(Circulation. 1999;100:1945-1950.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Physiologically Assessed Coronary Collateral Flow and Intracoronary Growth Factor Concentrations in Patients With 1- to 3-Vessel Coronary Artery Disease
From Cardiology, University Hospital, Bern, Switzerland. Correspondence to Priv Doz Dr Christian Seiler, MD, FACC, FESC, Swiss Cardiovascular Centre Bern, Cardiology, University Hospital, CH-3010 Bern, Switzerland.
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Abstract |
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Background—The purpose of this study was to test the hypothesis that there is a relation between collateral flow and intracoronary concentrations of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) and that the combined concentrations of both growth factors and the extent of coronary artery disease (CAD) play a role as covariables in such an association.
Methods and Results—In 76 patients undergoing balloon angioplasty, a collateral flow index (CFI, no units) was determined with sensor-tipped guidewires. Simultaneously, serum concentrations of bFGF and VEGF, obtained at the aortic root from the ostium of the collateralized coronary artery (n=76) and from the distal position of the occluded coronary artery (n=34), were determined. There was a direct correlation between CFI and distal VEGF (r=0.33, P=0.05) but not bFGF concentrations. Focusing on the proximal sampling site, there was a direct correlation between CFI and both bFGF (r=0.29, P=0.01) and VEGF concentrations (r=0.44, P<0.0001). The sum of the concentrations of both growth factors was directly associated with CFI irrespective of the proximal (r=0.51, P<0.0001) or distal sampling site (r=0.34, P=0.048). There was a trend toward higher proximal VEGF concentrations in patients with higher numbers of coronary stenotic lesions (r=0.25, P=0.03).
Conclusions—In patients with CAD, there is an association between a directly measured index of collateral flow and intracoronary concentrations of bFGF and VEGF. This direct relation is dependent on the site of blood sampling within the coronary artery tree. The association is closest when the combined bFGF and VEGF concentrations are taken into account. In the case of VEGF, it is influenced by the degree of coronary atherosclerosis.
Key Words: coronary disease • collateral circulation • growth substances
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Introduction |
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During the past 2 decades, evidence has accumulated favoring a clinically relevant role of the collateral circulation in patients with coronary artery disease (CAD).1 Accordingly, study of the human collateral growth adaptation appears to be important, because insight into these evolving mechanisms is essential for establishing new therapeutic modalities promoting collateral development. On the basis of experimental data, the sprouting of coronary collateral capillaries is considered to be induced by a chemical signal from the ischemic myocardium, leading to DNA synthesis and to mitosis of vascular cells.2 Angiogenic growth factors have been isolated from human cardiac tissue,3 and they were found in elevated concentrations among patients with acute myocardial infarction4 and unstable angina pectoris.5 Patients undergoing coronary artery bypass surgery for unstable angina pectoris have recently been shown to have elevated pericardial fluid concentrations of basic fibroblast growth factor (bFGF) compared with patients undergoing cardiac surgery for reasons other than CAD.6 Recently, the first angiographic indication has even been provided that treatment with bFGF of patients with CAD might be effective.7
In patients suffering from stable, effort-induced angina pectoris, repeated myocardial ischemic stimuli for angiogenic growth factor production can be expected to continuously sustain collateral growth and remodeling.2 Direct and quantitative physiological measurements of the collateral circulation in patients with stable CAD and simultaneously determined growth factor concentrations have not been performed. However, they are indispensable to elucidate which angiogenic factors8 are effective, alone or in combination,9 in promoting collateral growth and which are least strongly associated with atherogenesis or the extent of CAD.10 Therefore, we tested the hypotheses that there is a relation between quantitative measures of collateral flow and bFGF and vascular endothelial growth factor (VEGF) concentrations and that the combined concentrations of both growth factors and the extent of CAD play a role as covariables in such an association.
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Methods |
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Patients
Seventy-six patients (63±10 years old; 66 men, 10 women) with 1- to 3-vessel CAD were included in the study. All underwent percutaneous transluminal coronary angioplasty (PTCA) of 1 stenotic lesion because of symptoms related to stable CAD. Patients were prospectively selected on the basis of the following criteria: (1) any angiographic degree of coronary collaterals,11 (2) no previous infarction in the myocardial area undergoing PTCA, (3) no baseline ECG ST-segment abnormalities, (4) no clinical or laboratory signs of acute or chronic inflammatory illness, and (5) absence of overt neoplastic disease. The present investigation was approved by the institutional ethics committee, and the patients gave informed consent to participate in the study.
Study Outline
The study population was divided into 2 groups according to the
intracoronary (IC) Doppler- or pressure-derived collateral
flow index (CFI): group CFI
0.3 and group CFI<0.3. In all 76
patients, CFI and bFGF as well as VEGF concentrations were determined
simultaneously. Growth factor concentrations were
determined at the coronary ostium (proximal sampling site) in
all cases and (because of technical sampling difficulties) distal to
the occluded stenosis in 34 cases.
Cardiac Catheterization and Coronary
Angiography
Patients underwent left heart catheterization
for diagnostic purposes. Aortic pressure was measured with
the PTCA guiding catheter. Biplane left ventriculography was performed,
followed by coronary angiography. Coronary artery
stenoses were estimated quantitatively as percent diameter
reduction. Angiographic collateral degrees (0 to 3) were determined
before PTCA: 0, no filling by contrast of the distal vessel via
collaterals; 1, small side branches filled; 2, major side branches of
the main vessel filled; and 3, main epicardial vessel filled by
collaterals.11
Coronary Collateral Assessment
In all study patients, coronary collateral flow relative
to normal antegrade flow through the nonoccluded coronary
artery (CFI) was determined by use of either IC velocity or pressure
measurements, whereby both values are
interchangeable.12
Doppler-Derived CFI
The velocity-derived CFI was determined with a 0.014-in
Doppler guidewire (Flowire, Endosonics) located distal to the
stenosis to be dilated (Figure 1
). CFI was calculated as the ratio of
flow velocity time integral distal to the occluded stenosis
(Vioccl, cm) divided by that obtained at the
identical location after PTCA (ie, not occluded,
Viø-occl, cm):
Vioccl/Viø-occl (Figure 1). In patients revealing temporally shifted bidirectional
velocity signals, antegrade and retrograde Vi were added to obtain
Vioccl. The validation of this device to measure
relative collateral flow has been described elsewhere.12
Doppler-derived CFI was determined in 3 patients of the CFI0.3
group and in 13 patients of the CFI<0.3 group.
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Pressure-Derived CFI
A 0.014-in fiberoptic pressure monitoring wire (Pressureguide,
Radi Medical) was set at zero, calibrated, advanced through the guiding
catheter, and positioned distal to the stenosis to be dilated.
The IC pressure-derived CFI was determined by simultaneous
measurement of mean aortic pressure (Pao,
mm Hg, via the angioplasty guiding catheter) and the distal
coronary artery pressure during balloon occlusion
(Poccl, mm Hg, Figure 1
). Central
venous pressure (CVP) was estimated to be 5 mm Hg. CFI was
calculated as
(Poccl-CVP)/(Pao-CVP).13
Pressure-derived CFI was determined in 7 patients of the CFI0.3 group
and in 53 patients of the CFI<0.3 group.
Determination of Growth Factor Concentrations
The blood samples obtained distal to the occluded,
collateralized coronary artery and from the ostium of the
vessel (Figure 1) were collected in sterile tubes
(anticoagulant: EDTA), placed on ice, treated by
centrifugation at 3000g for 10 minutes at
4°C, and frozen at -40°C. Concentrations of bFGF were measured by
an ELISA with a murine monoclonal antibody specific for bFGF
(Quantikine, R&D Systems).14 This assay was performed
by use of the quantitative sandwich enzyme immunoassay technique. The
aforementioned antibody had been coated onto the microtiter plate.
Standards and samples were pipetted into the wells, and any bFGF
present was bound by the immobilized antibody. The
wells were covered with the adhesive strip provided and incubated for 2
hours at room temperature. After any unbound proteins had been washed
away with a 25-fold concentrated solution of buffered surfactant, an
enzyme-linked polyclonal antibody specific for bFGF was added to the
wells to sandwich the bFGF immobilized during the first
incubation. The wells were incubated again for 2 hours at room
temperature. After removal of unbound antibody-enzyme reagent, a
substrate solution of hydrogen peroxide and tetramethylbenzidine was
added to the wells and color-developed in proportion to the amount of
bFGF bound in the initial step. The color development was stopped by
addition of 2N sulfuric acid, and the intensity of the color was
measured with a spectrophotometer at 450 nm. A curve had been prepared,
plotting the optical density versus the concentration of recombinant
human bFGF in the 7 standard wells. By comparing the optical density of
the samples with this standard, the concentration of bFGF in the
unknown samples could be determined. VEGF concentrations were measured
with a method similar to that for bFGF, ie, with a monoclonal antibody
specific for VEGF and an enzyme-linked polyclonal antibody against VEGF
for the quantitative sandwich immunoassay technique (Quantikine, R&D
Systems). The measurement of concentrations of bFGF and VEGF was
repeated on a different day with another ELISA kit. The difference in
values between the 2 measurements was within ±10%.
Study Protocol
After diagnostic coronary angiography, an
interval of 10 minutes was allowed for dissipation of the vasomotor
effect of the nonionic contrast medium (Ioversol 300). IC or oral
nitroglycerin was given. A multifunctional, occlusive
probing catheter and the Doppler or pressure guidewire were
positioned at and distal to the stenosis to be dilated,
respectively. From the angioplasty guiding catheter (ostial or proximal
sampling site in the aortic root, ie, arterial blood) and
from the multifunctional probing catheter (distal sampling site), 4 mL
of blood was collected into a tube. Simultaneously,
Vioccl or Poccl was
determined to confirm coronary occlusion by the probing
catheter, with the subsequent respective values during balloon
occlusion used for comparison. During the entire protocol, an IC ECG
obtained from the guidewire and a 3-lead surface ECG were recorded.
After removal of the multifunctional probing catheter, the Doppler
or pressure guidewire was used to transport the PTCA balloon. PTCA was
performed. Measurements of Vioccl or
Poccl and simultaneous
Pao as well as ECG recordings were
performed (Figure 1). After completion of PTCA and after
cessation of reactive hyperemia,
Viø-occl was measured distal to the dilated
stenosis in the cases in which Doppler-derived CFI was
determined.
Statistical Analysis
Between-group comparisons of continuous demographic,
angiographic, hemodynamic, growth factor, and
collateral flow index data were performed by an unpaired Student’s
t test. A 
2 test was used for
comparison of categorical variables between the 2 study groups.
Linear regression analysis was used for assessing the relation
between collateral flow index values and distal or proximal growth
factor concentrations. Mean values±SD are given. Statistical
significance was defined at a value of P<0.05.
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Results |
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Patient Characteristics and Clinical Data
There were no statistically significant differences between the 2 study groups regarding age of the patients, sex, frequency of cardiovascular risk factors, and the use of vasoactive and lipid-lowering substances as well as heparin immediately before PTCA. The frequency of peripheral artery disease was similar between the 2 groups.
Angiographic and Coronary Collateral Data
The Canadian Cardiac Society class of angina pectoris, the
occurrence of myocardial infarction in non-PTCA territory, and the
number of vessels affected by CAD did not differ between the study
groups. There were no statistical differences between the study groups
regarding the frequency of the vessels or the site of the
stenosis treated by PTCA. LV ejection fraction was similar in
the study groups. The duration of angina pectoris was higher in
patients with CFI0.3 than in those with CFI<0.3: 14±21 weeks versus
8±12 weeks, respectively (P=0.002). Total coronary
occlusions in the vessel to be dilated were more frequent in patients
with CFI0.3 (7 of 10) than in those with CFI<0.3 (10 of 66;
P<0.0001). Percent diameter stenosis before PTCA
was 92±9% in patients with CFI0.3 and 83±10% in those with
CFI<0.3 (P=0.01).
Qualitative and quantitative variables for the assessment of the
collateral circulation were significantly different between the groups
(Table).
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Coronary Collateral Flow Data and Growth Factor
Concentrations
bFGF and VEGF concentrations as well as the sum of both
concentrations irrespective of the sampling site were higher in the
group with CFI0.3 than in the group with CFI<0.3 (Table).
This difference reached statistical significance only for proximally
obtained VEGF and the pooled values of proximally or distally obtained
bFGF+VEGF. CFI values were not related to bFGF concentrations from
samples taken distal to the occluded stenosis, and there was a
trend toward a correlation between CFI and distal VEGF concentrations
(Figure 2). Focusing on the proximal
sampling site at the ostium of the collateralized vascular bed, there
was a direct correlation between CFI and both bFGF and VEGF
concentrations (Figure 2). The pooled concentrations of both
growth factors were directly associated with CFI irrespective of the
sampling site (Figure 3). The
correlations for proximal and distal values were as follows:
bFGFdistal=16.3+0.63bFGFproximal;
r=0.30, P=0.09;
VEGFdistal=5.0+0.49VEGFproximal;
r=0.46, P=0.009.
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There was a trend toward higher proximal VEGF concentrations in patients with more extended CAD (number of vessels diseased, #VD, ie, number of vessels with percent stenoses of >50% diameter): VEGF=8.3+9.1 #VD, r=0.25, P=0.03. This trend was absent in the case of distal growth factor concentrations and proximal bFGF concentrations.
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Discussion |
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This study in patients with CAD documents, for the first time, an association between a directly measured index of collateral flow and IC concentrations of bFGF and VEGF. This relation is less close for bFGF than VEGF, it is dependent on the site of blood sampling within the coronary artery tree, the association is closest when the combined bFGF and VEGF concentrations are taken into account, and in the case of VEGF, it is influenced by the degree of coronary atherosclerosis.
Collateral Angiogenesis and Growth Factors
It has been experimentally documented that vascular growth in
adult organisms advances via sprouting of capillaries (angiogenesis)
and via enlargement of preexisting arteriolar connections into
collateral arteries.2 15 Investigations in animal models
have disclosed mechanisms leading to angiogenesis with bFGF and VEGF as
the major components.3 16 Therapeutic angiogenesis in the
situation of peripheral or coronary artery disease
has been attempted experimentally by direct growth factor peptide
injection and infusion or transfer of growth factor
genes.17 18 19 In most of those studies, end-point
variables such as ventricular ejection fraction,
myocardial infarct size, capillary density, collateral resistance, or
collateral backflow have been used to assess the effect of the growth
factor treatment. In the clinical setting of coronary artery
disease, no study has used quantitative measurements of collateral flow
to assess its relation to bFGF and/or VEGF.
The fact that distal occlusive bFGF and VEGF concentrations taken
separately did not show a statistically significant relation to
collateral flow may have methodological/technical, statistical, and/or
biological reasons. Figure 2 illustrates that in many instances,
it was not possible to obtain blood samples from the site distal to the
occluded coronary artery because of technical difficulties in
completely obstructing the stenotic lesion by the
multifunctional probing catheter, a procedure that had to be chosen
because no blood could be withdrawn via an inflated balloon angioplasty
catheter. Aside from the statistical problem of missing data points,
prolonged manipulation (>2 minutes) of the probing catheter in the
stenosis may have led to increased biological variability due
to transient acute stress on the heart.20 In the absence
of technical sampling problems, ie, withdrawal of blood via the
proximally located guiding catheter, there was a direct, although weak,
relation between both growth factors and collateral flow. Considering
some of the earlier studies on the serum content of heparin-binding
endothelial mitogens, it is interesting to find this
relation, because they have reported the absence of such an activity in
human blood.5 21 However, 1 study has shown bFGF-like
immunoreactivity in serum.22 The serum concentrations of
bFGF and VEGF measured in our study were lower by a factor of 100 and
similar to those determined in pericardial fluid of patients with
CAD.6 Compared with LV myocardial tissue samples, bFGF
concentrations in our study were lower by a factor of
104.5
Growth factor concentrations were different between proximal and distal sampling sites, showing, on average, higher distal than proximal values in the case of bFGF and lower distal values for VEGF. It can only be speculated that the higher distal concentrations of bFGF were related to the catheter manipulations at the site of the stenosis, and the higher proximal concentrations of VEGF may reflect the degree of systemic atherosclerosis, for which it is a better indicator than bFGF.
One of the principal findings of our study, ie, that the pooled
concentrations of bFGF and VEGF were closely associated with collateral
flow irrespective of the sampling site (Figure 3), is in
agreement with the only experimental investigation of this kind that
found a synergistic effect of both growth factors on the blood pressure
ratio between the ischemic and nonischemic limbs
compared with either factor alone.9 Although the serum
concentrations of bFGF and VEGF in our study were rather low, the
interpretation of a synergistic effect still appears reasonable in
light of the recently published study by Baumgartner et
al23 in patients with peripheral
atherosclerotic disease showing that the average serum concentration of
VEGF after treatment with intramuscular injection of naked plasmid DNA
phVEGF165 was 148 pg/mL. However, considering
that 75% of the collateral flow variability is related to factors
other than the sum of the concentrations of bFGF and VEGF
(r=0.51, r2=0.26, Figure 3, left), alternative parameters possibly influencing
both collateral flow and the growth factors examined have to be taken
into account.
Collateral Arteriogenesis and Growth Factors
An aspect partly responsible for the variability in the
bFGF+VEGF-to-CFI relation is that collateral flow as assessed in our
study probably does not exactly represent the "flow"
induced by the growth factors measured. A more adequate
parameter for collateral flow inducible by angiogenic
growth factors such as bFGF and VEGF would be myocardial perfusion via
collaterals rather than epicardially measured CFI. This concept relates
to the recent finding of a spatial dissociation of bFGF- and
VEGF-induced capillary sprouting (angiogenesis) in an ischemic
region and the growth of "conductance" collaterals
(arteriogenesis).15 The measurement site of collaterals in
our study corresponds more to the area of arteriogenesis rather than
angiogenesis. The fact that there is a certain association between the
variables determined in our study is in accordance with the
currently held pathophysiological view of
collateral development, whereby the ischemia-induced
angiogenesis leads to a certain increase in collateral flow and to a
flow-induced, nitric oxide– or even growth-factor–mediated
vasodilatation in newly formed as well as preformed
collaterals.2 24 Subsequently, structural vascular
remodeling, probably influenced by other growth factors such as
monocyte chemotactic protein-1, occurs and leads to a large epicardial
collateral artery.25
Atherogenesis and Growth Factors
A factor further confounding the relation between collateral flow
and growth factors is the extent of coronary as well as
systemic atherosclerosis. Neovascularization in
atherosclerotic plaques may be mediated by the overexpression of growth
factors and by local hypoxia and may contribute to the growth
and rupture of plaques.26 This implies that the
therapeutic administration of angiogenic peptides may have a dual
effect in patients with CAD: promoting collateral formation but
simultaneously exacerbating atherogenic processes. In this
context, Lazarous and coworkers10 have demonstrated in
dogs that bFGF enhanced coronary collateral development without
increasing neointimal accumulation at sites of vascular
injury, whereas VEGF did not promote collateral growth but provoked
neointimal accumulation. The present data on a
significant trend to more extended coronary atherosclerotic
lesions in patients with higher VEGF concentrations corroborate the
aforementioned experimental investigation.
Study Limitations
Aside from the limitations alluded to above, there are other
confounders of the relation between growth factors and CFI, such as
measurement errors in the assessment of collaterals. Compared with IC
Doppler-derived measurements of the collateral flow index, the
standard error of estimate using pressure measurements is
0.08.12 If CVP is assumed instead of directly measured for
the calculation of pressure-derived collateral flow index, another
source of variability is introduced, which weighs more in the lower
than the upper range of collateral flow indices.
It is conceivable that angiogenic growth factors would have been more concentrated in the venous effluent at the coronary sinus than in the arterial system. Coronary sinus sampling, however, was not performed to avoid an increased risk for the patients.
The fact that the angiogenic growth factors investigated are heparin-binding peptides causes potential measurement errors in their concentration in dependence of the serum heparin concentration.3 27 The dose of heparin administered to all patients immediately before PTCA was almost identical in the study groups, which made it unlikely that growth factor concentration differences between the groups were due to varying heparin concentrations. Furthermore, determination of the growth factor concentration under different heparin concentrations in 1 of the samples did not yield varying concentrations.
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Acknowledgments |
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This study was supported by grant 32-49623.96 from the Swiss National Science Foundation.
Received May 3, 1999; revision received June 24, 1999; accepted July 9, 1999.
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 G. S. Werner, E. Jandt, A. Krack, G. Schwarz, O. Mutschke, F. Kuethe, M. Ferrari, and H. R. Figulla Growth Factors in the Collateral Circulation of Chronic Total Coronary Occlusions: Relation to Duration of Occlusion and Collateral Function Circulation, October 5, 2004; 110(14): 1940 - 1945. [Abstract] [Full Text] [PDF]
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 A. D Blann Angiogenesis and platelets: the clot thickens further Cardiovasc Res, August 1, 2004; 63(2): 192 - 193. [Full Text] [PDF]
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 M.H. Tayebjee, G.Y.H. Lip, and R.J. MacFadyen Collateralization and the response to obstruction of epicardial coronary arteries QJM, May 1, 2004; 97(5): 259 - 272. [Abstract] [Full Text] [PDF]
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M. Heil, T. Ziegelhoeffer, S. Wagner, B. Fernandez, A. Helisch, S. Martin, S. Tribulova, W. A. Kuziel, G. Bachmann, and W. Schaper Collateral Artery Growth (Arteriogenesis) After Experimental Arterial Occlusion Is Impaired in Mice Lacking CC-Chemokine Receptor-2 Circ. Res., March 19, 2004; 94(5): 671 - 677. [Abstract] [Full Text] [PDF]
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N A Chung, C Lydakis, F Belgore, F L Li-Saw-Hee, A D Blann, and G Y H Lip Angiogenesis, thrombogenesis, endothelial dysfunction and angiographic severity of coronary artery disease Heart, December 1, 2003; 89(12): 1411 - 1415. [Abstract] [Full Text] [PDF]
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 D. J. Lenihan, A. Osman, V. Sriram, J. Aitsebaomo, and C. Patterson Evidence for association of coronary sinus levels of hepatocyte growth factor and collateralization in human coronary disease Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1507 - H1512. [Abstract] [Full Text] [PDF]
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 D.C Felmeden, A.D Blann, and G.Y.H Lip Angiogenesis: basic pathophysiology and implications for disease Eur. Heart J., April 1, 2003; 24(7): 586 - 603. [Full Text] [PDF]
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M. Heil, T. Ziegelhoeffer, F. Pipp, S. Kostin, S. Martin, M. Clauss, and W. Schaper Blood monocyte concentration is critical for enhancement of collateral artery growth Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2411 - H2419. [Abstract] [Full Text] [PDF]
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 H. Franz Alber, J. Dulak, M. Frick, W. Dichtl, S. Paul Schwarzacher, O. Pachinger, and F. Weidinger Atorvastatin decreases vascular endothelial growth factor in patients with coronary artery disease J. Am. Coll. Cardiol., June 19, 2002; 39(12): 1951 - 1955. [Abstract] [Full Text] [PDF]
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T. Pohl, C. Seiler, M. Billinger, E. Herren, K. Wustmann, H. Mehta, S. Windecker, F. R. Eberli, and B. Meier Frequency distribution of collateral flow and factors influencing collateral channel development: Functional collateral channel measurement in 450 patients with coronary artery disease J. Am. Coll. Cardiol., December 1, 2001; 38(7): 1872 - 1878. [Abstract] [Full Text] [PDF]
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T Pohl, P Hochstrasser, M Billinger, M Fleisch, B Meier, and C Seiler Influence on collateral flow of recanalising chronic total coronary occlusions: a case-control study Heart, October 1, 2001; 86(4): 438 - 443. [Abstract] [Full Text] [PDF]
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P. Lambiase, R. Edwards, C. A. Bucknall, M. S. Marber, C. Seiler, M. Fleisch, M. Billinger, F. R. Eberli, A. R. Garachemani, and B. Meier Physiologically Assessed Collateral Flow and Intracoronary Growth Factor Concentrations in Patients With 1- to 3-Vessel Coronary Artery Disease Response Circulation, January 30, 2001; 103 (4): e22 - e22. [Full Text] [PDF]
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