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(Circulation. 1999;99:2921-2926.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Prevalence of Myocardial Viability as Detected by Positron Emission Tomography in Patients With Ischemic Cardiomyopathy
From the Ahmanson Biological Imaging Clinic/Nuclear Medicine, Department of Molecular and Medical Pharmacology, UCLA School of Medicine and Long Beach Community Medical Center, Los Angeles, Calif.
Correspondence to Johannes Czernin, MD, UCLA School of Medicine, AR-259 CHS, Los Angeles, CA 90095-6942.
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Abstract |
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Background—Detection of myocardial viability is important in patients with ischemic cardiomyopathy. Restoration of blood flow to viable myocardium is associated with improved left ventricular function and improved patient prognosis. However, the prevalence of viable myocardium in patients with ischemic cardiomyopathy is unknown.
Methods and Results—To determine the prevalence of myocardial
viability, clinical
[13N]ammonia/18F-deoxyglucose PET studies
performed in 283 patients (age, 63±10 years) with ischemic
heart disease (mean ejection fraction, 26±8%) were visually
analyzed for the presence and extent of viable and nonviable
myocardium. The myocardium was divided into 19
segments. The extent of viable myocardium was considered
"functionally" significant if 
5 segments (
25% of the left
ventricular myocardium) exhibited a blood
flow/metabolism mismatch and "prognostically"
significant if 1 to 4 left ventricular segments did so. Of
all patients, 41% had no evidence of viable myocardium,
55% had viable myocardium, and 4% had normal blood flow
and metabolism within an enlarged left ventricle.
Functionally significant viability was found in 27% and prognostically
significant viability in 28% of the patients.
Multivariate analysis revealed the presence of
angina to be the only clinical parameter associated with
the presence of functionally significant viability.
Conclusions—Revascularization might improve patient prognosis in 55% and result in improved left ventricular function in 27% of all patients with ischemic cardiomyopathy.
Key Words: coronary disease • viability • myocardium • tomography • cardiomyopathy
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Dysfunctional myocardium might exhibit improved contractile performance after revascularization if extensive areas of myocardial viability are present in hypoperfused tissue.1 2 However, even small areas of viability might be of considerable prognostic importance. Di Carli et al3 have recently demonstrated an increased risk for cardiac death if >5% of the left ventricle exhibits dysfunctional but viable myocardium.
The determination of presence and extent of myocardial viability is therefore important for patients with ischemic cardiomyopathy who might benefit from coronary revascularization as an alternative treatment to cardiac transplantation or medical therapy.4 5 6 Numerous studies have documented the value of blood flow/glucose metabolic imaging with PET in determining myocardial viability.1 2 3 4 5 7 However, the prevalence of myocardial viability in patients with ischemic cardiomyopathy is unknown.
The aim of this study was to determine with PET in patients with ischemic cardiomyopathy the prevalence of viable myocardium and to evaluate whether the presence of myocardial viability can be predicted from clinical parameters.
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Methods |
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Study Population
The study population consisted of 283 patients (242 men, 41 women; mean age, 63±10 years) who were referred to the UCLA PET Center between June 1989 and June 1998. After approval by the UCLA Human Subject Protection Committee, clinical data were obtained retrospectively by chart review.
Of the 700 clinically reimbursed PET studies performed in patients
with ischemic heart disease since 1989, 283 were randomly
selected for visual interpretation and chart review by pulling 30
studies per year from a file cabinet. This approach provided us a
representative sample of patients who had solid
clinical indications for PET viability studies, ie, heart failure
symptoms in the setting of ischemic heart disease. Of these
patients, 21 (7.4%) had been enrolled in previous clinical PET trials
from this institution. To avoid any selection bias, they were not
excluded from the present study.
All patients had ischemic cardiomyopathy as documented angiographically and/or by history of myocardial infarctions. All had various degrees of congestive heart failure. Left ventricular ejection fraction, available in 208 patients (73%) from 2-dimensional echocardiography (n=57) or cine ventriculography (n=151) performed within 4±13 months of the PET study, averaged 26±8% (range, 7% to 48%). Coronary angiography, available in 201 patients (71%), revealed single-vessel disease in 8%, double-vessel disease in 22%, and triple-vessel disease in 70%. A complete history was available by chart review for 171 patients (60%). Of these, 78% had histories of myocardial infarction, and 47% had undergone coronary artery bypass surgery. Thirty-three percent reported anginal symptoms, and 36% had diabetes mellitus. The clinical management decision to proceed with medical therapy, revascularization, or cardiac transplantation was available for 110 patients (39%).
PET Image Acquisition
[13N]ammonia and
18F-deoxyglucose (FDG) were used as tracers of
myocardial blood flow and glucose consumption. From January 1989 until
December 1996, an ECAT/931 (CTI/Siemens; intrinsic resolution, 6
mm at full width–half maximum [FW-HM]), which acquires 15 transaxial
images simultaneously, was used; since January 1997, the
CTI/Siemens ECAT/EXACT HR+ (intrinsic resolution, 4.5 mm at
FW-HM), which acquires 62 transaxial image planes
simultaneously, was used.
After a 20-minute transmission scan, [13N]ammonia (10 to 15 mCi) was injected, and 5 minutes later, a 20-minute image of the myocardial [13N]ammonia distribution was obtained. Forty to 50 minutes later, 10 mCi of FDG was injected, and after an uptake period of 40 minutes, a 20-minute image of the exogenous myocardial glucose use was acquired.
To obtain high-quality glucose metabolic studies, the
patients were studied after an overnight fast. Blood glucose levels
were measured before administration of FDG. If serum glucose levels
were <120 mg%, 50 g glucose was administered orally. Patients
with glucose levels between 120 and 150 mg% were imaged without oral
glucose loading. If serum glucose levels were >150 mg%, insulin was
administered until serum glucose had declined by 20%. Once glucose
levels had declined by 20%, FDG was administered
intravenously.8 Patients with
insulin-dependent diabetes mellitus were asked to adhere to their
regular diet and insulin regimen. Patients on oral antidiabetic
medication were asked to remain fasted after midnight and to take their
oral antidiabetic medication.
Visual Analysis of PET Images
The left ventricle was divided into 19 segments: the basal,
middle, and apical portions of the anterior septum and anterior wall,
anterolateral and inferolateral walls, and inferior wall
and inferior septum; and the apex as a single myocardial
segment. Two readers (Drs Auerbach and Czernin) who were unaware of the
patients' histories consensually graded
[13N]ammonia and FDG uptake defects on a
4-point scale: 0=normal, 1=mildly reduced, 2=moderately reduced, and
3=severely reduced.
Myocardium was defined as normal if the
[13N]ammonia uptake was scored as 0 regardless
of FDG uptake. A concordant reduction in
[13N]ammonia and FDG activity scores was
classified as blood flow/metabolism match indicating scar
tissue, subsequently referred to as nonviable myocardium. A
reduction in [13N]ammonia uptake more severe
than the reduction in glucose metabolic activity by 1
point was defined as a blood flow/metabolism mismatch,
subsequently referred to as viable myocardium.
Failure to revascularize viable myocardium of any extent
might be associated with poor patient prognosis,3 whereas
only extensive areas or myocardial viability encompassing 20% to 30%
of the left ventricular
myocardium1 2 is associated with functional
improvement after revascularization. Therefore, the
terms "functionally" and "prognostically" significant viability
were introduced as follows: Viability in 5 of the 19 myocardial
segments (26% of the left ventricular mass) was
considered functionally significant, and viability found in 1 to 4 left
ventricular segments was considered prognostically
significant.
Statistical Analysis
All continuous data are presented as mean±SD. The
paired t test was used for comparisons within individuals.
Stepwise multiple regression and all-possible subsets regression with
Mallow's Cp criterion9 10 were
performed to assess the relationships among independent variables
and the presence of viability. Additionally, stepwise logistic
regression was performed to determine which independent variables
might be associated with the presence of viable myocardium.
The BMDP statistical software package11 was used for data
analysis. The Wilcoxon rank-sum test was used to
compare relative reductions in myocardial blood flow between viable and
nonviable myocardium. The 
2 test
was used to compare the frequency of possible flow reductions occurring
in viable and nonviable myocardium. A value of
P<0.05 was considered statistically significant.
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Results |
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Prevalence of Viability
Of the 283 patients, 116 (41%) exhibited nonviable myocardium, 156 (55%) had viable myocardium of various extents, and 11 (4%) had enlarged but normally perfused myocardium. Functionally significant and prognostically significant viability occurred in 27% and 28% of the study population, respectively (Figure 1
).
Interestingly, only 21 of the 283 patients (7%) had viable tissue
without evidence of additional nonviable myocardium. Viable
and nonviable myocardium coexisted in 135 patients (48%).
All of the 11 patients with normal blood flow/metabolic
patterns had markedly enlarged left ventricles.
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Resting Blood Flow and Viability
Thirty percent of all viable segments had mild, 42% had moderate,
and 27% had severe reductions in myocardial blood flow. Mild,
moderate, and severe reductions were found in 20%, 28%, and 52% of
nonviable segments, respectively (all P<0.0001). Overall,
myocardial blood flow was less severely reduced in viable than in
nonviable myocardium (1.97±0.76 versus 2.3±0.78,
P<0.0001) (Figure 2).
However, there was considerable overlap in the degree of flow
reductions between viable and nonviable myocardium.
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Clinical Characteristics and Prevalence of Viability
Multiple regression analysis revealed no statistically
significant relationship between the presence of viability and any of
the following factors: patient age, sex, history of
revascularization and myocardial infarction,
diabetes mellitus, angina, angiographic extent of disease, left
ventricular size, and left ventricular ejection
fraction. Functionally significant viability occurred in 30% of
patients with and 35% of those without histories of
revascularization, 28% with and 34% of those
without histories of infarction, and 27% of patients with and 28% of
those without diabetes mellitus (all P=NS).
Logistical regression analysis determined that in patients with anginal symptoms, functionally significant viability was more prevalent than prognostically significant viability (P=0.038). A history of myocardial infarction tended to be associated with nonviable tissue by PET (P=0.051).
Clinical Management Decisions
A clinical management decision was available for 110 patients
(39%). Of these, 55 underwent coronary
revascularization, 19 had cardiac transplantation,
and 36 remained under medical treatment (Figure 3).
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Prerevascularization and postrevascularization ejection fractions were available in 14 of 25 patients with functionally significant, 4 of 12 patients with prognostically significant viability, and 6 of 18 patients without viable myocardium. They improved significantly only in patients with functionally significant viability (26±8% to 33±9%, P=0.0024), not in those with prognostically significant viability (39±5% versus 40±10%, P=NS) and those without viable myocardium (32±10% versus 33±8%, P=NS). The extent of myocardial viability by visual analysis (ie, the number of myocardial segments exhibiting a blood flow/metabolism mismatch pattern) tended to be correlated with changes in left ventricular ejection fraction after revascularization (r=0.36, P=0.083).
Of the 19 patients who underwent cardiac transplantation, 3 had functionally significant, 5 had prognostically significant, and 11 had no evidence of myocardial viability. Of the 36 patients who remained on medical therapy, 9 had functionally significant, 6 had prognostically significant, and 21 had no evidence of myocardial viability.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Coronary revascularization might prognostically benefit all patients with viable myocardium (55%) and result in improvements in left ventricular function in 27% of all patients with ischemic cardiomyopathy.1 2 3 4 5 12
Importantly, myocardial viability cannot be predicted from clinical parameters.
Prevalence of Myocardial Viability
The prevalence of myocardial viability in patients with
ischemic heart disease and compromised left
ventricular function is unknown. Christian et
al13 measured ejection fraction in 86 patients with
ischemic cardiomyopathy (mean left
ventricular ejection fraction, 39±8%) who underwent
revascularization without a specific presurgical
viability assessment. Functional improvement was observed in 21% of
the patients after
revascularization,13 suggesting the
presence of extensive areas of presurgical viability.
Using PET, Go et al14 studied 155 patients and observed the blood flow/metabolism mismatch pattern in 29% of patients. In their study, the extent of viable myocardium was considered significant if 12.5% of the left ventricular mass exhibited a blood flow/metabolism mismatch pattern. Because this threshold is lower than the cutoff point for functionally significant viability in the present study, a higher prevalence of viable myocardium would have been expected. However, this previous and the present investigations yielded similar prevalence data. One explanation is that the former study included only patients with a history of myocardial infarction, a clinical parameter that tended to be associated with a lower prevalence of myocardial viability in the present investigation.
Using symptomatic improvement as the study end point, Di
Carli et al12 determined that viability encompassing
18% of the left ventricular myocardium
identified best those patients who exhibited improvements in heart
failure symptoms after revascularization. A similar
threshold was established by Hausmann et al,15 who used
2-dimensional echocardiography and
201Tl SPECT imaging to predict functional
improvement after bypass surgery. However, most studies selecting
postsurgical changes in ejection fraction as a study end point used a
somewhat higher threshold. For instance, Tillisch et al1
and Louie et al2 demonstrated that 2 of 7 left
ventricular segments (28.5%) needed to exhibit viability
by PET to expect a postsurgical improvement in left
ventricular function.
Thus, the current arbitrary definition of "functionally"
significant viability (5 of 19 segments, or 25%) appears to
reflect previous reports with reasonable accuracy. This classification
was chosen to emphasize that extensive areas of myocardial viability
are associated with improvements in contractile
function,1 2 6 16 17 higher daily life activity levels,
and reduced heart failure symptoms12 after
revascularization. It takes into account that the
presence of any amount of myocardial viability might have important
prognostic implications: Medically treated viable
myocardium is associated with an increased risk of cardiac
death or myocardial infarction, as demonstrated by Eitzman and
coworkers.5 In their study, 6 of 18 medically treated
patients (33.3%) with evidence of viability by PET died during a
12-month follow-up period, and 3 other patients suffered myocardial
infarction. In contrast, only 1 of 26 patients with PET evidence of
viability who underwent revascularization died, and
no myocardial infarction occurred in this subgroup.
Consistently, Lee et al4 reported that during a
17±9-month follow-up period, 48% of medically treated patients with
evidence of myocardial viability by PET had ischemic cardiac
events as opposed to only 8% of those who underwent
revascularization. However, these authors did not
observe increased mortality in patients with viable
myocardium who remained under medical treatment.
Important information was provided by Di Carli et al,3 who concluded that even the presence of small amounts (>5%) of myocardial viability by PET identifies a high-risk subgroup with a poor 1-year survival.
The findings of the present study support the validity of the term
"functionally" significant viability. The left
ventricular ejection improved only in those patients who
had 5 viable segments, not in those who had smaller areas or no
myocardial viability. Nevertheless, the term "prognostically"
significant viability awaits further prospective validation.
In 4% of the patients (n=11), left ventricular enlargement was the only abnormal PET finding. No significant abnormalities in blood flow or glucose use were noted. Importantly, only 4 of these patients underwent additional pharmacological stress studies during intravenous dipyridamole. Three of these patients exhibited stress-induced ischemia. Thus, myocardial stunning might have accounted for the impaired left ventricular function in these patients. However, normally perfused, normometabolic, yet dysfunctional myocardium does not necessarily denote viable tissue (ie, reversible contractile dysfunction). Ventricular remodeling in patients with ischemic or hypertensive heart disease or an additional myopathic component might account for this finding.18 19 In fact, 2 of the 11 patients had histories of ethanol abuse, and 2 others had prior cancer chemotherapy.
Relationship Between Resting Blood Flow and Myocardial
Viability
The degree of flow reductions has been proposed as a marker of
myocardial viability. Gewirtz et al20 reported that
myocardial segments with blood flows <0.25 mL ·
min-1 · g-1 rarely
exhibited substantial glucose metabolic activity and were
therefore likely to represent scar tissue. Both viable and
nonviable myocardium was found in segments with blood flows
ranging from 0.25 to 0.39 mL · min-1
· g-1. Similarly, Duvernoy et
al21 observed that intermediate reductions in relative
blood flow discriminated poorly between viable and nonviable
myocardium. Go et al22 failed to find any
correlation between the relative severity in decreased perfusion and
myocardial viability in irreversible perfusion defects.
The present study confirms these previous observations. Relative resting blood flow was significantly lower in nonviable than in viable myocardium. However, the considerable overlap in relative blood flow indicates that relative perfusion imaging without metabolic imaging cannot reliably distinguish between viable and nonviable myocardium.
Relationship Between Clinical Parameters and
Myocardial Viability
The present study revealed that the prevalence of myocardial
viability is independent of the patient's sex, age, history of
revascularization, diabetes mellitus, extent of
coronary artery disease, left ventricular size, or
left ventricular ejection fraction. This observation is in
agreement with a previous report that failed to demonstrate a
significant relationship between myocardial viability and these
clinical variables.12 However, logistical regression
analysis identified the presence of angina as a significant
discriminator between functionally and prognostically significant
viability. In fact, angina occurred in 38% of patients with extensive
areas of viability but in only 18% of those with smaller,
prognostically significant amounts of myocardial viability. Thus, the
presence of anginal symptoms is related to the presence of functionally
significant myocardial viability. A similar trend was observed for
history of myocardial infarction, which, not surprisingly, tended to be
associated with predominantly nonviable tissue.
Clinical Management Decisions
The presence of myocardial viability influenced the clinical
decision making. Sixty-eight percent of patients with functionally
significant, 52% of those with prognostically significant, but only
36% of those without viability underwent
revascularization (Figure 3
). However, the
reasons for these clinical management decisions remain poorly
understood. Discrepancies between the original clinical and the
retrospective interpretation of the PET studies accounted for 4 of the
12 patients with functionally significant viability who remained under
medical therapy. Inadequate target vessels, systemic diseases such as
cancer or diabetes with renal failure, or patient refusal might have
accounted for the others. Conversely, several patients without
extensive myocardial viability underwent coronary
revascularization. Again, discrepancies between the
original clinical and the retrospective interpretations (n=6), a
history of angina pectoris (n=10) or stress-induced ischemia on
perfusion images (n=3), and aneurysmectomy or concomitant
repair of dysfunctional valves (n=4) probably influenced some of these
clinical management decisions. It is therefore important to note that
not all patients with PET viability are surgical candidates and
conversely that clinical symptoms such as angina result in
revascularization even in the absence of PET
viability.
Study Limitations
This study has several limitations. The current prevalence data
might not apply to the general population of heart failure patients;
they might be biased toward the most severely compromised patients.
Future studies are required to determine the prevalence of viable
myocardium in larger groups of patients with
coronary artery disease and relatively maintained left
ventricular function.
All limitations pertaining to retrospective investigations apply to this study. A clinical history was available in only 60% and the clinical management decision in only 37% of the patients. Changes in left ventricular ejection after revascularization could be determined only in 24 patients. However, the contribution of PET to clinical management decisions was available in 110 patients, representing the largest patient population to date in which this issue has been investigated.
Another limitation is that insufficient clinical outcome data were available to further validate the concept of "prognostically significant" viability. However, 3 independent studies have previously concluded that nonrevascularized viable myocardium of any extent is associated with adverse cardiac events and/or a higher incidence of cardiac death.3 4 5
The PET studies were interpreted visually. No semiquantitative polar map analysis was performed. This method was chosen because the original visual clinical image interpretation clearly directed patient management toward revascularization, transplantation, or conservative treatment. Nevertheless, because no clinical attempt was made to "quantify" the extent of viability, the imaging studies had to be to reinterpreted, which raises issues regarding the reproducibility of visual image analysis. To determine whether the original clinical and current image interpretations differed significantly, the extent of viability was estimated from the conclusion of the original clinical readout: Viability was considered functionally significant if revascularization was recommended, prognostically significant if small areas of viability were mentioned but no revascularization was recommended, and absent if no viability was mentioned in the original report. Discrepancies between the original and current interpretations that would have led to different clinical recommendations were found in <5% of all studies, suggesting a low interobserver variability of visual image interpretation.
To further validate the visual image analysis approach, we examined the pathology reports available for 10 of the 19 explanted hearts. These reports described areas of extensive myocardial infarctions but did not provide detailed histopathological evaluations of noninfarcted myocardium. A blood flow/metabolism match pattern predicted the location of myocardial infarctions by pathological inspection in 8 of the 10 patients. In the 2 remaining patients, PET predicted normal or viable tissue, whereas the pathology report revealed nontransmural myocardial infarctions. These results are in keeping with previous studies suggesting a high negative predictive value of the blood flow/metabolism match pattern for myocardial viability.
Further support for the validity of the current approach was recently
provided by Duvernoy et al,23 who demonstrated that polar
map analysis and visual analysis yielded similar
results for determining myocardial viability. Moreover, the currently
reported prevalence of functionally significant myocardial viability of
25% is consistent with previous reports.13 14
Finally, the significant improvement in left ventricular
ejection fraction after revascularization, observed
only in patients with functionally significant viability, validates the
current approach.
Clinical Implications
Functionally significant viability can be expected in 25% of all
patients with ischemic heart disease and left
ventricular dysfunction who might be suitable candidates
for coronary revascularization.
Most common among the clinical tests for assessing myocardial viability are 2-dimensional echocardiography during inotropic stimulation,24 25 26 various SPECT imaging protocols using 201Tl as a marker of cell membrane integrity,27 28 29 30 and PET with tracers of myocardial blood flow and glucose use.1 17 31 32 33 34 These tests differ in diagnostic accuracy and costs. The current data should serve as useful prerequisites for determining the cost-effectiveness of noninvasive tests aimed at identifying those patients with left ventricular dysfunction who might benefit from coronary revascularization.
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Acknowledgments |
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This work was supported by research grant HL-33177 from the National Institutes of Health, Bethesda, Md. Johannes Czernin is the recipient of a clinician-scientist award from the American Heart Association. We want to thank Michael Fishbein, MD, for reviewing the pathology specimen. We also want to thank Ron Sumida, Larry Pang, Francine Aguilar, Der-Jenn Liu, Priscilla Contreras, and Sumon Wongpiya for their excellent technical assistance in performing the PET studies; N. Satyamurthy, PhD, and his cyclotron staff for the preparation of radioisotopes; and Diane Martin and David Twoey for preparing the artwork.
Received November 24, 1998; revision received March 1, 1999; accepted March 23, 1999.
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