et al27
produced a distinct improvement in the blood flow in ischemic
tracheal segments implanted subcutaneously in rabbits by injecting
growth factor–enriched fibrin glue locally.
After growth factor was injected into the ischemic rat
heart,4 7 we were able to observe induced
neoangiogenesis and confirm it angiographically. We were also able to
prove histologically that this neoangiogenesis brings
about the development of new vascular structures with a three-layered
vessel wall. Angiographic imaging confirmed that these are anatomically
normal capillaries and other blood vessels.
The production of human FGF-I by our molecular biological
method has proved to be a complex but readily reproducible procedure.
From the bacterial cultures, we are able to isolate the factor as a
pure substance in sufficient quantities. By in vitro assay and as a
result of extensive animal experiments, we were able to exclude the
possible pyrogenic effects of FGF-I.
In earlier animal experiments,4 we were
able to demonstrate the proliferative and mitogenic effects
of the growth factor on human saphenous vein
endothelial cells. Endothelial cell
cultures with added growth factor induced a confluent monolayer after
only 5 to 9 days, whereas the monolayer was not complete before 7 to 11
days in the control group. In addition to determining the total cell
count with a cell counter, we also confirmed this result by analyzing
the rate of DNA synthesis by measuring the incorporation of
3 H-thymidine into the endothelial
cell nuclei using the method of Klagsbrun and
Shing.28 The cell proliferative potency of FGF-I
could be further intensified by adding heparin, a
glycosaminoglycan protecting the growth factor from
inactivation by cellular enzymes and from heat and chemical
denaturation.29
On the basis of these in vitro and in vivo experiments, we
established for the first time the efficacy of FGF-I for the treatment
of CHD, and were able to demonstrate that it can induce neoangiogenesis
in situ in the ischemic human heart. This possibility has been
widely discussed for many years but never before attempted.
A dense capillary network appeared around the site of injection
of the factor in the myocardium of all our treated
patients. This capillary network is a true de novo vascular system.
Emerging from the proximal segment of the LAD, it sprouts out into the
surrounding myocardium, bringing about a twofold to
threefold increase in the local blood supply through these newly formed
functional vessels. We were able to use the recognized
physiological effects of FGF-I (as they occur in
the repair mechanism of wound healing or in collateralization of
ischemic tissue) to induce neoangiogenesis in the human
ischemic heart.
We also consider that administration of FGF-I (produced in this
way by genetic engineering), combined with operative myocardial
revascularization, may well be an especially
appropriate treatment for patients with additional
peripheral stenoses that cannot be treated
surgically.
In our opinion, neoangiogenesis induced by FGF-I opens up new
possibilities for the treatment of ischemic myocardial disease.
Furthermore, it could become a new therapeutic concept in the
management of diffuse CHD after alternative methods of administration
have also been developed. This method of inducing neoangiogenesis is
also conceivable as a therapeutic option in other regions of the
cardiovascular system in which arterial
occlusion has led to ischemia.30 However,
before any such possibilities are realized, many more clinical
investigations will have to be performed.
Received January 9, 1997;
revision received December 1, 1997;
accepted December 1, 1997.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Induction of Neoangiogenesis in Ischemic Myocardium by Human Growth Factors
First Clinical Results of a New Treatment of Coronary Heart Disease
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—The
present article is a report of our animal experiments and also of
the first clinical results of a new treatment for coronary
heart disease using the human growth factor FGF-I (basic fibroblast
growth factor) to induce neoangiogenesis in the ischemic
myocardium.
Key Words: growth substances • angiogenesis • coronary disease
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
For the cardiac
surgeon who is attempting to treat CHD, the use of sections of
autologous blood vessels as bypass material is subject to severe
limitations. Autologous arterial conduits are in short
supply, and segments of the saphenous vein do not remain patent for
very long.1 2 Furthermore, "complete"
revascularization is limited if diffuse
coronary arteriosclerosis is present
and extensive, especially if there are additional
peripheral stenoses.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Production and Purification of FGF-I
The production and purification of human FGF-I is a
biochemically elaborate technique. The individual experimental steps
have been reported elsewhere.4 7
This established method, which provides a direct demonstration
of the effect of growth factors on living tissue, was used to
investigate the angiogenetic effect of
FGF-I.19 20 The growth of the allantoic systems
can be directly observed by light microscopy. After incubation of 20
fertilized hen eggs for 13 days, the growth factor was applied to the
membrane and covered with tissue culture coverslips. Four days later,
the membrane was examined under the light microscope and directly
compared with controls untreated with FGF-I or treated with
heat-denatured FGF-I (70°C for 3 minutes).
Varying concentrations of FGF-I (0.01, 0.5, or 1.0 mg/kg body
weight) were injected subcutaneously, intramuscularly, or
intravenously into 27 New Zealand White rabbits, the
solvent alone being used for an additional 13 controls. Thereafter, the
rectal temperature was taken every half hour for 3 hours, hourly for
the rest of the day, and every 8 hours for 12 days. A daily white cell
count was also repeated for 12 days (see "Results"). In addition to
this, the erythrocyte sedimentation rate and the C-reactive protein
values were determined on the 3rd, 6th, 9th, and 12th days after the
injection.
Supplementary to our earlier
experiments,4 7 the effect of FGF-I was also
investigated in the ischemic hearts of inbred Lewis rats (a
total of 275 animals, including 125 controls treated with
heat-denatured FGF-I, 70°C for 3 minutes). The pericardium was opened
via the abdominal wall and diaphragm, and two titanium clips were
inserted at the apex of the left ventricle to induce myocardial
ischemia. Growth factor (mean concentration of 10 µg) was
then injected locally into the site. The coronary vessel system
was imaged by aortic root angiography after 12 weeks and, finally, a
specimen from the same myocardial region was evaluated
histologically.
This study was approved by the Medical Research Commission at
the Phillips University of Marburg on August 10, 1993 (No. 47/93). This
is the usual ethics commission for our hospital. Twenty patients
without any history of infarction or cardiac surgery (14 men and 6
women; minimum age, 50 years) were subjected to an elective bypass
operation for multivessel coronary heart disease. The growth
factor was applied directly during the operation. As a control group,
20 patients who underwent the same procedure were given heat-denatured
FGF-I (70°C for 3 minutes). The choice of treatment was completely
random, the names being placed in sealed envelopes and selected in a
blinded manner. 
). In the control group, heat-denatured
FGF-I was substituted for FGF-I. After 12 weeks, the IMA bypasses of
all the patients were imaged selectively by transfemoral,
intra-arterial, and digital subtraction angiography.
View larger version (121K):
[in a new window]
Figure 1. Intraoperative administration of growth
factor.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
After separation, purification, and stabilization, we were able to
isolate human FGF-I in all 40 bacterial cultures and demonstrate its
high degree of purity. Fig 2 shows an
HPLC profile of the growth factor after routine purification. The peak
values at the beginning and end of the profile represent
impurities that could be identified as E coli proteins.
FGF-I could be further separated by fractionated collection, and the
control HPLC (Fig 3) merely shows the
peak value of this fraction on an otherwise even baseline.
View larger version (11K):
[in a new window]
Figure 2. HPLC profile before high purification. HBGF-I
indicates human FGF-I; %E, extinction.
View larger version (8K):
[in a new window]
Figure 3. HPLC profile after high purification. HBGF-I
indicates human FGF-I; %E, extinction. ).
These structures were completely absent from the control group, and a
normally developed reticular vascular pattern could be discerned (Fig 4B).
View larger version (76K):
[in a new window]
Figure 4. A, Chorioallantoic membrane assay with application
of the growth factor. B, Chorioallantoic membrane assay of the control
group. HBGF-I indicates human FGF-I. ), whereas such an
accumulation of contrast medium did not appear in any of the control
animals (Fig 5B). Histological examination of the
myocardium revealed a threefold increase in the capillary
density per square millimeter around the site of the FGF-I
injection.
View larger version (65K):
[in a new window]
Figure 5. A, Administration of the growth factor in
ischemic rat heart with a clearly discernible accumulation of
contrast medium at the site of injection. B, No discernible
accumulation of contrast medium in the control group. HBGF-I indicates
human FGF-I. 
3 to 4 cm, distal to
the IMA/LAD anastomosis (Fig 6A). In the
control angiograms of patients to whom only heat-denatured FGF-I had
been given, the IMA/LAD anastomosis was also recognizable, but the
accumulation of contrast medium described above was absent (Fig 6B).
The angiograms of both the treated and control groups were recorded
at a rate of four images per second, and these show comparable
distances between the beginning of the injection and visualization of
the medium.
View larger version (70K):
[in a new window]
Figure 6. A, Angiography after injection of the growth
factor into the human heart shows a pronounced accumulation of contrast
medium compared with the control group. B, Angiography in the control
group does not show any increased accumulation of contrast medium
around the IMA/LAD anastomosis. HBGF-I indicates human FGF-I. ).
Such "neocapillary vessels" can also provide a collateral
circulation around additional distal stenoses of the LAD (Fig 7B) and bring about retrograde filling of a short segment of the artery
distal to the stenosis. In none of the angiograms of the
treated patients taken 12 weeks after the operation were any new
stenoses of the LAD detectable.
View larger version (67K):
[in a new window]
Figure 7. A, Collateralization of stenoses (arrow):
a diagonal branch occluded just distal to its origin is filled through
the newly grown capillaries. B, Collateralization of stenoses
(arrow) by newly grown capillaries: the peripherally
stenosed LAD is filled through these vessels. HBGF-I indicates human
FGF-I. ) gave a mean gray value of 124 for the
vessels. The control myocardium reached a gray value of
only 20, and that of the myocardium injected with FGF-I
gave a value of 59 (Fig 8).
View larger version (24K):
[in a new window]
Figure 8. Quantitative gray value analysis of
contrast medium accumulation in the angiography shows a twofold to
threefold increase in the local blood flow at the site of injection.
HBGF-I indicates human FGF-I.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
Normal capillaries have a cell population with a low
turnover rate of months or years. On occasion, however, a high turnover
rate of this cell population is possible even under
physiological conditions, and this naturally leads
to the rapid growth of new capillaries and other blood vessels. Such a
physiological process occurs in the development of
the placenta, in fetal growth, and in wound healing, as well in the
formation of collaterals in response to tissue ischemia.
"Angiogenetic growth factors," which are biochemically
polypeptides, are essential for such processes as capillary growth or
neoangiogenesis. These growth factors (for instance, the human
heparin-binding FGF-I) bring about their effect by significantly
increasing cell proliferation, differentiation, and migration via a
high-affinity receptor system on the surfaces of the
endothelial cells.8 10 11 12
Selected Abbreviations and Acronyms
CHD
=
coronary heart disease
EDP
=
electronic data processing
FGF
=
basic fibroblast growth factor
HPLC
=
high-pressure liquid chromatography
IMA
=
internal mammary artery
LAD
=
left anterior descending coronary artery
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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G. Zakine, E. Martinod, P. Fornes, M. Sapoval, D. Barritault, A. F. Carpentier, and J. C. Chachques Growth factors improve latissimus dorsi muscle vascularization and trophicity after cardiomyoplasty Ann. Thorac. Surg., February 1, 2003; 75(2): 549 - 554. [Abstract] [Full Text] [PDF]
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I. Friehs and P. J. del Nido Increased susceptibility of hypertrophied hearts to ischemic injury Ann. Thorac. Surg., February 1, 2003; 75(2): S678 - 684. [Abstract] [Full Text] [PDF]
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F. W. Sellke and M. Ruel Vascular growth factors and angiogenesis in cardiac surgery Ann. Thorac. Surg., February 1, 2003; 75(2): S685 - 690. [Abstract] [Full Text] [PDF] |