Medical Review of F-18 Fluorodeoxyglucose Positron Emission Tomography (F-18 FDG PET) 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.a 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.

F-18 FDG is an analog of glucose that contains the radionuclide Fluorine F-18. Fluorine F-18 decays by positron (ß+) emission and has a physical half-life of 109.7 minutes. The principal photons useful for diagnostic imaging are the 511 keV gamma photons, resulting from the interaction of the emitted positron with an electron (i.e., positron annihilation). As a glucose analog, F-18 FDG is transported into myocytes by the glucose transporter and can enter metabolic glucose pathways. After phosphorylation by hexokinase, F-18 FDG is not metabolized further, and the reverse reaction (dephosphorylation by glucose-6-phosphatase) is minimal. Phosphorylated F-18 FDG is therefore trapped within myocytes.

Under normal aerobic conditions, the myocardium meets the bulk of its energy requirements by oxidizing free fatty acids, and most of the exogenous glucose taken up by the myocyte is converted into glycogen. However, under ischemic conditions, the oxidation of free fatty acids decreases, exogenous glucose becomes the preferred myocardial substrate, glycolysis is stimulated, and glucose taken up by the myocyte is metabolized immediately instead of being converted into glycogen. Under these conditions, as described above, phosphorylated F-18 FDG accumulates in the cell and can be detected with PET imaging.

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 systolic dysfunction maybe able to regain some, or all, of its 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.

Because uptake and phosphorylation of F-18 FDG are active cellular processes, the localization of F-18 FDG in asynergic myocardium has been investigated as being a marker for myocardial viability. On PET imaging, increased accumulation of F-18 FDG in myocardial regions with reduced perfusion, or flow-metabolism mismatch, has been used to detect hibernating myocardium. Conversely, a matched defect, with concordant reductions in both perfusion and F-18 FDG accumulation, has been viewed as being 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. However, none of these other methods have indications for the evaluation of myocardial hibernation.

II. Evaluating the Effectiveness Data for F-18 FDG PET Imaging for Identifying Myocardium with Reversible Loss of Systolic Function 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, I selected ten articles of prospective studies in patients with coronary artery disease and left ventricular dysfunction in which cardiac imaging with F-18 FDG was used to assess regional myocardial hibernation. Each article allowed the results of cardiac PET F-18 FDG imaging to be compared with the functional outcome of the left ventricle ("truth"), asdescribed 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 the ten principal 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 in identifying myocardium with residual glucose metabolism and reversible loss of systolic function 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 systolic 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 systolic 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. Truth is not ascertained by comparing the results of PET imaging with F-18 FDG to those of a "gold standard." The various technologies by which this recovery of systolic function was assessed in each of these studies (including echocardiography, radionuclide ventriculography, and contrast ventriculography) are each sufficiently valid and reliable to allow such determinations of functional outcome to be made.

Stated differently, some of the principal studies assessed myocardial hibernation by additional methods (e.g., stress echocardiography with dobutamine). Although the results of these other methods were noted in this review for completeness, these results were not used to assess the efficacy of PET imaging with F-18 FDG. That is, the efficacy of PET F-18 FDG was assessed on its own merits and by its ability to predict systolic recovery (i.e., by evaluating its predictive validity). Efficacy was not assessed by comparison of PET imaging with F-18 FDG to other modalities or to a gold standard (i.e., by evaluating its criterion validity). Efficacy was evaluated by comparing predictions of functional recovery (made with PET F-18 FDG before revascularization) with actual functional outcome after revascularization.

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.

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 withreversible loss of systolic function in patients with coronary artery disease and left ventricular dysfunction.

A draft of this review was shared with FDA's Medical Imaging Drugs Advisory Committee on 28 June 1999, and after consideration of the Committee's comments and recommendations, the draft review was modified as appropriate.

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 systolic function 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, alongwith 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: 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: 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 :g/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. Themanuscript 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: 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 four 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: 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: 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 systolic 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 systolic 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: Differences of wall thickening scores at rest, during dobutamine infusion and after revascularization for patients with and without dobutamine systolic 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: 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. The ages of these 42 patients were not specified.

Segment disposition and functional outcome: 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: 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 coronaryrevascularization. Analyses were performed by-segment as well as by-patient for each imaging modality.

PET, by-segment analysis: 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 3. Performance of PET When Used to Predict Improved Wall Motion in Asynergic Myocardial Segments (By-Segment Analysis)
Performance Measure	Value (no. of segments)	95% CI
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: 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 5. Performance of PET When Used to Predict Improvement in Regional Wall Motion (By-Patient Analysis)
Performance Measure	Value (no. of patients)	95% CI
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: 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 7. Performance of Dobutamine Transesophageal Echocardiography When Used to Predict Improved Wall Motion in Asynergic Myocardial Segments
Performance Measure	Value (no. of segments)	95% CI
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: 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 9. Performance of Dobutamine Transesophageal Echocardiography When Used to Predict Improvement in Regional Wall Motion (By-Patient Analysis)
Performance Measure	Value (no. of patients)	95% CI
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: 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: 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: 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: 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: 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 :g/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: 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: 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 volumesof 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 be 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 by a published method, and 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: For purposes of assessing return of systolic 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: Groups were compared for categorical data by Fisher's exact test or the P² test, when the minimum expected cell size was >5. A Mann-Whitney rank-sum test was used to assessdifferences 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: 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: 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 11. Performance of PET When Used to Predict Improved Wall Motion in Asynergic Anterior-Wall Myocardial Segments
Performance Measure	Value (no. of segments)	95% CI
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 dysfunctional segments 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 :mol/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 :mol/min/100 g, p=NS).

Other Findings: 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: 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: 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: 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: 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: 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: 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: 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 (k₁). 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 k₁ 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 k₁ 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: 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: 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: 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: 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 13. Performance of PET F-18 FDG Uptake, Normalized to Flow, When Used to Predict Improved Wall Motion in Asynergic Myocardial Segments
Performance Measure	Value (no. of segments)	95% CI
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: 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: The safety of positron emission tomography with F-18 FDG or with C-11 acetate were not addressed in the manuscript.

Conclusions in manuscript: 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: 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 at 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: 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: 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: 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: 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. Patients were positioned supine in a tomograph with a measured axial resolution of 6.7 mm and 6.5 mm in plane. Correction forphoton attenuation was performed. 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 systolic function 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: 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: 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 systolic 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: 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: 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: 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: 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 15. Performance of PET F-18 FDG Uptake When Normal* Values are Used to Predict Improved Wall Motion in Asynergic Myocardial Segments
Performance Measure	Value (no. of segments)	95% CI
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%.

Other findings: 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: The safety of positron emission tomography with F-18 FDG was not addressed in the manuscript.

Conclusions in manuscript: 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: 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-methoxyisobutylisonitrile 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: 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: 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 repea