Medical Review of F‑18 Fluorodeoxyglucose for Cardiac Indications

Victor F.C. Raczkowski, MD, MS

I. Introduction

The purpose of this review is to determine whether existing clinical
data are sufficient to demonstrate the safety and efficacy of F‑18 FDG
PET imaging in support of an indication for cardiac use. Positron
emission tomography (PET) imaging with F‑18 fluorodeoxyglucose
(F‑18 FDG) has been used in cardiology primarily to evaluate myocardial
\"hibernation.\" This review summarizes and evaluates a number of
literature studies in which PET imaging with F‑18 FDG was used to assess
myocardial hibernation in patients with coronary artery disease and left
ventricular dysfunction.

Myocardial hibernation is defined as chronic, reversible left
ventricular dysfunction due to coronary artery disease.[^1] The ability
to identify hibernating myocardial tissue is potentially of great
clinical significance. Hibernating myocardium with longstanding
dysfunction may be able to regain some, or all, of its contractile
function after successful coronary revascularization with procedures
such as coronary artery bypass grafting (CABG) or coronary angioplasty.
However, infarcted or scarred myocardium will not regain function after
such procedures. Thus, the ability to distinguish hibernating from
infarcted tissue before revascularization may be useful clinically in
helping to predict the likelihood of left ventricular functional
recovery after revascularization.

The ability of some noncontracting myocardium to metabolize glucose, as
assessed with PET by myocardial uptake of F‑18 FDG, has been interpreted
as being a marker of cellular viability. Accordingly, increased
accumulation of F‑18 FDG in myocardial regions with reduced perfusion,
or flow-metabolism mismatch, has been viewed as a marker for hibernating
myocardium. In contrast, a matched defect, with concordant reductions in
both perfusion and F‑18 FDG accumulation, has been viewed as a marker
for a myocardial scar. Other imaging methods which have been used to
assess myocardial hibernation include stress echocardiography with
dobutamine, single-photon-emission-computed tomography (SPECT) with
thallium‑201, radionuclide imaging with technetium‑99m sestamibi, and
PET imaging with C‑11 acetate.

II\. Evaluating the Effectiveness Data for F‑18 FDG PET Imaging for
Identifying Myocardium with Reversible Loss of Contractility in Patients
with Coronary Artery Disease and Left Ventricular Dysfunction

A. Data Sources

FDA\'s Center for Drug Evaluation and Research (CDER) conducted a
literature search of recent peer-reviewed medical journals to evaluate
the F‑18 FDG effectiveness data. The search criteria included the
following items: studies published from January 1990 to July 1, 1998
identified as human clinical studies with F‑18 FDG in PET, written in
English, found by searching on-line databases of Medline (n=250), Embase
(n=274), Derwent (n=38), Cochrane (n=33), Cancerlit (n=25), Biosis
(n=9), and HSTAR (n=3). Of the articles generated by this search, the
medical reviewer further narrowed the search by use of the search terms
\"viability\" and \"hibernation.\" FDA also solicited references from
the PET community on the use of F‑18 FDG in cardiac PET imaging from any
time period published in peer-reviewed journals. Review articles on F‑18
FDG PET cardiac imaging were identified, including one recent pooled
analysis.[^2] To ensure completeness, the reference list of Guidelines,
Scientific Statements, and Position Statements from three professional
organizations were reviewed, as were the reference sections of some of
the articles identified in the above searches.[^3]^,^[^4]^,^[^5] One
abstract was also identified because of the number of patients enrolled
and because it describes a multicenter study.[^6]

For primary review, the medical reviewer selected ten articles of
prospective studies in patients with coronary artery disease and left
ventricular dysfunction. Each article allowed the results of cardiac PET
F‑18 FDG imaging to be compared with the functional outcome of the left
ventricle (\"truth\"), as described in the next section. In addition,
several other selected articles were reviewed in support of the
potential clinical usefulness of such cardiac F‑18 FDG PET evaluations.
Each of these ten studies was considered to be well controlled, and in
aggregate, the articles provide an adequate data base upon which to
judge the effectiveness of F‑18 FDG for identifying myocardium with
reversible loss of contractility in patients with coronary artery
disease and left ventricular dysfunction.

B. Approach to the Review

In a dysfunctional left ventricle, hibernating myocardium may be
identified operationally by determining whether myocardial regions
regain contractile function after coronary revascularization. In each of
the principal studies summarized in this review, the performance of PET
imaging with F‑18 FDG is therefore measured against a functional
outcome: the recovery (or lack of recovery) of regional contractile
function after myocardial revascularization with either CABG or
angioplasty. Thus, in these studies, \"truth\" is ascertained by a
functional outcome\--recovery or lack of recovery\--after
revascularization. The performance of PET imaging with F‑18 FDG is not
compared with the \"gold standard\" results of some other test, such as
findings on histopathology. The various technologies by which functional
recovery (or lack of recovery) was assessed in each of these studies
(including echocardiography, radionuclide ventriculography, and contrast
ventriculography) are sufficiently valid and reliable to allow
determinations of functional outcome to be made.

The studies are all of a similar design, even though different
technologies may have been used to make the various assessments. Thus,
enrolled patients were typically patients with coronary artery disease
and left ventricular dysfunction who were scheduled for coronary
revascularization. These patient entry criteria were typically
documented with coronary arteriography and with either contrast or
radionuclide ventriculography.

Before revascularization, except as noted, the following core parameters
were assessed:

• Myocardial metabolism (by positron emission tomography with F‑18 FDG).

• Myocardial perfusion (by PET with N‑13 ammonia, PET with Rb‑82,
thallium‑201 scintigraphy, SPECT with Tc‑99m sestamibi, or PET with C‑11
acetate, depending on the study). However, in some cases, myocardial
perfusion was not assessed as part of the study.

• Ventricular function, such as segmental wall motion (by
two‑dimensional echocardiography, radionuclide ventriculography,
contrast ventriculography, or transesophageal echocardiography,
depending on the study).

After revascularization with either CABG or angioplasty, ventricular
function was reassessed (with two‑dimensional echocardiography,
radionuclide ventriculography, contrast ventriculography, or
transesophageal echocardiography, depending on the study).

The performance of PET F‑18 FDG imaging has been emphasized in the
results section of each study, even if the manuscript had other
principal objectives. For each study, the results of F‑18 FDG PET
imaging as a predictor of functional recovery have been displayed in 2x2
tables as in the prototype below. Diagnostic performance measures such
as sensitivity, specificity, positive predictive value (PPV), negative
predictive value (NPV), accuracy, likelihood ratio(+), and likelihood
ratio(‑), were calculated with conventional formulas. Confidence
intervals for these binomial parameters were calculated with statistical
software by either the normal theory method or the exact method, as
appropriate. Other results and statistical evaluations are included in
this review as they were described in the manuscript.

+--------------------------------+------------------+-----------------+
| Table 1: Prototype of 2x2      |                  |                 |
| Table                          |                  |                 |
+--------------------------------+------------------+-----------------+
|                                | Improved         |                 |
|                                | Function after   |                 |
|                                | R                |                 |
|                                | evascularization |                 |
|                                | (i.e., truth)    |                 |
+--------------------------------+------------------+-----------------+
| Prediction of Functional       | Yes              | No              |
| Recovery F‑18 FDG PET          |                  |                 |
|                                |                  |                 |
| (i.e., test results)           |                  |                 |
+--------------------------------+------------------+-----------------+
| Yes                            | true positive    | false positive  |
+--------------------------------+------------------+-----------------+
| No                             | false negative   | true negative   |
+--------------------------------+------------------+-----------------+

Given the relatively small number of patients in each study, the
performance measures from any particular study should be interpreted
with caution. Because of the small sample sizes, the widths of the
confidence intervals for these measures are rather broad, and these
measures may not be generalizable to larger populations. Moreover,
performance measures such as positive predictive value, negative
predictive value, and accuracy will vary depending on prevalence and
should therefore be interpreted even more carefully. Finally, the
studies divided the left ventricle into different numbers of segments
and divided the left ventricle in different ways. This means that a
diagnostic performance measure made \"by segment\" in one study,
including sensitivity, specificity, PPV, NPV, and accuracy, may have a
somewhat different clinical meaning than the corresponding diagnostic
performance measure in other studies.

As used in this review, the terms \"hibernation\" and \"viability\" are
used synonymously because in the manuscripts they have been used by
different authors to describe essentially the same myocardial state. For
the purposes of this review, these terms refer to myocardium with
reversible loss of contractility in patients with coronary artery
disease and left ventricular dysfunction.

C. Published Literature

The published clinical studies are described below, listed in
alphabetical order by the last name of the first author. These published
studies allowed FDA to evaluate the effectiveness of F‑18 FDG PET in the
assessment of reversible loss of contractility in patients with coronary
artery disease and left ventricular dysfunction. The studies shared the
following design elements: 1) Each study allowed the predictive
performance of F‑18 FDG to be compared with \"truth\" in terms of a
functional outcome. 2) Each study was prospective and the enrolled
patients (when considered in aggregate) are sufficiently similar, though
not identical, to the population in which F‑18 FDG will likely be used.
3) Each study specified the methods by which F‑18 FDG PET images were
analyzed and the criteria used to make predictions of functional outcome
(e.g., predictions of reversible vs. irreversible). 4) Each study
specified the methods by which myocardial function was analyzed (e.g.,
by echocardiography, radionuclide ventriculography, or contrast
ventriculography), the ways in which the corresponding images were
interpreted, and the criteria used to determine whether functional
improvement had occurred (e.g., improved myocardial function vs.
unimproved myocardial function). 5) In many studies adequate procedures
had been followed to minimize potential bias: for example, a) blinding
the wall-motion analysis to the outcome of the PET F‑18 FDG and
perfusion studies; b) blinding the interpretation of the PET F‑18 FDG
and perfusion images, particularly when the interpretation is
qualitative, to the results of the wall-motion analysis, and;
c) attempts to avoid selection bias in the choice of patients or
myocardial segments for inclusion in the study (e.g., evaluation of
consecutive patients) or for inclusion in the analysis (e.g., not
restricting the analysis to myocardial segments with obvious patterns of
flow-metabolism match or mismatch).

As will be discussed in greater detail at the end of this review, other
highly desirable features noted in some, but not all of these studies,
include the following design elements: 1) an adequate accounting of
patient disposition; 2) an adequate accounting of segment disposition;
3) a full description of the characteristics of the patients enrolled in
the studies; 4) an assessment of the reproducibility of the assessments
of wall motion, the PET F‑18 FDG scans, and the perfusion scans (e.g.,
by formally evaluating reproducibility and/or by the use of multiple
readers); 5) a definition of the term \"blinded,\" (e.g., a description
of the specific information to which the readers were blinded); 6) a
method of evaluating the success of the revascularization procedure; 7)
a description of how alignment (e.g., segmental concordance) was ensured
across imaging modalities, or even within the same imaging modality
(e.g., PET imaging with N‑13 ammonia to assess perfusion and F‑18 FDG to
assess metabolism at different times); 8) a full description of all
drugs used in the study, particularly of F‑18 FDG and drugs used to
assess perfusion, along with the conditions of their administration
(e.g., such information includes the method of preparation,
radiochemical purity, radiation dose, mass dose, route of
administration, frequency of administration, and glucose state of the
patient); 9) full details of image acquisition; 10) full details of
image analysis (e.g., quantitative, qualitative, normalization, external
control group, description of myocardial segments); 11) a formal
statistical description of the prospective hypotheses that were to be
tested, along with a description of the originally statistical analytic
plan; 12) inclusion of analyses \"by patient,\" as well as analyses \"by
segment;\" 13) comparison of the diagnostic performance of F‑18 FDG PET
with the performance of other diagnostic techniques used to assess the
reversibility of left ventricular function; 14) repeat evaluation of
PET FDG‑18 and perfusion imaging after revascularization; 15) serial
evaluations after revascularization of the reversibility of left
ventricular dysfunction (e.g., to assess the time course of myocardial
recovery); 16) evaluations of the functional outcomes of segments that
were not successfully revascularized, 17) evaluation of endpoints that
include not only regional ventricular function, but also global left
ventricular function and clinical outcomes, and; 18) descriptions of how
safety was monitored and of the safety results.

**1. Baer FM, Voth E, Deutsch HJ, et al. Predictive Value of Low Dose
Dobutamine Transesophageal Echocardiography and Fluorine‑18
Fluorodeoxyglucose Positron Emission Tomography for Recovery of Regional
Left Ventricular Function after Successful Revascularization. J Am Coll
Cardiol 1996;28:60‑9.**

**Description of Study:**

[Objective]{.underline}: The objective of this study was to compare the
predictive value of myocardial viability, as assessed by dobutamine
transesophageal echocardiography and F‑18 FDG positron emission
tomography, for left ventricular functional recovery after
revascularization in patients with chronic left ventricular dysfunction.

[Design and sequence of events]{.underline}: This was a prospective
study that enrolled consecutive patients with coronary artery disease
and regional left ventricular akinesia or dyskinesia documented by
angiography and ventriculography. Patients were evaluated in random
sequence with a) positron emission tomography with F-18 FDG, and
b) transesophageal echocardiography at rest and under stress (with
low-dose dobutamine at 5 and 10 μg/kg/min). The PET and transesophageal
echocardiography studies were performed within one week of each other.
Myocardial perfusion was not assessed. Four to six months after CABG or
angioplasty was performed, the success of revascularization was assessed
by coronary angiography. In patients with successful revascularization,
transesophageal echocardiography studies were repeated at rest to
evaluate segmental and regional improvement in myocardial function.

Transesophageal echocardiography studies were evaluated by two blinded
readers who did not know the results of left ventriculography and F‑18
FDG positron emission tomography. In case of disagreement in segmental
gradings, a third reader reviewed the study and the subsequent majority
judgment was binding. The F‑18 FDG PET scans were evaluated
quantitatively. The manuscript did not specify whether these PET scans
were read blindly, without knowledge of the results from the
post-operative assessments of wall motion, nor did it specify the number
of readers for these evaluations.

[Subjects]{.underline}: To be included, subjects were required to have
angiographically-documented coronary artery disease (at least one
infarct-related major coronary artery with ≥80% diameter stenosis) and
regional akinesia or dyskinesia by left ventriculography. Only patients
with regional akinesia or dyskinesia that persisted for at least months
after the ischemic event were included in the study. Patients were
excluded if they had global left ventricular dysfunction due to multiple
myocardial infarcts, severe three vessel disease, diabetes mellitus,
unstable angina, or a history of sustained ventricular tachycardia.
Beta-adrenergic blocking agents were withdrawn before testing. All
patients received a long-acting nitrate before the echocardiographic and
tomographic studies to optimize perfusion.

[F‑18 FDG positron emission tomographic studies]{.underline}: Positron
emission tomography was performed by using a whole body scanner with an
axial field of view of 16.2 cm and equipped with germanium‑68/gallium‑68
retractable line sources for transmission scans. Each patient received a
solution of 50 g of glucose one hour before the administration of F‑18
FDG. Images were corrected for attenuation by using coefficients
measured by a transmission scan of 30 minutes duration. Emission scans
(6x5 minutes) were started 30 minutes after injection of 370 MBq
(10 mCi) of F‑18 FDG. The transaxial resolution was 6‑mm full width at
half maximum.

[Image analysis]{.underline}: For the blinded echocardiographic
segmental analysis, each left ventricle was divided into 28 segments.
Segmental myocardial wall motion and systolic wall thickening were
graded on a four-point ordinal scale: 1 = normal or hyperkinetic,
2 = hypokinesia (i.e., reduced but not absent systolic wall thickening
and inward wall motion), 3 = akinesia (i.e., absent wall thickening and
wall motion), 4 = dyskinesia (i.e., systolic outward movement of the
endocardial border and absent systolic wall thickening or systolic wall
thinning). Akinetic and dyskinetic segments at rest were graded viable
before revascularization if dobutamine-induced wall thickening could be
observed (i.e, score improvement from 3 or 4 when at rest to 1 or 2 on
dobutamine).

After successful revascularization, improvement of contractile function
was defined if systolic wall thickening became apparent in a segment
graded akinetic or dyskinetic at rest before revascularization (score
improvement from 3 or 4 before revascularization to 1 or 2 after
revascularization). Infarct region-related recovery of contractile
function after revascularization was based on apparent systolic wall
thickening (score 1 or 2) in ≥50% of akinetic or dyskinetic segments at
rest.

For PET images, F-18 FDG accumulation in the segments was assessed
quantitatively. For each segment the mean F‑18 accumulation was
calculated in percent of the segment with the maximal F‑18 FDG
accumulation. This segment was required to be perfused by a coronary
artery with ≤50% diameter stenosis, and to have normal wall motion. PET
segments were predicted to be viable if the mean segmental F‑18 FDG
accumulation was ≥50% of the maximal accumulation.

[Statistics]{.underline}: Differences of wall thickening scores at rest,
during dobutamine infusion and after revascularization for patients with
and without dobutamine contractile reserve were analyzed with the
Student t test. Analysis of variance with Bonferroni correction was used
to assess the significance level of mean segmental F‑18 FDG accumulation
and the mean infarct-related wall thickening score for different
transesophageal echocardiographic categories based on wall thickening
analysis.

**Results:**

[Patient disposition and characteristics]{.underline}: Overall, 121
consecutive patients were considered for the study. Four patients were
excluded: two because of diminished quality of F‑18 FDG positron
emission tomographic images and two because they refused to swallow the
transesophageal probe. Of the remaining 117 patients, 59 underwent
coronary angiography 4 to 6 months after revascularization (to assess
the success of the revascularization). Of these 59 patients, 42 had a
successful revascularization. The results from these 42 patients were
included in the analyses.

The 42 patients (38 men, 4 women) had a mean ejection fraction of 40 ±
13% (range 18% to 55%), a mean infarct age 25 ± 47 months. Twenty (20)
had undergone successful catheter-based interventional therapy, and 22
had patent bypass grafts. Eleven (11) patients had one-vessel, 18 had
two-vessel, and 13 had three-vessel coronary artery disease. A totally
occluded infarct-related vessel was found in 21 patients (50%), a
subtotal occluded infarct-related artery (high grade stenosis and slow
anterograde opacification of the vessel) was present in 10 patients. The
other 11 patients had ≥80% diameter stenosis of the infarct-related
coronary vessel.

[Segment disposition and functional outcome]{.underline}: These 42
patients had 1176 transesophageal echocardiographic segments (28 per
patient). Of the 1176 segments 72 (6%) were excluded because of
inadequate image quality for transesophageal echocardiographic wall
thickening analysis, 699 (60%) were normokinetic or hypokinetic at rest,
and 405 (34%) were graded akinetic or dyskinetic. Of these latter 405
segments, 371 could be assigned to successfully revascularized infarct
regions, whereas the other 34 belonged to regions not revascularized or
unsuccessfully revascularized. These 371 akinetic or dyskinetic segments
were related to 42 individual infarct zones, and were the segments used
to evaluate functional recovery. Postoperatively, 180 of these 371
segments (49%) improved, whereas the remaining 191 (51%) did not.

[Imaging results]{.underline}: The tables below summarize the
performance of F‑18 FDG positron emission tomography and of low-dose
dobutamine transesophageal echocardiography when these tests are used to
predict whether depressed myocardial function can be reversed by
coronary revascularization. Analyses were performed by-segment as well
as by-patient for each imaging modality.

[PET, by-segment analysis]{.underline}: Mean segmental F-18 FDG
accumulation was significantly lower (p\<0.0001) in dyskinetic segments
(n=43, 39±14%) than in akinetic segments (n=328, 64±18%).

Among the 371 asynergic segments that had been adequately
revascularized, PET imaging with F‑18 FDG predicted that wall-motion
abnormalities would reverse in 232 segments and would be irreversible in
139 segments. Reversibility was predicted correctly in 167 of 232
segments (PPV=72.0%). Lack of reversibility was predicted correctly in
126 of 139 segments (NPV=90.6%). These results are summarized in the two
tables below.

  ------------------------- --------------- -------------- ---------------
  **Table 2. Number of                                     
  Asynergic Myocardial                                     
  Segments with Improved                                   
  Segmental Wall Motion                                    
  after Revascularization:                                 
  Relation to F‑18 FDG                                     
  Accumulation**                                           

                            **Improved                     
                            Segmental Wall                 
                            Motion**                       

  **F-18 FDG Accumulation** **Present**     **Absent**     **Total**

  **≥50% of maximum**       **167**         **65**         **232**

  **\<50% of maximum**      **13**          **126**        **139**

  **Total**                 **180**         **191**        **371**
  ------------------------- --------------- -------------- ---------------

+-----------------------+----------------------+----------------------+
| **Table 3.            |                      |                      |
| Performance of PET    |                      |                      |
| When Used to Predict  |                      |                      |
| Improved Wall Motion  |                      |                      |
| in Asynergic          |                      |                      |
| Myocardial Segments** |                      |                      |
+-----------------------+----------------------+----------------------+
| **Performance         | **Value**            | **95% CI**           |
| Measure**             |                      |                      |
|                       | **(no. of            |                      |
|                       | segments)**          |                      |
+-----------------------+----------------------+----------------------+
| **Sensitivity (%)**   | **93 (167/180)**     | **(88, 96)**         |
+-----------------------+----------------------+----------------------+
| **Specificity (%)**   | **66 (126/191)**     | **(59, 72)**         |
+-----------------------+----------------------+----------------------+
| **PPV (%)**           | **72 (167/232)**     | **(66, 78)**         |
+-----------------------+----------------------+----------------------+
| **NPV (%)**           | **91 (126/139)**     | **(84, 95)**         |
+-----------------------+----------------------+----------------------+
| **Accuracy (%)**      | **79 (293/371)**     | **(75, 83)**         |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **2.7**              |                      |
| (+)**                 |                      |                      |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **0.11**             |                      |
| (‑)**                 |                      |                      |
+-----------------------+----------------------+----------------------+

[PET, by-patient analysis]{.underline}: Among the 42 patients with
successful revascularization, left ventricular functional recovery
occurred in 26 (62%) and did not occur in 16 (38%). PET imaging with
F‑18 FDG had predicted that regional wall motion would improve in 30 and
would not improve in 12. Reversibility was predicted correctly in 25 of
30 patients (PPV=83%), and lack of reversibility was correctly predicted
in 11 of 12 patients (NPV=92%). These results are summarized in the two
tables below.

  ------------------------- --------------- -------------- ---------------
  **Table 4. Number of                                     
  Patients with Improved                                   
  Regional Wall Motion                                     
  after Revascularization:                                 
  Relation to F‑18 FDG                                     
  Accumulation**                                           

                            **Improved                     
                            Regional Wall                  
                            Motion**                       

  **F-18 FDG Accumulation** **Present**     **Absent**     **Total**

  **≥50% of maximum**       **25**          **5**          **30**

  **\<50% of maximum**      **1**           **11**         **12**

  **Total**                 **26**          **16**         **42**
  ------------------------- --------------- -------------- ---------------

+-----------------------+----------------------+----------------------+
| **Table 5.            |                      |                      |
| Performance of PET    |                      |                      |
| When Used to Predict  |                      |                      |
| Improvement in        |                      |                      |
| Regional Wall Motion  |                      |                      |
| (By-Patient           |                      |                      |
| Analysis)**           |                      |                      |
+-----------------------+----------------------+----------------------+
| **Performance         | **Value**            | **95% CI**           |
| Measure**             |                      |                      |
|                       | **(no. of            |                      |
|                       | patients)**          |                      |
+-----------------------+----------------------+----------------------+
| **Sensitivity (%)**   | **96 (25/26)**       | **(80, 100)**        |
+-----------------------+----------------------+----------------------+
| **Specificity (%)**   | **69 (11/16)**       | **(41, 89)**         |
+-----------------------+----------------------+----------------------+
| **PPV (%)**           | **83 (25/30)**       | **(65, 94)**         |
+-----------------------+----------------------+----------------------+
| **NPV (%)**           | **92 (11/12)**       | **(61, 100)**        |
+-----------------------+----------------------+----------------------+
| **Accuracy (%)**      | **86 (36/42)**       | **(71, 95)**         |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **3.1**              |                      |
| (+)**                 |                      |                      |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **0.06**             |                      |
| (‑)**                 |                      |                      |
+-----------------------+----------------------+----------------------+

[Dobutamine, by-segment analysis]{.underline}: In the 204 segments with
dobutamine-induced systolic wall thickening, mean segmental F‑18 FDG
accumulation was significantly higher than in the remaining 167 segments
that remained akinetic (73±15% vs. 48±15%, p\<0.001). The ability of
rest and stress transesophageal echocardiography to predict functional
outcome after successful revascularization in myocardial segments is
summarized in the two tables below:

  ------------------------- --------------- -------------- ---------------
  **Table 6. Number of                                     
  Asynergic Myocardial                                     
  Segments with Improved                                   
  Segmental Wall Motion                                    
  after Revascularization:                                 
  Relation to Dobutamine                                   
  Transesophageal                                          
  Echocardiography.**                                      

                            **Improved                     
                            Segmental Wall                 
                            Motion**                       

  **Dobutamine-induced Wall **Present**     **Absent**     **Total**
  Thickening**                                             

  **Present**               **161**         **43**         **204**

  **Absent**                **19**          **148**        **167**

  **Total**                 **180**         **191**        **371**
  ------------------------- --------------- -------------- ---------------

+-----------------------+----------------------+----------------------+
| **Table 7.            |                      |                      |
| Performance of        |                      |                      |
| Dobutamine            |                      |                      |
| Transesophageal       |                      |                      |
| Echocardiography When |                      |                      |
| Used to Predict       |                      |                      |
| Improved Wall Motion  |                      |                      |
| in Asynergic          |                      |                      |
| Myocardial Segments** |                      |                      |
+-----------------------+----------------------+----------------------+
| **Performance         | **Value**            | **95% CI**           |
| Measure**             |                      |                      |
|                       | **(no. of            |                      |
|                       | segments)**          |                      |
+-----------------------+----------------------+----------------------+
| **Sensitivity (%)**   | **89 (161/180)**     | **(85, 94)**         |
+-----------------------+----------------------+----------------------+
| **Specificity (%)**   | **77 (148/191)**     | **(72, 83)**         |
+-----------------------+----------------------+----------------------+
| **PPV (%)**           | **79 (161/204)**     | **(73, 84)**         |
+-----------------------+----------------------+----------------------+
| **NPV (%)**           | **89 (148/167)**     | **(84, 93)**         |
+-----------------------+----------------------+----------------------+
| **Accuracy (%)**      | **83 (309/371)**     | **(80, 87)**         |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **3.9**              |                      |
| (+)**                 |                      |                      |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **0.14**             |                      |
| (‑)**                 |                      |                      |
+-----------------------+----------------------+----------------------+

[Dobutamine, by-patient analysis]{.underline}: The ability of rest and
stress transesophageal echocardiography to predict functional outcome on
a by-patient basis after successful revascularization is summarized in
the two tables below:

  ------------------------- --------------- -------------- ---------------
  **Table 8. Number of                                     
  Patients with Improved                                   
  Regional Wall Motion                                     
  after Revascularization:                                 
  Relation to Dobutamine                                   
  Transesophageal                                          
  Echocardiography.**                                      

                            **Improved                     
                            Regional Wall                  
                            Motion**                       

  **Dobutamine-Induced Wall **Present**     **Absent**     **Total**
  Thickening**                                             

  **Present**               **24**          **2**          **26**

  **Absent**                **2**           **14**         **16**

  **Total**                 **26**          **16**         **42**
  ------------------------- --------------- -------------- ---------------

+-----------------------+----------------------+----------------------+
| **Table 9.            |                      |                      |
| Performance of        |                      |                      |
| Dobutamine            |                      |                      |
| Transesophageal       |                      |                      |
| Echocardiography When |                      |                      |
| Used to Predict       |                      |                      |
| Improvement in        |                      |                      |
| Regional Wall Motion  |                      |                      |
| (By-Patient           |                      |                      |
| Analysis)**           |                      |                      |
+-----------------------+----------------------+----------------------+
| **Performance         | **Value**            | **95% CI**           |
| Measure**             |                      |                      |
|                       | **(no. of            |                      |
|                       | patients)**          |                      |
+-----------------------+----------------------+----------------------+
| **Sensitivity (%)**   | **92 (24/26)**       | **(75, 99)**         |
+-----------------------+----------------------+----------------------+
| **Specificity (%)**   | **88 (14/16)**       | **(62, 98)**         |
+-----------------------+----------------------+----------------------+
| **PPV (%)**           | **92 (24/26)**       | **(75, 99)**         |
+-----------------------+----------------------+----------------------+
| **NPV (%)**           | **88 (14/16)**       | **(62, 98)**         |
+-----------------------+----------------------+----------------------+
| **Accuracy (%)**      | **90 (38/42)**       | **(77, 97)**         |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **7.7**              |                      |
| (+)**                 |                      |                      |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **0.09**             |                      |
| (‑)**                 |                      |                      |
+-----------------------+----------------------+----------------------+

[Safety]{.underline}: No serious side effects or complications occurred
during the low-dose dobutamine infusions. The safety of positron
emission tomography with F‑18 FDG was not addressed in the manuscript.

[Conclusions in manuscript]{.underline}: Both dobutamine transesophageal
echocardiography and F-18 FDG positron emission tomography were highly
sensitive in predicting functional recovery of chronically akinetic or
dyskinetic myocardium after successful revascularization. Dobutamine
transesophageal echocardiography is a clinically valuable alternative to
F‑18 FDG positron emission tomography for assessing residual viability
and predicting functional recovery after revascularization.

[Reviewer\'s comments]{.underline}: This study had several strengths.
Although none of the principal studies had more than fifty patients
included in the analysis, this study was one of three with more than
forty patients analyzed (n=42). Consecutive patients were prospectively
studied, limiting potential selection bias during patient enrollment.
The analysis of wall motion, the primary functional outcome of interest,
was performed by two readers who did not know the results of the F‑18
FDG PET scans. This was one of the few principal studies that performed
a \"by-patient\" analysis of the results. The study compared different
diagnostic modalities, and the predictive performance of both F‑18 FDG
PET and dobutamine echocardiography were evaluated with respect to the
functional outcome (\"truth\"). Such direct head-to-head comparisons of
diagnostic test performance provide information that is very useful
clinically. That is, such comparisons provide health care providers
facing choices among diagnostic tests with data upon which to base their
selections. The study is also notable in that it had a good accounting
of patients and segments, most of whom/which were included in the
analyses. This allows for assessments of diagnostic performance that are
closer to what might be experienced in actual use. This study was also
notable in that the success of coronary revascularization was assessed
with a rigorous technique (coronary arteriography).

The study had several limitations. Perfusion was not assessed, and so
the diagnostic performance of perfusion-metabolism match/mismatch could
not be evaluated. The manuscript did not specify whether the PET scans
were analyzed blindly nor did it specify the number of readers for these
evaluations. However, the PET image analysis was quantitative, which
likely decreases substantially the extent of potential bias that could
enter into such an unblinded analysis. The definition of wall motion
improvement was based only on systolic wall thickening, and not on wall
motion. Optimally, it should have been based on both. No assessments of
global improvements in ventricular function or in clinical outcomes were
included in the study. The evaluations of wall motion improvement after
revascularization (\"truth\") were made with echocardiography, which was
also one of the test modalities. In general, this is undesirable because
findings with a modality under one setting are somewhat likely to
correlate with findings with the same modality under a different
setting.

**2. Gerber BL, Vanoverschelde JJ, Bol A, et al. Myocardial Blood Flow,
Glucose Uptake, and Recruitment of Inotropic Reserve in Chronic Left
Ventricular Ischemic Dysfunction: Implications for the Pathophysiology
of Chronic Myocardial Hibernation. Circulation 1996;94:651‑659.**

**Description of Study:**

[Objectives]{.underline}: The objectives of this study were a) to
delineate the flow and metabolic correlates of the reversibility of left
ventricular ischemic dysfunction in patients with chronic coronary
artery disease and b) to test the hypothesis that, even in unselected
patients with chronic reversible dysfunction, regional contraction is
disproportionately reduced compared with resting perfusion.

[Design and sequence of events]{.underline}: This was a study
consecutive patients with chronic coronary artery disease and left
ventricular dysfunction undergoing coronary revascularization. The study
was designed to assess whether \"match\" or \"mismatch\" patterns on
positron emission tomography with N‑13 ammonia and F‑18 FDG can predict
wall-motion recovery of the region of the left ventricle supplied by the
left anterior descending coronary artery, where disease of the left
anterior descending coronary artery was identified angiographically.

At baseline, subjects underwent selective coronary arteriography and
left ventriculography to evaluate coronary artery disease and left
ventricular function. Positron emission tomography studies were
performed with N‑13 ammonia and F‑18 FDG to evaluate myocardial
perfusion and metabolism. Control positron emission data were obtained
from six healthy volunteers. Left ventricular function was evaluated by
two-dimensional echocardiography at rest and during low-dose dobutamine
infusion (5‑10 μg/kg/min). Postoperative angiographic follow-up to
assess the adequacy of revascularization by CABG or angioplasty was
requested prospectively in every patient, but could not be obtained in
all. Approximately five months after revascularization, two-dimensional
echocardiography (at rest) was repeated to assess changes in wall
motion. The manuscript did not specify the number of readers who
evaluated the two-dimensional echocardiography or PET images, or whether
these readers were blinded.

[Subjects]{.underline}: Patients with chronic coronary artery disease
and left ventricular dysfunction who were undergoing coronary
revascularization were considered for the study. Patients were
considered eligible for inclusion in the study if they had a) severe
dysfunction in the anterior wall at contrast cineventriculography, b)
proximal disease of the left anterior descending coronary artery
suitable for CABG or PTCA, c) revascularization of all dysfunctional
segments, d) absence of perioperative or periprocedural myocardial
infarction, and (e) adequate transthoracic echocardiograms to assess
wall motion in every segment of the left ventricle.

[F‑18 FDG and N‑13 ammonia positron emission tomographic studies and PET
image analysis]{.underline}: Volunteer subjects were used as controls to
measure absolute myocardial blood flow and glucose uptake. All patients
and volunteers were studied during application of the hyperinsulinemic
euglycemic glucose clamp technique. Glucose plasma levels were
maintained between 75 and 95 mg/dl throughout the study.

N‑13 ammonia (dose not specified) and F‑18 FDG (dose not specified) were
injected intravenously over 30 seconds with an infusion pump. One
dynamic midventricular transaxial study per patient was analyzed for
dynamic imaging. Three large irregular volumes of interest were assigned
to each image of the left ventricular myocardium, and a circular volume
of interest was assigned to the center of the left ventricular blood
pool. One of the volumes of interest encompassed the interventricular
septum, another the anterior wall (the primary region of interest for
this study), and the remaining the lateral free wall of the left
ventricle. The lateral free wall was considered to be the remote normal
segment if no dysfunction was present on two-dimensional
echocardiograms. Counts were corrected for spatial-volume spillover
effects by use of a specially developed Monte Carlo simulation, as well
as for dead-time losses. The volumes of interest drawn on the F‑18 FDG
study were copied onto the N‑13 ammonia study. Identical placement of
the volumes of interest on all dynamic studies was ascertained, and
manual correction for patient movement was done if necessary.

N‑13 ammonia and F‑18 FDG localization: N‑13 ammonia and F‑18 FDG
cross-sectional images were analyzed with an operator-interactive
computer program using circumferential profiles. The program normalized
F‑18 and N‑13 counts within a given myocardial cross section to maximal
activity in the same ventricular slice. Each cross section of the left
ventricle was divided into serial 10^o^ segments. Activity within each
segment was expressed in relative terms (reported as F‑18 and N‑13
accumulation) as percentage of maximal activity.

Flow-metabolism match and mismatch: A pattern of flow-metabolism
\"match\" was considered to present when there was a concordant
reduction (\<70%) of F‑18 FDG and N‑13 ammonia activity in a given
myocardial segment. A pattern of flow-metabolism \"mismatch\" was
considered to be present in segments when the relative N‑13 ammonia
accumulation was lower than the minimal range of the normal volunteers
(i.e., \<70%) and when the ratio of F‑18 FDG to N‑13 ammonia activity
was 1.2 or greater. For this analysis, both F‑18 FDG and N‑13 ammonia
activity were normalized to peak N‑13 ammonia activity.

Tomographic data were quantified regional myocardial perfusion was
quantified by use of a previously validated three-compartment model.
Glucose uptake, normalized glucose uptake, glucose extraction, and
normalized glucose extraction were calculated.

[Wall motion analysis]{.underline}: For purposes of assessing return of
contractile function, two-dimensional echocardiograms were obtained at
rest and approximately five months after revascularization. Regional
function was interpreted in 16 myocardial segments (basal,
midventricular, and apical levels of the septum and lateral, anterior,
and inferior walls; and basal and midventricular levels of the
anteroseptal and posterior walls) and was graded on a 3‑point ordinal
scale as normal (1), hypokinetic (2), or akinetic (3). Normal wall
motion was defined as ≥5 mm of endocardial excursion and obvious
systolic wall thickening. Hypokinesis was defined as \<5 mm of
endocardial excursion and reduced wall thickening. Akinesis was defined
as near absence of endocardial excursion or thickening. A wall motion
score for the segments supplied by the left anterior descending coronary
artery was calculated by summing up the scores of the midanterior,
lateroapical, and anteroapical segments.

Dysfunctional myocardium at baseline was considered to have improved
functionally after revascularization if wall motion decreased by one
full grade in any of the three segments assigned to the left anterior
descending coronary artery after revascularization or to remain
persistently dysfunctional if no change was noted.

[Statistics]{.underline}: Groups were compared for categorical data by
Fisher\'s exact test or the χ^2^ test, when the minimum expected cell
size was \>5. A Mann-Whitney rank-sum test was used to assess
differences in continuous variables between patients with and without
improved wall motion. One-way ANOVA was used to compare anterior
segments that improved wall motion with those that did not, with remote
segments, and with segments from normal volunteers. Post hoc comparisons
were made by Scheffés test. All tests were two-sided.

**Results:**

[Patient disposition and characteristics]{.underline}: Thirty-nine
consecutive patients were enrolled, and data from all 39 were included
in the analysis. Six healthy volunteers served as control subjects for
measurement of absolute myocardial blood flow and glucose uptake.

The 39 patients included 34 men and 5 women and had a mean age of 60±9
years (range 39-75 years). The patients had a mean ejection fraction of
33±10% and a mean wall motion score of 8.1±0.9. Twenty three patients
had sustained a previous anterior Q-wave myocardial infarction, the most
recent occurring 13 days before inclusion in the study. Thirty-two of
the 39 patients were in NYHA class III and IV, and the remaining seven
were in NYHA class I or II. Thirty-three of the 39 patients had two- or
three-vessel coronary artery disease, and the remaining six had
one-vessel disease. Seven patients had type II diabetes mellitus, of
which six were treated with sulfonylurea and one with insulin. Thirty
one patients underwent CABG, and eight underwent PTCA. All of the six
volunteers were men and were nonsmokers. The volunteers had a mean age
of 24±3 years, with a range of 21 to 28 years.

[Segment disposition and functional outcome]{.underline}: For PET
analysis, regions of the left ventricle that encompassed the anterior
wall for each of the 39 patients were included in the analysis. At a
mean of 5.0±1.9 months after revascularization, the anterior wall motion
score improved in 24 patients (from grade 8.0±1.0 to 5.7±1.6) and did
not change in the other 15 patients (from grade 8.3±0.7 to 8.4±0.6). A
pattern of flow-metabolism mismatch was present in 18 of 24
dysfunctional regions that improved functionally after revascularization
(sensitivity=75%) but was absent in 10 of 15 regions that remained
dysfunctional revascularization (specificity=67%). These results are
summarized in the two tables below.

  ------------------------- --------------- -------------- ---------------
  **Table 10. Number of                                    
  Asynergic Anterior-Wall                                  
  Myocardial Regions with                                  
  Improved Segmental Wall                                  
  Motion after                                             
  Revascularization:                                       
  Relation to PET Patterns                                 
  with F‑18 FDG and                                        
  N‑13 ammonia**                                           

                            **Improved                     
                            Regional Wall                  
                            Motion**                       

  **PET Pattern**           **Present**     **Absent**     **Total**

  **Mismatch**              **18**          **5**          **23**

  **Match**                 **6**           **10**         **16**

  **Total**                 **24**          **15**         **39**
  ------------------------- --------------- -------------- ---------------

+-----------------------+----------------------+----------------------+
| **Table 11.           |                      |                      |
| Performance of PET    |                      |                      |
| When Used to Predict  |                      |                      |
| Improved Wall Motion  |                      |                      |
| in Asynergic          |                      |                      |
| Anterior-Wall         |                      |                      |
| Myocardial Segments** |                      |                      |
+-----------------------+----------------------+----------------------+
| **Performance         | **Value**            | **95% CI**           |
| Measure**             |                      |                      |
|                       | **(no. of            |                      |
|                       | segments)**          |                      |
+-----------------------+----------------------+----------------------+
| **Sensitivity (%)**   | **75 (18/24)**       | **(53, 90)**         |
+-----------------------+----------------------+----------------------+
| **Specificity (%)**   | **67 (10/15)**       | **(38, 88)**         |
+-----------------------+----------------------+----------------------+
| **PPV (%)**           | **78 (18/23)**       | **(56 92)**          |
+-----------------------+----------------------+----------------------+
| **NPV (%)**           | **62.5 (10/16)**     | **(35, 85)**         |
+-----------------------+----------------------+----------------------+
| **Accuracy (%)**      | **72 (28/39)**       | **(55, 85)**         |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **2.3**              |                      |
| (+)**                 |                      |                      |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **0.37**             |                      |
| (‑)**                 |                      |                      |
+-----------------------+----------------------+----------------------+

Before revascularization and as assessed by PET with N‑13 ammonia,
absolute myocardial blood flow in anterior regions was higher in
reversibly compared with compared with persistently dysfunctional
segments (84±27 versus 60±26 ml/min/100 g, p=0.007). In segments with
reversible dysfunction, values of myocardial blood flow were similar to
those in the remote segments of the same patients (82±22 ml/min/100 g)
or in anterior segments of normal volunteers (88±22 ml/min/100 g). Only
4 of 24 dysfunctional segments that improved after revascularization had
baseline levels of absolute myocardial blood flow below the lowest value
of the normal volunteers, i.e., 60 ml/min/100 g).

During glucose clamp F‑18 FDG uptake was higher (69±17% versus 49±18%, p
\<0.01) but myocardial glucose uptake was not different (38±20 versus
29±19 μmol/min/100 g, p=NS) in reversibly compared with persistently
dysfunctional anterior segments. During glucose clamp, estimates of
myocardial glucose uptake in remote segments reached values similar to
those found in normal volunteers (47±17 versus 53±11 μmol/min/100 g,
p=NS).

[Other Findings]{.underline}: With dobutamine, wall motion improved in
17 of 24 reversibly dysfunctional segments and did not change in 13 of
15 segments with persistent dysfunction. Thus, the performance of
dobutamine as a predictor of functional recovery of the anterior wall
may be summarized with the following performance measures:
sensitivity=71% (17 of 24 regions), specificity=87% (13 of 15 regions),
PPV=89% (17 of 19 regions), NPV=65% (13 of 20 regions), accuracy=77% (30
of 39 regions), likelihood ratio(+)=5.3; likelihood ratio(‑)=0.34.

[Safety]{.underline}: The safety of positron emission tomography with
F‑18 FDG and N‑13 ammonia was not addressed in the manuscript. However,
hemodynamic consequences of infusion of dobutamine were summarized.

[Conclusions in manuscript]{.underline}: The study indicates that
chronic but reversible ischemic dysfunction is associated with almost
normal resting myocardial perfusion, with maintained FDG uptake, and
with recruitable inotropic reserve. These data support the contention
that chronic hibernation is not the consequence of a permanent reduction
of transmural myocardial perfusion at rest.

[Reviewer\'s comments]{.underline}: The study had several strengths.
Consecutive patients were prospectively enrolled, limiting possible
selection bias during patient enrollment. Data were included from all 39
patients. Such inclusion of all patients in the study and in the
analysis decreases the likelihood that potential biases might have been
introduced by selective exclusion of patients from the study or the
analysis. Moreover, as a consequence of only focusing on one region of
the heart (i.e., the anterior wall) per patient, the segmental analysis
is identical to the by-patient analysis. Such by-patient analyses
facilitate assessments of clinical benefit as compared to risk. The
study compared different diagnostic modalities, and the predictive
performance of both F‑18 FDG PET and dobutamine echocardiography were
evaluated with respect to the functional outcome (\"truth\"). Such
direct head-to-head comparisons of diagnostic test performance provide
information that is very useful clinically. For the evaluation of
absolute levels of regional glucose uptake and of absolute levels of
myocardial blood flow, the study utilized external controls (from
healthy subjects). Wall-motion assessments included evaluation of not
only the excursion of the wall, but also of systolic wall thickening,
increasing the specificity of these assessments.

The study also had several limitations. Doses of F‑18 FDG and N‑13
ammonia were not specified in the manuscript. The manuscript did not
specify the number of readers who evaluated the two-dimensional
echocardiograms or PET images, or whether these readers were blinded.
However, because both of these readings were quantitative (particularly
the analyses of the PET images with F‑18 FDG and N‑13 ammonia), possible
biases from unblinded readings were mitigated. The study focused only on
functional recovery of the anterior wall of the left ventricle, the
region supplied by the left anterior descending coronary artery, and
performance of PET F‑18 FDG may not be similar for other ventricular
regions. The adequacy of revascularization was not assessed in several
patients. No assessments of global improvements in ventricular function
or in clinical outcomes were included in the study.

**3. Gropler RJ, Geltman EM, Sampathkumaran K, et al. Comparison of
Carbon-11-Acetate with Fluorine-18-Fluorodeoxyglucose for Delineating
Viable Myocardium by Positron Emission Tomography. J Am Coll Cardiol
1993;22:1587‑97.**

**Description of Study:**

[Objective]{.underline}: The objective of this study was to determine in
patients with advanced coronary disease whether prediction of recovery
of mechanical function after coronary revascularization (as assessed by
two-dimensional echocardiography, radionuclide ventriculography, or
contrast ventriculography) could be accomplished more effectively by PET
with carbon-11 acetate than by PET with F‑18 FDG.

[Design and sequence of events]{.underline}: This study enrolled
patients with left ventricular wall motion abnormalities and
angiographically documented coronary artery disease. At baseline,
patients underwent cardiac catheterization and selective coronary
angiography to document coronary artery disease and left ventricular
dysfunction. Baseline assessments of regional left ventricular wall
motion were performed by 2‑D echocardiography, contrast
ventriculography, and radionuclide ventriculography. Positron emission
tomography was performed with C‑11 acetate to assess myocardial
oxidative metabolism and regional myocardial perfusion (in relative
terms), and with F‑18 FDG to assess metabolism of glucose.

After revascularization by either CABG or angioplasty, the adequacy of
the revascularization was verified by review of the operative reports
documenting the successful placement of bypass grafts and, in the case
of coronary angioplasty, by angiographic documentation of successful
balloon dilitation. After revascularization, patients had repeat
assessments of regional left ventricular wall motion (by 2‑D
echocardiography, contrast ventriculography, and radionuclide
ventriculography). Wall-motion assessments were made by two observers
blinded to both PET and clinical data. The PET scans with F‑18 FDG and
C‑11 acetate were evaluated quantitatively. The manuscript did not
specify whether these PET scans were read blindly, without knowledge of
the results from the post-operative assessments of wall motion, nor did
it specify the number of readers for these evaluations.

[Subjects]{.underline}: The study enrolled patients with left
ventricular wall motion abnormalities secondary to angiographically
documented coronary artery disease. Patients with diabetes mellitus were
excluded. Healthy volunteers were evaluated to develop tomographic
criteria of tissue viability and of nonviability (i.e., values for
oxidative metabolism and utilization of glucose in patients were
referenced to mean values obtained in these control subjects).

[F‑18 FDG and C‑11 acetate positron emission tomographic studies and
image analysis]{.underline}: All subjects were studied in the
postprandial state after the consumption of a high carbohydrate meal 2
to 3 hours before and 75 grams of glucose 1 to 2 hours before the
administration of F‑18 FDG . An initial transmission scan was performed
to correct subsequent emission scans for attenuation. C‑11 acetate (0.25
to 0.40 mCi/kg) was then administered intravenously, followed by an
1,800-s list mode data collection performed 45 min later. To ensure that
each patient was positioned consistently within the PET system for all
data collections, position was checked with the use of a low energy
laser and indelible marks placed on the torso.

Regional myocardial perfusion in relative terms was based on the early
myocardial uptake of C‑11 acetate (i.e., regional distribution of
activity within the myocardium from 60 to 180 sec after the
administration of C‑11 acetate). Myocardial oxidative metabolism was
quantified by determining the myocardial turnover rate constant of
acetate (k~1~). Regional myocardial utilization of glucose was assessed
on the basis of composite images of relative F‑18 FDG activity.

Myocardial images were reformatted from the transaxial orientation to
true short-axis views, with the heart divided into 8 to 12 tomographic
slices on which circumferential profiles of C-11 acetate, k1, and F‑18
FDG were generated for each. The left ventricular myocardium was
segmented into eight segments as for studies of wall motion.

Average values for myocardial uptake of C-11 acetate, k1, and F‑18 FDG
were calculated for each segment. Carbon-11 acetate myocardial
localization and F‑18 FDG activity were normalized to peak myocardial
activity for C-11 acetate and F-18 FDG, respectively, to yield relative
values for myocardial blood flow and utilization of glucose. In
addition, myocardial utilization of glucose was normalized to blood flow
within each segment by dividing normalized F‑18 FDG activity by dividing
normalized myocardial localization of C-11 acetate for the same segment.

*Threshold Criteria for viability*: Tomographic criteria of tissue
viability and of nonviability were developed by referencing values for
oxidative metabolism and utilization of glucose to mean values obtained
in control subjects for each of the eight segments. *Definition of
viability using C‑11 acetate (oxidative metabolism)*: dysfunctional but
viable myocardium was considered present when values for k~1~ were
within 2 SD of the mean value for a particular segment in the control
group. Conversely, non-viable myocardium was considered present when
values for k~1~ were lower than the mean value minus 2 SD in the control
group. *Definition of viability using F‑18 FDG (glucose utilization)*:
dysfunctional but viable myocardium was defined by values for myocardial
utilization of glucose within 2 SD of the mean value in the control
group. Values for myocardial utilization of glucose normalized to flow
that were \>2 SD above the mean value in the control group were defined
as indicative of dysfunctional but still viable myocardium. Conversely,
reductions in myocardial utilization of glucose (\>2SD below the mean
value in the control group) that were not associated with increased
utilization of glucose normalized to flow were defined as indicative of
nonviable myocardium. *Resected segments:* Segments that were resected
(e.g., during left ventricular aneurysmectomy) were classified as
nonviable.

[Wall motion evaluation and image analysis]{.underline}: To quantify
regional systolic function, the left ventricular myocardium was
segmented into eight regions. With all three modalities
(echocardiography, radionuclide ventriculography, and contrast left
ventriculography), regional systolic function was graded as follows:
1=normal, 2=hypokinetic, 3=akinetic, 4=dyskinetic, and 5=aneurysmal.
Wall motion analyses were performed by two observers blinded to both PET
and clinical data. The average wall motion score reflecting values
assigned by both observers was tabulated for each segment in each study.

As assessed by these blinded observers, improvement in wall function in
initially dysfunctional segments (i.e., segments that were hypokinetic,
akinetic, dyskinetic or aneurysmal before revascularization) as assessed
by echocardiography or radionuclide ventriculography was defined as an
improvement in wall motion score of at least one full grade after
revascularization.

[Statistics]{.underline}: Comparisons of paired frequency data were
performed with a continuity-corrected McNemar test. Receiver operating
characteristic curves were compared with the methods of Hanley and
McNeil.

**Results:**

[Patient disposition and characteristics]{.underline}: Data were
obtained from 34 patients, and from 10 control patients. The 34 patients
included 26 men and 8 women, and had a mean age of 60 years (range 30 to
77 years). Twenty-one patients had sustained at least one myocardial
infarction from 11 days to 10 years before enrollment in the study. In
17 patients, the myocardial infarction had occurred ≥1 month before
enrollment. Eight patients had angiographically defined lesions in a
single vessel, 8 had lesions in two vessels, and 18 had lesions in three
vessels. In 24 patients, CABG was performed, and 10 underwent PTCA.

The ten control subjects included 9 men and 1 woman, and had a mean age
of 24±3 years. These subjects had no history and a low likelihood for
coronary artery disease.

[Segment disposition and functional outcome]{.underline}: The left
ventricle in each of the 34 patients was divided into eight segments,
yielding a total of 272 segments for possible analysis. Of these 272
possible segments, 131 had normal wall motion and 141 were
dysfunctional. Of the 141 dysfunctional segments, 25 segments were
excluded, leaving 116 dysfunctional segments for analysis. Of these
dysfunctional segments, 46 had reversible wall motion abnormalities and
70 did not. The patients had repeated assessments of regional left
ventricular wall motion (by 2‑D echocardiography, contrast
ventriculography, or radionuclide ventriculography) at a mean of 2.0
months (range, 0.5‑7 months) after revascularization.

Using the threshold criteria described above, positron emission
tomography with F‑18 FDG normalized to flow correctly predicted wall
motion improvement in 38 of 46 reversibly dysfunctional segments
(sensitivity=83%) and correctly predicted that wall motion would not
improve in 35 of 70 segments with persistent dysfunction
(specificity=50%). These results are summarized in the tables below.

  ------------------------- --------------- -------------- ---------------
  **Table 12. Number of                                    
  Asynergic Myocardial                                     
  Segments with Improved                                   
  Segmental Wall Motion                                    
  after Revascularization:                                 
  Relation to F‑18 FDG                                     
  Uptake, Normalized to                                    
  Flow**                                                   

                            **Improved                     
                            Segmental Wall                 
                            Motion**                       

  **F‑18 FDG Uptake,        **Present**     **Absent**     **Total**
  Normalized to Flow**                                     

  **Viable**                **38**          **35**         **73**

  **Nonviable**             **8**           **35**         **43**

  **Total**                 **46**          **70**         **116**
  ------------------------- --------------- -------------- ---------------

+-----------------------+----------------------+----------------------+
| **Table 13.           |                      |                      |
| Performance of PET    |                      |                      |
| F‑18 FDG Uptake,      |                      |                      |
| Normalized to Flow,   |                      |                      |
| When Used to Predict  |                      |                      |
| Improved Wall Motion  |                      |                      |
| in Asynergic          |                      |                      |
| Myocardial Segments** |                      |                      |
+-----------------------+----------------------+----------------------+
| **Performance         | **Value**            | **95% CI**           |
| Measure**             |                      |                      |
|                       | **(no. of            |                      |
|                       | segments)**          |                      |
+-----------------------+----------------------+----------------------+
| **Sensitivity (%)**   | **83 (38/46)**       | **(68, 92)**         |
+-----------------------+----------------------+----------------------+
| **Specificity (%)**   | **50 (35/70)**       | **(38, 62)**         |
+-----------------------+----------------------+----------------------+
| **PPV (%)**           | **52 (38/73)**       | **(40, 64)**         |
+-----------------------+----------------------+----------------------+
| **NPV (%)**           | **81 (35/43)**       | **(67, 92)**         |
+-----------------------+----------------------+----------------------+
| **Accuracy (%)**      | **63 (73/116)**      | **(54, 72)**         |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **1.7**              |                      |
| (+)**                 |                      |                      |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **0.35**             |                      |
| (‑)**                 |                      |                      |
+-----------------------+----------------------+----------------------+

[Other results]{.underline}: When the threshold criteria for viability
described above were applied, positron emission tomography with C‑11
acetate correctly predicted wall-motion improvements in 40 of 46
reversibly dysfunctional segments and correctly predicted that wall
motion would not improve in 50 of 70 segments with persistent
dysfunction. Thus, the performance of positron emission tomography with
C‑11 acetate as a predictor of wall-motion recovery may be summarized
with the following performance measures: sensitivity=87% (40 of 46
segments), specificity=71% (50 of 70 segments), PPV=67% (40 of 60
segments), NPV=89% (50 of 56 segments), accuracy=78% (90 of 116
segments), likelihood ratio(+)=3.0; likelihood ratio(‑)=0.18.

Analysis of receiver operating characteristic curves indicated that
estimates of oxidative metabolism (with C‑11 acetate) were more robust
in predicting functional recovery than were estimates of glucose
metabolism (p\<0.02). Moreover, threshold criteria with C‑11 acetate
exhibited superior positive and negative predictive values (67% and 89%,
respectively), than did the criteria with F‑18 FDG (52% and 81%,
respectively), p\<0.01. In segments with initially severe dysfunction,
estimates of oxidative metabolism with C‑11 acetate tended to be more
robust than estimates of glucose metabolism in predicting functional
recovery. Moreover, in such segments, the threshold criteria with C‑11
acetate tended to exhibit superior positive and negative predictive
values (85% and 87%, respectively) than did the criteria with F‑18 FDG
(72% and 82%, respectively), although statistical significance was not
achieved.

[Safety]{.underline}: The safety of positron emission tomography with
F‑18 FDG or with C‑11 acetate were not addressed in the manuscript.

[Conclusions in manuscript]{.underline}: In patients with advanced
coronary artery disease, the extent to which functional recovery can be
anticipated after coronary revascularization can be delineated
accurately by quantification of regional oxidative metabolism by PET
with C‑11 acetate. The analysis of wall motion, the primary functional
outcome of interest, was performed by two readers who did not know the
results of the F‑18 FDG PET scans. The blinding of these readers
increases the validity of the estimates of F‑18 FDG performance.
Moreover, the use of multiple readers allows for potential assessment of
interreader variability and decreases the likelihood that the results
reflect the idiosyncracies of any particular reader (i.e., the results
are more likely to be generalizable to other similar readers).

[Reviewer\'s comments]{.underline}: The study had several strengths. The
wall-motion analysis, the primary functional outcome of interest, was
performed by two readers who did not know the results of the PET scans
or the clinical data. The blinding of these readers and the use of
multiple readers are highly desirable characteristics. Such
characteristics minimize potential bias and make possible assessments of
interreader variability and increase the generalizability of the
readings. The alignment of the different imaging modalities was well
discussed, increasing the likelihood that the observed segmental results
are valid. The authors performed ROC analysis, making full use of the
generated data and allowing the performance characteristics of the
tested methodologies to be assessed as different thresholds. That is,
the performance of these two drugs was compared over the full spectrum
of possible sensitivities and specificities by using different threshold
criteria for each (as is inherent in such an ROC analysis). The study
compared different diagnostic modalities, and the predictive performance
of both F‑18 FDG PET and C‑11 acetate PET were evaluated with respect to
the functional outcome (\"truth\"). Such direct comparisons of
diagnostic test performance provide useful information. The study used
healthy volunteers to establish normal values for oxidative metabolism
(as assessed by C‑11 acetate) and for glucose metabolism (as assessed by
F‑18 FDG).

The study had several limitations. The dose of F‑18 FDG was not
indicated. A relatively unconventional marker for perfusion was employed
(PET with C‑11 acetate). Moreover, C‑11 acetate was also one of the test
modalities, and this may confound the interpretation of the direct
comparison of F‑18 FDG with C‑11 acetate. That is, the method of
evaluating perfusion was independent of one of the test agents (F‑18
FDG) but not of the other (C‑11 acetate). The manuscript did not specify
the number of readers who evaluated the PET images, or whether these
readers were blinded. However, because the PET readings were
quantitative, potential bias from an unblinded interpretation was
minimized. Although the success of revascularization was documented as
part of the study, analyses were not provided for segments that were not
successfully revascularized (if any). Such analyses would have provided
useful data on the diagnostic performance as might be expected in actual
use as compared to under ideal circumstances. No assessments of global
improvements in ventricular function or in clinical outcomes were
included in the study.

**4. Knuuti MJ, Saraste M, Nuutila P, et al. Myocardial viability:
Fluorine-18-deoxyglucose positron emission tomography in prediction of
wall motion recovery after revascularization. Am Heart J 1994;
127:785‑96.**

**Description of Study:**

[Objectives]{.underline}: The objective of this study was to assess the
value of positron emission tomography imaging with F-18 FDG in
predicting cardiac wall motion recovery (as assessed by two-dimensional
echocardiography) after revascularization. The study also compared
prediction of functional recovery by evaluation of normalized F‑18 FDG
uptake and of F‑18 FDG uptake relative to perfusion.

[Design and sequence of events]{.underline}: This was a study of
consecutive patients with previous myocardial infarctions and wall
motion abnormalities at rest. At baseline, patients underwent selective
coronary angiography and angioventriculography to document coronary
artery disease and left ventricular dysfunction. Baseline assessments of
regional left ventricular wall motion and systolic thickening were
performed with 2‑D echocardiography. Positron emission tomography was
performed with F‑18 FDG to predict myocardial viability. Baseline
myocardial perfusion was evaluated by SPECT with thallium‑201 or
technetium-99m-methoxy-isobutyl-isonitrile (TC99m-MIBI).

After revascularization by either CABG or angioplasty, a myocardial
segment was considered to be revascularized if a corresponding major
epicardial coronary artery branch had undergone a successful procedure.
Myocardial scars were detected and localized visually during bypass
surgery. Assessments of segmental left ventricular wall motion and
systolic wall thickening after revascularization were made with 2‑D
echocardiography. These assessments were made 2 to 6 months after CABG
or 3 to 8 weeks after angioplasty.

The 2‑D echocardiograms were read blindly by an experienced physician.
SPECT perfusion scans were read blindly by two experienced nuclear
medicine specialists. Discordances were resolved by conjunct reanalysis.
Positron emission scans with F‑18 FDG were analyzed semi-quantitatively.
The manuscript did not specify whether the PET scans were read blindly,
without knowledge of the results from the post-operative assessments of
wall motion and systolic thickening, nor did it specify the number of
readers for these evaluations.

[Subjects]{.underline}: Patients were included if they had a prior
myocardial infarction that had been confirmed both by
electrocardiographic and enzymatic criteria, and if they had stable,
angiographically confirmed coronary artery disease. Patients with
diabetes were excluded.

[F‑18 FDG positron emission tomographic studies and image
analysis]{.underline}: All studies were performed after the patients had
fasted for 12 hours overnight. Patients took only nitrates, if needed,
for the last 24 hours before the PET study. The patients ingested 50 g
glucose 60 minutes before the intravenous injection of 260 ± 60 MBq (7.0
±1.5 mCi) of F‑18 FDG. Imaging was continued for 60 minutes.

The myocardium was divided into eight segments (anterobasal, anterior,
anteroseptal, lateral, inferoseptal, apical, inferior, and
posterobasal). The mean segmental count rate measured during 30 to 60
min after tracer injection was used for further calculations. Assuming
that glucose metabolism is normal in myocardial regions with
noncompromised blood flow, the uptake of F‑18 FDG was normalized
relative to the uptake of the segment with the highest tracer uptake
observed visually in resting SPECT perfusion imaging (typically an
anterior or lateral segment). In those five patients with no SPECT
imaging, the noninfarcted lateral or anterior segment supplied by a
normal or nonsignificantly stenosed coronary artery was used as a
reference.

To calculate the range of F‑18 FDG uptake in normal segments, the
segments that gave normal results by all non-PET methods were
identified. Recovery of contractility was predicted by normalized F‑18
FDG uptake by making the assumption that F‑18 FDG uptake above the lower
limit (mean-2SD) represented viable myocardium.

[Perfusion studies and image analysis]{.underline}: Patients were
administered 1 mCi of Tl‑201 or 20 mCi of Tc-99m‑MIBI one hour before
imaging in all but one patient, who was studied at rest 4 hours after
Tl‑201 stress imaging (4 hour washout). Tomographic images of the heart
were reconstructed in 10 mm thick transaxial slices and three
perpendicular planes. The tracer uptake in the eight anatomic segments
was assessed qualitatively and blindly by two experienced nuclear
medicine specialists. The results from resting images were scored
according to the following scale: (1) normal, (2) mild defect, (3)
moderate defect, and (4) severe or complete defect. Discordances were
resolved by conjunct reanalysis.

[Wall motion analysis]{.underline}: Wall motion analyses were performed
by 2-D-echocardiography. Standard long-and short-axis views were
obtained and videotaped. The echocardiograms were analyzed by a blinded,
experienced physician. These readings of the separate echocardiograms
were verified by a paired comparison of the echocardiograms that were
performed before revascularization with the echocardiograms that were
performed after revascularization.

Segmental left ventricular wall motion and systolic thickening were
visually scored according to the following scale: 1) normal, 2)
hypokinetic wall motion with systolic thickening, 3) akinetic wall
motion with no systolic thickening, and 4) dyskinetic motion with no
systolic thickening. Improvement of contractile function was diagnosed
if systolic thickening (corresponding to score 1 or 2) became apparent
in a segment that had been akinetic or dyskinetic, or if normal motion
was detected in a previously hypokinetic segment. Improvement in
function was acknowledged only if it was apparent in a central area of
the segment.

[Statistics]{.underline}: Independent variables were compared by
analysis of variance and Bonferoni testing when appropriate. To test
different F‑18 FDG uptake levels in predicting functional recovery, the
discriminant analysis of SAS statistical program was used.

**Results:**

[Patient disposition and characteristics]{.underline}: 48 patients were
enrolled and included in the analysis of positron emission tomography
with F‑18 FDG. Forty-three patients also underwent SPECT perfusion
imaging at rest (25 patients with thallium‑201 and 18 patients with
Tc-99m-MIBI).

The 48 patients included 46 men and 2 women and had a mean age of 54±7
years. The mean ejection fraction was 53±11% (n=38). The mean number of
abnormal segments at rest was 2.2±1.3 (out of eight segments per
patient). Thirty-four patients (71%) had a Q-wave myocardial infarction,
25 (52%) had an anterior wall myocardial infarction, and 23 (48%) had an
inferior or posterior wall myocardial infarction. Thirty-one patients
(65%) had three-vessel coronary artery disease, 10 (21%) had two-vessel
disease, and 7 (15%) had one-vessel disease. Considering angina, 3
patients (6%) were NYHA class I , 26 (54%) were NYHA class II, 15 (31%)
were NYHA class III, and the remaining 4 (8%) were NYHA class IV. For
revascularization, 37 (77%) of the patients underwent CABG, and 11 (23%)
underwent angioplasty.

[Segment disposition and functional outcome]{.underline}: The left
ventricle of each of the 48 patients was divided into 8 segments,
yielding a total of 384 possible segments: Of these, 264 had normal wall
motion, and 106 had abnormal wall motion. Fourteen segments were
excluded because of poor visualization. Of the 106 segments that had
abnormal wall motion at baseline, 90 were successfully revascularized,
and 16 were not. These 90 segments were used to evaluate the performance
of F‑18 FDG PET as a predictor of functional recovery. Of these 90
dysfunctional segments, 84 had SPECT perfusion results available. Of the
90 segments with abnormal wall motion at baseline that were successfully
revascularized, 27 recovered function and 63 did not.

To calculate the normal range of F‑18 FDG uptake, the segments that gave
normal results by all non-PET methods were identified. One hundred
fifty-eight of the 264 echocardiographically normal segments were also
normal by SPECT perfusion imaging and were associated with ≤75% stenosis
in the respective coronary artery.

[Imaging results]{.underline}: When F‑18 FDG uptake above the lower
limit of normal (mean - 2SD) was defined as viable myocardium, the
presence or absence of F‑18 FDG uptake by itself, without consideration
of perfusion of the segment, correctly predicted postinterventional wall
motion in 67 of the 90 asynergic segments (i.e., accuracy=74%). However,
only 27 (54%) of the 50 segments with preserved uptake were able to
recover functionally (i.e., PPV=54%). None of the 40 revascularized
segments with reduced (mean - 2SD) F‑18 FDG uptake recovered
(i.e., NPV=100%). These results are shown in the tables below.

The ability of F‑18 FDG uptake to distinguish between segments with and
without recovery was tested by discriminant analysis. When 85% to 90% of
normalized F‑18 FDG uptake by itself, without consideration of perfusion
to the segment, was used as a threshold value (i.e., an \"optimized\"
threshold, instead of the use of the lower limit of normal as a
threshold), a sensitivity of 85% and specificity of 84% to predict
functional recovery were reached simultaneously.

  ------------------------- --------------- -------------- ---------------
  **Table 14. Number of                                    
  Asynergic Myocardial                                     
  Segments with Improved                                   
  Segmental Wall Motion                                    
  after Revascularization:                                 
  Relation to Normal F‑18                                  
  FDG Uptake**                                             

                            **Improved                     
                            Segmental Wall                 
                            Motion**                       

  **Prediction by normal    **Present**     **Absent**     **Total**
  F-18 FDG Uptake\***                                      

  **Viable: uptake \> LLN** **27**          **23**         **50**

  **Nonviable: uptake       **0**           **40**         **40**
  \<LLN**                                                  

  **Total**                 **27**          **63**         **90**

  **\*Normal F‑18 FDG                                      
  uptake defined as F‑18                                   
  FDG uptake greater than                                  
  the lower limit of normal                                
  (LLN), where LLN = mean ‑                                
  2SD**                                                    
  ------------------------- --------------- -------------- ---------------

+-----------------------+----------------------+----------------------+
| **Table 15.           |                      |                      |
| Performance of PET    |                      |                      |
| F‑18 FDG Uptake When  |                      |                      |
| Normal\* Values are   |                      |                      |
| Used to Predict       |                      |                      |
| Improved Wall Motion  |                      |                      |
| in Asynergic          |                      |                      |
| Myocardial Segments** |                      |                      |
+-----------------------+----------------------+----------------------+
| **Performance         | **Value**            | **95% CI**           |
| Measure**             |                      |                      |
|                       | **(no. of            |                      |
|                       | segments)**          |                      |
+-----------------------+----------------------+----------------------+
| **Sensitivity (%)**   | **100 (27/27)**      | **(87, 100)**        |
+-----------------------+----------------------+----------------------+
| **Specificity (%)**   | **63 (40/63)**       | **(50, 75)**         |
+-----------------------+----------------------+----------------------+
| **PPV (%)**           | **54(27/50)**        | **(39, 68)**         |
+-----------------------+----------------------+----------------------+
| **NPV (%)**           | **100 (40/40)**      | **(91, 100)**        |
+-----------------------+----------------------+----------------------+
| **Accuracy (%)**      | **74 (67/90)**       | **(64, 83)**         |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **2.7**              |                      |
| (+)**                 |                      |                      |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **0.00**             |                      |
| (‑)**                 |                      |                      |
+-----------------------+----------------------+----------------------+
| **\*Normal F‑18 FDG   |                      |                      |
| uptake defined as     |                      |                      |
| F‑18 FDG uptake       |                      |                      |
| greater than the      |                      |                      |
| lower limit of normal |                      |                      |
| (LLN), where LLN =    |                      |                      |
| mean ‑ 2SD**          |                      |                      |
+-----------------------+----------------------+----------------------+

*F‑18 FDG uptake and functional recovery:* In the 158 normal segments,
the value of the lower limit (i.e., mean - 2SD) of normalized F‑18 FDG
uptake varied by segment location: anterobasilar 70%, anteroseptal 77%,
anterior 80%, lateral 90%, inferoseptal 72%, apical 61%, inferior 75%,
posterobasilar 79%. The overall value of the lower limit of normal of
F‑18 FDG uptake was 74%.

Recovery of function occurred only in segments with the highest F-18 FDG
uptake values. None of the 40 segments with reduced F‑18 FDG uptake
(i.e., uptake below the mean - 2SD) recovered. This pattern was
reflected in the mean uptake values for F‑18 FDG in different groups of
segments. Thus, the mean uptake of F‑18 FDG in the 158 normal segments
was 95%±11% (range 58% to 127%). Similarly, the mean uptake of F‑18 FDG
in the 27 asynergic segments with subsequent functional recovery was
110±22%. However, the mean uptake of F‑18 FDG in the 63 asynergic
segments without subsequent functional recovery was 65±24% (p\<0.05).

*Contribution of resting SPECT perfusion to predictions of viability
made with F‑18 FDG:* SPECT perfusion results were available in 84 of the
90 initially dysfunctional revascularized segments.

As shown in the table below, significantly higher mean F‑18 FDG uptake
values were detected in segments with functional recovery as compared to
the segments without recovery in the groups of moderate or severe
perfusion defects. In the segments with moderately or severely reduced
perfusion at rest, the positive and negative predictive values for
viability were 100%.

+---------------------+-----+---------+---+-----------------+--------+
| **Table 16:         |     |         |   |                 |        |
| Relationship of     |     |         |   |                 |        |
| Resting SPECT       |     |         |   |                 |        |
| Perfusion Defects,  |     |         |   |                 |        |
| Wall Motion         |     |         |   |                 |        |
| Recovery, and F‑18  |     |         |   |                 |        |
| FDG Uptake in 84    |     |         |   |                 |        |
| Revascularized      |     |         |   |                 |        |
| Segments with       |     |         |   |                 |        |
| Abnormal Wall       |     |         |   |                 |        |
| Motion\***          |     |         |   |                 |        |
+---------------------+-----+---------+---+-----------------+--------+
| **SPECT results**   | **T | **Rec   | * | **F‑18 FDG      | **p    |
|                     | ota | overy** | * | uptake**        | v      |
|                     | l** |         | N |                 | alue** |
|                     |     |         | o | **(Mean ± SD)** |        |
|                     | **N |         | * |                 |        |
|                     | o** |         | * |                 |        |
+---------------------+-----+---------+---+-----------------+--------+
| **Normal or mild    | **3 | **Yes** | * | **101±18**      | **     |
| defect\*\***        | 1** |         | * |                 | 0.09** |
|                     |     |         | 1 |                 |        |
|                     |     |         | 4 |                 |        |
|                     |     |         | * |                 |        |
|                     |     |         | * |                 |        |
+---------------------+-----+---------+---+-----------------+--------+
|                     |     | **No**  | * | **89±19**       |        |
|                     |     |         | * |                 |        |
|                     |     |         | 1 |                 |        |
|                     |     |         | 7 |                 |        |
|                     |     |         | * |                 |        |
|                     |     |         | * |                 |        |
+---------------------+-----+---------+---+-----------------+--------+
| **Moderate defect** | **1 | **Yes** | * | **128±28**      | **0    |
|                     | 7** |         | * |                 | .003** |
|                     |     |         | 6 |                 |        |
|                     |     |         | * |                 |        |
|                     |     |         | * |                 |        |
+---------------------+-----+---------+---+-----------------+--------+
|                     |     | **No**  | * | **69±12**       |        |
|                     |     |         | * |                 |        |
|                     |     |         | 1 |                 |        |
|                     |     |         | 1 |                 |        |
|                     |     |         | * |                 |        |
|                     |     |         | * |                 |        |
+---------------------+-----+---------+---+-----------------+--------+
| **Severe**          | **3 | **Yes** | * | **116±13**      | **0.   |
|                     | 6** |         | * |                 | 0006** |
|                     |     |         | 5 |                 |        |
|                     |     |         | * |                 |        |
|                     |     |         | * |                 |        |
+---------------------+-----+---------+---+-----------------+--------+
|                     |     | **No**  | * | **51±20**       |        |
|                     |     |         | * |                 |        |
|                     |     |         | 3 |                 |        |
|                     |     |         | 1 |                 |        |
|                     |     |         | * |                 |        |
|                     |     |         | * |                 |        |
+---------------------+-----+---------+---+-----------------+--------+
| **\* This table was |     |         |   |                 |        |
| taken from the      |     |         |   |                 |        |
| manuscript.**       |     |         |   |                 |        |
|                     |     |         |   |                 |        |
| **\*\*In five       |     |         |   |                 |        |
| segments, SPECT     |     |         |   |                 |        |
| perfusion at rest   |     |         |   |                 |        |
| was classified as   |     |         |   |                 |        |
| normal.**           |     |         |   |                 |        |
+---------------------+-----+---------+---+-----------------+--------+

[Other findings]{.underline}: In the 90 asynergic segments, the mean
F‑18 FDG uptake was lower depending on the severity of the ventricular
wall-motion abnormality. Thus, the 43 hypokinetic segments had a mean
F‑18 FDG uptake of 97±25%, the 38 akinetic segments had a mean uptake of
64±27%, and the 9 dyskinetic segments had a mean uptake of 52±24%.

A significant proportion of segments with preserved F‑18 FDG uptake was
found in each of the asynergic segment groups (i.e., hypokinetic,
akinetic, and dyskinetic segment groups). However, within each group
recovery occurred only in segments with the highest F‑18 FDG uptake
values.

[Safety]{.underline}: The safety of positron emission tomography with
F‑18 FDG was not addressed in the manuscript.

[Conclusions in manuscript]{.underline}: The results of this study show
that the presence of viable tissue indicated by preserved F‑18 FDG
uptake does not inevitably imply functional recovery after
revascularization. However, acceptable diagnostic accuracy for viability
might be reached by F‑18 FDG alone, providing that appropriate uptake
limits are use. The combined evaluation of F‑18 FDG uptake and perfusion
enables precise assessment of myocardial viability.

[Reviewer\'s comments]{.underline}: The strengths of the study include
the following items. Of the ten principal studies, this study had the
largest sample size of evaluated patients (n=48). The wall-motion
analysis, the primary functional outcome of interest, was performed
blindly. The analysis of SPECT perfusion was performed blindly by two
readers. Alignment of myocardial segments obtained by different methods
was described. The reproducibility of wall-motion analysis by the same
reader was assessed and documented. This is one of the only studies in
which F‑18 FDG localization in segments with normal wall motion was
assessed, or in which the various factors that are correlated with the
degree of F‑18 FDG localization were evaluated (e.g., severity of wall
motion dysfunction, diastolic wall thickness). The authors evaluated
different potential thresholds for F‑18 FDG localization, and therefore
provided a more complete picture of the performance of PET F‑18 FDG in
evaluating the reversibility of myocardial dysfunction in patients with
coronary artery disease and left ventricular dysfunction.

The study had several limitations. The manuscript is not specific about
to what information readers were blinded (i.e., the readers who
evaluated wall motion by echocardiograms and perfusion by SPECT). The
manuscript did not specify whether the PET F‑18 FDG images were
interpreted blindly or the number of readers. However, because the image
analysis was quantitative the possibility of introducing bias was
decreased. The wall motion analysis was performed by a single reader. An
analysis by patient was not performed.

**5. Lucignani G, Paolini G, Landoni C, et al. Presurgical
identification of hibernating myocardium by combined use of
technetium‑99m hexakis 2‑mehoxyisobutylisonitrile single photon emission
tomography and fluorine‑18 fluoro‑2‑deoxy‑D‑glucose positron emission
tomography in patients with coronary artery disease. Eur J Nucl Med
1992;19:874‑881**.

**Description of study:**

[Objective]{.underline}: The objective of this study was to identify
areas of hibernating myocardium by the combined assessment of perfusion,
using single photon emission tomography (SPET) with Tc-99m
2-methoxyisobutylisonitrile (Tc-99m MIBI), and metabolism using positron
emission tomography with F‑18 FDG.

[Design and sequence of events]{.underline}: This was a study that
enrolled patients waiting to undergo CABG who had chronic coronary
artery disease and left ventricular dysfunction. At baseline, coronary
angiography was performed to assess coronary artery disease. First-pass
radionuclide angiography (with Tc-99m MIBI) and ECG-gated planar
perfusion scintigraphy (with Tc-99m MIBI) were performed to evaluate
wall motion. Myocardial perfusion at rest and under stress was evaluated
by SPET scintigraphy with Tc99m MIBI. Positron emission tomography with
F‑18 FDG was performed to assess myocardial metabolism. Patients
underwent revascularization with CABG, and the imaging evaluations
described above were repeated. The success of revascularization was
verified by repeat coronary angiography. The timing of the repeat
wall-motion assessments

SPET perfusion studies at rest and during exercise were evaluated
concurrently and scored qualitatively (i.e., visually) by three
independent observers, who were unaware of the results of the PET
studies. The PET studies of metabolism were evaluated and scored
qualitatively (i.e., visually) by three other independent observers who
were unaware of the results of the SPET studies. The manuscript did not
specify whether wall-motion analyses were performed blindly nor did it
specify the number of readers for these evaluations.

[Subjects]{.underline}: Enrolled subjects were waiting to undergo CABG,
had stable or unstable angina, chronic multivessel coronary artery
disease, and moderate left ventricular dysfunction (ejection fraction
below 50%). No patient had diabetes mellitus.

[F‑18 FDG positron emission tomographic studies and image
analysis]{.underline}: Patients were studied after an overnight fast of
at least 16 hours. In each patient, two emission scans, lasting 10
minutes each, were carried out between 40 and 60 minutes after
intravenous administration of approximately 250 MBq (6.8 mCi) of F‑18
FDG. Data were reconstructed on the horizontal and vertical long axis
and the short axis.

A qualitative visual analysis was carried out on the tomographic images
of metabolism by dividing the left ventricle image into five segments
comparable with those selected for the wall motion analysis. The PET
studies of metabolism were evaluated and visually scored by three
independent observers who were unaware of the results of the SPET study.
Segments were assigned a scores on a four-point ordinal scale (0=no F‑18
FDG uptake, 1=low uptake, 2=moderate uptake, 3=high uptake). Myocardial
viability as assessed by F‑18 FDG was defined as any degree of F‑18 FDG
uptake based on the same scale.

[Analysis of perfusion]{.underline}: SPET scans were performed at rest
90 minutes after the first-pass angiography study (with Tc‑99m MIBI),
following a standard cholecystokinetic fatty meal at 30 minutes after
injection. Stress perfusion studies were performed within 72 hours
following the rest study. A qualitative visual analysis was carried out
on the tomographic images of perfusion by dividing the left ventricle
image into five segments comparable with those selected for the wall
motion analysis.

The SPET perfusion studies at rest and during exercise were evaluated
concurrently and visually scored by three independent observers, who
were unaware of the results of the PET study. The score ranged from 0 to
3 (0=markedly reduced or absent perfusion at rest, 1 = rest
hypoperfusion worsening after stress, 2 = hyperperfusion only under
stress, 3 = normal perfusion).

[Evaluation of wall-motion]{.underline}: First-pass radionuclide
angiography was performed at rest after an intravenous bolus injection
of approximately 900 MBq (24 mCi) of Tc‑99m MIBI. ECG-gated planar
perfusion scintigraphy was performed about 60 minutes later. Segmental
wall motion was assessed on a pixel by pixel basis of the RAO 30^o^
first-pass radionuclide angiography study displayed on a relative color
scale in the anterior, apical and inferior wall. The analysis of these
images was used for the segments in which the wall motion could not be
assessed by ECG gated planar perfusion scintigraphy due to the absence
of Tc 99m-MIBI uptake. Anterior and LAO 45^o^ projections were analyzed
to assess the wall motion in five segments: anterior, apical, inferior,
lateral, and septum.

Wall motion scores were given by three independent observers in each
segment from 0 to 4 (0 = dyskinesis, 1 = akininesis, 2 = severe
hypokinesis, 3 = hypokinesis, 4 = normal kinesis). Wall motion was
considered to be improved when the score increased by 1 or more from
before CABG to afterwards.

[Statistics]{.underline}: Statistical analyses were carried out on the
scores of perfusion, metabolism, and wall motion from the myocardial
segments. One-way ANOVA was used to test interobserver variability. A
stepwise multiple logistic analysis was carried out on the segments that
exhibited impaired wall motion prior to the intervention to estimate the
independent contribution of the preoperative perfusion and metabolism
scores on wall motion improvement. The maximum likelihood method was
used to assess the significance of each term in selecting the one to be
removed or entered in each step. The only statistical test carried out
on the 14 patients as a set of data was a two-tailed Student\'s t-test
to compare the mean values of the ejection fraction before and after
CABG.

**Results:**

[Patient disposition and characteristics]{.underline}: Data from 14
patients were included in the analysis. The 14 patients included 12 men
and 2 women. The patients had a mean age of 61.2 years (range 46‑70
years), and a mean ejection fraction of 37.5±4.9%. All had undergone
diagnostic coronary angiography within six months of the nuclear
studies. Twelve patients had three-vessel disease, one patient had two
vessel disease, and one had one-vessel disease. No patient had had an
acute myocardial infarction in the seven months before the study.

[Segment disposition and functional outcome]{.underline}: The left
ventricle of each of the 14 patients was divided into 5 segments,
yielding 70 segments overall. Fifty-four (54) of these segments had
abnormal wall motion. Wall motion improved in 40/54 (74%) segments after
CABG, and it remained unchanged in 14/54 (26%) segments.

The table below shows the distribution of the 54 asynergic segments by
degree of F‑18 FDG uptake and degree of perfusion.

  -------------------- ------------ ---------- -------------- ---------- -----------
  **Table 17: Number                                                     
  of Asynergic                                                           
  Segments as a                                                          
  Function of F‑18 FDG                                                   
  Uptake and Degree of                                                   
  Perfusion\***                                                          

                       **F‑18 FDG                                        
                       Uptake**                                          

  **Perfusion**        **Absent**   **Low**    **Moderate**   **High**   **Total**

  **Absent at rest**   **4**        **2**      **3**          **2**      **11**

  **Rest hypoperfusion **6**        **4**      **9**          **3**      **22**
  worsening after                                                        
  stress**                                                               

  **Stress             **5**        **7**      **3**          **5**      **20**
  hypoperfusion**                                                        

  **Normal**           **0**        **1**      **0**          **0**      **1**

  **Total**            **15**       **14**     **15**         **10**     **54**

  **\* This table was                                                    
  taken from the                                                         
  manuscript**                                                           
  -------------------- ------------ ---------- -------------- ---------- -----------

[Imaging results]{.underline}: Of the 39 segments that were predicted to
have reversible function by F‑18 FDG uptake, segmental wall motion
actually improved after revascularization in 37 segments (PPV=95%). Of
the 15 segments that were predicted to have irreversible loss of
function, segmental wall motion did not improve in 12 (NPV=80%). The
tables below summarize these results.

  ------------------------- --------------- -------------- ---------------
  **Table 18. Number of                                    
  Asynergic Myocardial                                     
  Segments with Improved                                   
  Segmental Wall Motion                                    
  after Revascularization:                                 
  Relation to F‑18 FDG                                     
  Uptake**                                                 

                            **Improved                     
                            Segmental Wall                 
                            Motion**                       

  **F-18 FDG Uptake**       **Present**     **Absent**     **Total**

  **Uptake present**        **37**          **2**          **39**

  **Uptake absent**         **3**           **12**         **15**

  **Total**                 **40**          **14**         **54**
  ------------------------- --------------- -------------- ---------------

+-----------------------+----------------------+----------------------+
| **Table 19.           |                      |                      |
| Performance of PET    |                      |                      |
| F‑18 FDG Uptake When  |                      |                      |
| Used to Predict       |                      |                      |
| Improved Wall Motion  |                      |                      |
| in Asynergic          |                      |                      |
| Myocardial Segments** |                      |                      |
+-----------------------+----------------------+----------------------+
| **Performance         | **Value**            | **95% CI**           |
| Measure**             |                      |                      |
|                       | **(no. of            |                      |
|                       | segments)**          |                      |
+-----------------------+----------------------+----------------------+
| **Sensitivity (%)**   | **92.5 (37/40)**     | **(80, 98)**         |
+-----------------------+----------------------+----------------------+
| **Specificity (%)**   | **80 (12/15)**       | **(52, 96)**         |
+-----------------------+----------------------+----------------------+
| **PPV (%)**           | **95 (37/39)**       | **(83, 99)**         |
+-----------------------+----------------------+----------------------+
| **NPV (%)**           | **80 (12/15)**       | **(52, 96)**         |
+-----------------------+----------------------+----------------------+
| **Accuracy (%)**      | **91 (49/54)**       | **(80, 97)**         |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **4.6**              |                      |
| (+)**                 |                      |                      |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **0.09**             |                      |
| (‑)**                 |                      |                      |
+-----------------------+----------------------+----------------------+

[Multiple Logistic Analysis]{.underline}:

Two multiple logistic analyses were performed on the scores of
metabolism and perfusion. The first was to predict wall motion
improvement, taking into account both perfusion and F‑18 FDG uptake. The
results provide estimates of wall motion recovery as a function of the
preoperative scores of perfusion and F‑18 FDG uptake. As shown in the
table below, the highest probability of wall motion recovery was
associated with the presence of high F‑18 FDG uptake and absent
perfusion at rest.

  ----------------------- ------------ ----------- -------------- -----------
  **Table 20: Estimated                                           
  Probability of Wall                                             
  Motion Improvement as a                                         
  Function of                                                     
  Preoperative F‑18 FDG                                           
  Uptake and Preoperative                                         
  Degree of Perfusion\***                                         

                          **F‑18 FDG                              
                          Uptake**                                

  **Perfusion**           **Absent**   **Low**     **Moderate**   **High**

  **Absent at rest**      **25**       **94**      **96**         **99**

  **Rest hypoperfusion    **14**       **89**      **92**         **97**
  worsening after                                                 
  stress**                                                        

  **Stress                **7**        **78**      **84**         **94**
  hypoperfusion**                                                 

  **Normal**              **-**        **4**       **-**          **-**

  **\*Values in each cell                                         
  indicate the estimated                                          
  percentage probability                                          
  of wall motion                                                  
  improvement. This table                                         
  was taken from the                                              
  manuscript.**                                                   
  ----------------------- ------------ ----------- -------------- -----------

The second multiple logistic analysis was performed on F‑18 FDG uptake
data. As shown in the table below, the likelihood of wall motion
improvement increased as F‑18 FDG uptake increased.

  -------------------------- ----------------------- ---------------------------- ------------------------
  **Table 21: Estimated                                                           
  Probability of Wall Motion                                                      
  Improvement as a Function                                                       
  of Preoperative F‑18 FDG                                                        
  Uptake\***                                                                      

  **F‑18 FDG Uptake**                                                             

  **[Absent]{.underline}**   **[Low]{.underline}**   **[Moderate]{.underline}**   **[High]{.underline}**

  **13**                     **79**                  **92**                       **96**

  **\*Values in each cell                                                         
  indicate the estimated                                                          
  percentage probability of                                                       
  wall motion improvement                                                         
  This table was taken from                                                       
  the manuscript.**                                                               
  -------------------------- ----------------------- ---------------------------- ------------------------

[Other Endpoints]{.underline}: The left ventricular ejection fraction
improved in 13/14 patients and remained unchanged in one. The
preoperative ejection fraction was 37.5±4.9% (mean±SD), whereas the
postoperative ejection fraction was 47.9±4.1 (p\<0.001).

[Safety]{.underline}: The safety of positron emission tomography with
F‑18 FDG was not addressed in the manuscript.

[Conclusions in manuscript]{.underline}: Despite the potential
limitations due to the semiquantitative analysis of the images, the
method appears to provide reliable information for the diagnostic and
prognostic evaluation of patients with coronary artery disease
undergoing CABG and confirm that the identification of hibernating
myocardium with F‑18 FDG is of paramount importance in the diagnosis of
patients undergoing CABG.

[Reviewer\'s comments]{.underline}: Although the analysis of this study
only included data from 14 patients, the study had several strengths and
relatively unique characteristics. The analyses of the F‑18 FDG PET
images and the SPET perfusion images were qualitative, suggesting that
quantitative analyses may not be always necessary to evaluate with F‑18
FDG PET whether left ventricular contractile dysfunction is reversible
in patients with coronary artery disease. The readers of the F‑18 FDG
PET images were blinded to the SPET perfusion images, and vice versa.
Three independent readers were used for these image analyses, allowing
assessments of interreader variability and increasing the
generalizability of the results. This was one of the few papers that
evaluated stress hypoperfusion, showing that F‑18 FDG PET imaging may
have useful predictive value not only when analyzed in relation to
resting perfusion deficits, but also in the expanded group of patients
who have perfusion deficits that are apparent only during stress. The
authors also evaluated probabilities of wall motion improvement for
different ratios of perfusion-metabolism mismatch (see Table 20),
thereby extracting additional information from the data. Localization of
F‑18 FDG was evaluated in all 70 segments, not just in the 54 that were
asynergic.

One of the greatest limitations of the study is its small sample size,
as is reflected in the wide confidence intervals for the performance
measures. This also limits the generalizability of the study. The
readers of the F‑18 FDG PET images and the SPET perfusion images were
apparently not blinded to the results of the wall-motion analysis. The
manuscript did not specify the number of readers for the wall-motion
analysis, or whether these readers were blinded. Analyses by patient
were not performed. Although an assessment of global ventricular
function was made (i.e., ejection fraction), the results were not
correlated with the degree of reversible ventricular dysfunction as
predicted by imaging with F‑18 FDG PET and SPET (for perfusion).
Clinical outcomes were not assessed.

**6. Maes AF, Borgers M, Flameng W, et al. Assessment of Myocardial
Viability in Chronic Coronary Artery Disease Using Technetium-99m
Sestamibi SPECT: Correlation with Histologic and Positron Emission
Tomographic Studies and Functional Follow-Up. J Am Coll Cardiol
1997;29:62‑8.**

**Description of study:**

[Objective]{.underline}: The objective of this study was to evaluate the
value of Tc-99m-sestamibi (2-methoxy-isobutyl isonitrile \[MIBI\]) as a
viability tracer in patients undergoing coronary artery bypass surgery.
The results of these SPECT studies were compared to the results of PET
metabolism and perfusion studies.

[Design and sequence of events]{.underline}: This was a prospective
study performed in patients with known coronary artery disease and
anterior wall motion abnormalities. Patients underwent coronary
angiography and contrast ventriculography to identify the location and
extent of coronary artery disease and to demonstrate left ventricular
dysfunction. Patients with severe stenosis of the left anterior
descending coronary artery (≥70%) and hypokinesia, akinesia or
dyskinesia on contrast ventriculography underwent radionuclide
angiography. Radionuclide angiography with Tc‑99m-labeled red blood
cells was performed to evaluate global and regional left ventricular
function. Rest Tc‑99m-MIBI SPECT studies were performed to evaluate
myocardial viability, and the results were compared with results from
PET studies performed with N‑13 ammonia and F‑18 FDG. A preoperative
transmural biopsy specimen was taken from the left ventricular anterior
wall, and morphometry was performed to assess percent fibrosis. Patients
underwent revascularization with CABG. The manuscript did not specify
whether the success of revascularization was assessed. Three months
after CABG, radionuclide angiography was repeated to assess changes in
myocardial function.

The analyses of the F‑18 FDG PET scans, N‑13 ammonia PET scans, and
Tc-99m MIBI SPECT scans were limited to a portion of the anterior left
ventricular wall. Analyses of these scans were quantitative. The
manuscript did not specify the number of readers, nor did it specify
whether the analyses of left ventricular function by SPECT were
performed blinded to the results of the PET scans. Conversely, the
manuscript did not specify whether the analyses of the PET scans were
performed blinded to the results of the SPECT scans.

[Subjects]{.underline}: Patients were included in the study if they had
known coronary artery disease, one- or two-vessel disease, an occlusion
or severe stenosis (≥70%) of the left anterior descending coronary
artery, and anterior wall abnormalities. Patients with diabetes mellitus
were excluded.

[PET studies and image analysis]{.underline}: Myocardial perfusion was
evaluated by administration of 20 mCi of N-13 ammonia in 5 ml of saline
followed by a 20 minute flush of saline. Acquisition started
simultaneously with the injection of N‑13 ammonia. In each patient, 19
dynamic frames were recorded. Total acquisition time was 10 minutes.

Regional myocardial utilization of exogenous glucose was evaluated with
F‑18 FDG. The metabolic studies were performed by using the euglycemic
hyperinsulinemic clamp technique. A total of 10 mCi of F‑18 FDG was
injected 50 min after N-13 ammonia injection. In each patient, 22
dynamic frames were recorded. Acquisition time was 70 min.

The 22 frames of the metabolic studies and the 19 frames of the
perfusion studies were reconstructed. The PET studies (of both N‑13
ammonia and F‑18 FDG) were divided into polar maps, with 33 sectors in
each map. Analysis of the sectors was limited to those in the anterior
wall (i.e., the average of two sectors covering the region from which
the biopsy specimen was taken). After absolute flow values for this
myocardial region, a flow index was calculated as the ratio of the flow
in the biopsy region divided by flow in the reference sector (no
stenosis or stenosis \<50% in the left circumflex or right coronary
artery). A metabolic index was calculated by determining the ratio of
glucose utilization in the biopsy region compared to that in the
reference sector. Regions were defined as PET viable with the ratio of
metabolic and flow index was \> 1.2.

[Wall motion analysis]{.underline}: Regional and global myocardial
function were assessed with radionuclide angiography using 20 mCi of
Tc-99m labeled red blood cells. Regional and global ejection fractions
were calculated. Regional function was considered to have improved if
the regional ejection fraction in the anterior wall was 5% higher three
months after revascularization than before revascularization.

[Tc-99m MIBI SPECT studies]{.underline}: Tc-99m MIBI SPECT studies were
performed at rest one or two days before and three months after
operation. A total of 15 mCi of Tc-99m MIBI was injected at rest 60
minutes before the start of acquisition. The Tc-99m MIBI images were
delineated with the same procedure applied to the PET images, and
comparable polar maps were constructed. Counts in the polar maps were
normalized to the maximal value of the entire map. The mean value of the
two sectors that corresponded to those used in the PET analyses was used
for further analysis of Tc-99m MIBI uptake.

[Statistics]{.underline}: Differences between groups were evaluated
statistically with the Student t test for paired data. For evaluation of
the relation between Tc-99m sestamibi uptake or normalized PET flow and
percent fibrosis, linear regression plots were used. Differences between
correlation coefficients were tested by using Fisher z transformation.
To calculate an optimal threshold for MIBI (100-% false positive - %
false negative) was maximized.

**Results:**

[Patient disposition and characteristics]{.underline}: Thirty patients
were enrolled. PET studies were not performed in four patients, and
global and regional ejection fraction were not followed up
postoperatively with radionuclide angiography in three additional
patients. Therefore, 23 patients were included in the PET analyses.

The 30 patients included 25 men and 5 women, and had a mean age of
63 ± 14 years. All had severe (≥70%) stenosis of the left anterior
descending coronary artery. Coronary artery bypass surgery was scheduled
for 22 of the 30 patients because of stable angina, for five because of
unstable angina, and for three because of heart failure. Four patients
had a previous anterior infarction. Preoperatively, the contrast
ventriculogram revealed regional hypokinesia in 8, severe hypokinesia in
12, and akinesia or dyskinesia in 10 patients.

[Segment disposition and functional outcome]{.underline}: Although the
PET studies were divided into polar maps, with 33 sectors per map,
analyses were limited to the anterior wall for each patient (i.e., the
average of 2 sectors covering the region from which the biopsy specimen
was taken). Thus, 23 anterior wall segments, one per patient, were
evaluated. Twelve of these segments showed functional improvement after
revascularization, and 11 did not.

[PET results]{.underline}: The performance characteristics of F‑18 FDG
and N‑13 ammonia in predicting functional recovery, using the PET
match/mismatch criteria, are described in the tables below.

  ------------------------- --------------- -------------- ---------------
  **Table 22. Number of                                    
  Asynergic Anterior                                       
  Myocardial Segments with                                 
  Improved Function after                                  
  Revascularization:                                       
  Relation to PET                                          
  match/mismatch findings**                                

                            **Improved                     
                            Regional                       
                            Ejection                       
                            Fraction**                     

  **PET Findings**          **Present**     **Absent**     **Total**

  **Mismatch of F‑18 FDG    **10**          **1**          **11**
  and N‑13 Ammonia Uptake**                                

  **Match of F‑18 FDG and   **2**           **10**         **12**
  N‑13 Ammonia Uptake**                                    

  **Total**                 **12**          **11**         **23**
  ------------------------- --------------- -------------- ---------------

+-----------------------+----------------------+----------------------+
| **Table 23.           |                      |                      |
| Performance of PET    |                      |                      |
| F‑18 FDG Uptake When  |                      |                      |
| Used to Predict       |                      |                      |
| Improved Wall Motion  |                      |                      |
| in Asynergic          |                      |                      |
| Myocardial Segments** |                      |                      |
+-----------------------+----------------------+----------------------+
| **Performance         | **Value**            | **95% CI**           |
| Measure**             |                      |                      |
|                       | **(no. of            |                      |
|                       | segments)**          |                      |
+-----------------------+----------------------+----------------------+
| **Sensitivity (%)**   | **83 (10/12)**       | **(52, 98)**         |
+-----------------------+----------------------+----------------------+
| **Specificity (%)**   | **91 (10/11)**       | **(58, 100)**        |
+-----------------------+----------------------+----------------------+
| **PPV (%)**           | **91 (10/11)**       | **(58, 100)**        |
+-----------------------+----------------------+----------------------+
| **NPV (%)**           | **83 (10/12)**       | **(52, 98)**         |
+-----------------------+----------------------+----------------------+
| **Accuracy (%)**      | **87 (20/23)**       | **(66, 97)**         |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **9.15**             |                      |
| (+)**                 |                      |                      |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **0.18**             |                      |
| (‑)**                 |                      |                      |
+-----------------------+----------------------+----------------------+

[N‑13 ammonia results]{.underline}: Predictive values for anterior-wall
functional recovery as assessed by N‑13 ammonia flow were separated out
from the overall PET criteria of flow and glucose uptake. An optimal
threshold was calculated by maximizing (100 ‑ % false positives ‑ %
false negatives). A threshold of 50 % flow was found, resulting in the
following performance characteristics: sensitivity = 92% (11/12);
specificity = 55% (6/11); PPV = 69% (11/16); NPV = 86% (6/7); accuracy =
74% (17/23); LR(+)= 2.0; LR(‑)=0.16.

[Tc‑99m MIBI results]{.underline}: Predictive values for anterior-wall
functional recovery as assessed by Tc‑99m MIBI were also calculated by
using an optimal threshold that was obtained by maximizing (100 ‑ %
false positives ‑ % false negatives). A threshold of 50% of peak
activity was found, resulting in the following performance
characteristics: sensitivity = 92% (12/13); specificity = 60% (6/10);
PPV = 75% (12/16); NPV = 86%; accuracy=78% (18/23); LR(+) = 2.3;
LR(‑)=0.13.

[Other Results]{.underline}: Global and regional ejection fraction was
followed up postoperatively with radionuclide angiography in 27
patients; in 13 global ejection fraction was improved and in 16,
regional contractile function was improved.

Significantly higher Tc‑99m MIBI values were found in the group with
myocardial viability as assessed by PET than in the group with
PET-assessed nonviability (p\<0.01). Significantly higher MIBI values
were found in the group with enhanced contractility at three months
(76±13% vs. 53±22%, p\<0.01). A linear relation was found between MIBI
uptake and percent fibrosis in the biopsy specimen (r=0.78, p\<0.00001).

[Safety]{.underline}: The safety of F‑18 FDG and N‑13 ammonia PET was
not discussed in this manuscript.

[Conclusions in manuscript]{.underline}: Tc-99m MIBI uptake was
significantly higher in PET-assessed viable areas and in regions with
enhanced contractility at three months. A linear relation was found
between percent fibrosis and Tc‑99m MIBI uptake. An optimal threshold of
50% was found for prediction of functional recovery with Tc‑99m MIBI.

[Reviewer\'s comments]{.underline}: Of the principal studies, this is
the only study which evaluated morphological correlates of imaging
studies in myocardium with reversible left ventricular function.
Although the results were expressed in terms of a correlation between
percent fibrosis and Tc‑99m MIBI uptake, a similar relationship likely
holds for F‑18 FDG. Moreover, as a consequence of only focusing on one
region of the heart (i.e., the anterior wall) per patient, the segmental
analysis is identical to the by-patient analysis. Such by-patient
analyses facilitate assessments of clinical benefit as compared to risk.
Moreover, the study compared different diagnostic modalities, and the
predictive performance of both F‑18 FDG PET and Tc‑99m MIBI SPECT were
evaluated with respect to the functional outcome (\"truth\"). Such
direct head-to-head comparisons of the performance of different imaging
modalities provide data that are potentially of substantial clinical
value.

One limitation of the study is the small sample size. The manuscript did
not specify the number of readers for the PET or SPECT scans, or whether
these images were analyzed blindly. However, this limitation is
mitigated by the quantitative nature of the image analyses. The study
focused only on functional recovery of the anterior wall of the left
ventricle; the predictive performance of PET F‑18 FDG may not be similar
in other ventricular regions. Although global ejection fraction was
evaluated postoperatively in many patients, these results were not
correlated with the PET F‑18 FDG predictions of functional recovery that
were made before revascularization. Thus, the ability of PET F‑18 FDG to
predict global improvement in left ventricular function was not
demonstrated. Clinical outcomes were not assessed.

**7. Marwick TH, MacIntyre WJ, Lafont A, et al. Metabolic Responses of
Hibernating and Infarcted Myocardium to Revascularization: A Follow-up
Study of Regional Perfusion, Function, and Metabolism. Circulation
1992;85:1347-53.**

**Description of Study:**

[Objective]{.underline}: The objective of this study was to examine the
metabolic response of hibernating tissue to revascularization, as
assessed by PET metabolic imaging with F‑18 FDG and PET perfusion
imaging with Rb‑82.

[Design and sequence of events]{.underline}: This study was performed in
patients with a previous myocardial infarction. At baseline, patients
underwent rest and stress myocardial perfusion imaging using Rb-82 PET.
Postexercise F‑18 FDG positron emission tomography was performed to
evaluate myocardial metabolism. Digitized two-dimensional
echocardiography was performed to evaluate regional wall motion.
Patients then underwent either CABG or angioplasty. Although the authors
assert that \"segments identified as potentially hibernating were
adequately revascularized,\" the manuscript did not specify how the
adequacy of revascularization was assessed. After revascularization, PET
imaging with Rb-82, PET imaging with F‑18 FDG, and digitized 2-D
echocardiography were repeated.

The evaluation of the 2-dimensional echocardiograms was performed by two
blinded readers. However, the manuscript did not specify to what
information these readers were blinded. Similarly, evaluation of the PET
Rb‑82 scans and the PET F‑18 FDG scans were each performed by two
blinded readers. Again, however, the manuscript did not specify to what
information these readers were blinded.

[Subjects]{.underline}: Patients with a previous myocardial infarction
who were undergoing coronary revascularization were included in the
study. Patients with unstable angina and asthma were excluded from the
study because dipyridamole was used as a pharmacological stressor.
Patients with elevated fasting blood glucose levels were excluded. No
patients with extensive coronary disease (involving all three major
epicardial coronary arteries) were entered into the protocol, as the
definition of normal F‑18 FDG uptake required the definition of a site
of normal perfusion.

[Perfusion studies and image analysis]{.underline}: Rest and stress PET
imaging with Rb‑82 were performed before and after surgery. Rb‑82 was
administered at a dose of 40 - 60 mCi, with the dose dependent on the
generator life. Resting imaging was started 75 seconds after the
conclusion of the injection and lasted for seven minutes. After resting
imaging, dipyridamole handgrip stress was performed. Another 40-60 mCi
was injected 8 minutes after commencement of this protocol, and stress
imaging was performed over 4 minutes, acquiring 20-40 million counts.

The left ventricle was evaluated over thirteen myocardial segments by
two blinded observers. Perfusion was graded as follows: (a) normal; (b)
reversible perfusion defect (identified by a 20% relative reduction of
Rb-82 activity after stress); (c) or a fixed perfusion defect (defined
by regions with \>20% fewer than maximum counts.

[F‑18 FDG positron emission tomographic studies and image
analysis]{.underline}: Fasting F‑18 FDG imaging was performed after
perfusion imaging. Four to 10 mCi of F‑18 FDG were injected 30 minutes
after maximum symptom-limited treadmill exercise, and imaging began 40
min later. Image acquisition lasted 20 minutes.

The left ventricle was evaluated by two blinded observers over the same
thirteen myocardial segments evaluated for Rb‑82 . For each patient, a
\"reference normal\" segment was determined for metabolic activity by
selecting the site of maximum resting flow without significant reduction
at stress perfusion imaging and subtended by a normal coronary artery.
Sites other than this reference normal segment with resting perfusion
within the normal range, supplied by normal coronaries and without
stress-induced defects, were then combined to establish a range of
normal F‑18 FDG uptake measured as a percentage below or above the
reference level. In each patient, the presence of F‑18 FDG activity
\>2SD (≥30%) above the reference normal segment was classified as
abnormal (i.e., having the potential to recover myocardial function, and
labeled as \"hibernating\").

[Wall motion analysis]{.underline} Wall motion was assessed by digitized
2-D echocardiography (parasternal long- and short-axis and apical four
and two-chamber views). The left ventricular myocardium was divided into
thirteen myocardial segments. Wall motion was scored by two blinded
observers on a 6-point ordinal scale (1=normal , 2=hypokinesia, 3 =
akinesia, 4=dyskinesia, 5=aneurysm, 6=akinesia or dyskinesia with
thinning of the myocardium). The presence of hibernation was defined by
improvement ≥1 point.

[Statistics]{.underline}: Groups were compared with regard to continuous
and noncontinuous variables by the t test or χ^2^ or Fisher\'s exact
test respectively (the latter depending on sample sizes).

**Results:**

[Patient disposition and characteristics]{.underline}: Sixteen patients,
14 men and two women, were enrolled and evaluated. The patients ranged
from 42 to 76 years of age. All patients had previous myocardial
infarction (5±11 months before the preinterventional studies). Nine
patients had one-vessel disease, seven had multivessel disease, but none
had disease in all three major coronary arteries. Revascularization was
accomplished in nine by coronary angioplasty and in seven by CABG. Six
patients had angina before revascularization.

[Segment disposition and functional outcome]{.underline}: The left
ventricle of each of the 16 patients was divided into 13 segments,
yielding a total of 208 segments for potential analysis. Overall, 85
segments showed fixed perfusion defects and resting wall motion
disturbances before revascularization. These 85 segments were those used
for analysis. At least two months (4.9±2.6 months) after intervention,
35 (41%) of these segments (in 12 patients) demonstrated improved
function. Fifty segments failed to improve at follow-up.

Preoperative perfusion and preoperative wall motion score did not
distinguish between the segments that were destined to improve after
revascularization and those destined not to improve. Specifically,
before revascularization, the 50 segments that failed to improve at
follow up had a mean perfusion scores (as assessed by regional Rb‑82
activity) that was 55±13% of the maximum score, and the 35 segments that
did improve at follow up had a perfusion score that was 57±11% of the
maximum (p=NS). Similarly, before revascularization, the 50 segments
that failed to improve at follow up had a mean segmental wall motion
score of 3.0±1.0, and the 35 segments that did improve at follow up had
a mean segmental wall motion score of 2.8±0.7 (p=NS).

[F‑18 FDG results]{.underline}: Considering the 85 segments with resting
wall motion disturbances, preoperative F‑18 FDG activity was
significantly higher in the 35 segments that demonstrated improved
function after revascularization than in the 50 segments that did not
(29 ±11% vs. 15±15% above reference normal, p\<0.001). As noted in the
previous section, preoperative perfusion did not distinguish between the
two groups, nor did preoperative wall motion score.

Of the 35 segments that improved in function after revascularization, 25
were correctly predicted to do so by F‑18 FDG (sensitivity = 71%). Of
the 50 segments that failed to improve in function, 38 were correctly
predicted to do so by F‑18 FDG (specificity = 76%). These results are
summarized in the tables below:

  ------------------------- --------------- -------------- ---------------
  **Table 24. Number of                                    
  Hypoperfused, Asynergic                                  
  Myocardial Segments with                                 
  Improved Segmental Wall                                  
  Motion after                                             
  Revascularization:                                       
  Relation to F‑18 FDG                                     
  Uptake**                                                 

                            **Improved                     
                            Segmental Wall                 
                            Motion**                       

  **F-18 FDG Uptake**       **Present**     **Absent**     **Total**

  **\>2 SD Above Uptake in  **25**          **12**         **37**
  Reference Normal                                         
  Segment**                                                

  **≤2 SD Above Uptake in   **10**          **38**         **48**
  Reference Normal                                         
  Segment**                                                

  **Total**                 **35**          **50**         **85**
  ------------------------- --------------- -------------- ---------------

+-----------------------+----------------------+----------------------+
| **Table 25.           |                      |                      |
| Performance of PET    |                      |                      |
| F‑18 FDG Uptake When  |                      |                      |
| Used to Predict       |                      |                      |
| Improved Wall Motion  |                      |                      |
| in Hypoperfused,      |                      |                      |
| Asynergic Myocardial  |                      |                      |
| Segments**            |                      |                      |
+-----------------------+----------------------+----------------------+
| **Performance         | **Value**            | **95% CI**           |
| Measure**             |                      |                      |
|                       | **(no. of            |                      |
|                       | segments)**          |                      |
+-----------------------+----------------------+----------------------+
| **Sensitivity (%)**   | **71 (25/35)**       | **(54, 85)**         |
+-----------------------+----------------------+----------------------+
| **Specificity (%)**   | **76 (38/50)**       | **(62, 87)**         |
+-----------------------+----------------------+----------------------+
| **PPV (%)**           | **28 (25/37)**       | **(50, 80)**         |
+-----------------------+----------------------+----------------------+
| **NPV (%)**           | **79 (38/48)**       | **(65, 89)**         |
+-----------------------+----------------------+----------------------+
| **Accuracy (%)**      | **74 (63/85)**       | **(63, 83)**         |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **3.0**              |                      |
| (+)**                 |                      |                      |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **0.38**             |                      |
| (‑)**                 |                      |                      |
+-----------------------+----------------------+----------------------+

[Other Findings]{.underline} Somewhat paradoxically, F‑18 FDG activity
fell significantly after revascularization both in the segments that
improved in function as well as in those that did not. Specifically, in
the 35 segments that improved in function, regional F‑18 FDG activity
fell from 29±11% to 16±17% above the reference normal segment after
revascularization (p\<0.001). In the 50 segments that did not improve in
function, a reduction of F‑18 FDG activity from 15±15 to 7±19% above the
reference normal segment also occurred (p\<0.001), despite failure of
regional wall motion and regional perfusion to improve after
revascularization.

At follow-up (4.9 ± 2.6 months after revascularization), hibernating
segments were characterized by reduction of wall motion score (from a
mean segmental wall motion score of 2.8±0.7 to 1.4±0.5; p\<0.001),
improvement of perfusion (from 57±11 to 69±13 percent of maximum;
p\<0.001), and reduction of F‑18 FDG activity (see previous paragraph,
p\<0.001). Of the 35 hibernating segments, however, 10 still had
abnormal elevation of FDG uptake (\>2 SD above normal) without differing
from other hibernating segments with respect to postoperative perfusion
or wall motion score. Segments with persistently abnormal metabolism
were characterized before intervention by more severe malperfusion
(p\<0.01) and greater FDG activity (p\<0.01).

Six patients had angina before revascularization, but none had ongoing
angina at the time of follow-up.

[Safety]{.underline}: The safety of PET F‑18 FDG was not addressed in
the manuscript.

[Conclusions in manuscript]{.underline}: Although wall motion and
perfusion improve with revascularization of hibernating tissue,
myocardial metabolism remains abnormal in a significant proportion of
segments. These segments are characterized by more extensive perfusion
and metabolic changes before revascularization.

[Reviewer\'s comments]{.underline}: Despite its small size, the study
had several strengths. The analyses of the two-dimensional
echocardiograms for wall motion, the PET F‑18 FDG scans for metabolism,
and the PET Rb‑82 for perfusion were performed in a blinded fashion.
Images were analyzed by two blinded readers. This was one of the few
principal papers that evaluated stress hypoperfusion (and also
post-exercise F‑18 FDG uptake) showing that PET imaging may have useful
predictive value not only when analyzed in relation to resting perfusion
deficits, but also in the expanded group of patients who have perfusion
deficits that are apparent only during stress. This is also one of the
few papers that performed PET imaging to evaluate perfusion and F‑18 FDG
uptake after revascularization.

One of the greatest limitations of the study is its sample size. The
manuscript did not specify the nature of the information to which the
readers were blinded. A by-patient analysis was not performed. Global
ventricular function was not assessed. Although the clinical outcome of
angina was assessed, this outcome was not correlated with the predictive
capabilities of PET findings with F‑18 FDG and Rb‑82.

**8. Tamaki N, Yoshiharu Y, Yamashita K, et al. Positron Emission
Tomography Using Fluorine‑18 Deoxyglucose in Evaluation of Coronary
Artery Bypass Grafting. Am J Cardiol 1989; 64:860‑865.**

**Description of Study:**

[Objective]{.underline}: The objective of this study was to assess the
\"clinical value\" of PET (i.e., perfusion imaging with N‑13 ammonia,
and metabolic imaging with F‑18 FDG) in the evaluation of CABG.

[Design and sequence of events]{.underline}: This study was performed in
consecutive patients with coronary artery disease who were undergoing
CABG. Prior to revascularization, patients underwent PET imaging with
N‑13 ammonia to evaluate myocardial perfusion and with F‑18 FDG to
evaluate myocardial metabolism. Radionuclide ventriculography was
performed before CABG to assess left ventricular wall motion. After
revascularization, radionuclide ventriculography (to assess wall motion)
and PET imaging with N‑13 ammonia and F‑18 FDG were repeated. Segmental
improvements in perfusion, as assessed quantitatively by N‑13 ammonia,
were used to assess the adequacy of revascularization.

The evaluation of wall motion was performed by three experienced
observers without knowledge of other radionuclide or postoperative
results. N‑13 ammonia and F‑18 FDG images were visually (qualitatively)
evaluated by three experienced observers. The manuscript did not specify
whether these latter three observers were blinded.

[Subjects]{.underline}: The study enrolled consecutive patients who were
to undergo CABG. Normal subjects served as controls for the evaluation
of perfusion.

[Perfusion studies and image analysis]{.underline}: To evaluate
perfusion, 10-20 mCi of N-13 ammonia was injected at rest, and
myocardial perfusion imaging was performed for 5 minutes. Immediately
after the first scan, a second scan was carried out for 8 minutes in a
position 8 mm caudal to the first scan. These two scans provided a total
of 14 contiguous transverse slices of the myocardium with 8-mm
intervals.

Perfusion scans were quantitatively analyzed by circumferential profile
analysis of three transverse slices of N-13 ammonia distribution in a
patient and the lower limit of a normal subject. The lower limit was
determined as the mean minus 2 SD from the values of ten normal
volunteers. The left ventricular myocardium was divided into five
segments (anterior, septal, apical, inferior, and lateral). Segments
with perfusion below the lower limits and covering at least 30^o^ of the
profiles were considered hypoperfused segments. The manuscript did not
specify whether this analysis of the N‑13 ammonia PET images was
blinded.

Perfusion was considered improved when the postoperative perfusion at
rest improved ≥10% in comparison with the preoperative perfusion on the
profile curves. When the postoperative perfusion decreased ≥10% versus
the preoperative perfusion on the profile curves, the perfusion was
considered deteriorated.

[F‑18 FDG positron emission tomographic studies and image
analysis]{.underline}: The F‑18 FDG study was separately performed
within a week after the N‑13 ammonia study. All patients fasted for at
least five hours before the study. Two to 7 mCi of F‑18 FDG were
injected at rest and, 60 minutes later, two emission scans were obtained
every eight to ten minutes.

For evaluation of the F‑18 FDG images, the left ventricle was divided
into five segments that corresponded to the segments obtained with N‑13
ammonia images. Three experienced observers visually interpreted the
uptake on both the N‑13 ammonia and F‑18 FDG images. The segments with
normal perfusion were defined as normal areas. Hypoperfused segments
with F‑18 FDG uptake definitely higher than N-13 ammonia uptake
(i.e., \"mismatch\" pattern) were defined as ischemia. Hypoperfused
segments with F‑18 FDG uptake less than or similar to N-13 ammonia
uptake were defined as myocardial scar (i.e., \"match\" pattern).

[Wall motion analysis]{.underline}: Regional wall motion was assessed
with radionuclide ventriculography (20 mCi of technetium‑99m in
vivo-labeled red blood cells were administered). The evaluation of wall
motion on these radionuclide ventriculograms was performed by three
experienced observers without knowledge of other radionuclide or
postoperative results. Scores for wall motion ranged from 2 to ‑1
(i.e., normal, hypokinetic, akinetic, and dyskinetic). Improved wall
motion was defined as an increase in the wall-motion score by ≥1 after
CABG. Deteriorated wall motion was defined as a decrease in the wall
motion score by ≥1. The septal segment was excluded from the wall motion
analysis because of frequent postoperative paradoxical motion.

[Statistics]{.underline}: Comparisons of proportions were performed by
chi-square analysis or Fisher\'s exact test.

**Results:**

[Patient disposition and characteristics]{.underline}: Twenty-two
consecutive patients were enrolled and evaluated. Of the 22 enrolled
patients, 20 were men and 2 were women. The patients had a mean age of
57 (range 36 to 68 years. Seventeen patients had a history of myocardial
infarction with a duration \>1 month after onset.

[Segment disposition and functional outcome]{.underline}: The left
ventricle of each of the 22 patients was divided into 5 segments,
yielding 110 segments for possible evaluation. Of the 110 segments, 46
had wall motion abnormalities (in 20 of the 22 patients). These 46
segments were used to evaluate functional recovery. Considering these 46
asynergic segments, wall motion improved after CABG in 23 (50%), was
unchanged in 19 (41%), and deteriorated in 4 (9%).

[F‑18 FDG and N‑13 ammonia results]{.underline}: Preoperative PET F‑18
FDG identified 23 segments as metabolically viable regions. Wall motion
abnormality improved in 18 (78%) of these segments, whereas the
remaining 5 segments did not improve postoperatively. In contrast, of 23
segments exhibiting metabolically inactive regions, 5 (22%) improved in
wall motion abnormality (p\<0.001). These results are summarized in the
tables below:

  ------------------------- --------------- -------------- ---------------
  **Table 26. Number of                                    
  Asynergic Myocardial                                     
  Segments with Improved                                   
  Segmental Wall Motion                                    
  after Revascularization:                                 
  Relation to PET Findings                                 
  with F‑18 FDG and N‑13                                   
  Ammonia**                                                

                            **Improved                     
                            Segmental Wall                 
                            Motion**                       

  **PET findings**          **Present**     **Absent**     **Total**

  **Mismatch pattern**      **18**          **5**          **23**

  **Match pattern**         **5**           **18**         **23**

  **Total**                 **23**          **23**         **46**
  ------------------------- --------------- -------------- ---------------

+-----------------------+----------------------+----------------------+
| **Table 27.           |                      |                      |
| Performance of PET    |                      |                      |
| F‑18 FDG and N‑13     |                      |                      |
| Ammonia When Used to  |                      |                      |
| Predict Improved Wall |                      |                      |
| Motion in Asynergic   |                      |                      |
| Myocardial Segments** |                      |                      |
+-----------------------+----------------------+----------------------+
| **Performance         | **Value**            | **95% CI**           |
| Measure**             |                      |                      |
|                       | **(no. of            |                      |
|                       | segments)**          |                      |
+-----------------------+----------------------+----------------------+
| **Sensitivity (%)**   | **78 (18/23)**       | **(56, 92)**         |
+-----------------------+----------------------+----------------------+
| **Specificity (%)**   | **78 (18/23)**       | **(56, 92)**         |
+-----------------------+----------------------+----------------------+
| **PPV (%)**           | **78 (18/23)**       | **(56, 92)**         |
+-----------------------+----------------------+----------------------+
| **NPV (%)**           | **78 (18/23)**       | **(56, 92)**         |
+-----------------------+----------------------+----------------------+
| **Accuracy (%)**      | **78 (36/46)**       | **(64, 89)**         |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **3.6**              |                      |
| (+)**                 |                      |                      |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **0.28**             |                      |
| (‑)**                 |                      |                      |
+-----------------------+----------------------+----------------------+

[Other Findings]{.underline}: Postoperative improvement in hypoperfusion
was observed more often in the metabolically active segments (62%) than
in the inactive segments (27%) on the preoperative PET study (p\<0.05).
As shown in the table below, of 19 asynergic segments showing increased
F‑18 FDG uptake before operation, the postoperative PET revealed a
decrease in F‑18 FDG uptake in 13 (68%) and persistent uptake in 6
(32%). The improvement in asynergy was observed in all the segments that
showed a postoperative decrease in F‑18 FDG uptake, but in only 50% of
those with persistent uptake (p\<0.01). On the other hand, 4 of 5
segments showing new F‑18 FDG uptake after operation revealed further
wall motion abnormality. Furthermore, the segments metabolically active
before operation were more likely to have patent grafts (95%) than the
metabolically inactive segments (70%) (p\<0.05).

+-----------------------+-----------+-----------+-----------+-----------+
| **Table 28:           |           |           |           |           |
| Correlation of        |           |           |           |           |
| Changes in F‑18 FDG   |           |           |           |           |
| Uptake with Wall      |           |           |           |           |
| Motion Changes in 46  |           |           |           |           |
| Segments that were    |           |           |           |           |
| Asynergic             |           |           |           |           |
| Preoperatively\*\***  |           |           |           |           |
+-----------------------+-----------+-----------+-----------+-----------+
|                       |           | **Post    |           |           |
|                       |           | operative |           |           |
|                       |           | Wall      |           |           |
|                       |           | Motion**  |           |           |
+-----------------------+-----------+-----------+-----------+-----------+
| **F‑18 FDG Change**   | **No. of  | **I       | **Un      | **Deter   |
|                       | S         | mproved** | changed** | iorated** |
|                       | egments** |           |           |           |
+-----------------------+-----------+-----------+-----------+-----------+
| **F‑18 FDG (+) →F‑18  | **13**    | **13**    | **0**     | **0**     |
| FDG (‑)**             |           |           |           |           |
+-----------------------+-----------+-----------+-----------+-----------+
| **F‑18 FDG (+) →F‑18  | **6       | **3**     | **3 (1)** | **0**     |
| FDG (+)**             | (1)\***   |           |           |           |
+-----------------------+-----------+-----------+-----------+-----------+
| **F‑18 FDG (‑) →F‑18  | **22      | **7 (1)** | **15      | **0**     |
| FDG (‑)**             | (5)**     |           | (4)**     |           |
+-----------------------+-----------+-----------+-----------+-----------+
| **F‑18 FDG (‑) →F‑18  | **5 (4)** | **0**     | **1 (1)** | **4 (3)** |
| FDG (+)**             |           |           |           |           |
+-----------------------+-----------+-----------+-----------+-----------+
| **Total**             | **46      | **23      | **19      | **4 (3)** |
|                       | (10)**    | (1)**     | (6)**     |           |
+-----------------------+-----------+-----------+-----------+-----------+
| **\*Parentheses       |           |           |           |           |
| denote number of      |           |           |           |           |
| segments supplied     |           |           |           |           |
| with occluded         |           |           |           |           |
| grafts.**             |           |           |           |           |
|                       |           |           |           |           |
| **\*\* This table was |           |           |           |           |
| taken from the        |           |           |           |           |
| manuscript.**         |           |           |           |           |
+-----------------------+-----------+-----------+-----------+-----------+

[Safety]{.underline}: The safety of PET F‑18 FDG imaging was not
addressed in the manuscript.

[Conclusions in manuscript]{.underline}: Preoperative metabolic imaging
using PET appears to be useful for predicting the response to CABG.
Improvement in metabolic derangement was associated with improvement in
regional function after CABG.

[Reviewer\'s comments]{.underline}: A strength of the study was that the
wall motion analysis was performed by several blinded readers. Another
strength was that the success of revascularization was assessed
quantitatively (with N‑13 ammonia PET imaging). The authors specified
how the N‑13 ammonia scans that were obtained before revascularization
were aligned with those obtained after revascularization. Similarly, the
alignment of different imaging modalities (e.g., radionuclide
ventriculography and positron emission tomography) was also addressed.
Another relatively unique aspect of the study was that F‑18 FDG PET
imaging was done after patients had fasted, and without a glucose load.

Limitations of the study included the paucity of information provided
about the study subjects. Such limited data make it difficult to know to
whom the results may be generalizable. The manuscript did not specify
whether the image analyses of match and mismatch patterns (of F‑18 FDG
and N‑13 ammonia) were blinded. In this situation, blinding is of
particular importance because these image analyses were qualitative
(i.e., were performed visually).

**9. Tamaki N, Kawamoto M, Tadamura E, et al. Prediction of Reversible
Ischemia after Revascularization: Perfusion and Metabolic Studies with
Positron Emission Tomography. Circulation 1995;91:1697-1705.**

[Objective]{.underline}: The objective of this study was to compare the
value of resting perfusion studies with PET, exercise perfusion studies
with PET, and metabolic studies with PET for predicting improvement in
wall motion, as assessed by contrast or radionuclide ventriculography,
after revascularization.

[Design and sequence of events]{.underline}: This study was performed in
consecutive patients with chronic myocardial infarction who were to
undergo coronary revascularization with either CABG or angioplasty.
Prior to revascularization, contrast ventriculography was performed to
assess the motion of the left ventricular wall and to measure the left
ventricular ejection fraction. Patients then underwent PET imaging with
N-13 ammonia at rest and under stress to evaluate myocardial perfusion,
and with F‑18 FDG after fasting to evaluate myocardial metabolism. After
either CABG or angioplasty, a follow-up angiogram was performed to
assess the success of revascularization. Four to eight weeks after
revascularization, regional wall motion was assessed by contrast
ventriculography or radionuclide ventriculography.

Left ventricular wall motion was assessed by three blinded, experienced
readers. However, the manuscript did not specify the nature of the
information to which the readers were blinded. The PET images with N‑13
ammonia and F‑18 FDG were evaluated quantitatively. The manuscript did
not specify the number of readers or indicate whether the readers were
blinded.

[Subjects]{.underline}: The study enrolled consecutive patients with
chronic myocardial infarction. Patients with insulin-dependent diabetes
were excluded.

[F‑18 FDG positron emission tomographic studies]{.underline}: Patients
fasted for at least five hours before the F‑18 FDG scan. A radiation
dose of 80-300 MBq (2.2 to 8.1 mCi) of F‑18 FDG was injected with the
patient at rest. Approximately 60 minutes later, a scan was performed
for 10 to 15 minutes.

[N‑13 ammonia positron emission tomographic studies]{.underline}: Rest
and stress perfusion scans were performed separately within one week of
the F‑18 FDG study. Approximately 400 to 600 MBq (10.8 to 16.2 mCi) of
N-13 ammonia were injected at rest, and resting perfusion scanning was
started three minutes later. Two hours later, patients performed graded
exercise using a supine ergometer. Another dose of N-13 ammonia was
injected at peak exercise and the exercise was continued for an
additional 30 to 60 seconds. The stress perfusion scan was performed 3
minutes after N‑13 ammonia administration.

[Image analysis]{.underline}: In each patient, resting and stress N‑13
ammonia images were normalized to a normal reference region. The left
ventricular myocardium was divided into five segments to calculate the
mean regional perfusion as percent activity of the maximal counts in the
normal reference regions by using a circumferential profile analysis of
four to six short-axis slices of the N-13 ammonia distribution. Stress
and resting N‑13 ammonia images were compared using a circumferential
profile analysis based on the corresponding short-axis slices.

In each segment, F‑18 FDG uptake was quantitatively measured as the
percent (corrected for body weight) of the injected dose per 100 g of
tissue. F‑18 FDG images were shown as a parametric display as F‑18 FDG
uptake index (not normalized to uptake).

The images from the PET perfusion and metabolic studies were used to
predict improvement in wall motion after revascularization: (a) For the
F‑18 FDG images, hypoperfused segments with an increase in F‑18 FDG
uptake above the normal range (based on an F‑18 FDG uptake index\--not
normalization) were predicted to show functional improvement after
revascularization. Those with no increase in F‑18 FDG uptake were
defined as PET scarring. The normal range of F‑18 FDG uptake was
obtained in healthy subjects. (b) For the N‑13 ammonia images obtained
at rest, asynergic segments were divided into two groups to compare the
improvement in wall motion after revascularization: those with perfusion
of more than 50% of the maximal value in the whole myocardium were
considered to have reversible ischemia; those with perfusion of less
than 50% of the maximal value in the whole myocardium were considered to
have irreversible ischemia. (c) For the stress N‑13 ammonia images,
segments with stress perfusion more than 10% lower than resting
perfusion were considered to have stress-induced hypoperfusion and
reversible ischemia; those with lesser degrees of stress-induced
hypoperfusion were considered to have irreversible ischemia.

Left ventricular wall motion was assessed by three blinded, experienced
observers who used a five-point ordinal scale (normal, mild hypokinesis,
severe hypokinesis, akinesis, and dyskinesis). Improved wall motion,
from before revascularization to after revascularization, was defined as
an increase by one or more points in the wall motion score.

[Statistics]{.underline}: Comparisons of the predictive value of each
study were performed with χ^2^ analysis or Fisher\'s exact test. No
adjustments in p values were made to correct for multiple comparisons.

**Results:**

[Patient disposition and characteristics]{.underline}: Sixty one (61)
consecutive patients with chronic myocardial infarction underwent
myocardial perfusion and metabolic studies with PET before
revascularization. Forty-three (43) of these patients had a successful
revascularization and were included in the analysis. The remaining 18
subjects had inadequate revascularization and were not included in the
analysis. Of these 43 patients, 24 underwent CABG and 19 underwent PTCA.

The 43 patients included 41 men and 2 women. The patients had a mean age
of 58.1 years (range: 36 years to 72 years). The mean left ventricular
ejection fraction was 41% (range: 21% to 64%) All patients had regional
wall motion abnormalities and a history of myocardial infarction that
occurred more than 1 month before onset. Two patients had
non-insulin-dependent diabetes.

[Segment disposition and functional outcome]{.underline}: The left
ventricle of each of the 43 patients was divided into 5 segments,
yielding a total of 215 segments for possible evaluation. Of the 215
possible segments, 130 (60%) were asynergic before revascularization.
These 130 segments were used to evaluate functional recovery. After
revascularization, 51 segments (39%) showed improvement in the wall
motion abnormality, whereas the remaining 79 segments did not.

[PET imaging results:]{.underline} Among the 130 asynergic segments, an
increase in F‑18 FDG uptake was seen in 59 segments and no increase was
seen in 71 segments. After revascularization, 45 of the 59 segments with
increased F‑18 FDG uptake showed improved regional wall motion
(PPV=76%), whereas 65 of the 71 segments without increased F‑18 FDG
uptake failed to improve (NPV=92%).

Overall, the positive and negative predictive values for improvement in
asynergy were 48% and 87% by the rest perfusion study, 63% (P=0.05
versus the rest value) and 87% by the rest-stress perfusion study, and
76% (P\<0.01 versus the rest value) and 92% by the F‑18 FDG study. The
tables below summarize the PET imaging results for F‑18 FDG, N‑13
ammonia at rest, and N‑13 ammonia under stress. These results are
summarized in the tables below.

  ------------------------- --------------- -------------- ---------------
  **Table 29. Number of                                    
  Hypoperfused, Asynergic                                  
  Myocardial Segments with                                 
  Improved Segmental Wall                                  
  Motion after                                             
  Revascularization:                                       
  Relation to F‑18 FDG                                     
  Uptake Index**                                           

                            **Improved                     
                            Segmental Wall                 
                            Motion**                       

  **F-18 FDG Uptake Index** **Present**     **Absent**     **Total**

  **Increased**             **45**          **14**         **59**

  **Not increased**         **6**           **65**         **71**

  **Total**                 **51**          **79**         **130**
  ------------------------- --------------- -------------- ---------------

+-----------------------+----------------------+----------------------+
| **Table 30.           |                      |                      |
| Performance of PET    |                      |                      |
| F‑18 FDG Uptake Index |                      |                      |
| When Used to Predict  |                      |                      |
| Improved Wall Motion  |                      |                      |
| in Hypoperfused,      |                      |                      |
| Asynergic Myocardial  |                      |                      |
| Segments**            |                      |                      |
+-----------------------+----------------------+----------------------+
| **Performance         | **Value**            | **95% CI**           |
| Measure**             |                      |                      |
|                       | **(no. of            |                      |
|                       | segments)**          |                      |
+-----------------------+----------------------+----------------------+
| **Sensitivity (%)**   | **88 (45/51)**       | **(76, 96)**         |
+-----------------------+----------------------+----------------------+
| **Specificity (%)**   | **82 (65/79)**       | **(72, 90)**         |
+-----------------------+----------------------+----------------------+
| **PPV (%)**           | **76 (45/59)**       | **(63, 86)**         |
+-----------------------+----------------------+----------------------+
| **NPV (%)**           | **92 (65/71)**       | **(82, 97)**         |
+-----------------------+----------------------+----------------------+
| **Accuracy (%)**      | **85 (110/130)**     | **(78, 91)**         |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **5.0**              |                      |
| (+)**                 |                      |                      |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **0.14**             |                      |
| (‑)**                 |                      |                      |
+-----------------------+----------------------+----------------------+

  ------------------------- --------------- -------------- ---------------
  **Table 31. Number of                                    
  Asynergic Myocardial                                     
  Segments with Improved                                   
  Segmental Wall Motion                                    
  after Revascularization:                                 
  Relation to Rest                                         
  Perfusion with N‑13                                      
  ammonia**                                                

                            **Improved                     
                            Segmental Wall                 
                            Motion**                       

  **Rest Perfusion with     **Present**     **Absent**     **Total**
  N‑13 Ammonia**                                           

  **≥50% of maximum**       **43**          **25**         **68**

  **\<50% of maximum**      **8**           **54**         **62**

  **Total**                 **51**          **79**         **130**
  ------------------------- --------------- -------------- ---------------

+-----------------------+----------------------+----------------------+
| **Table 32.           |                      |                      |
| Performance of Rest   |                      |                      |
| Perfusion with N‑13   |                      |                      |
| Ammonia When Used to  |                      |                      |
| Predict Improved Wall |                      |                      |
| Motion in Asynergic   |                      |                      |
| Myocardial Segments** |                      |                      |
+-----------------------+----------------------+----------------------+
| **Performance         | **Value**            | **95% CI**           |
| Measure**             |                      |                      |
|                       | **(no. of            |                      |
|                       | segments)**          |                      |
+-----------------------+----------------------+----------------------+
| **Sensitivity (%)**   | **84 (43/51)**       | **(71, 93)**         |
+-----------------------+----------------------+----------------------+
| **Specificity (%)**   | **68 (54/79)**       | **(57, 78)**         |
+-----------------------+----------------------+----------------------+
| **PPV (%)**           | **63 (43/68)**       | **(50, 75)**         |
+-----------------------+----------------------+----------------------+
| **NPV (%)**           | **87 (54/62)**       | **(76, 94)**         |
+-----------------------+----------------------+----------------------+
| **Accuracy (%)**      | **75 (97/130)**      | **(67, 82)**         |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **2.7**              |                      |
| (+)**                 |                      |                      |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **0.23**             |                      |
| (‑)**                 |                      |                      |
+-----------------------+----------------------+----------------------+

  ------------------------- --------------- -------------- ---------------
  **Table 33. Number of                                    
  Asynergic Myocardial                                     
  Segments with Improved                                   
  Segmental Wall Motion                                    
  after Revascularization:                                 
  Relation to Stress                                       
  Perfusion with N‑13                                      
  Ammonia**                                                

                            **Improved                     
                            Segmental Wall                 
                            Motion**                       

  **Stress Perfusion with   **Present**     **Absent**     **Total**
  N‑13 Ammonia**                                           

  **\> 10% Lower than       **47**          **51**         **98**
  Resting Perfusion**                                      

  **\<10% Lower than        **4**           **28**         **32**
  Resting Perfusion**                                      

  **Total**                 **51**          **79**         **130**
  ------------------------- --------------- -------------- ---------------

+-----------------------+----------------------+----------------------+
| **Table 34.           |                      |                      |
| Performance of Stress |                      |                      |
| Perfusion with N‑13   |                      |                      |
| Ammonia When Used to  |                      |                      |
| Predict Improved Wall |                      |                      |
| Motion in Asynergic   |                      |                      |
| Myocardial Segments** |                      |                      |
+-----------------------+----------------------+----------------------+
| **Performance         | **Value**            | **95% CI**           |
| Measure**             |                      |                      |
|                       | **(no. of            |                      |
|                       | segments)**          |                      |
+-----------------------+----------------------+----------------------+
| **Sensitivity (%)**   | **92 (47/51)**       | **(81, 98)**         |
+-----------------------+----------------------+----------------------+
| **Specificity (%)**   | **35 (28/79)**       | **(25, 47)**         |
+-----------------------+----------------------+----------------------+
| **PPV (%)**           | **48 (47/98)**       | **(38, 58)**         |
+-----------------------+----------------------+----------------------+
| **NPV (%)**           | **87.5 (28/32)**     | **(71, 96)**         |
+-----------------------+----------------------+----------------------+
| **Accuracy (%)**      | **58 (75/130)**      | **(49, 66)**         |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **1.4**              |                      |
| (+)**                 |                      |                      |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **0.22**             |                      |
| (‑)**                 |                      |                      |
+-----------------------+----------------------+----------------------+

[Safety]{.underline}: The safety of F‑18 FDG and N‑13 ammonia PET
imaging were not addressed in this manuscript.

[Conclusions in manuscript]{.underline}: F‑18 FDG PET provided the best
predictive value for improvement in wall motion after revascularization.
On the other hand, N‑13 ammonia PET is useful for predicting
nonreversible myocardial scarring when it shows severe hypoperfusion at
rest or hypoperfusion without stress-induced ischemia.

[Reviewer\'s comments]{.underline}: One of the strengths of this study
was that analyses were performed on 42 patients, the second largest
sample size among the principal studies. Wall-motion assessments were
performed blindly by multiple readers. The study compared different
diagnostic tests, and the predictive performance of F‑18 FDG PET, rest
perfusion with N‑13 ammonia, and stress perfusion with N‑13 ammonia were
each evaluated with respect to the functional outcome (\"truth\"). Such
direct comparisons of diagnostic test performance provide useful data to
the practicing health care providers, who often lack sufficient
comparative performance data upon which to base a choice. In this study,
the success of coronary revascularization was assessed with coronary
arteriography. Thus, the diagnostic performance data are not confounded
by non-drug factors, such as the success of coronary revascularization.
However, additional analyses that included all patients, including those
with unsuccessful revascularization, would have provided useful data on
the diagnostic performance as might be expected in actual use and would
have provided more information on the ultimate clinical usefulness of
the diagnostic test.

A limitation of the study is that the manuscript did not specify the
nature of the information to which the readers were blinded when they
performed the wall-motion analyses. The manuscript did not specify the
number of readers for the PET image analyses, nor did it indicate
whether these analyses were blinded. However, these analyses were
quantitative, limiting potential bias that might be introduced by
unblinded evaluations. \"By-patient\" analyses were not performed.
Global ventricular function and clinical outcomes were not assessed.

**10. Tillisch J, Brunken R, Marshall R, et al. Reversibility of Cardiac
Wall-Motion Abnormalities Predicted by Positron Tomography. N Engl J Med
1986;314:884‑888**.

**Description of Study**

[Objective]{.underline}: The objective of this study was to determine
whether preserved myocardial uptake of F‑18 FDG in a region with
abnormal wall motion at rest is an indication of myocardial metabolic
viability, and whether reversibility of the wall-motion disturbance (as
assessed by radionuclide or contrast ventriculography) by adequate
surgical revascularization can be predicted with these criteria.

[Design and sequence of events]{.underline}: The study enrolled
consecutive patients with resting regional wall-motion abnormalities who
were to undergo CABG. Prior to revascularization,

left ventricular wall motion was assessed with either radionuclide or
contrast ventriculography. PET studies with F‑18 FDG and N‑13 ammonia
were performed to assess myocardial metabolism and perfusion. After
CABG, adequate revascularization of an abnormally contracting region was
assessed by review of the operative report and the preoperative coronary
angiogram. Left ventricular wall motion was reassessed with radionuclide
or contrast ventriculography.

The wall motion assessment was performed by three experienced contrast
radiologists who were blinded to clinical or (sic) tomographic data. The
analysis of the PET studies with F‑18 FDG and N‑13 ammonia were
quantitative. The manuscript did not specify the number of readers of
these PET images, or whether these readers were blinded.

[N‑13 ammonia and F‑18 FDG positron emission tomographic
studies]{.underline}: Imaging was performed when patients were
post-prandial. Patients were administered 50 grams of glucose by mouth,
60-90 minutes before F‑18 FDG administration. N‑13 ammonia (15-20 mCi)
was injected intravenously, and three minutes later, six sequential
cross-sectional PET images 1.0-1.5 cm apart were obtained. Subsequently,
F‑18 FDG (10 mCi) was injected, and 45 minutes later cross-sectional
imaging was performed again.

[Image analysis]{.underline}: For PET images, the left ventricle was
divided into twelve 30^o^ sectors. N‑13 ammonia and F‑18 FDG counts were
normalized to maximum counts in all planes, and the counts were compared
sector by sector. Normalized N‑13 ammonia and F‑18 FDG counts for each
sector that had already been established were applied in this study.
Infarction was represented as a concordant reduction in normalized N‑13
ammonia and F‑18 FDG counts two standard deviations below normal for
each of three or more continuous sectors. Ischemia was indicated by a
difference between normalized F‑18 FDG and N‑13 ammonia counts that was
greater than two standard deviations above the normal value for the
difference in a given sector.

Resting regional wall-motion abnormalities were predicted preoperatively
to be reversible if F‑18 FDG uptake was normal or increased in the
region, and if N‑13 ammonia uptake was either normal or decreased. An
abnormality was predicted to be irreversible if both N‑13 ammonia and
F‑18 FDG uptake were depressed.

For wall-motion analysis, images from radionuclide or contrast
ventriculography were divided into seven regions. Regional wall-motion
was graded on a scale of 0 to 4 (normal, mildly hypokinetic, severely
hypokinetic, akinetic, or dyskinetic) by three blinded readers. Improved
wall motion, from before revascularization to afterwards, was defined as
an improvement of at least one grade.

Each PET image was anatomically correlated with a ventriculographic
image by reconstructing the PET image in 3 dimensions and assigning
anatomical regions on the PET scan to comparable regions on the
ventriculogram (isotopic or contrast). Regional concordance was then
maintained for each isotopic or contrast study.

[Statistics]{.underline}: Interobserver variation was determined by
analysis of variance. All other statistics were determined with a
two-tailed Student\'s t‑test.

**Results:**

[Patient disposition and characteristics]{.underline}: Seventeen
consecutive patients were included in the study, all of whom were
included in the analysis. The 17 patients included 16 men and 1 woman.
Eleven patients had a left ventricular ejection fraction of less than
40%. Sixteen patients had a previous myocardial infarction: two patients
were studied within two weeks of myocardial infarction; the other 15 had
infarction an average of 8 weeks (rang, 6 to 14) before the study.

[Segment disposition and functional outcome]{.underline}: Follow-up of
wall motion occurred 12-18 weeks after CABG in 13 patients, in 6-10
weeks in 2 patients, and in 3 weeks in 2 patients. For wall-motion
analysis, the left ventricle of each of the 17 patients was divided into
seven segments, yielding 119 segments for possible evaluation. Of the
119 possible segments, 73 had abnormal resting wall motion, of which 67
were considered to have been adequately revascularized. Thus, 67 of 119
(56%) segments were used to evaluate functional recovery.
Postoperatively, 37 of these 67 segments (51%) improved, whereas the
remaining 30 did not. Improvement of at least one full grade occurred in
9/21=43% mildly hypokinetic regions, 21/37 (57%) severely hypokinetic
regions, 6/14 = 43 % akinetic regions, and in the single dyskinetic
region.

The mean preoperative wall-motion score of the regions predicted to
improve was 2.0±0.8 (equivalent to severe hypokinesis), which improved
significantly to 0.6±0.6 postoperatively (p\<0.05). The mean
preoperative wall-motion score of those regions predicted not to improve
was 2.4±0.5, and the postoperative score 2.6±0.4 (difference not
significant).

[PET imaging results]{.underline}: Among the 67 asynergic segments that
had been adequately revascularized, 41 were predicted to have reversible
wall motion abnormalities. Specifically, of these 41 regions, 25 of
these had normal preoperative N‑13 ammonia and F‑18 FDG uptake (22
improved postoperative wall motion, 3 not improved). The remaining 16
regions had decreased N‑13 ammonia uptake, but either normal or
increased F‑18 FDG uptake (13 improved postoperative wall motion, 3 not
improved). Thus, 35 of the 41 predictions of reversible wall motion were
correct, yielding a positive predictive value of 85%. Conversely, of the
26 regions that were predicted to have irreversible abnormalities, 24
failed to improve, yielding a negative predictive value of 92%. These
results are summarized in the tables below.

+-------------------------+--------------+-------------+--------------+
| **Table 35. Number of   |              |             |              |
| Asynergic Myocardial    |              |             |              |
| Segments with Improved  |              |             |              |
| Segmental Wall Motion   |              |             |              |
| after                   |              |             |              |
| Revascularization:      |              |             |              |
| Relation to Pattern of  |              |             |              |
| F‑18 FDG and N‑13       |              |             |              |
| Ammonia Uptake**        |              |             |              |
+-------------------------+--------------+-------------+--------------+
|                         | **Improved   |             |              |
|                         | Segmental    |             |              |
|                         | Wall         |             |              |
|                         | Motion**     |             |              |
+-------------------------+--------------+-------------+--------------+
| **Pattern of F-18 FDG   | **Present**  | **Absent**  | **Total**    |
| and**                   |              |             |              |
|                         |              |             |              |
| **N‑13 Ammonia Uptake** |              |             |              |
+-------------------------+--------------+-------------+--------------+
| **Mismatch**            | **35**       | **6**       | **41**       |
+-------------------------+--------------+-------------+--------------+
| **Match**               | **2**        | **24**      | **26**       |
+-------------------------+--------------+-------------+--------------+
| **Total**               | **37**       | **30**      | **67**       |
+-------------------------+--------------+-------------+--------------+

+-----------------------+----------------------+----------------------+
| **Table 36.           |                      |                      |
| Performance of PET    |                      |                      |
| F‑18 FDG and N‑13     |                      |                      |
| Ammonia Uptake        |                      |                      |
| Patterns When Used to |                      |                      |
| Predict Improved Wall |                      |                      |
| Motion in Asynergic   |                      |                      |
| Myocardial Segments** |                      |                      |
+-----------------------+----------------------+----------------------+
| **Performance         | **Value**            | **95% CI**           |
| Measure**             |                      |                      |
|                       | **(no. of            |                      |
|                       | segments)**          |                      |
+-----------------------+----------------------+----------------------+
| **Sensitivity (%)**   | **95 (35/37)**       | **(82, 99)**         |
+-----------------------+----------------------+----------------------+
| **Specificity (%)**   | **80 (24/30)**       | **(61, 92)**         |
+-----------------------+----------------------+----------------------+
| **PPV (%)**           | **85 (35/41)**       | **(70, 94)**         |
+-----------------------+----------------------+----------------------+
| **NPV (%)**           | **92 (24/26)**       | **(75, 99)**         |
+-----------------------+----------------------+----------------------+
| **Accuracy (%)**      | **88 (59/67)**       | **(78, 95)**         |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **4.7**              |                      |
| (+)**                 |                      |                      |
+-----------------------+----------------------+----------------------+
| **Likelihood ratio    | **0.07**             |                      |
| (‑)**                 |                      |                      |
+-----------------------+----------------------+----------------------+

[Other Findings]{.underline}: The mean left ventricular ejection
fraction in the study population was 32±14% before CABG, and 41±15%
afterward (P\<0.05). In the subset of 11 patients in whom resting wall
motion in two or more regions improved postoperatively, the mean
ejection fraction increased from 30±11% to 45±14% (P\<0.05).

The predictive value of electrocardiograms was evaluated. Twenty-eight
of the 73 abnormally contracting regions were in areas believed to have
\"transmural\" infarcts as evidenced by Q waves with a duration of at
least 0.04 seconds. After revascularization, wall motion did not improve
in 12 of these 28 regions, yielding a negative predictive value of only
43%. Note, however, that unlike the evaluation of the predictive value
of PET imaging, the evaluation of the predictive value of
electrocardiography utilized all 73 asynergic segments, regardless of
whether adequately revascularized or not.

[Safety]{.underline}: The safety profiles of F‑18 FDG PET and N‑13
ammonia PET imaging were not addressed in this manuscript.

[Conclusions in manuscript]{.underline}: PET imaging with N‑13 ammonia
to assess blood flow and F‑18 FDG to assess the metabolic viability of
the myocardium is an accurate method of predicting potential
reversibility of wall-motion abnormalities after surgical
revascularization.

[Reviewer\'s comments]{.underline}: Published in 1986, this study is one
of the seminal articles for the use of F‑18 FDG PET in the evaluation of
the reversibility of left ventricular dysfunction in patients with
coronary artery disease. Although the study was relatively small (n=17),
many desirable features were incorporated into the design. The wall
motion assessments were performed by blinded readers, decreasing
potential bias that might arise from unblinded assessments. Wall motion
assessments were made by several readers, allowing interreader
variability to be assessed and increasing the generalizability of the
results. Consecutive patients were enrolled, decreasing potential
selection bias, and data on all were included in the analysis. The
success of revascularization was assessed. The manuscript describes how
regional concordance of myocardial segments was maintained when several
imaging procedures were performed.

One limitation of the study is its small sample size. In addition, the
manuscript did not specify the number of readers for the PET images, or
whether these readers were blinded. However, the quantitative nature of
the PET analysis decreases the amount of potential bias that might be
introduced by an unblinded image analysis. Few patient characteristics
were described, increasing the difficulty of being able to describe the
population to which the results apply most directly. As in several of
the other principal studies, only adequately revascularized segments
were included in the analysis, making more difficult the assessment of
the ultimate clinical benefit of performing the PET evaluation. The
study did not include \"by patient\" analyses, preventing direct
assessments of clinical benefit. Although changes in global left
ventricular function were evaluated, the results were not correlated
with the PET findings. Thus, it is unclear whether PET imaging allows
prediction of global functional improvement (in addition to segmental
functional improvement). Clinical outcomes were not assessed.

D. Secondary Published Literature

The review of the ten primary published articles focused on whether PET
imaging with F‑18 FDG, when used in combination with assessments of
myocardial perfusion, is able to predict the recovery of regional or
segmental contractile function in the left ventricle after myocardial
revascularization. Of greater clinical significance, is whether such
improvements in segmental ventricular function are also indicative of
improvements in global ventricular function. Moreover, the most
important concerns for the care of patients with coronary artery disease
are a) whether such predictions of regional recovery of ventricular
function influence clinical decision making appropriately, and
b) whether such improvements in regional or global ventricular function
lead to amelioration of symptoms, increases in exercise tolerance, or
enhancement of survival. The abstracts of several published literature
articles submitted by the Institute for Clinical PET that address these
issues are reproduced and briefly summarized below. These articles
provide support that cardiac PET imaging with F‑18 FDG in this context
provides information that is clinically useful. However, because of the
design of the studies (e.g., retrospective, nonrandomized, small size),
the articles fall short of providing sufficient evidence to support a
patient-management indication. Such a patient management indication
would specify explicitly that cardiac imaging with PET F‑18 FDG in this
context directly results in appropriate diagnostic or therapeutic
management of patients. The articles fall short of providing sufficient
evidence to support an indication that cardiac imaging with PET F‑18 FDG
is able to predict improvements in global ventricular function,
symptoms, clinical functioning, or survival.

**1. Di Carli MF, Davidson M, Little R, et al. Value of metabolic
imaging with positron emission tomography for evaluating prognosis in
patients with coronary artery disease and left ventricular dysfunction.
Am J Cardiol 1994;73:527‑533.**

Objective: The objective of this study was  to evaluate the prognostic
value of PET mismatch, and its interrelation with the choice of medical
therapy or revascularization for predicting survival and improvement in
symptoms of heart failure in patients with coronary artery disease and
left ventricular dysfunction

Description of study: The study evaluated 93 consecutive patients with
angiographic coronary artery disease and a mean left ventricular
ejection fraction of 25%. The patients underwent cardiac PET studies for
assessment of hypoperfused yet viable myocardium (\"mismatch pattern\")
using N‑13 ammonia and F‑18 FDG and were followed for an average of 13.6
months. Fifty patients underwent medical treatment and 43 underwent
revascularization.

Results: A stepwise Cox model analysis showed that the extent of
mismatch had a negative effect on survival (p=0.02), whereas
revascularization had a positive effect on survival (p=0.04). The annual
probability of survival of patients with mismatch receiving medical
therapy was lower than of those without mismatch (50 vs. 92%, p=0.007).
Patients who underwent revascularization had a higher survival rate than
those treated medically (88 vs 50%, p=0.03). The presence of mismatch
also predicted improvement in heart failure symptoms after
revascularization (p\<0.001).

Conclusions in manuscript: These results suggest that the presence of
mismatch in patients with coronary artery disease and severe left
ventricular dysfunction is associated with poor annual survival with
medical therapy. Revascularization in patients with PET mismatch appears
to be associated with improved survival and symptoms of heart failure.

Reviewer\'s comments: This was a retrospective, nonrandomized study,
which limits the conclusions that can be drawn.

**2. Di Carli M, Asgarzdie, BA, Schelbert HR, et al. Quantitative
relation between myocardial viability and improvement in heart failure
symptoms after revascularization in patients with ischemic
cardiomyopathy. Circulation 1995;92:3436‑3444.**

Objective: The purpose of this study was to test the hypothesis that
improvement in heart failure symptoms after CABG in patients with
ischemic cardiomyopathy would be related to the extent, magnitude, and
location of viable myocardium, as determined by quantitative analysis of
preoperative PET images.

Description of study: The study evaluated 36 patients with ischemic
cardiomyopathy and a mean left ventricular ejection fraction of 28% who
were undergoing CABG. Preoperative extent and severity of perfusion
abnormalities and myocardial viability (flow-metabolism mismatch) were
assessed by use of quantitative analysis of PET images with N‑13 ammonia
and F‑18 FDG. Each patient\'s functional status was determined before
and after CABG by use of a Specific Activity Scale.

Results: The total extent of PET mismatch correlated linearly with
percent improvement in functional status after CABG (r=0.87, p\<0.0001).
A blood flow-metabolism mismatch of ≥18% was associated with a
sensitivity of 76% and a specificity of 78% for predicting a change in
functional status after revascularization. Patients with mismatches ≥18%
achieved a significantly higher functional status compared with those
with mismatch \<5% (5.7±0.8 versus 4.9±0.7 metabolic equivalents,
p=0.009). This resulted in an improvement of 107% in patients with
mismatches ≥18% compared with only 34% in patients with mismatch \<5%

Conclusions in manuscript: These results suggest that in patients with
ischemic cardiomyopathy, the magnitude of improvement in heart failure
symptoms after CABG is related to the preoperative extent and magnitude
of myocardial viability as assessed by use of PET imaging. Patients with
larger perfusion-metabolism mismatches exhibit the greatest clinical
benefit after CABG.

Reviewer\'s comments: This was an observational study.

**3. Depré C, Vanoverschelde JJ, Gerber B, et al. Correlation of
functional recovery with myocardial blood flow, glucose uptake, and
morphologic features in patients with chronic left ventricular ischemic
dysfunction undergoing coronary artery bypass grafting. J Thorac
Cardiovasc Surg 1997;113:371‑8**

Objectives: The objective of this study was to investigate the influence
of preoperative myocardial ultrastructure and metabolism on recovery of
contractile function after coronary artery bypass grafting in patients
with coronary artery disease and left ventricular dysfunction.

Description of Study: Dynamic positron emission tomography with N‑13
ammonia and F‑18 FDG was used to assess myocardial perfusion and glucose
uptake in 53 patients scheduled for coronary revascularization because
of coronary artery disease and left ventricular dysfunction. The degree
of tissue fibrosis and the presence of potentially reversible
alterations of cardiomyocytes (loss of myofilaments and accumulation of
glycogen) were quantified from transmural biopsy specimens. These were
harvested from the center of the dysfunctional area during the operation
and analyzed with a light microscope. The recovery of contractile
performance was assessed from the changes in left ventricular function
at contrast ventriculography or echocardiography before and six months
after the operation.

Results: According to postoperative changes in regional wall motion,
left ventricular function was considered to have improved in 34
patients, whereas dysfunction persisted in 19 patients. In patients with
improved wall motion, ejection fraction rose by 12% and end-systolic
volume decreased by 28%. By contrast, in patients with persistent
dysfunction, ejection fraction decreased by 6% and end-systolic volume
increased by 25%. Before revascularization, myocardium with reversible
dysfunction displayed higher levels of absolute myocardial blood flow,
higher myocardial glucose uptake, less tissue fibrosis, and more altered
cardiomyocytes than myocardium with persistent dysfunction. Significant
correlations were found between regional blood flow and the surface of
the biopsy specimen covered by fibrosis, as well as between glucose
uptake and the density of altered cardiomyocytes.

Conclusions in manuscript: In patients with left ventricular ischemic
dysfunction, the recovery of regional and global left ventricular
function after surgical revascularization is associated with higher
preoperative blood flow and glucose uptake, with less tissue fibrosis
and a higher amount of viable cardiomyocytes in the dysfunctional area.

Reviewer\'s comments: This study provided morphologic associations of
PET with F‑18 FDG and N‑13 ammonia.

**4. Marwick TH, Nemec JJ, Lafont A, et al. Prediction by postexercise
fluoro-18-deoxyglucose positron emission tomography of improvement in
exercise capacity after revascularization. Am J Cardiol
1992;69:854‑859**

Objectives: This study was designed to determine whether the combined
extent of hibernating and transiently ischemic myocardium detected by
F‑18 FDG imaging could be used to predict the occurrence of functional
benefits from revascularization. The study examined the influence of the
amount of F‑18 FDG-avid myocardium on changes in left ventricular
function and exercise parameters after revascularization.

Description of Study: Echocardiography and exercise testing were
performed before and after intervention in 23 patients who had undergone
positron emission tomography for the evaluation of myocardial perfusion
(using Rb‑82), and postexercise F‑18 FDG imaging in the fasting state.
Follow-up echocardiography (22±14 weeks after revascularization) was
compared with preoperative FDG activity in 7 myocardial regions per
patient.

Results: Systolic function improved after intervention in 19 of 26
malperfused dysfunctional F‑18 FDG‑avid regions (73%), and did not
improve in 35 of 47 dysfunctional regions without increased F‑18 FDG
uptake (74%). The influence of the amount of F‑18 FDG-avid tissue on
changes in functional state was examined by comparing nine patients with
multiple (≥2) F‑18 FDG-avid regions with the remainder. Those with
multiple F‑18 FDG-avid regions demonstrated improvement in peak
rate-pressure product 20±4 to 26±4 x 10^3^, p\<0.02), and percentage of
maximal heart rate achieved at peak 84±10% to 93±6%, p=0.04), neither of
which changed significantly in the remaining patients. Exercise capacity
increased from 5.6±2.7 to 7.5±1.7 METS in the group with multiple F‑18
FDG-avid regions; this increase of 55±18% exceeded the increase of
13±10% in the remainder (p=0.04).

Conclusions in manuscript: Imaging of postexercise F‑18 FDG uptake in
patients with previous myocardial infarction may predict improvement of
regional systolic function and exercise parameters after
revascularization.

**5. Eitzman D, Al-Aouar Z, Kanter HL, et al. Clinical outcome of
patients with advanced coronary artery disease after viability studies
with positron emission tomography. J Am Coll Cardiol 1992;20:559‑65.**

Objectives: The objective of this study was to determine whether the
identification of jeopardized myocardium with positron emission
tomography predicts subsequent cardiac events and whether
revascularization affects the clinical outcome in patients with advanced
coronary artery disease and impaired left ventricular function. The
study also examined the relation between scintigraphic results and
subsequent change in functional status in this patient group.

Description of study: Eighty-two patients with advanced coronary artery
disease and impaired left ventricular function underwent PET imaging to
assess myocardial viability before coronary artery revascularization.

Results: Forty patients underwent successful revascularization. Patients
who exhibited evidence of metabolically compromised myocardium by PET
(decreased blood flow with preserved metabolism) who did not undergo
subsequent revascularization were more likely to experience a myocardial
infarction, death, cardiac arrest or late revascularization due to
development of new symptoms than were the other patient groups
(p\<0.01). Concordantly decreased flow and metabolism in segments of
previous infarction did not affect outcome in patients with or without
subsequent revascularization. Those with a compromised myocardium who
did undergo revascularization were more likely to experience an
improvement in functional class than were patients with preoperative PET
findings of concordant decrease in flow and metabolism.

Conclusions in manuscript: PET myocardial viability imaging appears to
identify patients at increased risk of having an adverse cardiac event
or death. Patients with impaired left ventricular function and PET
evidence for jeopardized myocardium appear to have the most benefit from
a revascularization procedure.

E. Safety Evaluation:

At the time of its approval in 1994, F‑18 FDG was found to be safe and
effective in PET imaging for the identification of regions of abnormal
glucose metabolism associated with foci of epileptic seizures. As
specified in the labeling, the recommended dose for this use in an adult
(70 kg) is 185‑375 MBq (5‑10 mCi), by intravenous injection. Since its
approval, no adverse event reports have been received for this use.

None of the reviewed articles for cardiac applications of F‑18 FDG
included any information about its safety. Thus, it is not clear whether
a) safety parameters were monitored and no adverse events were noted, or
b) safety parameters were monitored, and adverse events occurred but
were not reported. Doses that were used for cardiac imaging generally
were in the range of 185‑375 MBq (5‑10 mCi).

As summarized by Dr. Florence Houn in her review of possible oncologic
indications for F‑18 FDG, safety concerns were also not identified in
the safety studies performed by Edward Silberstein and Janet Ryan, and
by Dr. Silberstein and the Pharmacopeia Committee of the Society of
Nuclear Medicine (a retrospective and prospective study).

Because F‑18 FDG is often administered for cardiac imaging after
ingestion of a glucose load or may be administered after fasting,
possible safety concerns arise in patients with impaired glucose
homeostasis (e.g., patients with diabetes mellitus).

Otherwise, additional specific safety concerns have not been noted in
the review of the use of F‑18 FDG in cardiac imaging, or in the types of
patients who were included in these studies.

F. Overall Assessment

[Trial Design]{.underline}:

[Prospective studies]{.underline}: The ten principal studies were
prospective and several evaluated consecutive patients. Consecutive
enrollment of patients helps to decrease potential selection bias in the
choice of patients for inclusion in the study. Just as in prospective
randomized clinical trials of therapeutic agents in which patients are
assigned to treatment group, prospective study designs for diagnostic
agents decrease biases that may arise when patient outcomes and results
of imaging are already known (e.g., as in retrospective data analyses).
However, publication bias, in which only \"positive\" studies are
accepted for publication, may have limited the sample of studies that
were available for this review.

[Adequacy of controls]{.underline}: As discussed in the introduction,
the ten principal studies that were reviewed for efficacy were all of a
similar trial design. In each study, the performance of PET imaging with
F‑18 FDG was measured against a functional outcome: improvement of
segmental contractile function after myocardial revascularization. For
the purposes of this review, this functional outcome was the endpoint of
primary interest. Changes in myocardial function were assessed by
evaluating segmental wall motion before revascularization and
afterwards. The methods by which segmental wall motion were assessed
include echocardiography, radionuclide ventriculography, and contrast
ventriculography. All three of these methods are sufficiently valid and
reliable for the purpose of evaluating segmental wall motion. All three
methods are able to adequately assess the \"true\" functional status of
the myocardium. Thus, each of the ten principal studies was
appropriately controlled.

[Blinding]{.underline}: Because it helps to minimize potential bias,
blinding the readers during image analysis is one of the most important
design features of imaging trials. For the purposes of this review, two
types of blinding were deemed to be most critical: a) blinding of those
who evaluated changes in segmental contractile function to the results
of the PET imaging studies and, conversely, b) blinding of those who
analyzed the PET images to the results of the analysis of segmental
contractile function. Stated differently, readers who were analyzing
truth (i.e., segmental contractile function) should have been blinded to
the imaging results from the test article (i.e., PET F‑18 FDG scans),
and vice versa.

*Blinding of image analyses for assessment of ventricular function:* In
the ten principal studies, the analysis of segmental contractile
function was generally qualitative (e.g., an ordinal wall-motion scale
where 1=normal, 2=hypokinesia, 3=akinesia, 4=dyskinesia), whereas the
analysis of the PET images was generally quantitative. Qualitative
wall-motion analyses are visual and involve substantial judgement on the
part of the reader (as is also true for qualitative interpretation of
PET images). Thus, for the purposes of this review, blinding of those
who performed these qualitative analyses was felt to be particularly
important. Seven of the ten principal studies specified that the
analysis of segmental contractile function was performed by blinded
readers (i.e., studies 1, 3, 4, 7, 8, 9, and 10). Unfortunately, in four
of these studies the manuscripts specified only that these readers were
blinded, without indicating to what information they were blinded
(studies 4, 7, 9, and 10). For example, readers may be blinded to the
results of the PET studies, to clinical information, to the results of
imaging with other modalities, etc. However, it seemed likely that in
these four cases the readers were in fact blinded to the PET results, in
part because that interpretation is consistent with the conventional use
of the term \"blinding\" in imaging trials, and in part because the
trials were prospective, suggesting that the PET images obtained before
revascularization may have been analyzed before follow-up assessments
were made of ventricular function after revascularization.

*Blinding of PET image analyses:* Quantitative analyses of PET images
also may involve judgement by the reader, which may influence the
results of the analyses (e.g., operator-interactive programs,
identifying regions of interest, delineating segments, choosing the
sites from which counts are sampled). Generally, however, the
possibility of bias during quantitative analyses was felt to be
substantially less than during qualitative analyses. Most of the
principal studies employed quantitative or semi-quantitative analyses of
the PET images. Overall, therefore, blinding readers of the PET images
to the segmental contractile results was less of a concern than vice
versa. However, in one study (study #5) the PET images were analyzed
qualitatively and the manuscript did not specify that the readers were
blinded to the wall-motion analysis. These readers in this study were
blinded to the perfusion results. Similarly, in another study (study
#8), the PET images were analyzed visually for match-mismatch patterns,
but the manuscript did not indicate if the readers were blinded to the
wall-motion analysis.

Overall, considering these ten studies in aggregate, blinding of the
readers to critical information was sufficient, though not optimal, in
this set of articles.

[Study size]{.underline}: A total of 298 patients were evaluated in the
ten principal studies. As shown in the first column of the following
table, the smallest study evaluated 14 patients and the largest
evaluated 48 patients. Thus, even the largest study evaluated relatively
small numbers of patients. Larger sample sizes in each of these studies
would have been preferable because as a rule, the greater the number of
patients, the greater the generalizability of the study. Moreover, large
sample sizes typically provide better estimates of the diagnostic
performance of a drug and narrower confidence intervals than small
sample sizes (with all other things being equal).

+---------+--------+--------+--------+--------+----------+----------+
| **Table |        |        |        |        |          |          |
| 37:     |        |        |        |        |          |          |
| Number  |        |        |        |        |          |          |
| of      |        |        |        |        |          |          |
| P       |        |        |        |        |          |          |
| atients |        |        |        |        |          |          |
| and     |        |        |        |        |          |          |
| S       |        |        |        |        |          |          |
| egments |        |        |        |        |          |          |
| in the  |        |        |        |        |          |          |
| Ten     |        |        |        |        |          |          |
| Pr      |        |        |        |        |          |          |
| incipal |        |        |        |        |          |          |
| Tria    |        |        |        |        |          |          |
| ls^a^** |        |        |        |        |          |          |
+---------+--------+--------+--------+--------+----------+----------+
| **      | **No.  | *      | **No.  | **No.  | **Pr     | **Pr     |
| Study** | of     | *Total | of     | of     | evalence | evalence |
|         | Pa     | No. of | Asy    | Asy    | (%) of   | (%) of   |
|         | tients | Segm   | nergic | nergic | Hiber    | Patients |
|         | In     | ents** | Segm   | Se     | nating** | with     |
|         | cluded |        | ents** | gments |          | Hib      |
|         | in     |        |        | In     | **A      | ernating |
|         | Anal   |        |        | cluded | synergic | Myoc     |
|         | ysis** |        |        | in     | Se       | ardium** |
|         |        |        |        | Anal   | gments** |          |
|         |        |        |        | ysis** |          | **(# of  |
|         |        |        |        |        | **(# of  | pts)**   |
|         |        |        |        |        | segs)**  |          |
+---------+--------+--------+--------+--------+----------+----------+
| **1     | **42** | **     | **40   | **37   | **49     | **62%    |
| Baer**  |        | 1176** | 5^b^** | 1^b^** | (18      | (        |
|         |        |        |        |        | 0/371)** | 26/42)** |
+---------+--------+--------+--------+--------+----------+----------+
| **2     | **39** | **3    | **3    | **3    | **62     | **62%    |
| G       |        | 9^c^** | 9^c^** | 9^c^** | (24/     | (24/     |
| erber** |        |        |        |        | 39^c^)** | 39^c^)** |
+---------+--------+--------+--------+--------+----------+----------+
| **3     | **34** | *      | *      | *      | **40     | **\--**  |
| Gr      |        | *272** | *141** | *116** | (4       |          |
| opler** |        |        |        |        | 6/116)** |          |
+---------+--------+--------+--------+--------+----------+----------+
| **4     | **48** | *      | *      | **90** | **30     | **\--**  |
| K       |        | *384** | *106** |        | (        |          |
| nuuti** |        |        |        |        | 27/90)** |          |
+---------+--------+--------+--------+--------+----------+----------+
| **5     | **14** | **70** | **54** | **54** | **74     | **\--**  |
| Luci    |        |        |        |        | (        |          |
| gnani** |        |        |        |        | 40/54)** |          |
+---------+--------+--------+--------+--------+----------+----------+
| **6     | **23** | **2    | **2    | **2    | **52     | **52%    |
| Maes**  |        | 3^c^** | 3^c^** | 3^c^** | (12/     | (12/     |
|         |        |        |        |        | 23^c^)** | 23^c^)** |
+---------+--------+--------+--------+--------+----------+----------+
| **7     | **16** | *      | **85** | **85** | **41     | **\--**  |
| Ma      |        | *208** |        |        | (        |          |
| rwick** |        |        |        |        | 35/85)** |          |
+---------+--------+--------+--------+--------+----------+----------+
| **8     | **22** | *      | **46** | **46** | **50     | **91%    |
| T       |        | *110** |        |        | (        | (        |
| amaki** |        |        |        |        | 23/46)** | 20/22)** |
+---------+--------+--------+--------+--------+----------+----------+
| **9     | **43** | *      | *      | *      | **39     | **\--**  |
| T       |        | *215** | *130** | *130** | (5       |          |
| amaki** |        |        |        |        | 1/130)** |          |
+---------+--------+--------+--------+--------+----------+----------+
| **10    | **17** | *      | **73** | **67** | **55     | **\--**  |
| Til     |        | *119** |        |        | (        |          |
| lisch** |        |        |        |        | 37/67)** |          |
+---------+--------+--------+--------+--------+----------+----------+
| **      | *      | *      | *      | *      | **\--**  | **\--**  |
| Total** | *298** | *\--** | *\--** | *\--** |          |          |
+---------+--------+--------+--------+--------+----------+----------+
| **^a^   |        |        |        |        |          |          |
| Because |        |        |        |        |          |          |
| the     |        |        |        |        |          |          |
| left    |        |        |        |        |          |          |
| ve      |        |        |        |        |          |          |
| ntricle |        |        |        |        |          |          |
| was     |        |        |        |        |          |          |
| divided |        |        |        |        |          |          |
| into a  |        |        |        |        |          |          |
| di      |        |        |        |        |          |          |
| fferent |        |        |        |        |          |          |
| number  |        |        |        |        |          |          |
| of      |        |        |        |        |          |          |
| s       |        |        |        |        |          |          |
| egments |        |        |        |        |          |          |
| by the  |        |        |        |        |          |          |
| di      |        |        |        |        |          |          |
| fferent |        |        |        |        |          |          |
| investi |        |        |        |        |          |          |
| gators, |        |        |        |        |          |          |
| the     |        |        |        |        |          |          |
| total   |        |        |        |        |          |          |
| number  |        |        |        |        |          |          |
| of      |        |        |        |        |          |          |
| s       |        |        |        |        |          |          |
| egments |        |        |        |        |          |          |
| in a    |        |        |        |        |          |          |
| study   |        |        |        |        |          |          |
| does    |        |        |        |        |          |          |
| not     |        |        |        |        |          |          |
| have a  |        |        |        |        |          |          |
| c       |        |        |        |        |          |          |
| onstant |        |        |        |        |          |          |
| relat   |        |        |        |        |          |          |
| ionship |        |        |        |        |          |          |
| to the  |        |        |        |        |          |          |
| number  |        |        |        |        |          |          |
| of      |        |        |        |        |          |          |
| p       |        |        |        |        |          |          |
| atients |        |        |        |        |          |          |
| in the  |        |        |        |        |          |          |
| s       |        |        |        |        |          |          |
| tudy.** |        |        |        |        |          |          |
|         |        |        |        |        |          |          |
| **^b^   |        |        |        |        |          |          |
| A       |        |        |        |        |          |          |
| nalyses |        |        |        |        |          |          |
| were    |        |        |        |        |          |          |
| limited |        |        |        |        |          |          |
| to      |        |        |        |        |          |          |
| a       |        |        |        |        |          |          |
| kinetic |        |        |        |        |          |          |
| or      |        |        |        |        |          |          |
| dys     |        |        |        |        |          |          |
| kinetic |        |        |        |        |          |          |
| s       |        |        |        |        |          |          |
| egments |        |        |        |        |          |          |
| (i.e.,  |        |        |        |        |          |          |
| hypo    |        |        |        |        |          |          |
| kinetic |        |        |        |        |          |          |
| s       |        |        |        |        |          |          |
| egments |        |        |        |        |          |          |
| were    |        |        |        |        |          |          |
| not     |        |        |        |        |          |          |
| i       |        |        |        |        |          |          |
| ncluded |        |        |        |        |          |          |
| in the  |        |        |        |        |          |          |
| analy   |        |        |        |        |          |          |
| ses).** |        |        |        |        |          |          |
|         |        |        |        |        |          |          |
| **^c^   |        |        |        |        |          |          |
| Eval    |        |        |        |        |          |          |
| uations |        |        |        |        |          |          |
| were    |        |        |        |        |          |          |
| limited |        |        |        |        |          |          |
| to the  |        |        |        |        |          |          |
| a       |        |        |        |        |          |          |
| nterior |        |        |        |        |          |          |
| wall of |        |        |        |        |          |          |
| the     |        |        |        |        |          |          |
| left    |        |        |        |        |          |          |
| ve      |        |        |        |        |          |          |
| ntricle |        |        |        |        |          |          |
| for     |        |        |        |        |          |          |
| each    |        |        |        |        |          |          |
| patient |        |        |        |        |          |          |
| (i.e.,  |        |        |        |        |          |          |
| one     |        |        |        |        |          |          |
| segment |        |        |        |        |          |          |
| per     |        |        |        |        |          |          |
| pati    |        |        |        |        |          |          |
| ent).** |        |        |        |        |          |          |
+---------+--------+--------+--------+--------+----------+----------+

[Study Endpoints]{.underline}:

For purposes of this review, the ten principal studies all had a similar
endpoint that was of primary interest: the degree of recovery (or lack
of recovery) of regional contractile function after myocardial
revascularization with either CABG or angioplasty. Unfortunately, the
studies generally did not evaluate changes in global ventricular
function (e.g., ejection fraction), changes in patient functional status
(e.g., changes in NYHA functional category, exercise tolerance), changes
in symptoms (e.g., dyspnea, fatigue), or changes in survival as
predicted by PET imaging with F‑18 FDG. Had these been performed, these
additional study evaluations might have provided a clearer picture of
the potential clinical utility of PET cardiac imaging with F‑18 FDG.
Instead, other literature articles were identified in the literature
that suggested that PET cardiac imaging with F‑18 FDG has clinical
usefulness.

In most studies, the assessment of the degree of recovery of regional
contractile function was evaluated only at one time point after
revascularization (e.g., three months after revascularization). Hence,
the time course of myocardial recovery was not well described by any of
the studies. Not only would such information be helpful in optimizing
the efficiency and design of other clinical studies, but such
information has direct clinical usefulness.

[Patient Disposition and Characteristics]{.underline}:

The summary of each study in this review described the study\'s
enrollment criteria, specifically noted the disposition of enrolled
patients, and specified the characteristics of the patients who
ultimately were enrolled or included in the analyses. An adequate
accounting of patients helped in the determination of whether only
selected patients were retained for purposes of analysis, which could
have undermined the usefulness of the study for this review. Overall,
the description of patient disposition in the manuscripts was
acceptable, but not always optimal.

The patient characteristics of those enrolled and of those analyzed help
to delineate the population to whom the results of the study are
generalizable. All of the studies included patients with coronary artery
disease and left ventricular dysfunction. In most of the studies,
ventricular dysfunction was chronic, regional, and tended to be mildly
or moderately depressed. Thus, the results of the studies are most
relevant to similar patients and may not be directly generalizable to
others, such as patients with acute myocardial dysfunction, global
ventricular dysfunction, or in patients with profound ventricular
dysfunction. In particular, the diagnostic performance of F‑18 FDG PET,
as assessed by measures such as sensitivity and specificity, may differ
in these other clinical settings.

In general, the manuscripts only included a few major demographic
characteristics (e.g., sex, age) and a few baseline characteristics
(e.g., ejection fraction), and could have been strengthened by more
detail in this area.

[Segment Disposition, Characteristics, and Functional
Outcome]{.underline}:

This review also described in some detail the disposition of myocardial
segments. As with patient disposition, an adequate accounting of
segments helped in the determination of whether only selected segments
were retained for purposes of analysis, which could have undermined the
usefulness of the study for this review. For example, one study was
excluded from this review because the analysis included one segment per
patient, and that segment had \"clearly PET-documented blood flow
metabolism match or mismatch.\"[^7] Diagnostic performance measures
(e.g., sensitivity, specificity) based on data derived from such
segments are likely to be biased. However, as mentioned above,
publication bias may have further limited the sample of studies that
were available for this review. Overall, the description of segment
disposition in the manuscripts was acceptable, but not always optimal.

Just as noted above with patients, describing the characteristics of the
segments helps to delineate the segments to which the results of the
study are generalizable. For example, most of the studies included an
assessment of segmental function before revascularization across the
full spectrum of motion (e.g., normal, hypokinetic, akinetic,
dyskinetic). In general, however, only those segments with asynergy
before revascularization were included in analyses, and changes in
function for these asynergic segments were recorded after
revascularization. Thus, the performance of PET F‑18 FDG has been best
characterized in a subset of asynergic myocardial segments (but across
the full spectrum of asynergy). As the potential to recover contractile
function is the main parameter of clinical interest, such a limited
analysis was deemed acceptable. The value of PET F‑18 FDG imaging of
segments with normal motion before revascularization has not been
established.

In several studies, analyses were restricted not only to segments with
asynergy before revascularization, but were restricted only to those
segments that had been successfully revascularized. The ways in which
the success of revascularization was assessed, in those studies in which
it was assessed, ranged from being nearly anecdotal (e.g., reliance on a
surgical report) to the rigorous (e.g., cardiac catheterization after
revascularization, assessment of perfusion after revascularization).
Limiting the analysis to only those segments or patients with successful
revascularizations, as was done by many authors, provides estimates of
diagnostic performance that reflect the \"true\" capabilities of F‑18
FDG PET. That is, such analyses provide estimates of drug performance
that are not confounded by the vagaries of coronary revascularization.
However, additional analyses that included all segments or patients,
including those with unsuccessful revascularization, would have provided
useful data on the diagnostic performance as might be expected in actual
use. Such additional analyses would have provided more information on
the ultimate clinical usefulness of the PET F‑18 FDG as a diagnostic
test. That is,

Because the majority of patients included in the ten principal studies
had chronic myocardial dysfunction, spontaneous recovery of segmental
wall motion would be expected to be uncommon. Thus, if patients and
segments with unsuccessful revascularizations had been included in the
analysis, they generally would not be expected to improve in function.
On the other hand, factors other than revascularization (e.g., changes
in cardiac medications) could lead to improved segmental function in
some cases, even in the absence of successful coronary
revascularization.

Assuming that the unsuccessfully revascularized segments usually would
not improve in function, then sensitivity (and positive predictive
value) likely would have decreased, and specificity (and negative
predictive value) likely would have increased. Performing analyses under
both revascularization scenarios would have been helpful. However, the
absence of the latter analyses (i.e., inclusion of all segments or
patients regardless of the success of revascularization) was not
considered to be essential, so long as the consequences of such
omissions are understood and are explicit.

The data in this review speak primarily to the performance of PET F‑18
FDG under the ideal circumstance of successful coronary
revascularization. However, the clinical usefulness of being able to
identify myocardium with reversible dysfunction with PET F‑18 FDG
appears to be limited substantially by the possibility of unsuccessful
coronary revascularization. If the likelihood of successful
revascularization is very slight, then the clinical usefulness of
predictions with PET F‑18 FDG will be limited, regardless of how good
the diagnostic performance of PET F‑18 FDG may be. Therefore, in
clinical use, health care providers who are contemplating PET F‑18 FDG
studies should carefully consider the likelihood of successful
revascularization before performing the test.

In addition, evaluation of functional outcomes in segments that were not
successfully revascularized would also have provided an estimate of a
spontaneous recovery rate or improvements due to other causes (e.g.,
changes in medications). However, given that the patients in the
principal studies tended to have longstanding ventricular dysfunction,
the likelihood of spontaneous recovery was considered to be negligible
for the purposes of this review. Effects of medication changes or other
changes, however, can not be excluded.

[F‑18 FDG Preparation and Administration]{.underline}:

Few of the manuscripts described the methods and controls by which F‑18
FDG was prepared, and few described the specific activity and
radiochemical purity of the final product. Such information, or at least
a reference to such information, would be highly desirable in all
articles describing clinical studies with F‑18 FDG or other PET imaging
agents. However, because the focus of this review is on the clinical
data, and because regulatory standards for Chemistry, Manufacturing, and
Controls and for Good Manufacturing Practices (GMPs) for PET products
are being developed, this deficiency in the clinical study manuscripts
will not be addressed further in this review.

Most studies, but not all, specified the radiation dose of F‑18 FDG and
its route of administration. In studies where F‑18 FDG was
readministered to the patient (e.g., at rest and again after exercise),
the time interval between doses tended to be vague. Few studies
mentioned the rate of administration, and none of the studies mentioned
the mass dose of F‑18 FDG. Such information, or at least a reference to
such information, would be highly desirable in all articles describing
clinical studies with F‑18 FDG or other PET imaging agents. However,
because most of the ten principal manuscripts clearly specified the
radiation dose of PET F‑18 FDG (e.g., typically between 5‑10 mCi), the
product has a history of use that spans several decades, and one F‑18
FDG product has been approved for other uses, the omission of these
characteristics of drug administration was felt to be tolerable.

[F‑18 FDG PET Image Acquisition, and Image Interpretation]{.underline}:

Particularly for the clinical studies published in imaging journals, the
methods by which patients were prepared (e.g., fasting, glucose load)
and by which PET images with F‑18 FDG were obtained and analyzed tended
to be reasonably well described in the manuscripts. However, the
description of such methodology for some of the clinical studies was
rather sparse. A description of such information, or at least a
reference to such a description, would be highly desirable in all
articles describing clinical studies with F‑18 FDG or other PET imaging
agents.

In particular, for the purpose of this review, it was essential to
understand how two particular parameters were defined: a) the criteria
on PET F‑18 FDG (and perfusion) image analysis by which myocardial
segments were predicted to have reversible myocardial dysfunction
(i.e., criteria for \"viability\" and \"nonviability\"), and; b) the
criteria on image analysis of wall motion that were used to determine
whether a change in wall motion had occurred from before
revascularization to after revascularization. In most of the ten
principal studies, these criteria were specified adequately. It would be
highly desirable for the manuscripts to state explicitly whether these
criteria were specified prospectively (i.e., before any data had been
gathered), although this was virtually never done.

It should also be noted that because the evaluations of wall motion have
a subjective component and because the ordinal scale used in most
studies to assess wall motion is not linear, moving from one category to
the next was felt to be the minimally acceptable change in wall motion
that had clinical significance (e.g., moving from akinetic to
hypokinetic, or from hypokinetic to normal). Moreover, because changes
in wall motion from dyskinetic to akinetic are of uncertain clinical
meaning, it would have been desirable to limit the criteria further to
mean moving from a dyskinetic or akinetic state before revascularization
to a normal or hypokinetic state after revascularization. In some
studies this was done.

An assessment of the reproducibility of the analyses of wall motion, the
PET F‑18 FDG scans, and the perfusion scans was a highly desirable
feature that was described in some studies. For example, some studies
described formal evaluations of the reproducibility of image analysis.
Although several of the studies included image analysis by multiple
readers, none mentioned the degree to which the readers agreed with one
another. Such use of multiple readers allows for potential assessment of
interreader variability. Moreover, use of multiple readers decreases the
likelihood that the results reflect the idiosyncracies of any particular
reader (i.e., the results are more likely to be generalizable).

Some manuscripts also included a reasonably detailed description of how
segmental alignment was maintained when images were obtained with more
than one modality (e.g., PET with echocardiography) or when imaging was
done by the same modality but on different occasions (e.g., PET F‑18 FDG
imaging on one day, with PET N‑13 ammonia imaging on another day). This
feature of some manuscripts was highly desirable, because segmental
misalignments could undermine the integrity of the data.

[Analyses of Data]{.underline}:

All of the ten principal studies performed \"by segment\" analyses of
the results. A \"by-patient\" analysis was performed in addition in only
one study (study #1). However, in two studies (studies #2 and #6) the
by-segment analysis was interpreted in this review as being identical to
the by-segment analysis because analyses were limited to one segment per
patient (the anterior left ventricular wall). Because potential clinical
benefits and risks of diagnostic procedures are ultimately conferred
upon patients (i.e., patients, not wall segments, are the units of
ultimate interest), such by-patient analyses facilitate assessments of
clinical benefit as compared to risk. In addition, as noted by the
authors of study #1, such by-patient analyses decrease the potential
influence of segmental misalignments that may have occurred between F‑18
FDG PET studies and assessments of recovery of left ventricular
contractility. Performance of both by-segment and by-patient analyses
would have been a highly desirable feature of each of these studies.

As mentioned in the beginning of this review, given the relatively small
number of patients in each study, the performance measures (e.g.,
sensitivity, specificity, positive predictive value, negative predictive
value, accuracy) from any particular study should be interpreted with
caution. Because of the small sample sizes, the widths of the confidence
intervals for these measures are rather broad, and these measures may
not be generalizable to larger populations. Moreover, performance
measures such as positive predictive value, negative predictive value,
and accuracy will vary depending on prevalence and should therefore be
interpreted even more carefully. Finally, the studies divided the left
ventricle into different numbers of segments and divided the left
ventricle in different ways. This means that a diagnostic performance
measure made \"by segment\" in one study, including sensitivity,
specificity, PPV, NPV, and accuracy, may have a somewhat different
clinical meaning than the same measure in other studies.

Most manuscripts only provided perfunctory details of statistical
procedures and plans. A formal statistical description of the
prospective hypotheses that were to be tested, along with details of the
originally statistical analytic plan would have been highly desirable.
Such prospective statistical plans help limit potential biases that may
arise, for example, from retrospective analyses or subset analyses. Many
articles failed to correct for multiple endpoints or to address other
statistical issues. Therefore, statistical levels of significance as
specified in the articles should generally be interpreted with a great
deal of caution. In addition, none of the principal articles provided
confidence intervals for estimates of sensitivity, specificity, positive
predictive value, negative predictive value, or accuracy. However, these
were calculated by the FDA statistician.

[Safety]{.underline}:

None of the ten principal articles described safety monitoring or safety
results from performance of PET studies with F‑18 FDG. Thus, it is
unclear whether safety parameters were monitored as part of the studies,
or whether safety was monitored but the results were not reported.
However, as described earlier, the overall safety data base for F‑18 FDG
is adequate, though not optimal, in support of its safe use.

G. Conclusions

The published literature contains sufficient data to conclude that F‑18
fluorodeoxyglucose is effective for use in cardiac PET imaging in
patients with coronary artery disease and left ventricular dysfunction,
when used together with myocardial perfusion imaging, to identify left
ventricular myocardium with altered glucose metabolism and reversible
loss of contractility. This reversal of contractile dysfunction assumes
successful coronary revascularization, the likelihood of which should be
considered carefully by the health care provider before the PET
evaluation is performed. PET imaging with F‑18 FDG for this purpose
appears to be safe.

Additional references cited in text:

[^1]: 1\. Wijns W, Vatner S, and Camici, P. Hibernating Myocardium. N
    Engl J Med 1998;339:173‑181.

[^2]: 2\. Bax JJ, Wijns W, Cornel JH, et al. Accuracy of currently
    available techniques for prediction of functional recovery after
    revascularization in patients with left ventricular dysfunction due
    to chronic coronary artery disease: Comparison of Pooled Data. J Am
    Coll Cardiol 1997;30:1451‑60.

[^3]: 3\. Schelbert H., Bonow RO, Geltman E, et al. Position Statement:
    Clinical Use of Cardiac Positron Emission Tomography. Position Paper
    of the Cardiovascular Council of the Society of Nuclear Medicine. J
    Nucl Med 1993;34:1385‑1388.

[^4]: 4\. Bonow RO, Berman DS, Gibbons RJ et al. AHA Medical/Scientific
    Statement; Special Report; Cardiac Positron Emission Tomography: A
    report for health professionals from the Committee on Advanced
    Cardiac Imaging and Technology of the Council on Clinical
    Cardiology, American Heart Association. Circulation 1991;84:447‑454.

[^5]: 5\. O\'Rourke RA, Chatterjee K, Dodge HT, et al. Special Report;
    Guidelines for clinical use of cardiac radionuclide imaging,
    December 1986: A report of the American College of
    Cardiology/American Heart Association Task Force on Assessment of
    Cardiovascular Procedures (Subcommittee on Nuclear Imaging). JACC
    1986;8:1471‑83.

[^6]: 6\. Louvain B, Lyon F, Groningen NL et al. Predictive value of FDG
    imaging in 502 patients with chronic ischaemic left ventricular
    dysfunction enrolled in a prospective European multicentre viability
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[^7]: 7\. Carrel T, Jenni R, Haubold-Reuter S, et al. Improvement of
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