(Circulation. 1995;91:1016-1021.)
© 1995 American Heart Association, Inc.
Articles |
Residual 201Tl Activity in Irreversible Defects as a Marker of Myocardial Viability
Clinicopathological Study
Presented in part at the 66th Scientific Sessions of the American Heart Association, Atlanta, Ga, November 8-11, 1993.
From the Department of Cardiology (R.Z., B.R., J.Z., W.K.), the Institute of Pathology (G.M., M.G.), the Institute for Forensic Medicine (G.Z.), and the Departments of Nuclear Medicine (B.B.) and Cardiac Surgery (S.H.), Ruprecht-Karls-University, Heidelberg, and the Department of Cardiology (H.T.), University of Gießen (Germany).
Correspondence to Rainer Zimmermann, MD, Department of Cardiology, Ruprecht-Karls-University, Bergheimer Str 58, D-69115 Heidelberg, FRG.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background The objective of the present study was to characterize the relation between the residual 201Tl activity in irreversible perfusion defects and the extent of irreversible myocardial damage indicated by the volume fraction of myocardial interstitial fibrosis in patients with chronic coronary artery disease.
Methods and Results Stress planar 201Tl scintigraphy
with tracer reinjection at rest was performed in 37 patients with
75% stenosis of the left anterior descending coronary artery, and
anteroseptal 201TI activity was quantified by
computer-assisted placement of regions of interest from the serial
myocardial images. During coronary artery bypass grafting (performed
within 6±3 weeks after scintigraphy), two transmural biopsy specimens
were taken from the anterior wall of the left ventricle and the amount
of interstitial fibrosis was assessed by use of light microscopic
morphometry. A wide spectrum of interstitial fibrosis was obtained,
ranging from 15 vol% to 60 vol%. Interstitial fibrosis was similar in
patients with reversible (n=11) or irreversible (n=15) tracer
defects
in conventional stress-redistribution images. However, interstitial
fibrosis was significantly lower in patients who had enhanced regional
201Tl activity after tracer reinjection compared with those
who did not have enhancement of tracer activity after reinjection
(28±8 vol%, n=7, versus 41±12 vol%, n=8;
P=.031). The
correlation between relative poststenotic 201Tl activity
and interstitial fibrosis after tracer reinjection was significantly
improved compared with conventional redistribution images
(r=-.622 versus r=-.851,
n=15;
P<.01).
Conclusions The present data demonstrate that the level of regional 201Tl activity in redistribution and, in particular, reinjection images is significantly related to the mass of preserved viable myocytes in poststenotic left ventricular myocardium. Therefore, the residual 201Tl activity provides information about viability within irreversible perfusion defects and may itself serve as marker of myocardial viability.
Key Words: coronary disease • myocardium • imaging • stenosis
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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During the past decade, myocardial scintigraphy with 201Tl has achieved a preeminent position for its use in the clinical assessment of myocardial viability in patients with coronary artery disease. By use of modified imaging protocols, such as the rest-reinjection technique,1 2 3 4 5 6 it has been shown that 201TI scintigraphy identifies quite the same myocardial regions as viable or nonviable as positron-emission tomography imaging with [18F]fluorodeoxyglucose,7 the current reference tracer for the assessment of myocardial viability.
In most of the previous studies, however, the severity of the reduction in 201Tl activity within irreversible defects was not investigated. Because the residual tracer activity itself might serve as evidence of viable myocardium,7 8 9 10 in the present study, the regional myocardial 201Tl activity was directly related to the extent of structural damage, as indicated by the amount of interstitial fibrosis in the poststenotic myocardium. Interstitial fibrosis was determined from transmural left ventricular biopsy specimens that were obtained during aortocoronary bypass grafting from patients with chronic coronary artery disease.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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The study protocol was approved by the human study committee of the University of Heidelberg, and written informed consent was obtained from all patients.
Patients
The study group comprised 37 patients (n=3
women and 34 men;
mean age, 57±10 years old) with chronic coronary artery disease and
stable angina pectoris. Coronary arteriography demonstrated
three-vessel disease in 15 patients and two-vessel disease in 17
patients; 5 patients had one-vessel disease of the left anterior
descending coronary artery. All 37 patients had 75% proximal
stenosis of the left anterior descending coronary artery. The site of
the stenosis was proximal to the first septal perforator in 17
patients. In the other patients, the stenosis was distal to the origin
of the first septal branch but proximal to the origin of the second
diagonal branch. Fifteen of the 37 patients had a history of previous
anterior non–Q-wave myocardial infarction, and 7 patients had a
history of previous Q-wave anterior myocardial infarction. Patients
with a left ventricular aneurysm and/or a global left ventricular
ejection fraction <35% were excluded because of a potentially higher
risk for biopsy-related complications.
Patients underwent 201Tl scintigraphy within 10 weeks after coronary angiography (mean, 7±4 weeks) without intercurrent changes in their clinical status.
Cardiac Catheterization
Coronary arteriography and left
ventricular angiography were
performed by the Judkins technique with 35-mm cine filming by use of
multiple projections, including angulated views. At least five
projections were used for the left coronary artery, and at least two
projections were used for the right coronary artery. Coronary artery
stenoses were visually graded by two experienced cardiologists (R.Z.
and B.R.), who were unaware of the patients' clinical or scintigraphic
data.
Additionally, global and regional left ventricular performance
was
determined with the centerline method11 by use of the left
ventricular angiograms obtained in the right anterior oblique
projection. As previously described,12 regional wall
motion in the anterolateral segment was considered abnormal if wall
motion was 2 SD below the mean anterolateral wall motion obtained
from 64 normal patients.
201Tl Imaging
Patients were investigated after an
overnight fast and after
withdrawal of all long-acting antianginal medications; only sublingual
nitroglycerin was permitted as an antianginal treatment. Patients
engaged in an exercise program that used an upright bicycle ergometer
to implement a stepwise increase of workload (initial workload, 50 W,
with 25-W increases every 2 minutes). A positive response to stress was
defined as development of typical angina pectoris and/or 1.5-mm
horizontal or downsloping ST-segment depression at 80 milliseconds
after the J-point. One minute before the anticipated end of the
symptom-inducing limited-stress test, 80 MBq IV (2.2 mCi IV)
201Tl chloride was injected into the patient.
Planar scintigraphy was performed 5 minutes (poststress images) and 4 hours (redistribution images) after tracer injection in the anterior and the 30° left anterior oblique view with a Siemens Orbiter ZLC 7500 gamma camera equipped with a high-resolution parallel hole collimator and interfaced to a Siemens MicroDELTA system. Data were collected for 5 minutes per view with a peak energy setting at 75 keV and a 20% window.
In case of persistent 201Tl defects on the 4-hour delayed images, 40 MBq (1.1 mCi) 201Tl was reinjected at rest, immediately after redistribution imaging, and a third set of images (reinjection images) was taken within 30 minutes after the second tracer injection under the same imaging protocol.1
Quantitative Image Analysis
Quantitative image analysis was
performed off-line on
standard 80386 IBM-AT personal computers, as previously
described.13 In brief, after the MicroDELTA image data
were converted to a PC/MS-DOS format, the original 128x128-pixel
images were interactively centered, zoomed, and restored as
64x64-pixel images. After bilinear interpolative "background
subtraction,"14 sequential scintigrams were spatially
aligned with an automated image-superposition algorithm.15
The horizontal and vertical lags of sequential images are thereby
identified by calculating the peak values of the (one-dimensional)
cross-correlation function of the vertical and horizontal image-matrix
projections.
After operator-interactive selection of the left
ventricular cavity,
for each projection, seven 9-pixel regions of interest were
automatically drawn by the computer program (Fig 1
) from
the center of the left ventricular cavity along each of 45 radii at the
regional maximum of myocardial activity.16 These regions
of interest were identically placed in the poststress and spatially
aligned redistribution and reinjection scintigrams. Within each region
of interest, the relative tracer activity, which was normalized to the
peak activity obtained in the seven regions of interest within the
respective scintigram (100%), was calculated. Regional
201Tl activity in the perfusion territory of the left
anterior descending coronary artery was then calculated as the average
tracer activity obtained in the three anterolateral regions of interest
(anterior view) and the three septal regions of interest (30° left
anterior oblique view).
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In the poststress images, regional tracer
activity <80% in the
perfusion territory of the left anterior descending coronary artery was
defined as a perfusion defect.17 Perfusion defects were
classified as reversible if regional tracer activity achieved 80% in
subsequent redistribution images or if the regional tracer activity
increased by 10% on the redistribution images compared with the
poststress images. Otherwise, the defects were classified as
irreversible. Irreversible perfusion defects were further classified as
moderate if regional tracer activity achieved 65% in the
redistribution study and as severe if tracer activity remained
<65%.
Patients with irreversible defects were considered to have
enhanced
201Tl uptake after tracer reinjection ("fill-in") if
regional 201Tl activity was 80% in the reinjection
images or increased by 10% compared with the activity in the
redistribution images. Otherwise, defects were considered unchanged
after reinjection (no "fill-in").
Transmural Left Ventricular Biopsies
Patients underwent
coronary artery bypass grafting within 12
weeks (mean, 6±3 weeks) after 201Tl scintigraphy. During
cardiopulmonary bypass, two transmural biopsy specimens were taken from
the anterior wall of the left ventricle before cardioplegia was begun.
The site of the biopsy was selected by the surgeon (S.H.), who had
knowledge of the angiographic status. Transmural biopsy specimens were
obtained from the myocardial region surrounded by the left anterior
descending coronary artery and the first or second diagonal branch. The
site of the second biopsy was approximately 10 mm caudal to the first
biopsy site.
The cylindrical samples were acquired by use of a Tru-Cut biopsy needle (Travenol Laboratories, Inc) with 1.5-mm luminal diameter. Biopsies were immediately fixed with glutaraldehyde, postfixed in osmium tetroxide, dehydrated in ethanol, and embedded in epoxy resin. As previously described,18 semithin sections (0.5 µm) were prepared and double-stained with paraphenylene-diamine and toluidine blue for the morphometric investigations.
Morphometry
Morphometric evaluations were performed by two
investigators
(G.Z., M.G.), who were unaware of the patients' clinical or
scintigraphic data, by use of standard light microscopy and a
point-counting system, as previously described.12 18
Severe contraction bands, which are caused by mechanical disruption and are usually located at the border of the tissue samples, may occur artificially. Thus, only the central thirds of the sections were evaluated. Morphometry was performed with an eyepiece (Zeiss Integration Ocular, Zeiss) that provided 100 intersection points. At least 10 test areas were counted at x160 magnification, and the average interstitial nonmuscular tissue was calculated independently for the two transmural biopsy samples. For the statistical analyses, the average volume fraction of the interstitial nonmuscular tissue obtained in the two biopsy specimens was used.
The normal range for the
volume fraction of myocardial interstitial
fibrosis was considered to be 
12 vol%. This range was estimated from
the structural data previously gathered in our laboratory from normal
donor hearts before cardiac transplantation by applying identical
morphometric methods.12 A normal range of 12 vol% is
also in accordance with the data of other investigators, as assessed
from autopsy or intraoperative myocardial
samples.19 20 21 22
Statistical Analysis
Continuous data are given as
mean±1 SD. Correlations between
the tracer deposition and the structural data were determined from
least-squares linear regression analysis. The probability for a
statistically significant correlation was calculated by the
(nonparametric) Spearman rank statistics. To test for significant
differences between means, Student's t test for unpaired
data or ANOVA followed by Bonferroni's t test statistics
was used as appropriate. Comparison between the regression lines was
performed by Student's t test.
Statistical analyses were performed with the SAS statistical software package (SAS Institute Inc). For all tests, a value of P<.05 was considered indicative of a statistically significant difference.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Interstitial Fibrosis
A pathological volume fraction of interstitial fibrosis (>12 vol%) was obtained in each of the 37 patients (range, 14.5 vol% to 59.6 vol%). Interstitial fibrosis was most pronounced in patients with previous anterior Q-wave infarction and was significantly higher in this subgroup (P=.020) compared with patients with non–Q-wave infarction or those without previous infarction (Fig 2
).
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Thallium Stress-Redistribution Imaging
Regional
201Tl activity in the anterolateral and
septal myocardial segments was normal in 9 patients; 11 patients had
reversible and 15 patients had irreversible perfusion defects (Table
1). The irreversible defects were further graded as
moderate in 8 patients and severe in 7 patients. Two patients were not
assigned to a particular subgroup because their scintigraphic results
varied in the different views (ie, a reversible 201Tl
defect in one view and an irreversible defect in the other).
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As listed
in Table 1
, interstitial fibrosis in the anterior left
ventricular wall was not significantly different between the subgroups
of patients with normal regional tracer uptake, redistribution, or
persistent defects in conventional stress-redistribution images;
fibrosis tended only to be increased (P=.070) in patients
with severe irreversible defects.
Thallium Reinjection
Tracer reinjection was performed in the
15 study patients with
persistent defects in their conventional stress-redistribution images.
Enhanced regional 201Tl activity after thallium was
reinjected was obtained in 7 patients (5 with moderate and 2 with
severe apparently irreversible defects on stress-redistribution
images), whereas tracer activity was unaffected by reinjection in 8
patients (3 with moderate and 5 with severe defects). In these 8
patients, interstitial fibrosis was significantly higher (40.8±12.2
vol%) compared with the 7 patients with enhanced regional
201Tl uptake after tracer reinjection (27.5±8.4 vol%,
P=.031), whereas the clinical and angiographic data did not
show significant differences (Table 2).
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Relation Between Regional Thallium Activity and Interstitial
Fibrosis
Among the 15 patients with persistent defects in their
stress-redistribution images, a significant inverse relation between
the amount of interstitial fibrosis and the level of the regional
201Tl activity in the anterior wall was obtained in both
redistribution and reinjection images (Figs 3 and
4). The correlation coefficient, however,
was significantly higher (P<.01) for the reinjection images
(r=-.851) compared with the redistribution images
(r=-.622).
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The level of regional 201Tl activity in the poststress images was not related to the structural data.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The data from the present study demonstrate that the level of regional 201Tl activity in redistribution and reinjection images is related to the mass of preserved viable myocytes in poststenotic myocardium, and therefore this level may itself serve as a marker of myocardial viability. Compared with 4-hour delayed-redistribution imaging, tracer reinjection significantly improves the inverse relation between regional 201Tl activity and the extent of irreversible structural damage.
Fibrous tissue, generally considered a structural correlate of irreversible myocardial damage, represents the predominant component of the myocardial "interstitial nonmuscular space."23 24 25 Therefore, in agreement with other investigators,20 21 26 27 the term "interstitial fibrosis" was applied to describe the interstitial nonmuscular tissue.
Measurement of cardiac fibrosis allows for assessment of the extent of irreversible myocardial damage and estimation of the mass of viable myocytes, the latter being approximately equal to 100 vol% minus the volume fraction of fibrosis. In coronary artery disease, cardiac fibrosis arises from both interstitial and reparative (ie, replacement) fibrosis. Interstitial fibrosis is thereby characterized as intermyocardiocytic fibrosis in the absence of cell necrosis. Collagen synthesis may be stimulated as an underlying mechanism either directly, by increased wall stress, or indirectly, by neural or endocrine activation.28 A possible mechanism of myocardial repair by scar formation is that necrotic myocardium is removed and replaced by granulation tissue.29 30 In addition to these primary processes, fibrotic sheets between capillaries and myocytes may inhibit the transcapillary substrate exchange and thus induce secondary myocyte necrosis.12 31 32
Several lines of experimental evidence suggest that, after coronary
occlusion, ischemic myocytes do not die instantaneously: mildly
ischemic myocytes may survive indefinitely, and within the region that
is infarcted, not all myocytes die simultaneously.33 The
present clinical data are in accordance with this experimental
observance: in patients with 75% stenoses of the left anterior
descending coronary artery, interstitial fibrosis in the anterior left
ventricular wall varies in a continuous manner ranging from 14.5 vol%
to 59.6 vol%.
As expected, interstitial fibrosis was most pronounced in patients with
previous Q-wave myocardial infarction (Fig 2). However,
interstitial
fibrosis was also increased above the normal range in each of the
patients without previous anterior myocardial infarction. Because all
patients had high-grade stenosis of the left anterior descending
coronary artery, it seems conceivable that recurrent ischemic episodes
have led to focal irreversible injury in the poststenotic myocardium,
despite the lack of clinical evidence for myocardial
infarction.21 34 A further explanation derives from
the
fact that 21 of the 37 patients (57%) had a history of previous
posterior myocardial infarction, and increased wall stress due to
compensatory workload may have stimulated collagen synthesis in the
noninfarcted anterior left ventricular wall.
The introduction of the rest-reinjection technique has been demonstrated to improve precision when assessing myocardial viability with 201Tl scintigraphy.1 2 3 4 5 6 7 Two confirming aspects can be derived from the present data. First, interstitial fibrosis was significantly lower in myocardial segments with enhanced regional 201Tl activity after reinjection compared with segments with unchanged activity after reinjection (27.5±8.4 vol% versus 40.8±12.2 vol%, P=.031). Second, compared with the conventional redistribution images, the correlation between interstitial fibrosis and the level of 201Tl activity in irreversible perfusion defects is significantly improved after tracer reinjection (P<.01).
Methodological Considerations
Morphometry
To
minimize artificial damage, intraoperative assessment of the
two transmural biopsy specimens was performed during cardiopulmonary
bypass before cardioplegia was begun. A low sampling error has been
obtained with Travenol biopsy needles in clinical investigations and in
autopsy hearts.21 35 36 37
The inhomogeneous distribution of
structural alterations in coronary artery disease, however, may cause
an elevated sampling error. Therefore, in the present study, two
transmural biopsy specimens were obtained from the center of the
perfusion territory of the left anterior descending coronary artery and
the average value of the volume fraction of the interstitial fibrous
tissue was used for the statistical analyses.
Also, assessment of two biopsy specimens per patient allowed us to compare the intraindividual variance (differences between the two biopsy specimens) with the interindividual variance (differences among the individual patients) of the structural data; the intraindividual variance was significantly lower (P<.01). Furthermore, since interstitial fibrosis was significantly higher in patients with impaired compared with normal anterolateral left ventricular performance (37.8±9.2 vol%, n=16, versus 25.8±7.4 vol%, n=21; P<.001), this finding might also indicate a tolerable sampling error in the morphometric data.
The volume fraction of interstitial fibrosis was assessed by standard light microscopy as previously described18 and validated.12 Light microscopy was used because this technique permits the analysis of larger test areas than electron microscopy.
Scintigraphy
To eliminate the intrinsic
variability of visual image
interpretations, quantitative criteria were applied for the
classification of the scintigraphic studies as those with either
reversible or irreversible 201Tl defects.
With planar imaging, individual coronary artery perfusion territories are superimposed. This has to be considered in the present study because the majority of the patients suffered from multiple-vessel coronary artery disease, as evidenced by the more frequent indication for surgical revascularization in these patients.
To balance the effect
of superimposition of different perfusion
territories, we calculated the average value for the relative
anteroseptal tracer activity from the anterior and 30° left anterior
oblique views. As illustrated in Fig 1, this allows comparison
of
tracer activity in the perfusion territory of the left anterior
descending coronary artery with that in the other two vascular regions:
the perfusion territory of the right coronary artery (inferior wall) in
the anterior view and the perfusion territory of the left circumflex
coronary artery (lateral wall) in the 30° left anterior oblique
view.
Study Limitations
In addition to the methodological
considerations mentioned above,
when interpreting the present data, one should further consider
that patients with a left ventricular aneurysm or a global left
ventricular ejection fraction <35% were not included in the study
because transmural biopsies in these patients might be associated with
a higher risk for complications. Also, the study population included
only three women.
Conclusions and Clinical Implications
With scintigraphic
methods, the common definition of myocardial
viability is based on the evidence of elementary aspects of cell
function, such as cell membrane integrity or preserved intermediary
metabolism. Lack of evidence for the existence of one or both of these
components is considered a marker of cell necrosis. In view of the
present data, however, this binary classification into viable or
nonviable segments appears to be an oversimplification and does not
reflect the continuous nature of structural damage in coronary artery
disease.
The present results indicate that residual tracer activity in irreversible 201Tl defects (particularly after tracer reinjection) is proportional to the mass of preserved viable myocytes and therefore provides information about viability within perfusion defects. This suggests that quantification of residual 201Tl activity after rest-reinjection is a suitable tool to assess the possible value of therapeutic strategies.
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Acknowledgments |
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This study was supported by a grant from the Deutsche Forschungsgemeinschaft within the SFB 320 "Herzfunktion und ihre Regulation," Ruprecht-Karls-Universität, Heidelberg, Germany. We gratefully acknowledge the excellent technical assistance of Dorina Mack (Department of Nuclear Medicine) and Winfried Nottmeyer (Institute of Pathology). 201Tl was supplied by Du Pont Pharma GmbH, Bad Homburg, Germany. IBM, IBM-AT, and PC-DOS are trademarks of International Business Machines Corp; MicroDELTA, of Computer Design and Applications, Inc; and MS-DOS, of Microsoft Corp.
Received August 4, 1994; revision received September 19, 1994; accepted October 2, 1994.
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M. Faraggi The Continuing Story of 201Tl Reverse Redistribution: Reverse Redistribution Is Still Alive, but Is the Myocardium Still Viable? J. Nucl. Med., May 1, 2002; 43(5): 628 - 631. [Full Text] [PDF]
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J. Shirani, J. Lee, R. Quigg, R. Pick, S. L. Bacharach, and V. Dilsizian Relation of thallium uptake to morphologic features of chronic ischemic heart disease: evidence for myocardial remodeling in noninfarcted myocardium J. Am. Coll. Cardiol., July 1, 2001; 38(1): 84 - 90. [Abstract] [Full Text] [PDF]
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J. M. Cwajg, E. Cwajg, S. F. Nagueh, Z.-X. He, U. Qureshi, L. I. Olmos, M. A. Quinones, M. S. Verani, W. L. Winters, and W. A. Zoghbi End-diastolic wall thickness as a predictor of recovery of function in myocardial hibernation: Relation to rest-redistribution Tl-201 tomography and dobutamine stress echocardiography J. Am. Coll. Cardiol., April 1, 2000; 35(5): 1152 - 1161. [Abstract] [Full Text] [PDF]
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S. F. Nagueh, I. Mikati, D. Weilbaecher, M. J. Reardon, G. J. Al-Zaghrini, D. Cacela, Z.-X. He, G. Letsou, G. Noon, J. F. Howell, et al. Relation of the Contractile Reserve of Hibernating Myocardium to Myocardial Structure in Humans Circulation, August 3, 1999; 100(5): 490 - 496. [Abstract] [Full Text] [PDF]
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A. N. Kitsiou, G. Srinivasan, A. A. Quyyumi, R. M. Summers, S. L. Bacharach, and V. Dilsizian Stress-Induced Reversible and Mild-to-Moderate Irreversible Thallium Defects : Are They Equally Accurate for Predicting Recovery of Regional Left Ventricular Function After Revascularization? Circulation, August 11, 1998; 98(6): 501 - 508. [Abstract] [Full Text] [PDF]
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H. A. Dakik, J. F. Howell, G. M. Lawrie, R. Espada, D. G. Weilbaecher, Z.-X. He, J. J. Mahmarian, and M. S. Verani Assessment of Myocardial Viability With 99mTc-Sestamibi Tomography Before Coronary Bypass Graft Surgery : Correlation With Histopathology and Postoperative Improvement in Cardiac Function Circulation, November 4, 1997; 96(9): 2892 - 2898. [Abstract] [Full Text]
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U. Qureshi, S. F. Nagueh, I. Afridi, P. Vaduganathan, A. Blaustein, M. S. Verani, W. L. Winters, and W. A. Zoghbi Dobutamine Echocardiography and Quantitative Rest-Redistribution 201Tl Tomography in Myocardial Hibernation: Relation of Contractile Reserve to 201Tl Uptake and Comparative Prediction of Recovery of Function Circulation, February 4, 1997; 95(3): 626 - 635. [Abstract] [Full Text]
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R. O. Bonow Identification of Viable Myocardium Circulation, December 1, 1996; 94(11): 2674 - 2680. [Full Text]
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R. Medrano, R. W. Lowry, J. B. Young, D. G. Weilbaecher, L. H. Michael, I. Afridi, Z.-X. He, J. J. Mahmarian, and M. S. Verani Assessment of Myocardial Viability With 99mTc Sestamibi in Patients Undergoing Cardiac Transplantation: A Scintigraphic/Pathological Study Circulation, September 1, 1996; 94(5): 1010 - 1017. [Abstract] [Full Text]
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