Clinical Value of Absolute Quantification of
Myocardial Perfusion With 15O-Water in Coronary
Artery Disease
Sami A. Kajander, MD; Esa Joutsiniemi, MD; Markku Saraste, MD; Mikko Pietilä, MD, PhD;
Heikki Ukkonen, MD, PhD; Antti Saraste, MD, PhD; Hannu T. Sipilä, PhD;
Mika Teräs, PhD; Maija Mäki, MD, PhD; Juhani Airaksinen, MD, PhD;
Jaakko Hartiala, MD, PhD; Juhani Knuuti, MD, PhD
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Background—The standard interpretation of perfusion imaging is based on the assessment of relative perfusion
distribution. The limitations of that approach have been recognized in patients with multivessel disease and endothelial
dysfunction. To date, however, no large clinical studies have investigated the value of measuring quantitative blood flow
and compared that with relative uptake.
Methods and Results—One hundred four patients with moderate (30%–70%) pretest likelihood of coronary artery disease
(CAD) underwent PET imaging during adenosine stress using 15O-water and dynamic imaging. Absolute myocardial
blood flow was calculated from which both standard relative myocardial perfusion images and images scaled to a known
absolute scale were produced. The patients and the regions then were classified as normal or abnormal and compared
against the reference of conventional angiography with fractional flow reserve. In patient-based analysis, the positive
predictive value, negative predictive value, and accuracy of absolute perfusion in the detection of any obstructive CAD
were 86%, 97%, and 92%, respectively, with absolute quantification. The corresponding values with relative analysis
were 61%, 83%, and 73%, respectively. In region-based analysis, the receiver operating characteristic curves confirmed
that the absolute quantification was superior to relative assessment. In particular, the specificity and positive predictive
value were low using just relative differences in flow. Only 9 of 24 patients with 3-vessel disease were correctly assessed
using relative analysis.
Conclusions—The measurement of myocardial blood flow in absolute terms has a significant impact on the interpretation
of myocardial perfusion. As expected, multivessel disease is more accurately detected.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00627172.
(Circ Cardiovasc Imaging. 2011;4:678-684.)
Key Words: cardiac-gated imaging techniques 䡲 positron-emission tomography 䡲 coronary artery disease
䡲 perfusion
T
he detection of functional consequences of epicardial
coronary artery disease (CAD) has an established role in
the detection of the disease and the guidance of therapy.1 In
addition, the assessment of impairment in microcirculatory
reactivity recently has gained more interest. Estimates of
myocardial perfusion contain independent prognostic information about future major cardiac events and the effectiveness of risk reduction strategies.1
limitations. The assessment is based on the assumption that
the region with the best perfusion is normal and can be
used as a reference. In clinical scenarios, these shortcomings may arise, particularly with patients who have multivessel disease. In addition, global reduction of myocardial
perfusion caused by diffuse microvascular disease or
balanced multivessel disease may be completely missed
when assessment of myocardial perfusion is based on
relative uptake of radiotracer.
These limitations may be avoided when using absolute
quantification of myocardial blood flow (MBF). At present, the most robust technique to quantify MBF noninvasively in the human heart is PET. PET is a quantitative
technique and allows fast and effective imaging protocols
Editorial see p 607
Clinical Perspective on p 684
Although the standard interpretation of myocardial perfusion imaging is based on the assessment of relative
myocardial perfusion defects, this approach has obvious
Received October 13, 2010; accepted September 6, 2011.
From the Turku PET Centre (S.K., H.T.S., M.T., J.K.), Department of Medicine (E.J., M.P., H.U., A.S., J.A.), and Department of Clinical Physiology
and Nuclear Medicine (M.S., M.M., J.H.), University of Turku, Turku, Finland.
Correspondence to Sami A. Kajander, MD, Turku PET Centre, PO Box 52, FI-20521 Turku, Finland. E-mail [email protected]
© 2011 American Heart Association, Inc.
Circ Cardiovasc Imaging is available at http://circimaging.ahajournals.org
678
DOI: 10.1161/CIRCIMAGING.110.960732
Kajander et al
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with relatively low radiation burden in both rest and
stress.2– 6
Absolute quantification of MBF with PET is performed
using the tracer kinetic method, which is based on measuring
the in vivo kinetics of a tracer concentration during dynamic
acquisition. Normal MBF at rest is from 0.6 to 1 mL/g per
minute and increases by 3- to 5-fold in stress as the coronary
arteries dilate.7
The tracers most widely used for the quantification of
myocardial perfusion with PET are 15O-water and 13Nammonia. They provide absolute information of MBF over
a wide range of blood flows, but their production requires
a cyclotron.8 Absolute MBF can, however, be assessed
with the more widely used generator-produced perfusion
tracer 82Rb.9 Despite this, quantification of MBF with PET
mainly has been used in research protocols and studies in
which absolute perfusion has been measured on the global
level only. These studies have focused on the effect of
various risk factors on early coronary dysfunction.10,11
More recently, because of the increased use of PET (and
PET/CT) in clinical cardiology and the development of
analysis methods, simple and robust perfusion quantification has become available.12–15 However, large patient
studies demonstrating the value of absolute quantification
in the detection of CAD, as well as in the guidance of the
therapy, are still lacking. In a recent study by Hajjiri
et al,16 27 patients with known or suspected CAD were
studied. In their work, quantification improved the accuracy for the identification of CAD. The aim of the current
study was to investigate whether the additional information gained from absolute quantification of myocardial
perfusion has a significant clinical impact in a patient
population with a moderate pretest probability of CAD.
Methods
General Study Protocol
Initially, 107 consecutive patients with chest discomfort and 30% to
70% pretest likelihood of CAD were enrolled. Before invasive
coronary angiography, coronary CT angiography followed by PET
perfusion imaging during adenosine stress were performed in 104 of
these patients using 15O-water and dynamic nongated imaging (GE
Discovery VCT PET/CT; GE Healthcare; Waukesha, WI). In 3
subjects, a PET study was not possible because of technical reasons.
The main results of hybrid PET/CT imaging in this population have
been published recently.17 As the reference method, all patients
underwent invasive coronary angiography (ICA) with fractional flow
reserve (FFR) within 2 weeks, during which time no cardiac events
took place. During ICA, FFR measurements were performed for
stenoses ⬎30%. However, there were some stenoses not subject to
FFR because of logistics, the operator’s clinical and visual assessment of complicated lesions, or technical reasons in some extremely
tight stenoses.
Absolute Quantification of Myocardial Blood Flow
679
Table 1. Analysis of Quantitative Blood Flow, Results
per Patient
ICA⫹FFR
⫹
⫺
PET with quantitative blood flow (n⫽104)
⫹
36
6
⫺
2
60
ICA⫹FFR indicates invasive coronary angiography with fractional flow
reserve.
an adenosine-induced stress scan was performed. Adenosine was
started 2 minutes before the scan start and infused at 140 ␮g/kg
body weight per minute.17
ICA and FFR
All coronary angiographies were performed on a Siemens Axiom
Artis coronary angiography system (Siemens; Erlangen, Germany).
Quantitative analysis of coronary angiograms was performed using
software with an automated edge-detection system (Quantcore;
Siemens) by an experienced reader (M.P.) blinded to the results of
the PET, CT angiography, and FFR. Seventeen standard segments
were analyzed.
In the presence of 30% to 70% stenosis, FFR measurement was
performed using the ComboMap pressure/flow instrument and
0.014-inch BrightWire pressure guidewires (Volcano Corporation;
San Diego, CA). The pressure was measured distally to the lesion
during maximal hyperemia induced by 18 ␮g intracoronary boluses
of adenosine with simultaneous measurement of aortic pressure
through the catheter. FFR was calculated as the ratio of mean distal
pressure to mean aortic pressure.18 –20
Analysis and Interpretation of the Studies
The perfusion studies were analyzed using validated software. First,
absolute blood flow for the standard 17 myocardial segments were
calculated using a standard anatomic template and Carimas
software14,17 (www.turkupetcentre.net/carimasturku). The PET
images were fused with corresponding CT angiographic images at
a GE ADW workstation (CardIQ Fusion; GE Healthcare) to
determine the individual regions supplied by each artery. Absolute myocardial flow in any region of ⬍2.5 mL/g per minute
during stress was considered abnormal.17 In patient-based analysis, the result was interpreted as pathological if any region
showed abnormal perfusion.
Although it is customary in clinical practice to evaluate relative
perfusion abnormalities visually, we chose to use calculated MBF
values as the basis of the relative uptake analysis as well. The
region of the highest perfusion (regardless of the absolute flow)
was assigned a value of 1, after which all the other areas were
graded relative to that. For example, if the MBF were 2.0 mL/g
per minute in the left anterior descending coronary artery territory, 1.5 mL/g per minute in the left circumflex coronary artery
territory, and 1.0 mL/g per minute in the right coronary arterysupplied area, the corresponding relative values would be 1, 0.75,
and 0.5. The optimal cutoff for the relative uptake would be 0.8
Table 2.
Analysis of Relative Uptake, Results per Patient
ICA⫹FFR
PET Imaging
Rest-stress perfusion cardiac PET was performed with 900 to
1100 MBq of 15O-labeled water (Radiowater Generator; Hidex
Oy; Turku, Finland) at rest as an intravenous bolus over 15 s at an
infusion rate of 10 mL/min. A dynamic, nongated acquisition of
the heart over 4 minutes 40 s was performed (14⫻5 s, 3⫻10 s,
3⫻20 s, and 4⫻30 s). After 10-minute decay of the radioactivity,
⫹
⫺
⫹
28
18
⫺
10
48
PET with relative uptake (n⫽104)
Abbreviations as in Table 1.
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Circ Cardiovasc Imaging
November 2011
Figure 1. Patient-based assessment.
Quantitative blood flow versus relative
uptake is shown in adenosine-induced
stress with invasive coronary angiography
and fractional flow reserve as the reference method (n⫽104). Normal flow is
ⱖ2.5 mL/g per minute in quantitative
blood flow (blue bar) and ⱖ80% of the
maximal uptake in relative uptake (burgundy bar). NPV indicates negative predictive value; PPV, positive predictive
value.
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(ie, 80% of the maximal uptake in any region) on the basis of the
receiver operating characteristic curve.
Parametric images of the blood flow were produced from the
data. The scaling of the images was either automatic (with the
relative scale, the best perfused region always has the brightest
color regardless of the actual blood flow, and the other regions
have colors reflecting the flows relative to the best region) or
manual (with the absolute scale, the flow in mL/g per minute
relates to a predefined color).
When FFR was performed during ICA, stenoses with FFR ⬎0.8
were classified as nonsignificant,20 regardless of the degree of
narrowing. In cases without FFR, luminal diameter narrowing ⱖ50%
in quantitative analysis of coronary angiograms was considered
significant.
Statistical Analyses
Sensitivity, specificity, positive predictive value (PPV), negative
predictive value (NPV), and accuracy were calculated for both
quantitative blood flow and quantitative relative uptake. Receiver
operating characteristic analyses were performed with the Youden
index, and the areas under the curves were calculated. McNemar test
was performed to compare accuracy of quantitative blood flow and
quantitative relative uptake against the reference method (ICA with
FFR). A P⬍0.05 was considered statistically significant. The statis-
tical tests were performed with SAS version 9.1 (SAS Institute Inc;
Cary, NC) software.
Results
According to the reference method (ICA with FFR), 38 of
104 patients who underwent PET had significant CAD. Two
of the 3 patients without PET data had significant CAD, but
they were not included in the analysis. Of the 38 patients, 24
had multivessel disease, and 14 had single-vessel disease.
Eighteen patients had either a totally occluded vessel or
⬎90% stenosis in which FFR was not technically possible. In
4 other patients, FFR could not be performed because of
scheduling or technical reasons. A total of 238 of 312 arteries
were normal or had nonsignificant disease, and 74 were
significantly diseased.
Patient-Based Analysis
Quantitative blood flow analysis correctly identified 36 of the
38 patients with positive findings. There were 2 false negatives in which the flow was ⱖ2.5 mL/g per minute in all
regions and 6 false positives. Of these, 5 patients had
Figure 2. A, Regional (per-vessel) assessment (n⫽312). B, Regional (per-vessel)
assessment in patients with multivessel disease (n⫽312). Quantitative blood flow versus relative uptake is shown in adenosineinduced stress with invasive coronary
angiography with fractional flow reserve as
the reference method. Normal flow is ⱖ2.5
mL/g per minute in quantitative blood flow
(blue bar) and ⱖ80% of the maximal uptake
in relative uptake (burgundy bar). Abbreviations as in Figure 1.
Kajander et al
Absolute Quantification of Myocardial Blood Flow
Table 3. Analysis of Quantitative Blood Flow, Results
per Region
Table 4.
681
Analysis of Relative Uptake, Results per Region
ICA⫹FFR
ICA⫹FFR
⫹
⫹
⫺
⫹
70
20
⫺
4
218
PET with quantitative blood flow (n⫽312)
⫺
PET with relative uptake (n⫽312)
⫹
34
19
⫺
40
219
Abbreviations as in Table 1.
Abbreviations as in Table 1.
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diffusely reduced flow, whereas 1 patient had ⬍2.5 mL/g per
minute flow in just 1 vascular region. Quantitative analysis
resulted in a sensitivity of 95%, a specificity of 91%, a PPV
of 86%, and an NPV of 97%.
With relative myocardial uptake analysis, PET was able to
correctly identify only 28 of 38 patients with significant
CAD. There were 10 false negatives and 18 false positives.
This resulted in a sensitivity of 74% and a specificity of 73%.
PPV and NPV were 61% and 83%, respectively. The results
of the patient-based analysis are shown in Tables 1 and 2 and
in Figure 1.
Patients With Multivessel Disease
There were 24 patients with significant multivessel disease.
All but 1 (who had a false-negative result) were identified by
abnormal quantitative blood flow. In addition, there were 5
false positives with diffusely reduced MBF but no CAD
according to ICA and FFR.
Using relative uptake, we were able to detect in 22 of the
24 patients significant CAD, whereas 2 patients were erroneously interpreted as being without CAD (both had very low,
but diffusely reduced flow). In addition, 26 patients were
classified as having multivessel disease, although they did
not. The results of the analysis of patients with multivessel
disease are presented in Figure 2A and 2B.
In the present study, we compared the conventional approach of assessing relative radiotracer uptake with quantitative measurement of MBF and found that the latter
method was more sensitive and accurate. In particular, in
the presence of the multivessel disease, relative differences
in regional myocardial radiotracer uptake may underestimate the severity of CAD.
There are 3 main patient groups that account for the
differences between relative uptake and quantitative blood
flow. The first group is the patients with 3-vessel disease and
balanced, uniform reduction of perfusion. In this study, using
relative uptake analysis only, we would have totally missed
CAD in 2 such patients. Using absolute quantification,
however, balanced CAD usually is easily distinguished from
normal perfusion.
The second major group of discrepant findings comprised
13 other patients with multivessel disease. In these patients,
presence of CAD was detected using relative uptake analysis,
but only 1 region was considered pathological. This too is
easy to understand because the region with the best perfusion
is considered to represent normal flow in relative analysis,
which is, however, not usually the case in patients with
multivessel disease.
The third group of discrepancies comprised patients with
high MBF but inhomogeneous radiotracer uptake erroneously
Regional Analysis
In regional (vessel-based) analysis, quantitative blood flow
had a sensitivity and specificity of 95% and 92%, respectively, for the detection of significant CAD. PPV, NPV,
and accuracy were 78%, 98%, and 92%, respectively.
When relative flow analysis was used, PPV, NPV, and
accuracy were 64%, 85%, and 82%, respectively. The
results of the 2 analysis methods also were compared by
means of receiver operating characteristic analysis. The
area under the curve was 0.94 (quantitative blood flow)
and 0.73 (relative uptake).
The relative perfusion method failed to assess the underlying extent of the disease in 13 of 24 patients with multivessel CAD because the patients were believed to have
single-vessel disease only. In addition, 7 other patients given
a diagnosis of multivessel disease really had single-vessel
disease. The region-based results are presented in Tables 3
and 4 and in Figures 2 and 3.
Discussion
Myocardial perfusion yields independent and important
information about risk stratification in patients with CAD.
Figure 3. Receiver operating characteristic curves of regional
assessment methods. Quantitative blood flow (area under the
curve, 0.94 [solid line]) versus relative uptake (area under the
curve, 0.73 [dashed line]) is shown.
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Circ Cardiovasc Imaging
November 2011
Figure 4. False-positive finding in relative
uptake analysis. A, Relative uptake in
hybrid PET/CT angiography images (automatic color scale). The heterogeneity in
perfusion was erroneously interpreted as
reduced perfusion in the left anterior
descending and left circumflex coronary
artery territories. Normal perfusion is indicated by yellow or red and reduced perfusion by green or blue. B, Quantitative
blood flow with a preset color scale of 0
to 3.5 mL/g per minute. Normal perfusion
is ⱖ2.5 mL/g per min (yellow or red), and
reduced perfusion is ⬍2.5 mL/g per minute (green or blue). Invasive coronary
angiography and fractional flow reserve
were found to be normal.
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interpreted as perfusion defects. According to ICA and FFR,
these patients had no significant CAD. Such misinterpretation
is most likely to occur with tracers with a linear relationship
between the measured and the actual flow, even at a high
range, such as 15O-water, but also may be important with
other tracers with high extraction.21 This potential pitfall is
avoided when using quantitative blood flow analysis. Two
case examples of false findings in relative uptake and their
counterpart images based on the quantitative blood flow are
shown in Figures 4 and 5.
An interesting subgroup is the patients with normal (or
nearly normal) epicardial vessels but with diffusely reduced MBF. With quantitative PET, these patients with
possible microcirculatory disease often cannot be separated from those with epicardial multivessel disease. This
finding may have important implications for decisions
about referral to ICA, but it should be noted that hybrid
PET/CT imaging can lead to a correct diagnosis in such
patients. On the other hand, the relative perfusion method
frequently classifies these patients as normal. Of course,
the relative number of patients with multivessel and
single-vessel disease as well as impaired microcirculation
reflects a particular patient population and the pretest
probability of CAD in that group.
We used hybrid PET/CT images to visualize the location of
the actual coronary arteries and their territories. The normal
variation in anatomy is considerable, and possible nonanatomical pseudolesions in perfusion images are more easily
distinguished from real abnormalities. In our opinion, it is
advisable to use hybrid images for anatomy and flow values
for function if both are available.
A limitation of the current study is that the poor
performance of relative uptake analysis at a high perfusion
range should not be directly extrapolated to other perfusion
tracers used in PET imaging or conventional nuclear
medicine. Most tracers (eg, sestamibi, tetrofosmin, ammonia, rubidium) exhibit nonlinear flow characteristics between detected signal and actual perfusion, thus naturally
omitting heterogeneity in perfusion at the high end of the
normal perfusion range. These relationships are demonstrated in Figure 6.22
Another limitation is the lack of ECG gating in our
approach. Gated images provide information about wall
motion, and this information could improve the accuracy
of relative analysis. A third limitation of the study is the
relatively small number of patients with significant CAD
(n⫽38). This reflects the patient population but warrants
further study with more patients. On the other hand, this
population with intermediate likelihood of disease should
be ideal for assessing diagnostic methods, especially
because we avoided referral bias by performing ICA in all
patients.
Conclusions
Quantification of MBF is superior to the assessment of
relative uptake only. In particular, assessment of the absolute
Figure 5. False-negative finding in relative
uptake analysis. A, Relative uptake in
hybrid PET/CT angiography images (automatic color scale). This appeared normal in
all regions and was false-negative finding.
Normal perfusion is indicated by yellow or
red and reduced perfusion by green or
blue. B, Quantitative blood flow images
with a preset color scale of 0 to 3.5 mL/g
per minute. Normal perfusion is ⱖ2.5 mL/g
per minute (yellow or red color), and
reduced perfusion is ⬍2.5 mL/g and minute
(green or blue). Blue reflects severely
impaired perfusion in all 3 major vascular
territories. Invasive coronary angiography
and fractional flow reserve were found to
be abnormal in all 3 vessels.
Kajander et al
Absolute Quantification of Myocardial Blood Flow
4.
5.
6.
7.
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Figure 6. Graphical presentation of the relationship between
absolute myocardial perfusion and tracer uptake. The lines
are estimates of the tracer uptake characteristics. In all tracers except 15O-water, tracer extraction is reduced when perfusion is increased. MIBI indicates sestamibi. Reproduced
with permission from the American Society of Nuclear
Cardiology.22
flow improves the correct detection of multivessel disease. In
addition, patients with diffusely reduced flow but with no
significant epicardial stenoses are easily identified using
quantification methods. Furthermore, local variances within
normal high flow can be separated from regionally compromised perfusion. This is particularly important when tracers
with high extraction are used.
Acknowledgments
We thank Ville Aalto for his skillful statistical analysis. This study
was conducted within the Centre of Excellence in Molecular Imaging
in Cardiovascular and Metabolic Research, supported by the Academy of Finland, University of Turku, Turku University Hospital, and
Abo Academy.
8.
9.
10.
11.
12.
13.
14.
Sources of Funding
Financial support was obtained from the Finnish Cardiovascular
Foundation and the Hospital District of Southwest Finland.
Disclosures
15.
None.
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CLINICAL PERSPECTIVE
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The standard interpretation of perfusion imaging is based on the assessment of relative perfusion defects. This approach
has limitations, particularly in the detection of multivessel disease and microvascular dysfunction. Using PET, it is possible
to overcome these handicaps by measuring myocardial blood flow in absolute terms. We investigated 104 patients with a
moderate (30%–70%) pretest likelihood of coronary artery disease. The patients underwent PET during adenosine stress
using 15O-water and dynamic imaging. Absolute myocardial blood flow was calculated from which both standard relative
uptake images and images exhibiting quantitative myocardial blood flow were produced. The patients and the main vessel
regions then were classified as normal or abnormal and compared against the reference of conventional angiography with
fractional flow reserve. In patient-based analysis, the positive predictive value, negative predictive value, and accuracy of
quantitative blood flow in the detection of obstructive coronary artery disease were 86%, 97%, and 92%, respectively. The
corresponding values with relative uptake analysis were 61%, 83%, and 73%, respectively. In region-based analysis, the
receiver operating characteristic curves confirmed that the absolute quantification was superior to relative assessment. In
particular, the specificity and positive predictive value were low using just relative differences in flow. Only 9 of 24
patients with 3-vessel disease were correctly assessed using relative analysis. The measurement of myocardial blood flow
in absolute terms has a significant clinical impact on the interpretation of myocardial perfusion. As expected, particularly
multivessel disease is more accurately detected.
Clinical Value of Absolute Quantification of Myocardial Perfusion With 15O-Water in
Coronary Artery Disease
Sami A. Kajander, Esa Joutsiniemi, Markku Saraste, Mikko Pietilä, Heikki Ukkonen, Antti
Saraste, Hannu T. Sipilä, Mika Teräs, Maija Mäki, Juhani Airaksinen, Jaakko Hartiala and
Juhani Knuuti
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Circ Cardiovasc Imaging. 2011;4:678-684; originally published online September 16, 2011;
doi: 10.1161/CIRCIMAGING.110.960732
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