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(Circulation. 1995;92:2157-2162.)
© 1995 American Heart Association, Inc.

Articles

Coronary Artery Calcium Area by Electron-Beam Computed Tomography and Coronary Atherosclerotic Plaque Area

A Histopathologic Correlative Study

Presented in part at the 67th Annual Scientific Sessions of the American Heart Association, Dallas, Tex, November 14-17, 1994.

John A. Rumberger, PhD, MD; D. Brent Simons, MD; Lorraine A. Fitzpatrick, MD; Patrick F. Sheedy, MD; Robert S. Schwartz, MD

From the Departments of Cardiovascular Diseases and Internal Medicine (J.A.R., D.B.S., R.S.S.), Diagnostic Radiology (P.F.S.), and Endocrinology and Internal Medicine (L.A.F.), Mayo Clinic and Foundation, Rochester, Minn.

Correspondence to John A. Rumberger, PhD, MD, Department of Cardiovascular Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background Coronary calcium identified by electron-beam computed tomography (EBCT) correlates poorly with luminal atherosclerotic narrowing, but calcium, an intimate part of coronary plaque, may be more directly related to atheromatous plaque area.

Methods and Results Thirty-eight coronary arteries from 13 autopsy hearts were dissected, straightened, and scanned with EBCT in 3-mm contiguous increments. Coronary calcium area was defined as one or more pixels with a density >130 Hounsfield units (0.18 mm²/pixel). Each artery was divided into corresponding 3-mm segments, representative histological sections were stained, and atherosclerotic plaque area per segment (mm²) was quantified. Coronary artery calcium and coronary artery plaque areas were correlated for the hearts as a whole, for individual coronary arteries, and for individual coronary artery segments. The sums of histological plaque areas versus the sums of calcium areas were highly correlated for each heart and for each coronary artery. However, coronary plaque area was on the order of five times greater than calcium area. Furthermore, minimal diffuse segmental coronary plaque could be present despite the absence of coronary calcium detectable by EBCT.

Conclusions This histopathologic study confirms an intimate relation between whole heart, coronary artery, and segmental coronary atherosclerotic plaque area and EBCT coronary calcium area but suggests that there is a threshold value for plaque area below which coronary calcium is either absent or not detectable by this methodology.

Key Words: calcium • arteries • tomography • atherosclerosis • diagnosis

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Mural coronary artery calcium has been shown to be diagnostic of atherosclerotic coronary artery disease.^{1 2 3 4 5 6 7 8 9 10 11 12 13} Prior investigations using electron-beam computed tomography (EBCT) have related its potential for noninvasive quantification of coronary artery calcium in regard to atherosclerotic luminal narrowing in clinical angiographic^{1 2 3 4} and histopathologic correlative studies.^{5 6 7} However, concepts that rely on definition of percent luminal narrowing limit our understanding of atherosclerosis and its effects on the arterial wall. Recent studies have emphasized the weaknesses of visual estimates of luminal percent narrowing with angiography by challenging their reproducibility^{14 15} and value in predicting abnormalities in coronary artery flow and flow reserve.^{16 17} Glagov and associates¹⁸ showed in carefully performed histopathologic studies that coronary artery external diameter can increase in some circumstances concomitant with an enlarging coronary artery plaque area without evidence of significant luminal narrowing until late in the process. These concepts were extended by use of vascular ultrasound by McPherson et al.¹⁹ Such coronary artery remodeling, which may accompany atherosclerotic disease, has recently been emphasized by the studies of Clarkson et al,¹³ who found that, on average, lumen area correlated poorly with plaque area.

Recent studies from our laboratories^{20 21} and others^{22 23} have shown that arterial calcium development is intimately associated with vascular injury and atherosclerotic plaque development. We hypothesized that coronary artery calcium area quantified by EBCT would directly correlate with coronary atherosclerotic plaque area. To address this, we examined coronary artery specimens from 13 adult autopsy hearts scanned by EBCT in which quantitative measures of atherosclerotic plaque area were available.

	Methods

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Autopsy Specimens
Thirteen autopsy hearts were examined, and each heart was perfusion pressure fixed with formalin at 70 mm Hg to maintain coronary anatomic integrity. Two individuals had an antemortem diagnosis of heart disease and died of complications of myocardial infarction. Of the remaining individuals, 6 died of trauma, 3 of metastatic carcinoma, 1 of suicide, and 1 of a gunshot wound. There were 8 men (ages, 17 to 83 years; average age, 40±23 years; 25th percentile, 23 years; 75th percentile, 58 years) and 5 women (ages, 20 to 70 years; average age, 49±23 years; 25th percentile, 25 years; 75th percentile, 65 years). For the 13 hearts as a whole, the average age was 43±23 years; the 25th percentile, 25 years; and the 75th percentile, 63 years. Thus, the age distributions of hearts examined in men and women and for the samples as a whole were overlapping. After fixation, each of the three major epicardial coronary arteries was carefully dissected, separated from the underlying myocardium, straightened, and pinned to a radiolucent (wooden) backboard.

EBCT Scanner
EBCT (Ultrafast CT, Imatron C-100) can acquire consecutive ECG-triggered, contiguous, thin-slice tomograms at a rate of 40 images in as many seconds. For the present study, 100-ms, consecutive, 3-mm-thick tomograms were acquired by manual trigger with a 22-cm field of view and a matrix size of 512x512.^{5 6} Individual in-plane pixel dimensions were 0.43x0.43 mm (0.18 mm²/pixel).

EBCT Evaluation of Coronary Artery Segments
Methods for scanning and analysis of coronary artery luminal area narrowing as it relates to EBCT coronary calcium have been reported previously from this data set.^{5 6} In brief, sets of 3-mm-thick, contiguous EBCT scans were acquired perpendicular to each coronary artery cross section, with the most proximal image commencing at the anatomic origin of each artery. The left main artery was considered part of the left anterior descending coronary artery. Each EBCT image was analyzed with imaging software supplied by the manufacturer. From each scan, the examiner was able to identify and visually inscribe a region of interest that contained the tomographic coronary cross section. The image processing software then automatically searched the inscribed region of interest and determined the CT density of the individual pixels within the region. The presence of coronary artery calcium was defined as any pixel within the region of interest with a CT density >130 Hounsfield units in a fashion similar to that used previously.^{1 2 3 4 5 6 7} Scan data for each dissected artery usually consisted of 30 consecutive images, each 3 mm thick. For each individual coronary segment in each tomographic section, the tomographic area (0.18 mm²/pixel) with a CT density >130 Hounsfield units was determined and designated the "calcium area" for that coronary segment.

Histopathologic Examination of Coronary Segments
Immediately after scanning, the arteries remained pinned to the backboard while 3-mm sections of coronary arteries (corresponding to the 3-mm CT images) were cut and labeled. From each of the 3-mm coronary artery segments, a "representative" (random) 5-µm-thick section was prepared for microscopic analysis from the middle of each respective segment. Each histological section was stained with hematoxylin-eosin and elastic–van Gieson stains. Histological sectioning continued up to 9 cm for each artery or until the artery diameter was too small to sample properly. One artery was damaged during sectioning. From the remaining 38 coronary arteries, a total of 522 histological sections were prepared. The presence and extent of coronary atherosclerotic disease in each coronary histological section was quantified by planimetry using light microscopy. It is difficult, in the presence of variable degrees of atherosclerotic involvement, to reliably define the extent of the original (nondiseased) coronary lumen. Although it does not precisely define the nondiseased vessel dimensions, for consistency and in keeping with methods used in previous studies,^{5 6} the area of the "original" coronary lumen was defined as the area inscribed by the internal elastic lamina. In areas in which the integrity of the internal elastic lamina was damaged or was not readily apparent, an arc representing this portion of the circumference was visually interpolated from adjacent areas in which the internal elastic lamina was visible. The boundaries of the residual (diseased) lumen per section were then planimetered, and the area (in square millimeters) of atherosclerotic plaque was defined as the area of the original, nondiseased lumen minus the area of the residual, diseased lumen. Additionally, the percent luminal cross-sectional area obstructed by atherosclerotic disease was calculated between 0% and 100%. There were 522 histological segments and 522 corresponding CT segments. Analysis of the histological sections was done randomly and blinded to the CT analysis. Data were related for calcium area and plaque area for coronary segments, for individual coronary arteries, and for whole-heart coronary artery systems.

Statistics
Data are presented as mean±SD for calcium/plaque areas. Correlations between the square root of histological plaque area and the square root of coronary artery calcium area by EBCT were made by use of a linear model and definition of 95% CIs. The square-root transform was used to minimize the effects of data skewness (nonnormal distribution) on the correlations.⁷ Statistical significance of correlations was determined by Pearson's moment method. A one-way ANOVA followed by a Student-Newman-Keuls t test was used to determine significance for multiple thresholds of segmental atherosclerotic plaque area versus segmental coronary calcium area. Statistical significance (two-tailed) was assumed for P<.05.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Histological Distribution of Atherosclerotic Disease and EBCT Coronary Calcium
Although only 2 of the 13 autopsy hearts examined were from individuals who had died of complications of coronary disease, atherosclerotic disease severity at histological examination was variable. The distribution of "percent area stenoses" for the 522 histological segments examined was as follows: n=248 (48% of the total) with stenoses between 0% and 20%, n=112 (21%) with stenoses 20% but <50%, n=100 (19%) with stenoses 50% but <75%, and n=62 (12%) with stenoses 75%. When the extent of luminal narrowing per individual heart was examined, there were only 2 individuals in whom all sections evaluated showed histological grade 0 (ie, 0% stenosis) disease. There was 1 heart in which the maximum stenosis in any coronary segment examined was 20%. In 2 patients, maximum stenoses were between 20% and 50%; in 4, maximum coronary stenoses were between 50% and 75%; and in 4, maximum stenoses were >75% of lumen area.

The histological (internal elastic lamina) mean for the areas inscribed across the 522 sections evaluated was 5.32±4.17 mm², with a range of 0.2 to 22.6 mm². The vessel segments examined reflected both proximal and distal areas of the coronary arteries. These data indicated, with reservations as noted above, an estimation of the original, nondiseased lumen diameter (assuming a circular cross section) of between 0.5 and 5.4 mm. Residual, diseased, mean cross-sectional lumen areas were 2.67±2.23 mm², with a range of 0 to 13.68 mm². Mean total "plaque" areas were 2.65±2.83 mm², with a range of 0 to 16.1 mm². The mean cross-sectional area occupied by plaque across the 522 sections was 56.97%.

Of the corresponding 522 EBCT coronary segments examined, 331 (63%) had no detectable coronary artery calcium. The remaining segments had coronary calcium areas ranging from 0.18 to 4.3 mm².

Correlation of Whole-Heart Coronary Calcium and Plaque Areas
The square roots of the total (summed, whole-heart) coronary CT calcium and total (summed, whole-heart) histological plaque areas were correlated for the 13 individual hearts as shown in Fig 1 (r=.93, P<.001). Average whole-heart, summed histological coronary plaque area was 133.2±158.2 mm² (range, 1.3 to 510.5 mm²), and average whole-heart, summed calcium area by CT was 22.9±36.1 mm² (range, 0 to 112.2 mm²). Thus, the average whole-coronary-system calcium area by EBCT was on the order of one fifth the average total histological atherosclerotic plaque area.

View larger version (18K): [in this window] [in a new window]   Figure 1. Graph showing square-root sum of coronary calcium areas (mm) by electron-beam computed tomography vs square-root sum of atherosclerotic plaque areas (mm) for each of the individual autopsy hearts (n=13). Shown are the linear regression line and the 95% confidence limits.

Correlation of Individual Coronary Artery Calcium and Plaque Areas
Proximal portions of the left anterior descending (including left main), left circumflex, and right coronary arteries were examined in each heart. Thirty-eight individual coronary arteries were evaluated for total atherosclerotic plaque area and corresponding total EBCT coronary calcium area. The average sum of plaque areas per coronary artery was 45.5±57.4 mm² (range, 0.6 to 193 mm²), and the average sum of calcium areas per coronary artery was 7.9±13.4 mm² (range, 0 to 46.4 mm²). As before, the average sum of individual coronary calcium areas estimated by EBCT was on the order of one fifth the average sum of the corresponding histological plaque areas. Linear correlation of the square root of the sum of CT calcium areas (x) with the square root of the sum of histological plaque areas (y) and the 95% confidence limits of the estimate for the 38 individual coronary arteries are shown in Fig 2. Correlations were statistically significant (r=.90, P<.001).

View larger version (19K): [in this window] [in a new window]   Figure 2. Graph showing square-root sum of coronary calcium areas (mm) by electron-beam computed tomography vs square-root sum of atherosclerotic plaque areas (mm) for each of the individual coronary arteries studied (n=38). Shown are the linear regression line and the 95% confidence limits.

Segmental Coronary Artery Calcium and Plaque Areas
Fig 2 demonstrates a direct association between total histological coronary artery plaque area and EBCT coronary calcium area. However, several arteries had demonstrable atherosclerotic plaque but little or no associated coronary calcium. In particular, one artery exhibited a substantial amount of total plaque area (22.6 mm²) but zero detectable calcium by EBCT (data point at upper left y scale of Fig 2). Fig 3 shows segmental coronary plaque area and the corresponding segmental coronary calcium area from that individual artery (ie, statistical outlier) as a function of distance from the coronary ostium. As shown, there is obvious diffuse coronary plaque and no associated segmental coronary calcium detected by EBCT. In this example, the segmental plaque area varied generally around 3 to 4 mm², and in only two segments was the plaque area >5 mm².

View larger version (18K): [in this window] [in a new window]   Figure 3. Graph showing an example of segmental coronary artery plaque area and calcium area by electron-beam computed tomography as a function of distance from the coronary ostium. See text for details.

Fig 4 shows data presented in the format shown in Fig 3 but from another coronary artery. Here, although plaque areas were always greater than calcium areas, there was a general concordance between the distribution of segmental plaque and segmental calcium as one proceeded distally from the coronary ostium. Additionally, in most instances, segmental plaque areas >5 mm² were associated with segmental coronary calcium areas >1 mm². When segmental plaque area fell below 5 mm², the segmental calcium area was generally 1 mm² or less. The examples from two extremes shown in Figs 3 and 4 suggested that there could possibly be a threshold for segmental coronary plaque area below which little or no associated coronary calcium is detectable by EBCT.

View larger version (22K): [in this window] [in a new window]   Figure 4. Graph showing an example of segmental coronary artery plaque area and calcium area by electron-beam computed tomography as a function of distance from the coronary ostium. See text for details.

Fig 5 is a bar graph of segmental atherosclerotic plaque areas and associated segmental coronary calcium areas for the 522 separate histological CT correlates. As atherosclerotic plaque area increased, coronary calcium area increased, as would have been predicted from the data given in Figs 1 and 2. However, for plaque areas <1 mm², the EBCT coronary calcium areas were nearly zero. For plaque areas of 1 to 5 mm², the mean calcium area was 0.46 mm². Only when the coronary plaque areas were consistently in the range of 5 to 10 mm² per segment were the corresponding coronary calcium areas, on average, >1 mm². The value of 1-mm² coronary calcium area has an important clinical correlate. For many clinical EBCT studies, imaging is done with a 30-cm field of view. With a standard 512x512 matrix, pixel areas are 0.34 mm². A criterion of two contiguous pixels with a CT density of >130 (minimal area size of 0.68 mm²) has been used in previous clinical studies from our laboratory and others.^{1 2 3 4} However, recent data suggest that this minimal calcium area may be too small for consistently reproducible results in patients.²⁴ Using a requirement of three (1.03 mm²) or four (1.37 mm²) contiguous pixels may be more reliable for clinical studies. The present data suggest that using these minimal amounts of discrete calcification in patients is most consistently associated with atherosclerotic plaques of 5 mm² or larger but cannot reliably detect plaques of smaller segmental areas.

View larger version (38K): [in this window] [in a new window]   Figure 5. Bar graph showing individual coronary artery segment atherosclerotic plaque area vs segmental coronary artery calcium area. These data are from the total sample of 522 histological electron-beam computed tomography correlates. Statistical relations between each of the sections are as shown in the figure.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Conclusions
Previous studies from our laboratory and elsewhere in both clinical^{1 3 4 25 26} and histopathologic^{5 6 7} investigations have concentrated on coronary artery calcium by EBCT as it related to degrees of luminal stenosis by atherosclerotic disease. Data previously published from analysis of the same histopathologic specimens as presented here showed that quantification of EBCT calcium cannot be used to precisely define the degree of segmental coronary luminal narrowing⁵ but can be used to predict the likely extent of coronary narrowing on a segment-by-segment basis when data are divided into mild, moderate, and severe disease categories.⁶ Furthermore, the absence of coronary artery calcium, on a segmental basis or for a whole individual coronary artery, although it does not rule out atherosclerotic disease, is consistent with the absence of luminal obstructive disease.^{3 4 5} This most recent investigation has used these data to expand investigations regarding coronary calcium as it relates not to luminal disease but rather to plaque areas on a segment-by-segment, artery-by-artery, and heart-by-heart basis.

Three major conclusions from the present investigation can be added to those stated above. First, coronary calcium area per individual coronary artery and/or per whole heart as defined by EBCT is highly correlated with histologically quantified coronary plaque area (Figs 1 and 2). Second, coronary calcium as measured by EBCT, according to the criteria used in the present study, defines on average only about one fifth the total atherosclerotic plaque present at histological examination. There is increasing evidence that formation of calcium as associated with atherosclerotic disease in the form of calcium hydroxyapatite²⁷ is an active process either regulated by "calcifying vascular cells"²² or associated with smooth muscle cell or macrophage production of ectopic bone matrix proteins.^{20 21 23} Atherosclerotic plaque consists of a variety of amorphous materials, including fibrous debris, cholesterol lakes, and matrix materials such as calcium, and is characterized by smooth muscle cell proliferation. It is therefore not surprising that coronary calcium is related to the total area of the composite atherosclerotic "plaque"; but not all plaques contain calcium, and there may be some "threshold" for plaque composition that then is associated with coronary calcium detected by EBCT. Thus, on the whole, defining coronary calcium in this manner would appear to relate to only a portion of the atherosclerotic plaque actually present. Coronary calcium by EBCT could be interpreted as looking at only "the tip of the atherosclerotic iceberg." Although intravascular ultrasound is perhaps the best method available at present to quantify local atherosclerotic disease, it is used only as an adjunct in invasive coronary angiography, and only in certain circumstances. Since it provides information on the atherosclerotic process, quantification of coronary calcium by EBCT, on the other hand, may well be the best noninvasive method currently available to identify the site and potentially estimate (albeit probably underestimate) the extent of mural coronary atherosclerotic plaque. Third, as shown in Fig 3, diffuse, minimal segmental atherosclerotic disease can occur without coronary calcium detectable by EBCT. Furthermore, the data suggest that a segmental coronary artery EBCT calcium area of 1 mm², which, as previously noted, is also a practical "threshold" for clinical studies, is most consistently associated with a plaque area roughly fivefold greater in area. The absence of coronary calcium by EBCT, therefore, does not rule out the presence of atherosclerotic plaque, but once the segmental plaque area has reached a certain size, coronary calcium area by EBCT increases in a direct fashion with increasing atherosclerotic plaque area, as shown in Figs 1 and 2.

Clinical Implications
"Coronary remodeling" associated with the development and progression of atherosclerotic disease is a recently described phenomenon whereby the luminal cross-sectional area and/or external vessel dimensions enlarge in compensation for increasing areas of mural plaque. Coronary artery calcium is an intimate component of some plaques. In fact, Clarkson et al,¹³ in a recent histopathologic investigation, showed that plaques with microscopic evidence of mineralization were much larger and were associated with much larger coronary arteries than those sections without microscopic evidence of calcification. This was true in humans and in nonhuman primates. The compensatory enlargement of atherosclerotic coronary segments may explain why coronary angiography frequently underestimates the severity of coronary disease compared with histopathologic studies. This fact may also help in explaining the positive but poor correlation of coronary calcium with percent luminal stenosis in earlier reports from our laboratory.^{3 4 5 6}

Prognostication in patients with atherosclerotic disease is not always best determined by the severity of angiographically defined luminal stenoses. In the seminal study by Little et al,²⁸ coronary lesions resulting in plaque rupture and acute myocardial infarction were more likely angiographic lesions that represented only mild to moderate luminal obstruction. It is possible that prognosis is more closely related to the overall magnitude of atherosclerotic plaque "burden" within the coronary system than it is to single or multiple discrete luminal narrowing defined qualitatively by conventional coronary arteriography. The information contributed by the present study provides a foundation to expand the diagnostic and potentially prognostic potential for EBCT. Additionally, as imaging and software analysis methods improve, it is likely that progression²⁶ and possibly regression of atherosclerotic plaque can be followed serially with EBCT; however, further studies are necessary to expand the present histopathologic study to the care of patients in the clinical arena. Angiographic end points for disease progression and regression have been used in prior studies, and yet, such applications, even with the addition of quantitative coronary angiography, are fraught with problems. A means to study progression of atherosclerotic plaque area in a large subset of the population would be superior to this conventional approach. As such, noninvasive definition of coronary calcium area by EBCT might be used as a surrogate for arteriography in examining disease progression in response to pharmacological therapy.

Limitations
Some of the methodological limitations of this histopathologic correlative study have been discussed previously.^{5 6} These include the use of a single 5-µm histological sample to quantify the extent of coronary disease compared with a 3-mm-thick CT coronary image and the fact that coronary calcium defined by EBCT in this study cannot be inferred to quantify the exact coronary calcium content of precipitated calcium phosphate within that same coronary section. Additionally, scanning of the coronary arteries in direct cross section as done here cannot be duplicated easily in the clinical setting, where partial-volume errors in determining calcium mean and peak densities and total area may compound these deficiencies.

Three additional study limitations require comment as they relate to interpretation of the data presented. First, the number of hearts studied was small; however, the extent of histopathologic coronary narrowing evaluated was reflective of a broad distribution of luminal area stenoses that might be expected in a clinical setting. Increasing the number of samples in the data set may have allowed for a more uniform distribution of luminal narrowing across all ranges noted above, but it is doubtful that the overall conclusions of the investigation would be altered. Second, the potential contributions of differential tissue (wall and lumen) shrinkage as part of the processing of the autopsy specimens were not accounted for in the present study. These consequences may confound the interpretation of portions of the data. After fixation and processing, Siegel et al²⁹ found that the vessel wall area changed little in segments with minimal atherosclerosis but that it decreased significantly in the presence of moderate to severe atherosclerosis. However, the changes in (residual) lumen area with fixation and processing were just the converse, with significant decreases only in the presence of minimal atherosclerosis. Park et al³⁰ found that decreased lumen size and increased rigidity are induced by formalin fixation in noncalcified femoral arteries but not in calcified arteries. It is reasonable to assume that these effects would be similar in the coronary arteries. Thus, at the time of microscopic examination, these differential effects may cause calcified arteries to appear less severely obstructed than noncalcified arteries. Data from our previous publications and elsewhere basically have shown that calcification increases as disease "severity" increases. Thus, this information would imply that tissue fixation and processing would have little effect on correlations of mural plaque with calcium in segments with minimal disease. On the other hand, the segments with more "disease" and thus more mural plaque may actually be underestimated by correlations with EBCT calcification area. However, to separate these issues out in our study would be extremely problematic, since neither Siegel nor Park offered solutions to this dilemma. Additionally, there could be differential effects within the vessel wall, depending on the components or compositions of the adventitia and media. Thus, to what extent these limitations impact on the quantitative aspects of our study is difficult to determine, but it is unlikely that they would alter the qualitative implications of data presented in Figs 1 through 5. Third, the present study used 3-mm-thick EBCT scans. A 1.5-mm clinical scanning protocol for evaluation of coronary calcium by EBCT has recently been introduced. Thinner EBCT scans may have provided for a more quantitative method to define relations of calcium areas to plaque areas. Although some sampling errors due to this methodology could be anticipated, special efforts were made to be consistent with image and histological sample registration. The choice of 130 Hounsfield units as threshold to define the presence of coronary artery calcium mimics the values used in several previously published studies.^{1 2 3 4 5 6 7 25 26} Higher values for threshold may increase specificity but probably would have reduced sensitivity. The converse would be true if a lower Hounsfield density value were used for a threshold.

	Acknowledgments

 
This study was supported by an Established Investigator Award from the American Heart Association (Dr Rumberger), NIH grant HL-46292, the Mayo Graduate School for Medical Education, and the Mayo Clinic and Foundation.

Received December 5, 1994; revision received April 10, 1995; accepted May 10, 1995.

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