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(Circulation. 1996;94:1010-1017.)
© 1996 American Heart Association, Inc.
Articles |
Assessment of Myocardial Viability With 99mTc Sestamibi in Patients Undergoing Cardiac Transplantation
A Scintigraphic/Pathological Study
the Sections of Cardiology (R.M., R.W.L., J.B.Y., I.A., Z.-X.H., J.J.M., M.S.V.) and Cardiovascular Sciences (L.H.M.), Departments of Internal Medicine (R.M., R.W.L., J.B.Y., L.H.M., I.A., Z.-X.H., J.J.M., M.S.V.) and Pathology (D.G.W.), Baylor College of Medicine, and The Methodist Hospital, Houston, Tex.
Correspondence to Mario S. Verani, MD, FACC, FACP, Professor of Medicine, Baylor College of Medicine, Director, Nuclear Cardiology, The Methodist Hospital, 6550 Fannin, SM677, Houston, TX 77030.
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Abstract |
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Background 99mTc sestamibi and 201Tl are tracers that allow equivalent detection of myocardial infarction. However, because sestamibi does not undergo as much time-dependent redistribution as does 201Tl, it has been considered suboptimal for the detection of myocardial viability.
Methods and Results Fifteen consecutive patients with ischemic cardiomyopathy who underwent orthotopic cardiac transplantation received an intravenous injection of 99mTc sestamibi at 1 to 6 hours before transplantation. Rotational tomography of the excised, intact, native hearts was performed to quantify the extent of myocardial hypoperfusion. The hearts were then sliced and reimaged on a gamma camera, followed by pathological quantification of the extent and severity of scarred and normal myocardium. Samples of normally and abnormally perfused myocardium underwent gamma well counting to determine tissue radioactivity and were examined under light microscopy for delineation of myocardial structure after trichrome staining. The mean extent of scintigraphic scar quantified through the use of rotational tomography was 45±14% of the left ventricle and correlated closely with pathological scar size (r=.89), despite a slight overestimation. Scintigraphic scar size determined with planar imaging of the individual myocardial slices also correlated closely with pathological scar size (r=.88). A good correlation existed between tissue 99mTc sestamibi activity determined through well counting and histological evidence of myocardial viability (r=.89). Most hypokinetic and 40% of akinetic/dyskinetic myocardial segments contained scintigraphically and histologically normal myocardium.
Conclusions 99mTc sestamibi scintigraphy can be used to accurately quantify the extent of myocardial scarring. Furthermore, the relative sestamibi activity in perfusion defects, measured several hours after administration, is a good indicator of myocardial viability determined with microscopy.
Key Words: 99mTc • transplantation • myocardium
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Introduction |
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The recognition that hypoperfused, hypocontractile myocardium may be viable, hibernating tissue that can functionally improve after revascularization1 2 3 4 5 6 7 8 has stimulated a search for noninvasive markers of myocardial viability. Normal myocardial 201Tl uptake or only a mild-to-moderate reduction in uptake is good evidence of tissue viability, although the use of standard stress-redistribution thallium scintigraphy underestimates the extent of viable myocardium. Therefore, late (24 to 72 hours) imaging,8 reinjection of a "booster" dose of 201Tl,5 9 10 11 12 13 or rest-redistribution imaging6 has been advocated to enhance thallium uptake in markedly hypoperfused myocardium.9 10 11 12 13
The use of 99mTc sestamibi was introduced into clinical imaging a few years ago, with the expectation that it would overcome many of the limitations of 201Tl, most of which are related to the suboptimal physical characteristics of the latter when imaged with currently available gamma cameras. Unlike 201Tl, 99mTc sestamibi undergoes less redistribution within the myocardium.14 15 16 17 18 19 20 21 22 23 Although this is an advantage for assessing myocardial salvage after coronary reperfusion,21 the lack of greater redistribution of 99mTc sestamibi has been considered a deterrent for its broader use in evaluation of chronically hibernating myocardium. Recent experimental24 and clinical studies,25 26 however, have suggested that sestamibi does undergo significant redistribution within 3 to 4 hours after the initial injection. At the cellular level, both the uptake and retention of sestamibi are profoundly affected by metabolic derangements of the mitochondrial and cell membranes.23 As is the case with 201Tl, 99mTc sestamibi is not retained by perfused but nonviable myocardium. Thus, the uptake of 99mTc sestamibi should reflect not only flow but also myocardial viability.
In the present study, we prospectively investigated whether 99mTc sestamibi SPECT could be used to differentiate viable, histologically normal myocardial tissue from scarred, nonviable myocardium in patients with severe ischemic cardiomyopathy.
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Methods |
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Study Population
The study population consisted of 15 consecutive patients (14 men and 1 woman; mean age, 58±8 years) who underwent orthotopic cardiac transplantation due to ischemic cardiomyopathy. Patient selection for cardiac transplant was based on standard criteria.27 All patients had had a prior myocardial infarction (none within 2 months of transplantation) and were deemed to have end-stage heart failure and likely to benefit from heart transplant. Twelve patients had three-vessel coronary artery disease, whereas 2 patients had two-vessel disease and 1 patient had one-vessel disease. Fourteen patients had undergone prior coronary artery bypass graft surgery. None of these patients were considered candidates for coronary revascularization. The protocol was approved by the Institutional Review Boards of Baylor College of Medicine and The Methodist Hospital, and all patients gave written informed consent.
Echocardiographic and Hemodynamic Procedures
All patients underwent two-dimensional echocardiography, diagnostic right and left heart catheterization, and coronary angiography before heart transplantation. Hemodynamic measurements were performed 
12 weeks before transplantation (median, 134 days; range, 1 to 350 days), during periods of clinical stability. The broad time range between catheterization and transplantation was due to the often unpredictable delay between a patient's acceptance for transplantation and the availability of a properly matched donor heart. Each patient underwent a resting two-dimensional echocardiogram with a Hewlett-Packard Sonos 500 or 1000 ultrasound equipment with a 2.5-MHz transthoracic transducer. Images taken from parasternal and apical windows were recorded on 0.5-in VHS videotape. With an off-line analysis station (Digisonics, EC-500), images from each of the four standard views were digitized and displayed on a quad screen in cineloop format. For wall motion analysis, the left ventricle was divided into six regions: apex, anterior, septum, lateral, posterior, and inferior. Each region, with the exception of the apex, was divided into 3 segments, resulting in a 16-segment model. Wall motion was assessed with the use of a semiquantitative scoring system (1, normal; 2, hypokinetic; and 3, akinetic/dyskinetic). Ejection fraction was quantified with two-dimensional echocardiography as previously reported from our institution.28 To facilitate the matching between regional perfusion (scintigraphy) and regional wall motion (echocardiography) and to confine the analysis to clinically relevant and meaningful regions, the following myocardial segments were analyzed: anterior, septal, apical, posteroinferior, and lateral, by both scintigraphy and two-dimensional echocardiography.
Pathology Procedures
At surgery, the native heart was excised according to standard surgical techniques. The explanted heart was immersed in 10% phosphate-buffered formalin at room temperature and taken to the imaging laboratory. Immediately after tomography, the heart was fixed in formalin for an additional 3 hours before being sectioned by a cardiac pathologist. The hearts were sliced by the cardiac pathologist into five 1-cm-thick transverse slices from apex to base, perpendicular to the heart long axis. Great care was exercised to ensure that the slices were of uniform thickness throughout. The slices were numbered and photographed on both surfaces. High-resolution color photographs of the myocardial slices were projected onto a large screen, and slice contours, including both grossly normal myocardium, which appeared reddish brown, and scarred areas, which appeared white, were traced onto paper. The scar area was quantified through planimetry of both surfaces of each slice by averaging the areas of each slice and then summing the areas of all slices to obtain the total scar size for each heart. This quantification was performed by an observer who was blinded to all other clinical or scintigraphic data. Correction for wall thinning in areas of scarring was made as described previously.29 Transmural samples (5x5 mm) were obtained from areas that by gross pathology contained normal myocardium, transmural scar, or a mixture. The myocardial sections were divided into subendocardial, midwall, and subepicardial sections; weighed; and counted to determine 99mTc radioactivity with a Compugamma 1282 gamma counter (Wallac-Pharmacia LKB Biotechnology, Inc) with subtraction of background counts and correction for half-life decay. Count-ratios were calculated between abnormal myocardial sections and the normal control sections. These formalin-treated sections from grossly normal, scarred, and mixed myocardium were then stained with hematoxylin and eosin and trichrome vital stains.
An experienced cardiac pathologist who was blinded to patient clinical history and scintigraphic data analyzed each of the samples with the use of light microscopy and graded the extent of histologically normal myocardium and of fibrous tissue. On the trichrome-stained samples, computer-assisted light microscopy was used (Bioscan Optimas, Inc) to quantify the relative extent of normal and scarred myocardium. Myocardial samples containing 
30% of normal myocytes were considered predominantly scar tissue, those with 31% to 84% normal myocytes were considered a mixture of scarred and viable myocardium, and samples containing 
85% histologically normal myocardium were considered normal. Although this classification is admittedly arbitrary, it was based on the fact that 15% of normal myocardium contains connective tissue that stains positively with the trichrome stain. Furthermore, we reasoned that although regions containing slightly <50% of viable myocardium still have a substantial fraction of myocardium viable, those with 30% of normal myocardium are predominantly nonviable. This classification was used solely to facilitate the clinical correlation. However, the data regarding the extent of the sections that contained structurally viable myocardium have also been presented as a continuous variable.
Scintigraphic Procedures: Planar and Tomography Imaging
Patients received a 20- to 30-mCi dose of 99mTc sestamibi IV 1 to 6 hours before cardiac transplantation. In 14 patients, the images were acquired 5 to 8 hours after sestamibi administration, and in 1 patient, the images were acquired 3 hours after administration. SPECT imaging of the explanted hearts began within 15 minutes of cardiac explantation. Cloth mesh was packed into both ventricles to prevent collapse of the ventricular walls. The heart was then placed onto a 15-cm-thick foam cushion and positioned for tomographic imaging. Images were obtained over an 180° anterior arc, followed by standard transaxial reconstruction and reorientation as reported previously.30
The extent of myocardial hypoperfusion was quantified and displayed as polar maps for each heart with standard circumferential profile analysis.30 Individual polar maps were compared with those from a 99mTc sestamibi databank containing maps for 40 normal subjects for quantitative assessment of defect size (expressed as a percentage of the total left ventricular mass). Because the databank of normal maps is derived from images of the in situ, beating heart and the images in the present study were from excised, arrested hearts, we also compared the quantified defect sizes relative to the normal values with the scintigraphic defect sizes obtained through computer-assisted planimetry of the individual polar maps of excised heart before the comparison with the normal databank, using a fixed threshold of 60%. The correlation between these two methods was excellent (r=.94, P<.001). To enhance reproducibility and consistency in the measurements, we used the computer-derived data throughout (see "Results"). The 99mTc activity in the regions of the polar map coded as abnormal was determined by placing 5x5-pixel regions of interest directly over the center of each defect. Activities of >85%, 30% to 85%, and <30% of maximum were considered predominantly viable (normal), of mixed viability, and predominantly nonviable (scar), respectively.
Planar Scintigraphy of Individual Myocardial Slices
Each of the five 1-cm-thick left ventricular slices was then placed directly on the upturned gamma camera detector for planar scintigraphy. Planar images of 200 000 counts per frame were acquired on a 128x128 matrix and stored in a 33000 ADAC MicroVAX computer. The scintigraphically normal and abnormal left ventricular regions for each slice were then planimetered on the computer with the aid of a light pen and summed to calculate the total defect size as a percentage of the total left ventricle. This quantification was done by an observer who was completely blinded to all other clinical, scintigraphic, or pathological data. A threshold of 70% of peak count activity was used to define the border between normal and abnormal myocardium. In a subset of 17 randomly chosen slices, the reproducibility of the technique was assessed by two independent observers. The interobserver measurements were similar (33±20% versus 31±19%, P=NS), with a correlation coefficient of .95. The intraobserver measurements were 33±20% versus 32±20% (correlation coefficient, .95).
Statistical Analysis
Paired t tests were performed for comparison of defect sizes obtained through scintigraphy and pathology and for 99mTc sestamibi activity determined through scintigraphy and through well counting. Unpaired t tests were used to compare percent well count sestamibi activity in scarred myocardium versus activity in areas with confirmation of scar and viable myocardium. Scintigraphic and pathological defect sizes as well as abnormal/normal ratios of 99mTc activity in the myocardial samples and the percentage of histologically normal myocardium were compared with the use of linear regression analysis. The data are expressed as mean±SD. Significance was assessed at the P<.05 level.
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Results |
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Clinical and Hemodynamic Results
All patients had an ischemic cardiomyopathy that developed after a previous infarction, with progressive left ventricular dysfunction and severe heart failure necessitating cardiac transplantation (Table 1
). The hemodynamic characteristics of the patients are summarized in Table 2. A low cardiac index and a moderate elevation in both mean pulmonary artery and pulmonary capillary wedge pressures were universally present. These patients also received aggressive medical therapy, which included parenteral inotropic agents in 13 of 15 patients (87%).
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Scintigraphic/Pathological Correlations
The mean tomographic left ventricular perfusion defect size for the 15 explanted hearts was 44.9±13.5% (range, 20% to 61%), and 13 patients had defects of 30%. Individual patient scintigraphic and pathological results are shown in Table 3.
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The extent of pathological scar was slightly overestimated with both tomography and planar scintigraphy of the slices (Fig 1). However, scintigraphic defect size quantified with tomography (Fig 2) and planimetry of the myocardial slices (Fig 3) correlated closely with the extent of myocardial scar size by pathology. Fifteen of 20 segments (75%) classified as nonviable through tomography contained predominantly scar according to pathology (Table 4). The pathological and scintigraphic findings in a representative patient are shown in Figs 4 and 5. The microscopic extent of fibrosis is compared with the respective 99mTc sestamibi tissue activity in Fig 6. A good correlation existed between sestamibi activity determined through well counting and the percent of normal, mixed, or scarred myocardium determined through microscopy (Fig 7). Areas with normal sestamibi activity were always histologically normal. Predominantly scarred myocardium had significantly lower sestamibi activity than did areas with a mixture of scarred and viable myocardium (Fig 8).
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Echocardiographic/Scintigraphic/Pathological Correlations
Most patients (87%) had severe segmental wall motion abnormalities according to echocardiography (akinesis or dyskinesis). Among the 70 myocardial segments examined by microscopy, there were 25 with akinesis or dyskinesis according to echocardiography, of which 15 (60%) showed histological scar. However, most hypokinetic segments (91%) and 40% of akinetic/dyskinetic segments contained potentially viable myocardium as assessed with pathology. Conversely, none of the segments classified as scar by pathology had normal wall motion on echocardiography (Table 5). Overall, the global left ventricular ejection fraction correlated significantly with the extent of pathological scar (r=-.58, P<.05).
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Among the 70 myocardial segments examined with histology, only 8 (11%) had normal wall motion on echocardiography, of which 7 had either normal or only mild to moderate reduced sestamibi activity on tomography. Among the 37 segments with hypokinesis, 31 (86%) had either normal or a mild to moderate decrease in sestamibi activity, whereas among the 25 segments with akinesis or dyskinesis, only 11 (44%) had either normal or mild to moderate reduction in sestamibi activity (Table 6). Among the 25 segments with akinesis or dyskinesis, 15 contained histological scar, 14 of which were designated as scar and 1 as mixed viability according to tomography; 9 had mixed viability according to histology, all of which also had mixed viability according to tomography; and only 1 segment was normal according to both histology and tomography.
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Discussion |
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Quantification of Infarct Size With Sestamibi Tomography
99mTc sestamibi tomography imaging is a highly accurate technique for detecting the presence and quantifying the extent of acute myocardial infarction both in animal models19 20 21 30 31 and humans.32 33 34 35 36 37 38 Furthermore, because sestamibi undergoes only limited redistribution, imaging with this agent affords identification, as well as quantification, of salvaged myocardium after coronary reperfusion.32 33 34 35 36 37 38 Ironically, it is this lesser amount of redistribution that has been construed as a disadvantage of sestamibi in comparison with 201Tl imaging for the assessment of myocardial viability.
The present investigation is the first to validate quantification of infarct size with the use of sestamibi tomography imaging in humans with pathological infarct size as a reference standard. On the basis of our results, we can state that 99mTc sestamibi tomography is an accurate technique for quantifying the extent of healed myocardial infarction in humans. Our results indicate a close correlation between tomographic and pathological infarct size in patients with healed infarcts, albeit with a slight overestimation of infarct size by scintigraphy. This study was conducted under ideal conditions in that we performed tomography in the nonbeating, explanted heart, thereby circumventing artifacts due to cardiac motion and photon attenuation that may degrade the image quality and limit the accuracy of scintigraphic quantification of infarct size in vivo. Furthermore, in the intact, beating heart, other factors, such as alterations in left ventricular geometry and function, and possibly a partial volume39 effect, may also exert a confounding effect on the scintigraphic/pathological correlation. However, our previous experimental work showed a good correlation between perfusion defect extent and pathological infarct size in dogs with coronary occlusion followed by reperfusion.30 In any case, these factors are less relevant to our patient cohort, who had extensive scars from old infarcts but no recent infarcts. We40 and others41 have also demonstrated that 201Tl tomography imaging can accurately quantify infarct size in humans during life compared with enzymatic infarct size. Wackers et al42 previously reported a good correlation between infarct sizes assessed with 201Tl planar imaging and pathological infarct size. Recently, Delbeke et al43 showed a good correlation (r=.93) between infarct size assessed with the use of 13N ammonia positron emission tomography and pathology in 14 patients who underwent cardiac imaging an average of 86 days before cardiac transplantation.
99mTc Sestamibi as a Marker of Myocardial Viability
Our data demonstrate a linear correlation between 99mTc sestamibi activity and the extent of histologically normal myocardium. Myocardial segments with normal sestamibi uptake (85% of maximal activity) were either completely normal histologically or had <15% fibrosis based on trichrome staining. Conversely, areas containing <30% of histologically normal myocardium had very low sestamibi activity based on well counting (average, 31% of normal). Myocardial regions with a mixture of fibrosis and normal myocardium (containing 31% to 84% of normal myocardium) had an intermediate sestamibi activity, averaging 68% of normal.
Therefore, our data indicate that in patients with severe, extensive coronary artery disease; prior myocardial infarction; and congestive heart failure, the relative tissue count activity of sestamibi is a good marker of tissue viability. However, our data cannot determine whether myocardial sestamibi activity is independent of myocardial blood flow. In all likelihood it is not, since areas with a predominance of fibrosis are expected to also have low myocardial blood flow. Conversely, areas with a predominance of histologically normal viable myocardium usually have normal sestamibi uptake, with intermediate levels of sestamibi activity reflecting varying degrees of fibrosis and normal myocardium. The present echocardiographic results also demonstrate that histologically viable myocardium is present in most hypokinetic (91%) and many akinetic (40%) regions. The depressed regional contraction in these areas may be attributed to decreased resting flow, underlying myocardial stunning due to episodes of silent ischemia, or misregistration between the regions defined through echocardiography and pathology. Discordance between regional function and pathology has been observed previously44 45 and attributed to hypoperfusion with preserved myocardial integrity, conduction abnormalities, and tethering of adjacent areas of myocardial fibrosis.
Although the transport of 99mTc sestamibi, a lipophilic cationic compound, appears to be largely passive and regulated by the electronegative transmembrane gradient across the cell and mitochondrial membranes,23 sestamibi retention within the cell is dependent on metabolic activity. In experimental preparations, cell membrane and mitochondrial injury prevent the intracellular retention of sestamibi.22 23 Conversely, Sinusas et al17 showed that the uptake and retention of sestamibi are not significantly reduced in stunned myocardium after coronary occlusion and reperfusion. Although we observed a strong correlation between the 99mTc sestamibi activity and the amount of histologically viable myocardium (Fig 7
), the tracer activity underestimated the severity of myocardial fibrosis within the perfusion defects. This may, at least in part, be explained by the well known higher myocardial tracer extraction in areas with very low blood flow.46
The potential utility of 99mTc sestamibi as a marker of viability in humans has been a subject of controversy. Cuocolo et al47 found the use of cardiac scintigraphy after 201Tl reinjection to be superior to the use of resting sestamibi imaging for viability detection. These authors, however, did not provide an independent marker of viability and did not assess the tracer activity in the perfusion defects, which is a strong predictor of viability.12 48 Marzullo et al49 reported that 99mTc sestamibi imaging was used to predict improvement of wall motion after coronary revascularization with 79% accuracy, which was similar to the accuracy of 18F-fluorodeoxyglucose imaging previously reported by Tamaki et al.50 Altehoefer et al51 compared the use of rest sestamibi imaging with the use of 18F-fluorodeoxyglucose imaging in patients with prior myocardial infarction. The level of 99mTc sestamibi in the defects was related to myocardial viability, but the use of sestamibi imaging underestimated viability. More recently, Dilsizian et al26 concluded that the agreement between 201Tl and 99mTc sestamibi for detecting myocardial viability (independently assessed through 18F-fluorodeoxyglucose imaging) was 93%, provided the levels of tracer activities were quantified. These investigators,26 as well as Taillefer et al25 and Sinusas et al,24 demonstrated a more substantial redistribution of sestamibi than that reported previously.15 It is likely that some redistribution occurred in our patients, since the images were acquired 3 to 8 hours after the tracer administration, due to the protocol logistics.
In keeping with this assertion, Udelson et al52 recently reported that 201Tl and 99mTc sestamibi tomography are equally effective in predicting improvement in regional ventricular dysfunction after coronary revascularization. In that study, hypoperfused myocardial segments that exhibited only mild-to-moderate reduction in sestamibi activity (60% of normal) demonstrated enhanced wall motion after revascularization, whereas segments with more severe reduction in tracer activity failed to improve.
Our study does not directly address the putative phenomenon of resting hypoperfusion with viable myocardium (hibernation) in the absence of prior infarction and thus without extensive areas of myocardial scarring. Several investigators have shown subsequent improvement in rest wall motion in areas with persisting (after stress) or resting perfusion defects after coronary revascularization.4 6 7 8 9 13 48 However, the histological milieu has not been reported in any of these studies. Our data indicate that mild to moderate rest defects during sestamibi imaging often represent viable myocardium, whereas more severe degrees of reduction in tracer uptake denote the presence of fibrosis, with the severity of tracer reduction being proportional to the amount of fibrosis. Two other groups have also recently shown a good general correlation between normalized regional activity levels of 201Tl (with a stress-reinjection protocol) and histological findings.53 54
In conclusion, our study demonstrates the ability of the use of 99mTc sestamibi tomography to identify the presence and quantify the extent of myocardial scar. Furthermore, a close correlation exists between the uptake activity of 99mTc sestamibi, as assessed with scintigraphy several hours after the initial injection, and the histological presence of viable myocardium. Thus, 99mTc sestamibi appears to be a good marker of myocardial viability. Our results, however, may have been enhanced by the use of scintigraphic data that were obtained in the arrested, explanted heart several hours after sestamibi administration, thereby allowing some redistribution to occur. Although we did not directly address the frequency and completeness of redistribution of sestamibi, one should consider late imaging as a potential method of further enhancing the detection of viability. In live patients, the strength of our findings may be reduced because of practical imaging issues, such as photon attenuation and cardiac motion.
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Acknowledgments |
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We are grateful to DuPont de Nemours for providing a research grant that supported this study, to the DeBakey Heart Center, and to the NIH (grant HL-42550). Computational assistance was provided by the CLINFO Project, funded by the Division of Research Resources of the National Institutes of Health, Bethesda, Md. We are also grateful to George P. Noon, MD, for providing us with the explanted hearts; to Clay J. Goodman, MD, for assisting with the histological analysis; and to Anna Bravo for expert secretarial assistance.
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Footnotes |
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Guest editor was George A. Beller, MD, University of Virginia (Charlottesville).
Received December 5, 1995; revision received March 6, 1996; accepted March 13, 1996.
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