526
JACC Vol. 31, No. 3
March 1, 1998:526 –33
Which Variable of Stenosis Severity Best Describes the Significance of
an Isolated Left Anterior Descending Coronary Artery Lesion?
Correlation Between Quantitative Coronary Angiography, Intracoronary Doppler
Measurements and High Dose Dipyridamole Echocardiography
GIAN BATTISTA DANZI, MD, SALVATORE PIRELLI, MD, LUIGI MAURI, MD,
ROBERTO TESTA, MD, GUGLIELMA R. CILIBERTO, MD, DARIA MASSA, MD,
ATTILIO A. LOTTO, MD, LUIGI CAMPOLO, MD, OBERDAN PARODI, MD
Milan, Italy
Objectives. This study sought to investigate the angiographic or
intracoronary Doppler variables of stenosis severity that best
correlate with the results of dipyridamole echocardiography.
Background. Quantitative coronary angiography and intracoronary Doppler flow velocity assessments are the commonly
used techniques for the objective identification of significant
coronary artery stenosis.
Methods. Thirty patients with an isolated lesion of the left
anterior descending coronary artery (LAD) were studied by means
of on-line quantitative coronary arteriography, intracoronary Doppler flow velocity measurements and dipyridamole echocardiography
6 months after percutaneous transluminal coronary angioplasty. The
quantitative arteriographic analyses were performed on-line;
post-stenotic Doppler flow velocities were measured at baseline
and after adenosine infusion. Angiographic and Doppler measurements were compared with the corresponding dipyridamole echocardiographic data and analyzed by discriminant analysis.
Results. The dipyridamole echocardiographic response was
positive in 11 patients (37%). The best cutoff values for predicting
an abnormal echocardiographic response were 1) stenotic flow
reserve of 2.8 (p 5 0.0001); 2) 59% diameter stenosis (p 5 0.0001);
3) minimal lumen diameter of 1.35 mm (p 5 0.001); 4) coronary
flow reserve of 2.0 (p 5 0.0002); and 5) maximal peak velocity of
60 cm/s during hyperemia (p 5 0.04). Multivariate analysis
identified stenotic flow reserve as the only independent predictor
of ischemia during dipyridamole echocardiography.
Conclusions. Stenotic flow reserve is the variable that best
describes the functional significance of an isolated LAD lesion,
and a value of 2.8 is the best predictor of a positive dipyridamole
echocardiographic response. Furthermore, angiographic variables of stenosis severity relate to echocardiographic test results
better than intracoronary Doppler variables.
(J Am Coll Cardiol 1998;31:526 –33)
©1998 by the American College of Cardiology
On-line quantitative coronary angiography and intracoronary
Doppler flow velocity studies are the commonly used techniques for the objective assessment of the severity of coronary
artery stenosis during cardiac catheterization (1–5). Computerassisted edge detection methods have been developed to
reduce the inherent inaccuracy of visual assessments (6).
On-line quantitative coronary angiography is gaining wide
acceptance in routine clinical practice, providing angiographers with quantitative morphologic data useful for diagnostic
decision making. Among the angiographic variables, stenotic
flow reserve obtained by means of quantitative coronary
arteriography provides a measure of the integrated anatomic–
geometric severity of stenoses on arteriograms that is independent of physiologic variables (7,8).
The use of an intracoronary Doppler guide wire allows the
routine evaluation of coronary flow velocity indexes distal to a
coronary stenosis, thus providing an alternative means of
assessing lesion severity during coronary arteriography (4,5,9 –
15). Several groups of investigators have examined the relation
between the results of the noninvasive tests commonly used to
detect ischemia and those of quantitative coronary angiography or intracoronary Doppler guide wire measurements (16 –
20). However, the integrated value of both techniques in the
same cohort of patients has not yet been evaluated. Accordingly, we planned the current study of patients with isolated left
anterior descending coronary artery (LAD) stenoses to investigate the variable of stenosis severity that best correlates with
the development of transient contraction asynergy during
dipyridamole echocardiography and using angiographic and
intracoronary Doppler variables.
From the Department of Cardiology, CNR Institute of Clinical Physiology,
Section of Milan, Niguarda Hospital, and Department of Cardiac Surgery,
Centro Cardiologico Fondazione I. Monzino, Milan, Italy. This study was
presented in part at the 46th Annual Scientific Session of the American College
of Cardiology, Anaheim, California, March 1997.
Manuscript received June 20, 1997; revised manuscript received November
24, 1997, accepted December 4, 1997.
Address for correspondence: Dr. Gian Battista Danzi, Department of
Cardiology and CNR Institute of Clinical Physiology, Ospedale Niguarda Cá
Granda, Piazza Ospedale Maggiore 3, 20162 Milano, Italy. E-mail: [email protected].
©1998 by the American College of Cardiology
Published by Elsevier Science Inc.
0735-1097/98/$19.00
PII S0735-1097(97)00557-3
JACC Vol. 31, No. 3
March 1, 1998:526 –33
DANZI ET AL.
FUNCTIONAL SIGNIFICANCE OF CORONARY STENOSIS
Abbreviations and Acronyms
ECG 5 electrocardiogram
LAD 5 left anterior descending coronary artery
Methods
We studied 30 patients (24 men, 6 women; mean [6SD] age
61 6 12 years) who were enrolled in follow-up studies after
successful percutaneous transluminal coronary angioplasty and
were scheduled for a 6-month angiographic evaluation. At the
time of angioplasty, no patient had undergone intracoronary
stent implantation or treatment with any other percutaneous
devices. To be eligible for the study, each patient was required
to have an isolated lesion in the LAD; no clinical history or
electrocardiographic (ECG) evidence of a previous myocardial
infarction; normal ventricular function; and no echocardiographic evidence of left ventricular hypertrophy. In this small
study cohort, no patient was excluded because of an inadequate acoustic window or technically poor images during stress
echocardiography. All patients underwent coronary arteriography with on-line quantitative measurements, intracoronary
Doppler guide wire assessments distal to the lesion and high
dose dipyridamole echocardiography within 2 days of cardiac
catheterization. Antianginal therapy was stopped $48 h before
testing.
High dose dipyridamole stress echocardiography. Dipyridamole was intravenously infused at a dose of 0.56 mg/kg body
weight over 4 min, followed by 4 min of no dose and then a
subsequent dose of 0.28 mg/kg for 2 min, according to the
standard infusion protocol used in vasodilation stress echocardiography (21). During the procedure, blood pressure and a
12-lead ECG were recorded at each minute. Cross-sectional
echocardiograms were continuously monitored and recorded
during, and for 10 min after, dipyridamole infusion. All
patients received intravenous aminophylline (70 to 240 mg) at
the end of the test. The positivity of the test was linked to the
detection of transient contraction asynergy. The left ventricle
was divided into 16 segments, as proposed by the American
Society of Echocardiography (22). Segmental wall motion was
graded as follows: 1 5 normal; 2 5 hypokinesia; 3 5 akinesia;
and 4 5 dyskinesia. The wall motion score index was derived
by summing the individual segment scores and dividing the
result by the number of interpreted segments. In the positive
tests, the dipyridamole time (obtained by the number of
minutes from the beginning of drug infusion to the development of stress-induced dyssynergy) was also evaluated. In the
negative tests, the dipyridamole time was arbitrarily assumed
to be 15 min when aminophylline was given. Videotapes were
analyzed by two independent observers (G.R.G., D.M.) who
had no knowledge of the clinical and angiographic data; in the
case of any disagreement, a third observer (S.P.) reviewed the
study, and the majority judgment was accepted.
Coronary angiography. Coronary angiography was performed using the femoral approach with an 8F Judkins cath-
527
eter after the infusion of 200 mg of nitroglycerin. At least four
views were acquired for the left coronary system (including two
orthogonal views). Additional appropriate projections were
obtained in the case of the superimposition of side branches or
a foreshortening of the involved segment.
On-line quantitative coronary angiographic data analysis.
On-line quantitative coronary measurements were performed
using the Automated Coronary Analysis (ACA) package for
the Philips Digital Cardiac Imaging (DCI) System (Philips,
Eindhoven, The Netherlands) (23). This analytic software
package has been validated and described in detail elsewhere.
Briefly, the selection of the coronary segment to be analyzed
requires the user to indicate the beginning and the end point of
the segment. The contour detection technique is performed by
taking the first and second derivative values of brightness
profiles calculated along the scan lines perpendicular to the
model and by applying the minimal cost contour detection
algorithm. To obtain absolute measurements of vessel size,
image calibration was performed on the contrast catheter of
that particular arteriographic run, with all measurements being
made using end-diastolic frames with optimal vessel opacification. Stenotic flow reserve was automatically derived from the
length and percent of the stenosis and the absolute diameters
and shape of the angiographic image, assuming standardized
values for aortic pressure and normal maximal coronary flow,
as a way of compartmentalizing the stenosis itself separate
from the rest of the cardiovascular system, according to
Kirkeeide et al. (8). In our laboratory, the intraobserver and
interobserver variabilities of on-line quantitative coronary angiographic measurements were tested using the same frame in
25 coronary stenoses. The points for the start and end of the
segment to be measured were conventionally placed 5 mm
before and after the stenosis borders. Using this approach, the
intraobserver and interobserver variabilities were 1.1 6 9.7%
and 1.5 6 9.2% for percent diameter stenosis, 1.1 6 11.6% and
2.3 6 6.9% for minimal lumen diameter and 1.7 6 19.3% and
3.4 6 11% for stenotic flow reserve, respectively. Percent
diameter stenosis, minimal lumen diameter, reference diameter of the adjacent normal segments and stenotic flow reserve
were calculated as the mean of the values obtained in two
orthogonal views.
Coronary flow velocity measurements. Flow velocity measurements were obtained by using a previously validated
method (4), with a 0.0014-in. (0.0035-cm) steerable Doppler
guide wire (Cardiometrics, Inc.) (length 175 cm) with a
12-MHz piezoelectric ultrasound transducer integrated into its
tip, allowing a velocity acquisition with a high pulse repetition
frequency from a sampling depth of 5 mm. The forwarddirected, 25° divergent-angle ultrasound beam samples a large
portion of the coronary profile. Blood flow velocities are
determined from the Doppler frequency shift based on the
difference between the transmitted and returning signals calculated by means of the Doppler equation. The velocity data
are processed by on-line fast Fourier transformation. All
measurements were obtained at the conclusion of coronary
angiography, while the Doppler guide wire was carefully
528
DANZI ET AL.
FUNCTIONAL SIGNIFICANCE OF CORONARY STENOSIS
advanced to a position 2 to 3 cm distal to the stenosis to avoid
placement in a side branch or post-stenotic velocity jet. Baseline time-averaged peak velocity and the diastolic/systolic flow
velocity ratio were recorded. Furthermore, flow velocity spectra were recorded for 60 s after the bolus administration of
18 mg of adenosine. Distal coronary flow reserve was calculated
as the ratio of hyperemic and baseline average peak velocity.
The reproducibility of Doppler flow measurements in our
laboratory was tested in 18 coronary stenoses. The evaluation
was performed in duplicate, separated by 5-min intervals, with
the wire being placed in exactly the same position. The
variability was 0.3 6 6.9% for coronary flow reserve, 1.5 6
14.1% for average peak velocity and 1.6 6 10.7% for maximal
peak velocity during hyperemia.
Statistical analysis. Results are expressed as mean value 6
SD. To assess statistically significant differences, the Student t
test was used for unpaired data. The angiographic variables
(percent diameter stenosis, minimal lumen diameter and stenotic flow reserve) and the flow velocity variables (diastolic/
systolic flow velocity ratio, maximal peak velocity during
hyperemia and distal coronary flow reserve) were correlated
with the dipyridamole stress echocardiographic test results and
analyzed by means of discriminant analysis. Univariate and
multivariate analyses were carried out using the statistical
package for the Social Science (SPSS, SPSS Inc.) and Biomedical Computer Program (BMDP, Statistical Software Inc.). The
limited sample size makes it difficult to apply the split-sample
validation—that is, to estimate the discriminant function on a
subset of the data (the training set) and then to test the out of
sample classification performance of the derived discriminant
function on the remaining part of the data (the test set). We
applied leave-one-out cross-validation to circumvent the overoptimistic classification generated by using the same data set
for estimating and testing the discriminant function. In practice, the analysis is repeated a number of times equal to the
observations in the data set, leaving, in turn, one observation
out of the data used for the estimation. Then, the excluded
observation classifications are pooled to produce an overall
test classification. For the best discriminant variable, we also
carried out a split-sample analysis using a 2:1 and a 1:1 ratio for
the training and test set, respectively.
The variability of stenotic flow reserve, percent diameter
stenosis and coronary flow reserve with respect to dipyridamole stress echocardiographic time was analyzed separately in
patients who had a positive or negative result on the dipyridamole stress echocardiographic test. The test-positive patients
were analyzed by linear regression models, and the testnegative group was compared by evaluating the coefficient of
variation. Stenotic and coronary flow reserves were compared
using a simple linear regression model. A p value ,0.05 was
considered significant.
Results
The clinical and angiographic characteristics of the study
group are summarized in Table 1. The results of angiographic
JACC Vol. 31, No. 3
March 1, 1998:526 –33
Table 1. Clinical Data of the 30 Patients With Isolated Left
Anterior Descending Coronary Artery Lesions
Age (yr)
Men
Angina
Asymptomatic
Lesion location
Proximal LAD
Distal LAD
LVEF (%)
61 6 12
24
9
21
18
12
67 6 3
Data presented are mean value 6 SD or number of patients. LAD 5 left
anterior descending coronary artery; LVEF 5 left ventricular ejection fraction.
and Doppler measurements, as well as those of dipyridamole
stress echocardiography, are reported in Table 2.
High dose dipyridamole echocardiography. Transient contraction asynergy was detected in 11 patients (37%). Echocardiographic positivity was achieved after the low dose of dipyridamole (0.56 mg/kg) in four patients and after the high dose
in seven patients. In the 11 patients with positive studies, the
time to asynergy was 8.9 6 2.1 min (range 5 to 12), and the wall
motion score index at peak dipyridamole was 1.25 6 0.11.
On-line quantitative coronary angiography. Eighteen stenoses were located in the proximal segment and 12 in the
mid-third of the LAD. The mean percent diameter stenosis
was 48.2 6 21.19% (range 11.4% to 92.2%). The percent
diameter stenosis was #30% in 7 patients, between 31% and
60% in 13 patients and .60% in the remaining 10 patients.
The mean minimal lumen diameter was 1.5 6 0.7 mm (range
0.28 to 2.95). The mean stenotic flow reserve was 3.25 6 1.4
(range 0.70 to 4.9). The mean vessel reference diameter was
2.95 6 0.4 mm and was not statistically different between the
patients with a negative (2.92 6 0.4 mm) and a positive
dipyridamole echocardiographic response (3.01 6 0.5 mm).
Coronary flow velocity measurements. The mean timeaveraged peak flow velocity was 22 6 15 cm/s (range 5 to 68)
and was not statistically different between patients with a
negative (23 6 17 cm/s) and a positive dipyridamole echocardiographic response (20 6 10 cm/s). The mean diastolic/
systolic flow velocity ratio was 1.7 6 0.6 (range 0.5 to 3.1). The
mean maximal peak velocity during hyperemia was 75 6
56 cm/s (range 16 to 234 cm/s). The mean distal coronary flow
reserve was 2.33 6 1.0 (range 1.1 to 5.6).
Correlations between dipyridamole echocardiography,
quantitative coronary angiography and intracoronary Doppler
measurements. By discriminant analysis, the best angiographic cutoff values for predicting an abnormal echocardiographic test response were 1) stenotic flow reserve of 2.8
(sensitivity 100%, specificity 90%, p 5 0.001); 2) percent
diameter stenosis of 59% (sensitivity 91%, specificity 95%, p 5
0.0001); and 3) minimal lumen diameter of 1.35 mm (sensitivity 100%, specificity 74%, p 5 0.0001) (Table 3, Fig. 1).
For coronary flow velocity indexes, the best cutoff values for
predicting an abnormal echocardiographic test response were
1) coronary flow reserve of 2.0 (sensitivity 91%, specificity
JACC Vol. 31, No. 3
March 1, 1998:526 –33
DANZI ET AL.
FUNCTIONAL SIGNIFICANCE OF CORONARY STENOSIS
529
Table 2. Angiographic, Intracoronary Doppler Flow Velocity and Dipyridamole Stress Echocardiographic Data for 30 Study Patients
QCA
Doppler
Dipyridamole Echo
Pt No./
Gender
Age
(yr)
%DS
MLD
(mm)
SFR
Ref Diam
(mm)
APV
(cm/s)
DSVR
MPV
(cm/s)
CFR
Response
1/M
2/M
3/M
4/F
5/M
6/M
7/M
8/M
9/F
10/M
11/M
12/M
13/M
14/M
15/F
16/M
17/M
18/M
19/M
20/F
21/F
22/M
23/F
24/M
25/M
26/M
27/M
28/M
29/M
30/M
Mean
6SD
65
48
68
64
52
66
44
77
59
78
61
75
60
68
35
65
66
72
50
66
56
65
69
45
43
61
65
36
70
72
61
612
66.40
62.00
81.30
66.60
92.20
65.90
71.40
72.80
55.90
67.80
61.10
36.70
37.00
37.00
57.20
32.80
24.70
25.10
17.30
59.00
11.40
36.20
58.70
24.10
30.80
35.30
12.20
43.80
44.60
58.00
48.2
621.1
1.01
0.97
0.58
1.14
0.28
1.07
0.82
0.96
0.94
0.97
0.98
1.93
1.66
1.97
1.30
2.01
2.39
2.81
2.88
1.35
2.86
1.69
0.94
2.06
1.75
1.55
2.95
1.53
1.25
1.23
1.5
60.7
2.1
1.5
0.6
1.8
0.1
1.8
1.3
2.1
2.8
1.7
2.5
4.0
4.1
4.4
3.0
4.7
4.8
4.8
4.9
2.8
4.9
4.4
2.5
4.8
4.8
4.3
4.9
3.9
4.2
3.1
3.25
61.4
3.02
2.59
3.11
3.43
3.71
3.17
2.88
3.54
2.15
3.02
2.53
3.05
2.63
3.13
3.03
2.99
3.17
3.76
3.48
3.31
3.08
2.66
2.29
2.71
2.53
2.39
3.36
2.78
2.26
2.97
2.95
60.4
14
15
14
27
20
34
6
13
25
14
39
19
11
32
68
33
40
24
55
6
5
25
20
20
13
9
9
13
23
10
22
615
1.48
1.87
1.20
1.79
0.55
0.98
1.09
1.86
1.62
1.04
1.93
1.94
0.92
1.25
1.72
1.72
1.60
1.70
0.79
1.44
1.22
1.52
1.92
2.14
2.51
2.96
1.22
2.10
3.13
2.76
1.7
60.6
31
32
29
50
42
86
16
24
78
53
78
73
34
150
201
207
111
85
234
20
26
56
54
106
60
45
59
57
108
46
75
656
1.5
1.3
1.3
1.2
1.1
1.7
1.4
1.6
1.5
2.4
1.6
2.7
2.2
3.5
2.2
3.9
1.6
2.5
2.4
2.3
3.6
1.5
2.0
3.7
2.5
2.3
5.6
3.1
2.8
2.8
2.3
61.0
Pos
Pos
Pos
Pos
Pos
Pos
Pos
Pos
Pos
Pos
Pos
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Time
(min)
WMSI
12
11
8
9
5
8
9
11
6
10
9
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
12.7
63.2
1.18
1.25
1.37
1.12
1.43
1.25
1.25
1.12
1.43
1.18
1.25
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1.08
60.1
APV 5 average peak velocity; CFR 5 coronary flow reserve; DS 5 diameter stenosis; DSVR 5 diastolic/systolic velocity ratio; Echo 5 echocardiography; F 5
female; M 5 male; MLD 5 minimal lumen diameter; MPV 5 maximal peak velocity during hyperemia; Neg 5 negative; Pos 5 positive; QCA 5 quantitative coronary
angiography; Ref Diam 5 reference diameter; SFR 5 stenotic flow reserve; WMSI 5 wall motion score index.
84%, p 5 0.0002); and 2) maximal peak velocity during
hyperemia of 60 cm/s (sensitivity 73%, specificity 47%, p 5
0.04) (Table 3, Fig. 1).
Multivariate analysis identified the angiographically derived
stenotic flow reserve as the only independent variable for the
Table 3. Results of Discriminant Analysis
Variable
Sens
(%)
Spec
(%)
Acc
(%)
Cutoff
Value
p
Value
SFR
%DS
MLD (mm)
CFR
MPV (cm/s)
DSVR
100
91
100
91
73
—
90
95
74
84
47
—
93
93
83
87
57
—
2.8
59
1.35
2
60
—
0.0001
0.0001
0.0001
0.0002
0.004
NS
Acc 5 accuracy; Sens 5 sensitivity; Spec 5 specificity; other abbreviations as
in Table 2.
prediction of ischemia during dipyridamole echocardiography
(sensitivity 100%, specificity 90%, p 5 0.0001).
Good correlation was found between angiographically predicted stenotic flow reserve and the coronary flow reserve
measured distal to the stenosis (r2 5 0.46, p 5 0.0001) (Fig. 2).
Within the zone of a positive dipyridamole test, a linear
relation was found to be statistically significant with regard to
dipyridamole echocardiographic time in the analyses taking
stenotic flow reserve and percent diameter stenosis as the
response variables (p 5 0.0196, r2 5 0.51 and p 5 0.0214, r2 5
0.50, respectively); no such relation was supported by the data
when coronary flow reserve was the response variable considered. Within the zone of a negative dipyridamole test, stenotic
flow reserve showed the least spread of data (coefficient of
variation 19%, 42% and 34% for stenotic flow reserve, percent
diameter stenosis and coronary flow reserve, respectively) (Fig.
3). When the results of both positive and negative tests were
analyzed, stenotic flow reserve and percent diameter stenosis
530
DANZI ET AL.
FUNCTIONAL SIGNIFICANCE OF CORONARY STENOSIS
JACC Vol. 31, No. 3
March 1, 1998:526 –33
Figure 2. Comparison between angiographically derived stenotic flow
reserve and coronary flow reserve measured distal to the stenosis (r2 5
0.46, p 5 0.0001).
reliable predictor of the dipyridamole echocardiographic results.
Discussion
Figure 1. Representation of sensitivity and specificity as a function of
cutoff points over the whole spectrum of stenotic flow reserve (top),
percent diameter stenosis (middle) and coronary flow reserve (bottom).
correlated better with dipyridamole echocardiographic time
than with coronary flow reserve in the positive subgroup,
whereas in the negative subgroup, stenotic flow reserve showed
a reduced variability with respect to the other two variables.
Thus, stenotic flow reserve appears, globally, to be the most
Two major findings can be drawn from our study: 1) In this
selected patient cohort, angiographically derived stenotic flow
reserve was the variable of stenosis severity that best described
the functional significance of an isolated LAD stenosis, and a
value of 2.8 was the best predictor of a positive dipyridamole
echocardiographic response. 2) The angiographic variables of
stenosis severity correlated better with the results of dipyridamole echocardiography than with intracoronary Doppler variables.
Reference standard in stress testing. Myocardial ischemia
is the result of a supply– demand imbalance between coronary
blood flow and myocardial metabolic requirements, which
leads to a sequence of events in which blood flow maldistribution between territories supplied by stenotic and nonstenotic
coronary arteries precedes the development of regional wall
motion abnormalities and is followed by ECG changes and
angina (24 –26).
The noninvasive identification of coronary artery disease is
based on the detection of stress-induced markers of myocardial
ischemia. These markers include ECG ST-T wave changes,
perfusion defects on myocardial scintigraphy and regional wall
motion abnormalities. Echocardiographic imaging, combined
with exercise or pharmacologic stimuli, is increasingly being
used for the diagnosis of coronary artery disease (27). Stress
echocardiography has been shown (28,29) to provide useful
information on the presence, severity and distribution of
coronary artery disease, with a sensitivity and specificity comparable to that for radionuclide techniques. Among the different types of stress proposed, pharmacologic vasodilation by
dipyridamole is widely used in the clinical setting because of its
well established safety and accuracy in detecting single-vessel
and multivessel disease (30).
JACC Vol. 31, No. 3
March 1, 1998:526 –33
Figure 3. Relation of stenotic flow reserve (top), percent diameter
stenosis (middle) and coronary flow reserve (bottom) with dipyridamole echocardiographic time. Stenotic flow reserve appears, globally,
to be the most reliable predictor of the dipyridamole echocardiographic test results.
The high dose protocol is necessary to increase echocardiographic test sensitivity (21); it has also been shown (31) that
high dose dipyridamole leads to the same degree of vasodilation as that obtained during intracoronary adenosine infusion.
Comparison with previous studies. The concept of angiographic stenotic flow reserve was first proposed by Gould et al.
(7) and Kirkeeide et al. (8) as a simple and integrated
functional measurement of stenosis severity, reflecting all its
geometric dimensions. In experimental studies, this index
DANZI ET AL.
FUNCTIONAL SIGNIFICANCE OF CORONARY STENOSIS
531
proved to be highly specific, reproducible and independent of
physiologic conditions when applied to a discrete proximal
lesion, as in the case of our group of patients; in different
clinical situations (presence of multiple lesions or diffuse
atherosclerotic disease and acute coronary syndromes with
ulcerated plaque), this method is less reliable (7).
In the clinical setting, the correlations between angiographically derived stenotic flow reserve and intracoronary
Doppler coronary flow reserve have been poorly investigated.
Recently, Tron et al. (32) found no correlation between these
two variables in a heterogeneous patient group. These results
may be explained by the inherent limitations of both angiographic and Doppler flow velocity assessments in specific
clinical situations. Soon after acute myocardial infarction,
coronary flow reserve can no longer be considered a specific
marker of lesion severity, because it is affected by the temporary impairment of the microcirculation (7,33,34). In the case
of coronary angioplasty, angiography is an inaccurate means of
evaluating the immediate procedural result because of the
presence of possibly underestimated or undetected intimal
tears or dissections that can interfere with the correct measurement of all morphologically derived determinants of lesion
severity, such as stenotic flow reserve (35). For this reason, the
use of different techniques, such as intravascular ultrasound or
Doppler flow velocity studies, have been proposed (36). Unfortunately, in many patients, coronary flow reserve fails to
return to normal levels immediately after angioplasty and
therefore may not be useful for determining the significance of
residual epicardial stenosis (37).
The results of our study were obtained in a selected group
of patients with single-vessel coronary artery disease and
normal ventricular function to assess the true value of quantitative coronary angiography and intracoronary Doppler measurements in predicting an abnormal response to dipyridamole
echocardiography. This selected cohort may explain the good
correlation we found between angiographically derived flow
reserve and coronary flow reserve measured distal to the
stenosis in our patients.
Angiographic and intracoronary Doppler measurements
should therefore be considered complementary rather than
competitive approaches for describing the relevance of a given
coronary stenosis. Stenotic flow reserve reflects only the relative lesion-related impairment of coronary flow reserve and not
that of absolute coronary flow reserve, a value reflecting both
epicardial and myocardial flow capacity (7). The presence of
microvascular disease (which cannot be detected by stenotic
flow measurements) could explain the low values of Doppler
coronary flow reserve found in 2 of the 19 patients with a
negative dipyridamole echocardiographic response.
Regarding the second finding of our study, and similar to
Picano et al. (38,39), we found good correlation between the
angiographic variables and dipyridamole time, which provides
an indirect estimate of the physiologic severity of coronary
reserve impairment (Fig. 3).
Furthermore, among the angiographic variables, percent
diameter stenosis proved to be superior to minimal lumen
532
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FUNCTIONAL SIGNIFICANCE OF CORONARY STENOSIS
JACC Vol. 31, No. 3
March 1, 1998:526 –33
diameter in characterizing the functional significance of a
coronary stenosis. These data are in agreement with those of
previously reported studies in patients with limited coronary
artery disease (40 – 42). The greater accuracy of percent diameter stenosis (obtained by the mean values of two measures:
minimal diameter and “normal” reference diameter) over
minimal lumen diameter can be explained by the fact that, at
least theoretically, the larger the number of geometric variables considered, the closer the relation with the functional
assessment of the narrowing. This finding also suggests that in
the presence of diffuse coronary disease, multiple measurements may amplify the effect of measurement errors and lead
to a weaker functional depiction of the narrowing.
However, our angiographic cutoff values are slightly different from those observed by Arnese et al. (42), who looked at
the diagnostic accuracy of angiographic variables for the
prediction of an abnormal scintigraphic or exercise echocardiographic test response. This difference may be partially
explained by the fact that the off-line quantification used by
Arnese et al. relied on a higher degree of spatial resolution of
the 35-mm cine film than that of the digitally acquired arteriograms we used.
The decision to use dipyridamole echocardiography for the
noninvasive detection of ischemia can explain the good accuracy of both stenotic and coronary flow reserve in predicting an
abnormal response to stress echocardiography that we observed in our patients. This choice may also explain the
differences between our results and those of previous studies
(12,16,20) in which angiographic or geometric descriptors of
coronary obstruction did not correlate with stress-induced
ischemia or coronary flow reserve by Doppler echocardiography. Those studies used exercise stress to an ischemic end
point, particularly exercise thallium-201 perfusion imaging
(12,20).
During exercise stress testing, regional left ventricular
myocardial ischemia may result not only from an increase in
myocardial oxygen demand (43), but also from the limitation
of coronary flow as a result of coronary vasoconstriction and
the inability of vasodilation to occur near the site of an
atherosclerotic plaque (44).
The most important mechanism involved in the development of dipyridamole-induced ischemia is the flow maldistribution resulting from inappropriate coronary artery vasodilation (30), mainly from the subendocardium to the
subepicardium. Unlike exercise, dipyridamole is not associated
with coronary spasm, a comparable increase in oxygen demand
or the microcirculatory vasoconstriction produced by catecholamines. In the case of exercise stress, ischemic end points
are therefore observed at lower levels of coronary flow that
may not parallel the limitation of coronary flow observed after
dipyridamole infusion at rest and without alpha-adrenergic
stimulation by circulating catecholamines. Thus, the transient
asynergy of contraction during dipyridamole echocardiography
provides a pure measure of the hemodynamic severity of the
coronary stenosis.
Clinical implications. In an appropriately selected patient
group, simple variables obtained by means of on-line quantitative coronary angiography may allow the objective assessment of the severity of an isolated coronary artery stenosis
during cardiac catheterization, thus providing invasive cardiologists with morphologic and physiologic data useful for direct
diagnostic and therapeutic decision making and avoiding the
need for intracoronary Doppler studies or a further noninvasive functional evaluation, such as dipyridamole echocardiography and stress thallium-201 perfusion imaging.
Our data suggest that in the presence of a positive dipyridamole echocardiographic response, stenotic flow reserve faithfully reflects the time to ischemia, as assumed by dipyridamole
stress echocardiography. Furthermore, in the presence of a
negative dipyridamole echocardiographic test, the same variable appears to be highly specific (90%) in predicting a normal
test response.
The results of the present study cannot be extrapolated to
patients with diffuse coronary artery disease, in whom angiographic measurements are of limited value (45), because the
absence of a “normal” reference segment does not allow a
reliable determination of percent stenosis or the other derived
variables, such as stenotic flow reserve. In these patients,
intracoronary Doppler measurements distal to the stenoses
can provide information that cannot be obtained by quantitative coronary arteriography.
Study limitations. 1) Our study group is small because of
the strict inclusion criteria adopted for patient enrollment. 2)
We evaluated the patients at an angiographic follow-up visit 6
months after successful coronary angioplasty; therefore, angiographic morphologic and hemodynamic consequences of primary lesions were not determined. However, these features
should not alter the physiologic effect of coronary flow or the
angiographic determination, although the presence of complex
coronary artery lesion morphology could influence the diagnostic accuracy of dipyridamole echocardiography (46).
Conclusions. Angiographically derived stenotic flow reserve, as a single integrated measure of all the geometric
characteristics of a stenosis, is the variable that best describes
the functional significance of an isolated LAD lesion. Furthermore, in this selected group of patients with limited coronary
artery disease, the angiographic variables of stenosis severity
showed a better relation to the dipyridamole echocardiographic response than to the intracoronary Doppler variables.
We are grateful to Eugenio Picano, MD for helpful suggestions, Marina Parolini
for statistical consultation and Ilaria Citti for secretarial assistance.
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