Vol. 284, Issue 1, H17-H22, January 2003
In vivo measurement of coronary circulation angiotensin-converting enzyme activity in humans
Cezar
Staniloae1,
Andreas J.
Schwab2,
André
Simard2,
Richard
Gallo1,
Ihor
Dyrda1,
Gilbert
Gosselin1,
Jacques
Lespérance1,
James W.
Ryan1, and
Jocelyn
Dupuis1
1 Montreal Heart Institute and University of
Montreal, Montreal H1T 1C8; and 2 McGill University
Medical Clinics, Montreal General Hospital, Montreal, Quebec,
Canada H3G 1A4
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ABSTRACT |
Angiotensin-converting enzyme (ACE)
is present on the luminal surface of the coronary vessels, mostly on
capillary endothelium. ACE is also expressed on coronary smooth muscle
cells and on plaque lipid-laden macrophages. Excessive coronary
circulation (CC)-ACE activity might be linked to plaque progression.
Here we used the biologically inactive ACE substrate
3H-labeled benzoyl-Phe-Ala-Pro ([3H]BPAP) to
quantify CC-ACE activity in 10 patients by means of the
indicator-dilution technique. The results were compared with atherosclerotic burden determined by coronary angiography. There was a
wide range of CC-ACE activity as revealed by percent
[3H]BPAP hydrolysis (30-74%). The atherosclerotic
extent scores ranged from 0.0 to 66.97, and the plaque area scores
ranged from 0 to 80 mm2. CC-ACE activity per unit
extracellular space
(Vmax/KmVi),
an index of metabolically active vascular surface area, was correlated with myocardial blood flow (r = 0.738;
P = 0.03) but not with measures of the atherosclerotic
burden. These results show that CC-ACE activity can be safely
measured in humans and that it is a good marker of the vascular area of
the perfused myocardium. It does not, however, reflect epicardial
atherosclerotic burden, suggesting that local tissue ACE may be more
important in plaque development.
angiography; atherosclerosis; coronary disease; endothelial
function
| |
INTRODUCTION |
LARGE RANDOMIZED
TRIALS have established that angiotensin-converting
enzyme (ACE) inhibitors (ACEIs) reduce recurrent myocardial infarctions
(18). ACEIs confer similar benefits on patients with
evidence of vascular disease or risk factors for coronary artery
disease (CAD) (31). At least part of these benefits may be
related to improvement of coronary endothelial function
(15).
ACE, a dipeptidyl carboxypeptidase that converts ANG I to ANG II,
is mostly present on the luminal surface of the vascular endothelium,
particularly in the lung (3, 24). In the atherosclerotic heart, ACE is present not only on the coronary endothelium (11, 19) but also on coronary medial smooth muscle cells and plaque lipid-laden macrophages (8). In the noninfarcted
myocardium of both humans and rats, ACE is prominent on the endothelium
of arterioles and capillaries, with almost no activity in venous vessels (11). Coronary circulation (CC)-ACE may contribute
to plaque development because there is experimental evidence to support the hypothesis that ACEIs have antiatherogenic properties when administered to hypercholesterolemic animals (5, 25). It may also contribute to acute plaque instability because coronary atherectomy specimens from patients with acute coronary syndromes display higher ACE activity (14). Because coronary
endothelial dysfunction occurs early in the development of CAD
(28) and correlates with the number of risk factors for
CAD (29), it is possible that CC-ACE activity would be
modified by the severity of the disease process or could itself
modulate the development of CAD. Little is known, however, about the
role of CC-ACE in the pathophysiology of CAD. Such an evaluation could
help in establishing the relative importance of endothelium-bound
versus tissue ACE activity in CAD.
The hemodynamically inactive ACE substrate 3H-labeled
benzoyl-Phe-Ala-Pro ([3H]BPAP) has already been used in
the quantification of endothelium-bound ACE activity of human pulmonary
vascular bed (17) as well as in the coronary vasculature
of animals (13) by means of the indicator-dilution
technique. This technique has been well validated in measuring
pulmonary capillary endothelium-bound ACE activity that relates the
perfused capillary surface area in animals (20) and in
humans (17). In dogs, this approach has been suggested as
a means of evaluating the area of the perfused coronary capillary surface (13).
The aim of this study was to quantify CC-ACE activity in humans and to
compare it with the coronary atherosclerotic burden by measuring
[3H]BPAP kinetics combined with quantitative coronary
angiography (QCA) analysis.
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MATERIALS AND METHODS |
Patient population.
Ten patients participated in a protocol approved by the Research and
Ethics Committee of the Montreal Heart Institute after written informed
consent was obtained. They were recruited from a group of patients
already scheduled for diagnostic coronary angiography. Patients with
known ejection fraction of <40% or valvular heart disease, as well as
those receiving ACEI or ANG II receptor antagonist therapy, were
excluded. However, one subject taking the ACEI perindopril (2 mg
b.i.d.) was mistakenly studied. We nevertheless report the results of
the ACE kinetic analysis from this patient for informative purposes but
have excluded it from the correlation analysis.
Catheterization procedure.
Venous and arterial femoral sheaths were inserted. Standard projection
coronarographies were performed after the administration of
intracoronary nitroglycerin. At the end of the procedure, a left
Judkins catheter was positioned in the left main coronary artery to
serve as the injection site for the indicator-dilution curve. A
multipurpose catheter was then positioned in the coronary sinus and
connected to a collection pump.
Indicator-dilution technique.
All patients received one rapid bolus injection through the catheter
placed in the left main coronary artery. The bolus was prepared by
combining 30 µCi of [3H]BPAP (generous gift of Dr.
J. W. Ryan) and 2 µCi of [14C]sucrose (NEN,
Boston, MA) with 3 ml of 0.9% saline. Two milliliters of the bolus was
used for injection and the remainder for the preparation of dilution
curve standards. The 2-ml bolus was introduced into an extension line
connected to the left coronary catheter. The bolus was injected, and
the injection line was flushed with a syringe containing 10 ml of the
patient's blood. Collection of serial blood samples from the coronary
sinus was simultaneously initiated by a peristaltic pump at 80 ml/min
(MasterFlex L/S) and a fraction collector (Pharmacia LKB Frac-100)
advancing at one tube per 1.7 s. Each fraction collector tube
contained 1 ml of "stop" solution to inactivate any serum ACE
activity (6.8 mM 8-hydroxyquinoline-5-sulfonic acid) and 10 µl of
1,000 IU/ml heparin to prevent blood clotting. After centrifugation
(3,000 rpm, 10 min), 0.3 ml of the clear supernatant was transferred
into a scintillation vial containing 1 ml of HCl (0.1 M) and 1 ml of
toluene omnifluor (0.4%). The 3H extracted into the
toluene phase was measured. The next day, 14 ml of aqueous
scintillation liquid (Ready Safe, Beckman Instruments, Fullerton, CA)
was added to convert the two-phase toluene-aqueous mixture into a
single-phase solution and total 3H and 14C
activities were measured. The counts were corrected for background and
crossover activities. With this technique, the fractional extraction of
substrate or intact [3H]BPAP (fs)
in the toluene phase is 5% and that of its product of hydrolysis
(fp) [3H]benzoyl-Phe
(3H-BP) is 60%. The amount of product in each sample can
then be calculated as [3H]BP = ([3H]toluene 
fs × [3H]total)/fp fs, where fs and
fp are the fractional extractions of substrate
([3H]BPAP) and product ([3H]BP),
respectively, into the toluene layer.
QCA assessment.
Coronary atherosclerosis was quantitatively assessed by QCA. All
analyzable arteries of >1.5 mm were evaluated. The number, location,
and severity of lesions were recorded, and the data were analyzed to
determine an extent score (ES). This ES was developed to indicate the
angiographically detectable atherosclerotic burden of the coronary
arterial tree. The coronary vessels were divided into segments as
defined in the bypass angioplasty revascularization study (BARI; Ref.
27). Each segment received a multiplication factor in
proportion to its caliber and territory as inspired by the extent score
described by Sullivan et al. (26). Practically, the first
three segments of the right coronary artery (segments 1,
2, 3), the proximal and mid-left anterior
descending coronary artery (segments 12, 13), and
the ramus intermedius (segment 28) each received a factor of
20. The proximal, mid-, and distal circumflex artery (segments
18, 19, 19.1), the first three diagonal
branches (segments 15, 16, 29), all
obtuse marginal branches (segments 20-22), and all
posterolateral branches (left or right; segments 4-8,
24-27) received a factor of 10. The acute marginal
branches (segment 10) and ventricular branches
(segment 23) received a factor of 5. The left main coronary
artery (segment 11) received a factor of 5. The percent
diameter stenosis computed by QCA for each segment was multiplied by
the corresponding factor. Where multiple stenoses were present in one
segment, each was multiplied by the same factor. When a vessel was
occluded and the distal vessel was not visualized by collateral flow,
the proportion of vessel not visualized was given the mean ES of the
remaining vessels. Although the entire coronary tree was analyzed, only
the territory irrigated by the left coronary artery was reported in
this study, as the area of interest. All the values obtained from the
left coronary system were therefore added up to determine the ES.
In addition, the total plaque area (PA) was reported for the entire
left coronary tree. The PA was calculated as the integral of the
distances between the luminal contours and the original size of the
vessel at the stenosis before disease occurred (computer-derived interpolated reference technique), within the given obstruction limit
(in mm2) (21).
Mathematical modeling for determination of coronary
endothelium-bound ACE activity.
Using indicator-dilution techniques, we estimated under first-order
reaction conditions the single-pass transcoronary hydrolysis of the
synthetic ACE substrate [3H]BPAP by CC-ACE. Figure
1 represents the model.
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Fig. 1.
Model for benzoyl-Phe-Ala-Pro (BPAP) kinetics in the
coronary circulation. The synthetic substrate [3H]BPAP is
hydrolyzed by angiotensin-converting enzyme (ACE) present on the
luminal surface of the vascular endothelium. Two products are formed,
alanyl-proline (AP) and [3H]benzoyl-Phe
([3H]BP), depending on the rate constant for hydrolysis
(khyd) and flow.
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Modeling of sucrose kinetics.
The kinetics of sucrose transport within the coronary circulation was
described by a barrier-limited model, assuming heterogeneous transit
times of large vessels and capillaries that are linearly related to
each other (23). Sucrose is a diffusible substance that
may leave the capillaries to enter the extravascular space and later
return to the vasculature. We apply here a reformulation of the
original equations recently described in an investigation of serotonin
kinetics in the lung (10). The transit time of a path
through the coronary circulation can be partitioned into a capillary
part (
c), where exchange between the vascular and the
extravascular space takes place, and a large-vessel part
(l), comprising arterioles and venules, where no such
exchange occurs. The assumption of a linear relationship between the
capillary transit time c and the large-vessel transit
time l as a function of time of passage through the
heart t is formulated by the following relationship
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where b and t0 are constants,
with 0 < b <1. The parameter
t0 is related to the distribution of transit
times, and b is an index of transit time heterogeneity
through the heart.
The kinetic analysis requires data from a reference indicator that does
not leave the vasculature. As discussed below, labeled [3H]BPAP and its labeled product, [3H]BP,
remain in the vasculature, so that the sum of their concentrations can
be used as the vascular reference. The fractional recovery of sucrose
can then be expressed as
|
(1)
|
where kpi and kip
are sucrose transfer coefficients for transfer from plasma to the
interstitial space and return to the plasma space, respectively. In the
above equation, variables b and kpi
appear as a product and cannot be identified separately. CRef(t) is obtained by deconvoluting
the catheter function from the measured reference curve, and
CSuc(t) is convoluted with the catheter function before fitting to the measured sucrose curve, as
previously developed (10).
Optimized parameters were obtained by a nonlinear least-squares
procedure from Visual Numerics (Houston, TX). Data were weighted according to the inverse of the square root of their values.
Modeling of BPAP kinetics.
BPAP exists in the injection bolus as an equilibrium mixture of
cis- and trans-isomers. In the capillaries, the
trans-isomer is split by ACE, which is located at the
endothelial surface (Ref. 16; Fig. 1).
Cis-trans isomerization is slow compared with the time scale of the present data. Attempts to take into account isomerization within capillaries did not change the results of the
analysis; hence, it was ignored in the present model. The outflow of
[3H]BPAP can then be expressed as
![C<SUB>BPAP</SUB>(<IT>t</IT>)<IT>=C</IT><SUB>Ref</SUB>(<IT>t</IT>)[<IT>&thgr;+</IT>(1<IT>−&thgr;</IT>)<IT>e</IT><SUP>−<IT>bk</IT><SUB>hyd</SUB>(<IT>t−t</IT><SUB>0</SUB>)</SUP>]](/content/vol284/issue1/fulltext/H17/img006.gif)
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(2)
|
where 
is the previously measured value for the
cis-fraction (20) and
khyd is the transfer coefficient for enzymic
conversion of the trans-isomer. Catheter distortion was
taken into account, as in the case of sucrose, and
t0 was set to the value obtained from the
sucrose analysis.
The [14C]sucrose diffuses into the interstitial space of
the myocardium and is completely recovered without being metabolized. Its transit time relative to that of the tracer that remains within the
vascular space was previously validated to derive a parameter (
)
proportional to myocardial blood flow (22). Because the outflow profile for total 3H is identical to that of a
vascular tracer like albumin, was computed as flow per unit
extracellular space as previously described (9) and is
given by
where 
Ref and
Suc are the mean transit times of
the vascular reference and sucrose, respectively. The curves were
extrapolated with power law functions (1). Because in some
experiments extrapolation led to large or infinite sucrose transit
times (presumably because sucrose curves did not extend far enough in
time to provide sufficient information on tail behavior), parameters
from the following equation (23) were used to estimate
sucrose mean transit times
The rate of hydrolysis of BPAP is determined by the kinetic
constants of the enzyme, i.e., Vmax and
Km. At tracer concentrations of BPAP that are
small compared with Km, the ratio
Vmax/Km is equivalent to
intrinsic clearance or to the permeability-surface area product for a
permeating substance. In analogy to the latter case, the relation
between Vmax/Km per unit
extracellular space for BPAP hydrolysis and khyd
can than be found as follows (10)
This can be expressed as a function of the parameters identified
in the sucrose and BPAP curve analysis
Statistical analysis.
Individual data are reported as well as means ± SD. Where
appropriate, relationships between parameters were evaluated with Spearman's correlations. Differences were considered significant at a
value of P < 0.05.
| |
RESULTS |
Representative myocardial outflow profiles of total
3H, the surviving [3H]BPAP, and the
corresponding ACE hydrolysis product [3H]BP are depicted
in Fig. 2. Hydrolysis of
[3H]BPAP is evident, with a progressively lower outflow
profile compared with total 3H. In this example taken from
patient 4, percent [3H]BPAP hydrolysis by
CC-ACE was 68%. The myocardial interstitial space tracer
[14C]sucrose is delayed compared with total
3H and reaches a smaller and later peak by virtue of its
larger volume of distribution. Data derived from the indicator-dilution curves and optimized parameters derived from the modeling of
[3H]BPAP kinetics are presented in Table
1. The patient taking ACEI therapy
(patient 8) demonstrated very low
[3H]BPAP hydrolysis of 15%, whereas the others had
variable degrees of hydrolysis ranging from 30 to 74%. Patient
8 was excluded from the correlation analysis. The individual
coronary atherosclerosis burden scores derived from the QCA analysis
are also included in Table 1. The ES ranged from 0.0 to 66.97, and the
PA ranged from 0 to 80.
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Fig. 2.
Example of the myocardial outflow profiles of
experimental tracers. Indicator-dilution curve from patient
4. The total 3H activity of the effluent can be
separated into the intact ACE substrate [3H]BPAP and its
product of hydrolysis, [3H]BP. The
[14C]sucrose is an interstitial space tracer used in the
kinetic modeling of [3H]BPAP hydrolysis.
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An example of the fit for [3H]BPAP outflow profile from
modeling of the experimental data is shown in Fig.
3. There was a very good quality of fit
except for the tail end of the curves, where we observed a small
deviation from the experimental data. There was a direct correlation
between the estimate of coronary blood flow () and CC-ACE activity
as measured by the parameter
Vmax/KmVi (r = 0.738, P = 0.033; Fig.
4).
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Fig. 3.
Example of experimental fit of [3H]BPAP
outflow profile from the modeling of data from patient 4.
Each individual data point is represented, and the calculated outflow
profile predicted by the model is depicted by the solid
line.
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Fig. 4.
Correlation between coronary endothelium-bound ACE
activity
(Vmax/KmVi)
and plasma flow (). Values are means ± SD.
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ES and PA of the left coronary tree, however, did not significantly
correlate with CC-ACE activity (PA: r = 0.417,
P = 0.238; ES: r = 0.400,
P = 0.257).
| |
DISCUSSION |
BPAP is a pharmacologically inactive high-affinity ACE substrate.
It is rapidly hydrolyzed by ACE present at the luminal surface of
the vascular endothelium so that its volume of distribution is
restricted to the vascular space during a single transcoronary passage
(4). Using BPAP, we demonstrated the feasibility of measuring CC-ACE activity in human coronary vessels in vivo. In the rat
myocardium, autoradiographic studies revealed linear streaks of high
ACE activity corresponding to sections of coronary arteries (30); assuming that ACE is uniformly distributed
throughout coronary small vessels and capillaries, measurements of
CC-ACE activity could be a useful tool in estimating the perfused
capillary bed in humans. The results from the patient (patient
8) mistakenly studied while receiving ACEI therapy not only
validate our methodology but demonstrate for the first time the almost
complete inhibition of CC-ACE activity in a human subject taking this therapy.
It has already been shown in several indicator-dilution experiments in
animals and in humans that the capillary permeability-surface area
products of select solutes and metabolizable tracers such as
norepinephrine change in proportion to coronary flow changes (2,
6, 7, 9, 22). This increase with flow of the coronary capillary
exchange surface area reflects capillary recruitment and reaches an
asymptotic maximum at the highest level of blood flows
(22). Using BPAP as a marker of the metabolically active coronary vascular bed, Horvath et al. (13) demonstrated in
dogs that the reduction of CC-ACE activity corresponded to reduction in
myocardial blood flow induced by coronary artery ligation. Our data
support this view in human coronary arteries, because we practically
found a linear relationship between CC-ACE activity and coronary flow.
Because the patients were in the resting state, however, we did not
reach the asymptotic maximum in CC-ACE activity that could possibly be
achieved with higher coronary blood flows. Our findings therefore
support the concept that a reduction in coronary flow reduces the
surface area available for microcirculatory exchanges as a consequence
of capillary derecruitment (12).
In coronaries from patients with advanced atherosclerotic lesions, the
inflammatory cells of the endothelium of the neovasculature present in
the plaques exhibit substantial ACE activity (8). We found a wide variability in luminal CC-ACE activity, but this variability did not significantly correlate with the atherosclerotic burden measured by QCA. Although the sample size in our study is too
small to allow definite conclusions, the data suggest that luminal ACE
expression is determined by factors other than atherosclerotic burden.
Because atherosclerosis is mainly a disease of large- and medium-sized
vessels, its presence does not seem to alter the activity of CC-ACE at
the level of small vessels and capillaries. The linear correlation
found between the CC-ACE activity and the myocardial blood flow, and
the lack of influence by the atherosclerotic burden, suggest that
CC-ACE is practically uniformly distributed in the coronary
microcirculation and is not influenced by the disease process. The
known increase in endothelial plaque ACE may only represent a minor
contribution to overall myocardial CC-ACE activity, and because this
activity may be restricted to plaque content it is likely that it is
not accessible to a vascular substrate and hence was not measured in
the present study.
In conclusion, we showed that CC-ACE activity could be safely measured
in humans. This activity is proportional to myocardial blood flow and,
presumably, the metabolically active surface of perfused coronary
capillaries. However, we found that the variability in CC-ACE activity
could not be related to the coronary atherosclerotic burden. This
suggests that coronary luminal ACE activity may be less important than
tissue ACE activity in the pathophysiology of coronary atherosclerosis.
| |
FOOTNOTES |
Address for reprint requests and other correspondence: J. Dupuis, Montreal Heart Institute, Research Center, 5000 Belanger St.
East, Montreal, Quebec, Canada H1T 1C8 (E-mail:
dupuisj{at}icm.umontreal.ca).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpheart.00452.2002
Received 28 May 2002; accepted in final form 29 August 2002.
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