(Circulation. 2000;102:1795.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Independent and Incremental Prognostic Value of 201Tl Lung Uptake at Rest in Patients With Severe Postischemic Left Ventricular Dysfunction
From Salvatore Maugeri Foundation IRCCS, Cardiology Division, Veruno (No), Italy.
Correspondence to Claudio Marcassa, MD, Fondazione Maugeri, via Revislate 13, Veruno 28010, Italy. E-mail cmarcassa{at}fsm.it
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Abstract |
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Background—An elevated 201Tl lung uptake after stress is related to an adverse prognosis.
Methods and Results—The functional and prognostic significance of
resting 201Tl lung uptake was assessed in 124 consecutive
patients with ischemic heart disease and ejection fraction
35% undergoing rest-redistribution tomography to evaluate myocardial
viability. 201Tl lung uptake significantly correlated with
pulmonary wedge pressure (r=0.66;
P<0.01) and with a restrictive physiology by
Doppler echocardiography
(P<0.001). During a 13±13-month follow-up, 13 patients
died and 23 patients required hospitalization as the result of
worsening heart failure or nonfatal myocardial infarction (cumulative
events rate 29%). Patients with events had a significantly higher
201Tl lung/heart ratio (L/H) (P<0.001). A
L/H value >0.61 best separated patients with and without events (ROC
area under curve 0.82). Event-free survival was significantly lower in
patients with L/H >0.61 (P<0.001); L/H >0.61
(
2=10.8; P<0.001) and a restrictive
filling pattern (2=3.6; P<0.05) were
independent predictors of events. The prognostic value of L/H was
incremental over that obtained by clinical, echographic and Doppler
data (global 2=20.8).
Conclusions—In patients with severe postischemic left ventricular dysfunction undergoing rest-redistribution 201Tl imaging, an increased lung tracer uptake showed incremental prognostic value over clinical and other imaging findings, providing clinically useful risk assessment.
Key Words: heart failure • prognosis • scintigraphy
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Heart failure remains a critical target for therapeutic intervention. The prospective identification of patients with systolic dysfunction at greatest risk is elusive, and residual myocardial viability is assessed to identify who will most benefit from coronary revascularization. Recently, noninvasive markers of diastolic dysfunction have been shown to herald an unfavorable outcome and yield incremental information.
At 201Tl myocardial scintigraphy, an elevated lung uptake of the tracer after stress is a marker of severe coronary artery involvement and adverse prognosis.1 2 3 The increased 201Tl lung uptake has been related to the extent of reversible ischemia and stress-induced increase in left ventricular (LV) end-diastolic pressure.4 5
The clinical meaning of this additional scintigraphic finding at rest 201Tl imaging is less clear. In a small group of patients with acute coronary syndromes, an increased resting lung uptake was associated with a higher rate of in-hospital heart failure and increased short-term mortality.6 The aim of this study was to assess the clinical correlates and the prognostic significance of an elevated lung uptake at rest 201Tl tomoscintigraphy in clinically stable patients with severe LV dysfunction.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Study Cohort
We studied 124 consecutive patients with a history of ischemic heart disease and severe LV dysfunction (ejection fraction
35% at 2D echocardiography or
angiography) who were referred to our nuclear
cardiology laboratory from January 1994 to December
1996 for a 201Tl rest-redistribution study, to
assess the presence of residual viability in dysfunctioning myocardial
segments. All patients were clinically stable, with optimized
cardiovascular therapy and in New York Heart
Association (NYHA) functional class II or III. The study cohort
included 30 (24%) patients with severe heart failure, admitted to our
hospital for heart transplantation workup and who, after aggressive
medical treatment, improved their functional class, thus being able to
tolerate the supine position required for tomographic imaging. Patients
with unstable angina, recent (<1 month) myocardial infarction, or
overt heart failure were excluded. Recent (<3 months) coronary
angiography was available in 86 patients and showed the presence of a
>50% coronary diameter reduction of a major coronary
artery in 76 patients (88%). Right heart
catheterization data by Swan-Ganz
catheterization performed within 48 hours of the
201Tl study were also available in 19 patients.
The study protocol was approved by the local Ethics Committee for Human
Research. Informed consent was obtained from all patients.
201Tl Imaging and Analysis
201Tl 3 mCi (111 MBq) was injected at
rest, in fasting condition; cardioactive drugs were not withdrawn.
Images were obtained 10 minutes and 4 hours after injection. The
methods for imaging acquisition, reconstruction, and analysis
have been previously reported.7 For the quantification of
regional myocardial tracer uptake, a 20-segment LV model was adopted. A
segmental 201Tl uptake <75% of peak myocardial
activity was considered abnormal; the tracer uptake defect was
classified as severe if <50% and mild-moderate if 50% to 75% of
peak myocardial activity. A tracer defect was considered reversible
when its abnormal 201Tl uptake on rest images
increased >10% on redistribution images.7 The LV
201Tl distribution was also displayed as a polar
map and normalized for peak myocardial activity; regions with tracer
uptake 50% of peak uptake were considered "nonviable" and summed
to obtain the total "nonviable" myocardial extent, expressed as a
percentage of the LV surface.
The lung 201Tl uptake was assessed both
qualitatively and quantitatively from the earlier acquisition. Three
selected frames from 6° right anterior to 6° left anterior oblique
projections were added to one composite image
representing 150 seconds of data acquisition. The lung
tracer uptake was qualitatively assessed by 2 experienced investigators
unaware of clinical or hemodynamic data; all images
were analyzed without background subtraction, after
normalization for peak cardiac activity. By comparing the uptake in the
lungs with the uptake in the myocardium and mediastinum,
pulmonary uptake was scored on a 4-point grading system
(0=lungs poorly visualized; 1=mild; 2=moderate and 3=marked lung
uptake); a score 
2 was considered abnormal. The interobserver
agreement in grading the lung tracer uptake was 95%; discrepancies
were resolved by consensus.
For the quantitative analysis, 2 regions of interest were drawn over the left lung and the area of maximal myocardial activity, and the tracer lung/heart uptake ratio (L/H) was calculated as (mean counts/pixel left lung)/(mean counts/pixel myocardium).8
Echocardiographic Evaluation
Complete echocardiographic and Doppler
ultrasound evaluation were performed in all patients, as previously
reported.9 The left ventricle was divided into 13
segments, and systolic wall thickening and inward wall motion
were visually assessed off-line by 2 experienced operators who were
unaware of other information. In each segment, contraction was graded
on a 4-point scoring system (from 0=normal to 3=dyskinetic) and a wall
motion score index was calculated; in cases of discrepancies a
consensus was reached. LV volumes were calculated from orthogonal
apical views with the biplane area-length method, and the LV ejection
fraction was derived. At Doppler examination of mitral
diastolic inflow, peak early (E) and late (A) flow
velocities, the peak E/A wave velocity ratio and deceleration time of
early filling were measured.9 The restrictive filling
pattern was defined as an E/A ratio 2 or the combination of an E/A
ratio between 1 and 2 and a deceleration time 140 ms. Mitral
regurgitation was evaluated by color Doppler flow
imaging and scored as absent, mild, moderate or severe according to
Helmcke et al.10
Follow-Up and Statistical Analysis
Follow-up was obtained at regular intervals in our outpatient
clinic or through telephone interviews conducted by trained personnel,
personal communication with the patient’s physician, and, in the case
of new hospitalization, by reviewing the patient’s hospital
records. For the purposes of this study, hard events signified
cardiac death or nonfatal myocardial infarction; major events included
hard events plus rehospitalization for heart failure.
Continuous data are reported as mean±SD. A Student’s t
test for unpaired data or ANOVA was used to test differences between
groups, with Bonferroni’s correction when indicated, and differences
in rates of occurrence of categorical variables were compared by
the 2 test with Yates’ correction. Linear
regression analysis was used to assess the correlation between
L/H and hemodynamic, echocardiographic
variables, and the extent of "nonviable" LV area.
Receiver-operating characteristic (ROC) curves for the prediction of
major events were generated with the use of individual L/H values;
cut-points were generated at regular intervals and the best threshold
was automatically identified as the value minimizing the expression
[(1-sensitivity)2+(1-specificity)2].
The area under the curve was obtained according to Hanley and
McNeil.11 Differences in event rates between patients
with L/H above or below the cut-point value were analyzed with
Kaplan-Meier survival curves and compared by means of the log-rank
test.
A Cox logistic regression analysis was used to identify the baseline variables that were independently correlated to hard or major events among those significantly associated on univariate analysis. Patients who underwent surgery were included in the survival analysis up to the time of the revascularization or transplantation. All tests of significance were 2-tailed, and a P value of <0.05 was considered significant.
To assess the incremental prognostic information from the addition of demographic, clinical, echocardiographic, and scintigraphic variables, data analysis was also performed according to a modified stepwise procedure in which individual factors were included in the model in the same order in which they would be considered in the clinical practice (demographic and clinical data first, followed by echocardiographic variables, then Doppler findings, and finally the 201Tl lung uptake). The demographic and clinical variables considered were age, history of congestive heart failure, rales, and third sound; the echocardiographic and Doppler variables considered were LV volumes, ejection fraction, and the presence of a restrictive filling pattern. Increment in information of the model at each step was considered significant when the log-likelihood difference adjusted for differences in degrees of freedom associated with each model had a P value of <0.05.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The mean age of the study group was 62±12 years (range 33 to 79 years; 83% men) and the average LV ejection fraction was 23±6%; at coronary angiography, single-vessel and multivessel coronary artery diseases were detected in 16 (19%) and 60 (70%) patients, respectively. At 201Tl imaging, 5.1±3.4 myocardial segments had a tracer uptake <50%, and the extent of "nonviable" area at polar map was 28±15%. The average lung uptake score was 1.7±0.8 and the average L/H was 0.64±0.14. The significant relation between the 201Tl lung uptake at quantitative analysis and the corresponding visual score is reported in Figure 1
. The
clinical, echocardiographic, and scintigraphic findings
of the study cohort are reported in Table 1.
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201Tl Lung Uptake: Correlation With Functional and
Hemodynamic Variables
At qualitative analysis, lung 201Tl
uptake was elevated in 74 patients (60%) and normal in 50 (40%); the
clinical and instrumental findings of the study cohort according to the
presence of an elevated or normal lung 201Tl
uptake are reported in Table 2. At
multivariate analysis, severe mitral
regurgitation (2=6.8,
P<0.05) and peak A-wave velocity
(2=4.2, P<0.05) were independently
correlated with an increased lung uptake.
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A significant inverse relation was documented between L/H and peak flow
velocity of A wave (r=-0.53; P=0.0005) (Figure 2) or peak E/A flow ratio
(r=-0.50; P=0.0007); no significant correlation
was observed between L/H and LV volumes, ejection fraction, wall motion
score index, E-wave peak velocity and E-wave deceleration time, or
extent of nonviable myocardial area. When L/H and right heart
catheterization data were compared, a significant
correlation was found only between L/H and wedge pressure
(r=0.66; P=0.008) (Figure 2).
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Follow-Up Data
Patients were followed up for a period of 13±13 months, and
follow-up data were obtained in all patients. There were 29 (23%)
patients who underwent revascularization and 11
other patients (9%) who underwent heart transplantation. Among the
remaining 85 (68%) medically treated patients,
revascularization was not planned in 37 patients
because of stenotic coronaries supplying an extensive nonviable
LV area, and it was not performed in 14 patients because the target
vessel was unsuitable for revascularization. In 34
other patients (27%) judged to be at high risk because of severely
depressed LV function (ejection fraction <20% and LV
end-diastolic volume index >120 mL/mq), additional
invasive procedures were not scheduled. At follow-up, 1 patient had a
new nonfatal myocardial infarction, 13 patients (10%) died, and 22
(18%) other patients required hospital admission for worsening
congestive heart failure. Overall, 36 patients (29%) had major events:
Clinical and instrumental findings in patients with and without
unfavorable outcome are summarized in Table 3.
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On the basis of ROC analysis, an L/H value >0.61 best
separated patients with and without major events at follow-up
(area-under-curve=0.82; sensitivity 83%, specificity 74%) (Figure 3). The clinical and instrumental
findings of patients with versus without L/H >0.61 are reported in
Table 4. In patients with L/H >0.61, 31
(42%) had a major event, compared with only 5 (10%) patients with L/H
0.61 (P<0.001; relative risk 3.91, 95% CI 1.69 to 9.1).
The Kaplan-Meier analysis showed that the 4 years survival free
of major events was significantly lower in patients with L/H >0.61
than in those with L/H 0.61 (P<0.001) (Figure 4). Survival without cardiac death
(P<0.05) as well as without rehospitalization as the result
of worsening heart failure (P<0.005) was also significantly
lower in patients with increased tracer lung uptake (Figure 5).
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When the variables that significantly correlated with an adverse
outcome at follow-up by univariate analysis were
introduced in the logistic regression analysis, an L/H value
>0.61 (2=10.8; P<0.001) and the
presence of a restrictive filling pattern
(2=3.6; P<0.05) were the sole
independent predictors of major events.
Incremental Prognostic Value of Diagnostic Procedures
At the interactive stepwise procedure, the power of models
developed at various steps in hierarchic order (clinical data; clinical
and echocardiographic results; clinical,
echocardiographic, and Doppler results; clinical,
echocardiographic, Doppler, and
201Tl results) to predict major events is shown
in Figure 6. The global
2 value achieved by the addition of the L/H
value to the clinical, echocardiographic, and
Doppler variables was significantly higher (global
2=20.8), indicating that
201Tl lung uptake still added significant
prognostic information.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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An elevated lung 201Tl uptake on stress images is considered the result of an increased LV filling pressure caused by transient LV dysfunction.3 5 Other proposed mechanisms include increased lung transit time, lung water content, and vascular permeability.3 Thus, an elevated lung 201Tl uptake is a noninvasive marker of stress induced pulmonary congestion. This scintigraphic finding has been documented as a powerful predictor of extensive coronary artery disease and adverse prognosis.1 2
The functional and prognostic significance of an elevated lung 201Tl uptake at rest has been less investigated. A significant correlation between the amount of lung 201Tl uptake and wedge pressure was documented by Martinez et al12 in 16 patients with cardiomyopathy and congestive heart failure. A high lung 201Tl uptake was documented in 36% of patients with acute myocardial infarction by Jain et al6 ; it was associated with more severe LV dysfunction and higher event rates during hospitalization.
The present study is the first assessing the clinical and prognostic significance of resting lung 201Tl uptake in comparison with clinical, echocardiographic, and hemodynamic findings in a selected, large cohort of clinically stable patients with severe LV dysfunction. The resting lung uptake of the tracer significantly correlated with other indexes of increased LV filling pressure. Moreover, an elevated lung uptake proved a powerful predictor of adverse outcome, its prognostic information being incremental over that obtained by clinical, echocardiographic, and Doppler examination.
Lung 201Tl Uptake and Diastolic Function
Doppler analysis of mitral flow is a noninvasive
technique widely used to assess LV diastolic function in
different pathological settings.9 13 14 A close
correlation between Doppler-derived diastolic function
and invasively-derived hemodynamic
parameters has been reported by several
authors.13 14 15 Finkelhor et al14 correlated
peak E- and peak A-wave velocities with L/H in 56 patients undergoing
exercise perfusion scintigraphy: higher E-wave velocities
were observed in patients with high L/H values. In the present
study, severe mitral regurgitation and peak A-wave
velocity were the sole independent predictors of increased
201Tl lung uptake, and a significant inverse
linear relation between L/H and A was found. Peak A velocity reflects
left atrial loading and systolic function: In the presence of
an elevated LV stiffness, a reduced blood volume moves through the
mitral valve, irrespective of atrial contraction, causing a reduction
in peak A velocity and a rise in mean atrial pressure. This mechanism
could also explain an increased L/H. In the subgroup of patients
undergoing right heart catheterization, we also
documented a significant correlation between L/H and wedge pressure;
this result further supports the hypothesis that a high resting L/H
reflects elevated LV filling pressure.12
Prognostic Implications
Patients with severe LV systolic dysfunction are at high
risk of death; assessment of diastolic function has been
recently suggested to add information regarding their risk
stratification. An abnormal relaxation pattern characterized by a
restrictive physiology frequently occurs in patients with extensive
damage and, in patients with depressed LV function,
diastolic dysfunction may play an important role in
determining clinical signs and symptoms. A significant correlation
between hemodynamic indexes of pulmonary
congestion and survival has been documented16 : This
relation supports the link between a restrictive filling pattern at
Doppler analysis and prognosis. Patients with a restrictive
LV physiology after acute myocardial infarction were found to be in a
particularly high-risk subgroup.9 17 Of note, in our
study, 2 markers of diastolic dysfunction (an L/H >0.61
and a restrictive Doppler filling pattern) emerged as the sole
independent predictors of poor prognosis. Since abnormalities of
systolic and diastolic function frequently coexist,
a marker of global LV dysfunction such as an increased
201Tl lung uptake may result a powerful marker of
poor outcome. Unlike other studies that used a >0.50 L/H as a cutoff
to identify high-risk patients undergoing stress
201Tl imaging, in our study, based on resting
imaging, a higher L/H cutoff value (ie, 0.61) was found by ROC
analysis to best discriminate patients at increased risk of
major events. Differences in pulmonary mean transit time,
pulmonary pressures, or vascular permeability at rest or during
stress could explain the discrepancy in cutoff values. We also
determined how well an increased resting 201Tl
lung uptake performs when clinical and echo-Doppler findings have
already been taken into account.
In the whole study cohort, roughly 75% of the left ventricle, on average, was viable. Since the LV ejection fraction was only 23%, this suggests that most of the viable segments were dysfunctional and presumably hibernating. For various reasons, however, only 23% of the patients underwent subsequent coronary revascularization. A consistent amount of myocardial viability in LV dysfunctioning regions is a powerful predictor of outcome18 19 20 . In patients with >7 viable segments out of 11 myocardial segments at preoperative rest-redistribution 201Tl imaging, Ragosta et al18 showed that mean LV ejection fraction significantly improved after coronary surgery. Pagley et al19 showed that the 201Tl extent of myocardial viability was the best predictor of transplant-free survival. Moreover, the extent of viable and potentially jeopardized myocardium has been shown a powerful predictor of mortality in medically treated patients.20 In contrast to these retrospective studies, in our study, which evaluated a more selective population with severe LV dysfunction, advanced functional class, and predominant symptoms of heart failure, the myocardial viability extent did not emerge as significant predictor either of hard or of major events at follow-up.
Limitations
Our results were obtained in patients with ischemic heart
disease and may not apply to patients with LV dysfunction of different
causes. We found a significant correlation between the capillary
"wedge" pressure and L/H, although invasive measurements were
obtained in a limited number of patients and were performed within 48
hours of the scintigraphic study. If some degree of discordance in
results is expected between invasive and noninvasive studies performed
over separate days, any misclassification, however, would attenuate the
results; so the true relations are likely to be even stronger than
observed. We noninvasively assessed LV filling pressures by
echocardiographic mitral inflow Doppler
analysis; other accurate methods have been recently
proposed.21 Finally, results of
201Tl imaging regarding the amount of LV viable
tissue influenced the decision to perform coronary surgery in
some patients; on the other hand, the degree of the thallium lung
uptake, the topic of our study, played no role in the surgical
decision.
Conclusions
Our data suggest that in patients with severe LV dysfunction
undergoing 201Tl scintigraphy for the
assessment of residual viability, an elevated tracer uptake in the
lungs should also be considered by clinicians as having powerful
prognostic significance. Abnormal L/H is easily and automatically
detectable by standard 201Tl imaging and
identifies a subgroup of patients with poor prognosis and in whom a
very aggressive management seems warranted.
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Acknowledgments |
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The authors are grateful to Rosemary Allpress, MA, for editorial assistance.
Received March 14, 2000; revision received May 5, 2000; accepted May 19, 2000.
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References |
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