Author + information
- Received May 19, 2000
- Revision received March 7, 2001
- Accepted March 23, 2001
- Published online July 1, 2001.
- Jamshid Shirani, MD, FACCa
- Jaetae Lee, MD†
- Rebecca Quigg, MD, FACC
- Ruth Pick, MD‡
- ↵*Address for correspondence:
Dr. Vasken Dilsizian, National Institutes of Health, Cardiology Branch, NHLBI, Building 10, Room 7B-15, Bethesda, Maryland 20892-1650
The aim of this study was to investigate the disparity between the extent of myocardial injury as assessed by thallium and the severity of left ventricular (LV) dysfunction in chronic ischemic heart disease.
Although it is believed that thallium differentiates between viable and nonviable myocardium, in some patients with chronic ischemic heart disease, viable regions by thallium may fail to improve function after revascularization.
Thirteen transplant candidates with chronic ischemic heart disease (LV ejection fraction = 14 ± 6% at rest) were studied prospectively with stress-redistribution-reinjection thallium single-photon emission computed tomography. We examined pretransplantation quantitative thallium uptake and post-transplantation extent and the histological distribution of collagen replacement in infarcted and noninfarcted myocardium and in 13 age-matched control hearts.
The volume fraction of collagen varied inversely with wall thickness (r = −0.70, p < 0.001) and was higher in irreversible (30.9 ± 15.8%) compared with reversible (20.2 ± 12.6%, p < 0.001) or normal thallium segments (15.0 ± 8.7%, p < 0.001). The irreversible thallium segments had lower wall thickness and more severe coronary artery narrowing (9.7 ± 2.8 mm and 95 ± 8%) compared with reversible (11.7 ± 2.7 mm and 87 ± 13%, p < 0.001) and normal thallium segments (12.8 ± 2.6 mm and 80 ± 14%, p < 0.001). Mean volume fraction of collagen was significantly lower in noninfarcted than it was in infarcted segments (13 ± 6% vs. 36 ± 13%, p < 0.001) but exceeded that in the control hearts (4 ± 2%, p < 0.001). Noninfarcted segments had predominantly interstitial fibrosis with either microscopic or patchy areas of replacement fibrosis.
In chronic ischemic heart disease with severe LV dysfunction, patterns of normal, reversible and irreversible thallium uptake correlated with the magnitude of collagen replacement, segmental wall thickness and severity of coronary artery narrowing. The finding of scattered areas of replacement fibrosis in noninfarcted myocardium may explain the observed disparity between LV contractile dysfunction and the extent of myocardial injury assessed by thallium.
Recent studies suggest an important role of myocardial viability assessment for decision making in patients with chronic ischemic heart disease and severe left ventricular (LV) dysfunction (1–4). Many patients with chronic ischemic heart disease (with or without myocardial infarction) do not exhibit symptoms of heart failure. However, a subset of these patients can present clinically with symptomatic LV dysfunction (5), and this disease state has been termed ischemic cardiomyopathy (6). Among patients with ischemic cardiomyopathy who are being considered for heart transplantation, the identification of viable, potentially reversible dysfunctional myocardium may alter the therapeutic strategy from transplantation to revascularization.
Because potassium is the major intracellular cation in muscle and is essentially absent in scar tissue, potassium analogues, such as thallium, are particularly well-suited for differentiating viable from nonviable myocardium (7–9). The demonstration of normal or reversible thallium uptake identifies viable myocardium, with potential for recovery of function after revascularization (3,4,10). However, some myocardial segments with normal or reversible thallium uptake may fail to improve function after revascularization (10,11). Such observations indicate that structural factors other than the magnitude of myocardial replacement fibrosis may influence the relation of segmental thallium uptake and contractile function. Therefore, in patients with chronic ischemic heart disease undergoing heart transplantation, we determined whether, beyond the extent of myocardial injury, the pattern of myocardial injury (transmural vs. nontransmural) and the distribution of collagen replacement in the noninfarcted segments could provide an explanation for the disparity between the severity of LV dysfunction at rest and the extent of ischemic myocardial injury assessed by thallium (myocardial remodeling).
Twenty-five ambulatory patients with stable chronic ischemic heart disease and severe LV dysfunction who were previously listed for cardiac transplantation (Medical College of Virginia, Richmond, Virginia and Fairfax Hospital, Falls Church, Virginia) were prospectively enrolled in our protocol. All patients had severe (New York Heart Association functional class III to IV) heart failure or angina and were listed as outpatients at the time of enrollment. All had angiographically documented multivessel coronary artery disease, and one had diabetes mellitus. Patients with recent acute myocardial infarction or unstable angina were excluded from the study. Twelve of the original 25 patients were eventually excluded from the study due to death, myocardial revascularization or presence of interim unstable symptoms of myocardial ischemia or heart failure. The remaining 13 patients (mean age 54 ± 7 years; range 41 to 62 years) constitute the subjects included in this report. Orthotopic cardiac transplantation was performed within a mean of 6 ± 2 months after the nuclear imaging studies. The study protocol was approved by the Institutional Review Board on Human Research of the National Institutes of Health, and written informed consent was obtained from each patient.
Thallium single-photon emission computed tomography (SPECT) imaging
All patients underwent stress-redistribution-reinjection thallium SPECT as previously described (10). Patients exercised on a treadmill according to the Naughton protocol in seven patients, Bruce protocol in five patients and modified Bruce protocol in one patient. Mean exercise durations were 4 min 36 s, 6 min 2 s and 9 min 0 s, respectively. Because the severity of angina and heart failure symptoms precluded discontinuation of medical therapy, all studies were performed on cardiac medications.
Quantitative thallium analysis
Short-axis tomograms from the three sets of thallium images (stress, redistribution and reinjection) were analyzed objectively using a semiautomated quantitative circumferential profile (10). The myocardial activity was subdivided into eight segments, and mean counts per pixel within each myocardial segment on the stress, redistribution and reinjection images were computed.
The explanted hearts were initially fixed in 10% phosphate-buffered formaldehyde. The cardiac ventricles were then sliced transversely with a mean thickness of approximately 8 mm per slice. Left ventricular cavity diameter and circumference were measured at the midventricular cavity level.
Gross replacement fibrosis
The extent of gross LV myocardial fibrosis in each heart was evaluated by computerized planimetry. This was accomplished by outlining on both sides of each LV slice the outer and inner edges of the myocardium and all visible scar tissue with a fine-point marker. Percent gross myocardial fibrosis was then measured by dividing the mean aggregate surface area of the scar tissue on both sides of the LV slice by the mean surface area of the myocardium. The volume of scar tissue in each slice was also calculated by multiplying the mean surface area of gross fibrous tissue by the thickness of the LV transverse slice. The sum of fibrous tissue volumes in all LV slices in each heart relative to the LV myocardial volume constituted the percent gross scar tissue in each heart.
Histologic assessment of myocardial fibrosis
Histologic examination of the myocardial segments used for quantitative studies showed no detectable myocyte necrosis. As with the thallium images, myocardial slices were divided into eight segments (Fig. 1). For each patient, a single approximately 5-μm thick slice was cut from the 8 mm mid-LV slices and stained with picrosirius red, a collagen-specific stain. Collagen volume fraction was then quantified in these approximately 5-μm slices using a semiautomated computerized image analysis system (Quantimet 520, Cambridge Laboratories, Inc., Cambridge, Massachusetts) as described in detail previously (12). Collagen volume fraction measured by this method has been shown to correlate closely with the hydroxyproline content of the myocardial tissue (13).
Histologic assessment of cross-sectional coronary artery narrowing
All major epicardial coronary arteries and the available portions of the saphenous vein bypass grafts (in 8 of the 13 patients with previous coronary artery surgery) were removed intact from each explanted heart. After decalcification, each coronary artery or bypass graft was sectioned transversely at approximately 5-mm intervals, each of which was then prepared for histologic examination after staining with Movat pentachrome stain. The degree of cross-sectional luminal narrowing in each coronary artery section was subsequently determined by computerized planimetry (14). Cross-sectional luminal narrowing of greater than 75% (corresponding to 50% of coronary artery stenosis by coronary angiography) was considered significant (14).
To further evaluate the extent of myocardial fibrosis in the explanted hearts, the quantity of the total collagen volume fraction in these hearts was compared with that in large myocardial sections of structurally normal adult hearts. The control hearts were obtained at autopsy from individuals matched for age with the study patients (mean age 59 ± 8 years), were prepared for histology in a similar manner as the explanted hearts and fulfilled the criteria for normalcy by preautopsy, autopsy and histologic criteria (15). The collagen volume fraction of the myocardium in the control hearts was also determined in a similar manner as the study hearts, that is, computerized videodensitometry of the picrosirius red-stained sections.
Quantitative thallium uptake
The myocardial segment with the highest thallium activity on each of the stress tomograms was used as the normal reference segment for computing relative thallium uptake. The same segment in the redistribution and reinjection thallium studies was identified and used as the reference segment for those tomograms. The activity of thallium in all other myocardial segments was then expressed as a percentage of the activity measured in the reference segment for each of the stress, redistribution and reinjection tomograms. Myocardial segments were grouped on the basis of severity of reduction in thallium activity: normal (>85% of peak activity), mild-to-moderately reduced (51% to 85% of peak) and severely reduced (<50% of peak) activity, as previously described (16). On the basis of previous reproducibility measurements in our laboratory (16), a segment with reduced activity on thallium stress was considered reversibly ischemic if the normalized thallium activity on the subsequent redistribution or reinjection images for that segment increased by 10% or more. A defect was classified as severely irreversible, regardless of any possible increase in thallium activity, if the activity on both redistribution and reinjection images remained <50% of the normal reference segment. Final thallium content was defined as the higher of the redistribution or reinjection thallium activity in each segment.
Volume fraction of collagen
To compare histomorphologic data with segmental myocardial thallium uptake, a mid-LV slice that best matched the corresponding thallium tomogram with similar wall thickness was selected. This was accomplished by identifying the right ventricular insertion site as well as by measuring the distance from the apex to the midventricular slice both on the pathologic slices and scintigraphic images. Among patients with large apical infarcts, the distance from the base of the heart to the midventricular slice was utilized. The volume fraction of collagen was measured in each of the eight myocardial segments. In addition, the predominant pattern of myocardial collagen distribution was determined in each myocardial segment. A segment with replacement fibrosis involving <50% of the inner LV wall was considered a nontransmural infarct. A segment was classified as transmural infarct if the replacement fibrosis involved >50% of the LV wall. Segments without transmural or nontransmural infarcts were designated as noninfarcted segments. In the latter segments, presence or absence of interstitial fibrosis (matrix expansion) and microscopic (<1 cm2in surface area) or patchy (>1 cm2in surface area) replacement fibrosis was determined by light microscopy.
Transmural thickness of each LV segment was measured by averaging three measurements, one from each edge and the third from the midsection. Relative wall thickness was calculated by dividing the thickness of each section by that of the thickest segment in the same mid-LV slice. A segment was considered to have reduced wall thickness if it measured less than 80% of the reference segment.
Gated blood pool cardiac scintigraphy was performed in the supine position using red blood cells labeled in vivo with 20 to 25 mCi of technetium-99m. Left ventricular ejection fraction (LVEF) was derived by computerized analysis of the scintigraphic data as previously described (17). Using this technique, the lower limit of normal LVEF at rest is 45% for our laboratory. Mean LVEF among the 13 patients was 14 ± 6% at rest. Quantitative segmental analysis was also performed by subdividing the LV region of interest into five annular segments, each emanating from the diastolic LV center of gravity, as previously described (18,19). Segmental ejection fractions were then examined in relation to percent collagen replacement in the anterior, septal, inferior and lateral segments.
Data are expressed as mean ± SD or frequency (%). Differences between continuous variables were assessed with the unpaired Student ttest. Proportions were compared by chi-square or Fisher exact test. Univariate linear regression analysis was performed to assess the degree to which thallium activity correlated with particular histomorphologic parameters.
Gross pathologic findings
Excluding the atria, the explanted hearts from the 13 patients weighed 375 to 590 g (mean 491 ± 65) with mean LV cavity diameter of 55 ± 6 mm. An average of 3.1 ± 0.7 of the four major epicardial coronary arteries (left main, left anterior descending, left circumflex and right) were narrowed significantly by atherosclerotic plaque. A total of 26 saphenous graft conduits were present in eight (62%) hearts, 19 (73%) of which showed significant cross-sectional luminal narrowing. By computerized planimetry, an average of 21 ± 9% of the LV myocardium of the 13 hearts was replaced by gross fibrosis.
Relation of thallium defects to gross pathology
From a total of 65 regions analyzed (five regions per patient), 42 (65%) had evidence of prior (healed) myocardial infarction by gross pathology: 12 in the anterior, 9 in the septum, 9 in the apex, 7 in the inferior and 5 in the lateral region. Thallium scintigraphy identified 37 of the 42 (88%) infarcted regions. The final thallium content on redistribution-reinjection images was significantly lower in the 42 regions with prior myocardial infarct compared with the 23 regions without myocardial infarct, as shown by gross pathology (46 ± 17% vs. 86 ± 10%, p < 0.001).
Histologic assessment with picrosirius red stain of myocardial fibrosis was performed in 104 mid-LV segments (eight segments per patient) with a mean surface area of 3 ± 1 cm2, transmural thickness of 11 ± 3 mm and collagen content of 24 ± 15%. There was an inverse relationship between volume fraction of collagen and wall thickness among all segments studied (r = −0.70, p < 0.001) (Fig. 2). Similarly, there was an inverse relationship between volume fraction of collagen and segmental ejection fraction (r = −0.52, p < 0.01). Mean volume fraction of collagen was not significantly different in the anterior (29.7 ± 15.1%), septal (20.9 ± 15.1%), inferior (19.3 ± 13.3%) or lateral (24.3 ± 12.5%) segments (p = NS).
Relation of thallium uptake to volume fraction of collagen
An overall inverse correlation existed between thallium uptake and percent myocardial collagen content in the 104 segments analyzed (r = −0.61, p < 0.001). Of the 104 myocardial segments, 27 (26%) were considered to be normal, and 77 (74%) were considered to be abnormal by quantitative analysis of the stress thallium data. Twenty-eight of the 77 segments identified as abnormal by stress imaging were reversible on redistribution-reinjection imaging, and 49 remained irreversible. Among the 49 segments with irreversible thallium defects, 27 (55%) had mild-to-moderate and 22 (45%) had severe reduction in thallium activity.
Percent collagen was significantly lower in the 27 normal thallium segments (15 ± 9%) than it was in the 28 reversible (20 ± 13%, p = 0.001) and 49 irreversible (31 ± 16%, p < 0.001) thallium segments (Fig. 3). Furthermore, among the 49 segments with irreversible thallium defects, volume fraction of collagen was significantly lower in the 27 mild-to-moderate compared with the 22 severe irreversible thallium segments (27 ± 15% vs. 36 ± 16%, p < 0.05).
Relation of thallium uptake to wall thickness and coronary artery narrowing
In addition to collagen content, significant morphologic differences existed between segments with various patterns of stress-redistribution-reinjection thallium uptake. Wall thickness was significantly higher in normal thallium segments (12.8 ± 2.6 mm) than it was in reversible (11.7 ± 2.7 mm) and irreversible (9.7 ± 2.8 mm) thallium segments. In addition, irreversible thallium segments with mild-to-moderate defects had significantly thicker walls (10.3 ± 3.2 mm) compared with those with severe defects (8.9 ± 1.9 mm). The degree of cross-sectional coronary artery narrowing also differed significantly among segments with different patterns of thallium uptake. Maximum cross-sectional coronary artery narrowing was significantly lower in normal thallium segments (80 ± 14%) compared with reversible (87 ± 13%) and irreversible (95 ± 8%) segments (p < 0.01).
Histomorphologic analysis of infarcted and noninfarcted segments: insights into myocyte viability and remodeling of the nonmyocyte compartment
Fifty of the 104 (48%) segments were identified as infarcted segments and 54 (52%) as noninfarcted segments by microscopic examination. Mean volume fraction of collagen was significantly higher in infarcted segments compared with noninfarcted segments (36 ± 13% vs. 13 ± 6%, p < 0.001). In addition, mean wall thickness and final thallium content were significantly lower in infarct segments (8.7 ± 1.6 mm and 66 ± 20%) compared with noninfarcted segments (13.2 ± 2.2 mm and 87 ± 17%, p < 0.001 for both).
Infarcted segments: transmural and nontransmural
Among the 50 infarcted segments, 29 were transmural, and the remaining 21 were nontransmural. Segments with transmural and nontransmural infarcts differed significantly with respect to collagen content (41 ± 13% vs. 29 ± 9%, p < 0.001) and wall thickness (8.2 ± 1.6 mm vs. 9.4 ± 1.5 mm, p < 0.007). Furthermore, 25 of 29 (86%) segments with transmural infarct showed irreversible thallium defects compared with 10 of 21 (47%) segments with nontransmural infarct (p < 0.03). The final thallium content was significantly lower in segments with transmural (59 ± 20%) compared with those with nontransmural infarct (76 ± 15%, p < 0.001). In addition, there was an inverse relationship between thallium uptake and volume fraction of collagen in segments with transmural infarct (r = −0.70, p < 0.001) but not in those with nontransmural infarct. Totally occluded epicardial coronary arteries were observed in 22 of 29 (76%) segments with transmural infarct compared with six of 21 (29%) segments with nontransmural infarct (p < 0.001). An example of the correlation between thallium scintigraphy, gross pathology and histomorphology is shown in Figure 4.
Noninfarcted segments: comparison with age-matched control hearts
Among the 54 noninfarcted segments, 23 (43%) showed reduced relative wall thickness (12.7 ± 2.4 mm) and patchy areas of collagen replacement, and the remaining 31 (57%) showed preserved relative wall thickness (13.7 ± 1.9 mm) without extensive collagen replacement. The mean volume fraction of collagen was significantly higher in segments with reduced wall thickness (15 ± 6%) compared with those with preserved wall thickness (11 ± 4%, p = 0.015). In addition, the severity of cross sectional coronary artery narrowing was significantly higher in segments with reduced wall thickness (89 ± 13%) compared with segments with preserved wall thickness (77 ± 14%, p = 0.02). Microscopic sections from the infarcted and noninfarcted segments stained with picrosirius red are shown in Figure 5.
The mean volume fraction of collagen in the 54 noninfarcted segments significantly exceeded that in the 13 age-matched control hearts (13 ± 6 vs. 4 ± 2%, p < 0.001) as shown in Figure 6. Including the atria, the control hearts weighed 315 to 375 g (mean 355 ± 30) with a mean LV cavity diameter of 3.2 ± 0.6 cm.
Assessment of myocardial viability with thallium is now an integral part of the management of patients with chronic ischemic heart disease and severe LV dysfunction. However, there is often disparity between the severity of LV dysfunction at rest and the extent of myocardial injury assessed by thallium. In this study, we examined whether structural factors other than segmental thallium uptake and contractile function provide insight into this clinically germane disparity.
Histomorphologic confirmation of clinical observations with thallium
Thallium is the most time-tested and widely utilized tracer for viability assessment. The idea that reversible or normal thallium uptake on stress-redistribution-reinjection studies represents viable myocardium and that irreversible thallium defect represents scarred myocardium has been substantiated in clinical studies (10,11,20,21). The results of this study provide a histomorphologic confirmation of prior clinical observations. Volume fraction of collagen is significantly higher in irreversible (30.9 ± 15.8%) compared with reversible (20.2 ± 12.6%, p < 0.001) or normal thallium segments (15.0 ± 8.7%, p < 0.001). The higher collagen content in irreversible thallium segments is associated with lower wall thickness and more severe cross-sectional coronary artery narrowing (9.7 ± 2.8 mm and 95 ± 8%) when compared with reversible (11.7 ± 2.7 mm and 87 ± 13%) and normal thallium segments (12.8 ± 2.6 mm and 80 ± 14%).
The relation between the magnitude of thallium uptake and the degree of myocardial fibrosis has been described previously (22–24). A significant inverse relation between the magnitude of thallium activity in both redistribution and reinjection images and the amount of myocardial fibrosis determined from intraoperative transmural LV biopsies of the anterior wall has been described (22). These studies have relied on small (<2 mm in width) transmural LV biopsies (generally limited to the anterior wall) for assessment of myocardial histomorphology and percent collagen. Although useful insights have been gained from such studies, the limited size of the myocardial biopsy sample may not always be representative of the entire LV or the relatively larger segment assessed by nuclear imaging. In addition, the resolution of the currently available SPECT systems are far less than the tissue sample size obtained at transmural biopsy. In our study, despite utilizing larger histological sections compared with biopsy samples, some misregistration between thallium tomograms and histology is inevitable. While the demonstration of correlation between the thallium uptake on stress-redistribution-reinjection imaging and collagen content is reassuring, in some patients with chronic ischemic heart disease, the severity of LV dysfunction at rest may be disproportionate to the extent of ischemic myocardial injury as assessed by thallium (3,10,11). Moreover, some asynergic segments will not improve function after successful revascularization despite the demonstration of viability by thallium (4,11). In this regard, factors other than the magnitude of fibrous tissue may affect the contractile function at rest or outcome of individual asynergic segments after revascularization.
Pattern of myocardial injury and the distribution of collagen replacement in the noninfarcted myocardium
The findings in this study suggest that, beyond the extent of myocardial injury, the pattern of myocardial injury (transmural vs. nontransmural) and the distribution of collagen replacement in the noninfarcted segments could provide an explanation for the disparity between the severity of LV contractile function at rest and the extent of ischemic myocardial injury assessed by thallium. In our patients with chronic ischemic heart disease and LV dysfunction, collagen occupied approximately one-fourth of the total volume of the LV myocardium. Such relatively small proportion of fibrous tissue appears adequate to cause severe LV dysfunction at rest because replacement fibrosis is often distributed in the form of transmural or subendocardial infarct, which involves approximately 50% of the inner surface of the LV. In addition, 43% of noninfarcted segments show significant remodeling characterized by reduced wall thickness and scattered areas of microscopic or patchy replacement fibrosis. Mean volume fraction of collagen in these noninfarcted segments (13 ± 6%) significantly exceeded that in the age-matched control hearts (4 ± 2%, p < 0.001). It is likely that the patchy areas of replacement fibrosis in the remodeled segments represent myocyte necrosis due to prolonged persistent myocardial hypoperfusion or microvascular atherothrombotic or embolic occlusion. This is supported by the observation that the severity of coronary artery narrowing was significantly worse in remodeled noninfarcted segments (89 ± 13%) compared with the nonremodeled segments (77 ± 14%, p = 0.02). Given the distribution and quantity of replacement fibrosis and reduction in wall thickness, this may provide an explanation for the observed disparity between the severity of LV contractile dysfunction at rest and the extent of ischemic myocardial injury assessed by thallium.
Our data also provide insight into why some asynergic segments that are viable by thallium may not improve function after successful revascularization. Noninfarcted myocardium immediately adjacent to a healed infarct is often supplied by markedly narrowed epicardial coronary artery and shows reduced wall thickness and patchy areas of replacement fibrosis, which may preclude its functional recovery. Other segments show small islands of viable tissue tethered to areas with healed infarct or in the epicardial aspect of nontransmural infarcts. Thus, similar to the infarct segments, functional recovery may not be possible for these remodeled noninfarcted segments of the LV after revascularization.
In chronic ischemic heart disease with severe LV dysfunction, patterns of normal, reversible and irreversible thallium uptake correlated well with the magnitude of collagen replacement, segmental wall thickness and severity of coronary artery narrowing. The finding of scattered areas of replacement fibrosis in noninfarcted myocardium may explain the observed disparity between LV contractile dysfunction and the extent of myocardial injury assessed by thallium.
☆ Supported by the Intramural Research Program of NHLBI.
- left ventricle
- left ventricular ejection fraction
- single-photon emission computed tomography
- Received May 19, 2000.
- Revision received March 7, 2001.
- Accepted March 23, 2001.
- American College of Cardiology
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